Category Archives: 6. ART 2011

6.1. Perspective

Christian Hoffmann –

The development of antiretroviral therapy has been one of the most dramatic evolutions in the history of medicine. Few other areas have been subject to such fast progress and sometimes short-lived trends. Those who have experienced the rapid developments of the last few years have been through many ups and downs.

The early years, from 1987-1990, brought great hope and the first modest advances using monotherapy (Volberding 1990, Fischl 1990). But when the results of the Concorde Study arrived (Hamilton 1992, Concorde 1994) both patients and clinicians plunged into a depression that would last several years. AZT (zidovudine) was first tested on humans in 1985, and was introduced as a treatment in March 1987 with great expectations. Initially it did not seem to be very effective, at least as monotherapy. The same was true for the nucleoside analogs ddC (zalcitabine), ddI (didanosine) and d4T (stavudine) which were introduced between 1991 and 1994. The lack of substantial treatment options led to a debate that lasted for several years about which nucleoside analog should be used, when, and at what dose. One typical question was, “Should the alarm clock be set to go off during the night for a sixth dose of AZT?”

Many patients infected during the early and mid-80s were dying. Hospices were established as well as support groups and ambulatory nursing services. One became accustomed to AIDS and its resulting death toll. There was, however, definite progress in the field of opportunistic infections (OI) – cotrimoxazole, pentamidine, gancyclovir, foscarnet and fluconazole saved many patients’ lives, at least in the short-term. Some clinicians started to dream of a kind of “mega-prophylaxis”. But the general picture was still tainted by an overall lack of hope. Many remember the somber, still mood of the IXth World AIDS Conference in Berlin in June 1993. Between 1989 and 1994 little had changed.

Then in September 1995, the preliminary results of the European-Australian DELTA Study (Delta 1995) and the American ACTG 175 Study (Hammer 1996) attracted attention. It became apparent that combination therapy with two nucleoside analogs was more effective than monotherapy. Indeed, the differences made in the clinical endpoints (AIDS and death) were highly significant. Both studies demonstrated that it was of great importance to immediately start treatment with two nucleoside analogs, as opposed to using the drugs sequentially.

This was by no means the final breakthrough. By this time, the first studies with protease inhibitors (PIs), a completely new class of drugs, had been under way for several months. PIs had been designed in the lab using the knowledge of the molecular structure of HIV and protease and their clinical value was initially uncertain. Preliminary data, along with many rumors, were circulating. Great impatience pervaded patients and clinicians. By the fall of 1995, a fierce competition had started up between three companies: Abbott, Roche and MSD. The licensing studies for the three PIs, ritonavir, saquinavir and indinavir, were pursued with intense effort. The monitors of these studies lived for weeks at the participating clinical sites. Deep into the night, case report files were perfected and thousands of queries were answered. These efforts led to fast track approval for all three PIs between December 1995 and March 1996 – first saquinavir, followed by ritonavir and indinavir – for the treatment of HIV.

Many clinicians (including this author) were not really aware of what was happening during these months. AIDS remained ever-present. Although the incidence of AIDS had dropped by half between 1992 and 1996, many were still dying. Doubts remained. Hopes had already been raised too many times in the previous years by alleged miracles. Early in January 1996, during the 5th AIDS convention in Munich, other topics were higher on the agenda: palliative medicine, pain management, even euthanasia. Here and there a few speeches on “new approaches”, nothing much. Faint and latent optimism was the highest of emotions anyone dared show. Noone dared to proclaim a breakthrough.

In February 1996, during the 3rd Conference on Retroviruses and Opportunistic Infections (CROI) in Washington, many caught their breath as Bill Cameron reported the first data from the ABT-247 Study during the late breaker session. The auditorium was absolutely silent. Riveted, listeners heard that the mere addition of ritonavir oral solution decreased the frequency of death and AIDS from 38% to 22% (Cameron 1998). These results were sensational in comparison to everything else that had been previously published.

The World AIDS Conference in Vancouver a few months later in June 1996, where the great potential of PIs became fully apparent, developed into a celebration. Even regular news channels reported in great depth on the new “AIDS cocktails”. The strangely unscientific expression “highly active antiretroviral therapy” (HAART) began to spread irreversibly.

By this time, David Ho, Time magazine’s “Man of the Year” in 1996, had shed light on the hitherto completely misunderstood kinetics of HIV with his breakthrough research (Ho 1995, Perelson 1996). A year earlier, Ho had already initiated the slogan “hit hard, hit early”, and almost all clinicians were now taking him at his word. With the new knowledge of the incredibly high turnover of the virus and the relentless daily destruction of CD4 T cells, there was no longer any consideration of a latent phase – and no life without antiretroviral therapy. In many centers almost every patient was treated with HAART. Within only three years, 1994-1997, the proportion of untreated patients in Europe decreased from 37% to barely 9%, whilst the proportion of patients on HAART rose from 2% to 64% (Kirk 1998).

Things were looking good. By June 1996, the first non-nucleoside reverse transcriptase inhibitor nevirapine was licensed and hence a third drug class introduced. One now had a great selection of medications at hand. Most patients seemed to tolerate the drugs. 30 pills a day? Not much of a problem, if it helped. And how it helped! The number of AIDS cases was drastically reduced. Within only four years, between 1994 and 1998, the incidence of AIDS in Europe was reduced from 30.7 to 2.5 per 100 patient years – i.e., to less than one tenth of what it was. Some of the most feared opportunistic infections now only rarely occurred (Mocroft 2000). HIV-specialized ophthalmologists began looking for new areas of work. The large OI trials, planned only a few months before, faltered due to a lack of patients. Hospices, which had been receiving substantial donations, shut down or changed their focus. The first patients began to leave the hospices and went back to work; ambulatory nursing services shut down. Patients with other diseases occupied AIDS wards.

In early 1997, some patients began to complain of an increasingly fat stomach, but was this not a good sign after years of wasting and supplementary nutrition? The lower viremia was thought to use up far less energy. It was assumed that, because patients were less depressed and generally healthier, they would eat more. At most, it was slightly disturbing that the patients retained thin faces. However, more and more patients also began to complain about the high pill burden.

In June 1997, the FDA published the first warning about the development of diabetes mellitus associated with the use of PIs. In February 1998, CROI in Chicago finally brought home the realization among clinicians that protease inhibitors were perhaps not as selective as had long been believed. One poster after another, indeed whole walls of pictures, showed fat abdomens, buffalo humps, thin legs and faces. A new term was introduced at the beginning of 1998 which would influence antiretroviral therapy for years to come: lipodystrophy. And so the old medical saying was shown to hold true for ART as well: all effective drugs have side effects. The actual cause of lipodystrophy remained completely unclear. Then, in early 1999, a plausible hypothesis emerged from the Netherlands, mitochondrial toxicity (Brinkmann 1999). It has become an ubiquitous term in HIV medicine today.

The dream of eradication (and cure), widely hoped for in the beginning, was eventually abandoned. Mathematical models were evidently not real life. In 1997, it was estimated that viral suppression with a maximum duration of three years was necessary; in this time it was predicted that all infected cells would die. Since then, the duration has constantly been adjusted upwards. More recent estimates have evolved to around 60 to 70 years (Silicano 2003). These numbers show just one thing: HIV will not be cured with standard ART for some time to come. More recent studies have come to the sobering conclusion that HIV remains detectable in latent infected cells, even after long-term suppression. Regardless, we need to talk about being able to cure the disease someday, however utopian it may seem now. We will never get there without a vision.

In fact, today’s reality seemed impossible ten years ago: HIV infection is a chronic disease which, although incurable, is controllable lifelong with therapy, even in patients with resistant virus. CCR5 antagonists as well as integrase inhibitors have opened up new possibilities of treatment. It has become increasingly possible to lower viral loads below detection in most patients. The pioneer drugs maraviroc and raltegravir have shown to be well-tolerated, even to the degree of causing distrust. The new drug classes will bring about fundamental changes to current ART. The dogma of always using two nucleoside analogs as the backbone of every therapy may start to change. Many of the currently widespread drugs will disappear over the next few years. The end of HIVID®, Agenerase® or Fortovase® is just the beginning. Veteran agents like AZT, d4T, ddI, nelfinavir or indinavir are not recommended by guidelines anymore although they served us in HIV management in the nineties. Will we be needing saquinavir, fosampranavir, nevirapine or even efavirenz and lopinavir as much as we do today five years from now?

A normal life expectancy seems possible today. Therapy is likely to last for decades. This will pose a tremendous challenge for patients, physicians and for the pharmaceutical industry. The comfortable situation at present doesn’t mean one can lean back. New drugs are urgently needed. However, there is still uncertainty about whether modern drugs will stand the test of time over decades. Effects on the heart, kidney, bones and other organs in an aging HIV population are difficult to foresee. Supposing a cure is delayed in coming, over the decades one will need a longer breadth, and the range of drugs has to increase. It will not be easy for new drugs to prevail as the example of vicriviroc has shown. How do you prove the advantages of a new drug over other successful therapies today? Approval for new drugs is becoming more strict and the market is tightening. Already one can observe the pharmaceutical industry’s caution. The days are over when a HIV drug got from the laboratory to the market within five years. New strategies are needed.

At the same time, the simple question of “when to start” with ART remains unanswered. Instead of David Ho’s recommendation from the nineties “hit hard, hit early”, today we hear “hit HIV hard, but only when necessary” (Harrington 2000). This sounds sensible. However, when is it actually necessary? At a count of 350 CD4 T cells? What roles do the following play: viral load, CD4 T cell changes, CD4 percentages, age, gender, host elements and viral tropism? What about acutely infected patients? These strategically important questions will hopefully find some answers through big studies like START that are underway now. Until then, this issue requires great sensitivity.

HIV clinicians are well-advised to keep an open mind to new approaches. Those who do not make an effort to broaden their knowledge often at conferences will not be able to provide adequate treatment for their patients in a field that is still growing and learning and changing direction every two to three years. Those who adhere strictly to evidence-based medicine and only treat according to guidelines are quickly outdated. HIV medicine is ever-changing. Treatment guidelines remain just that, and are often out of date by the time of publication. There are no laws set in stone. However, those who confuse therapeutic freedom with random choices, and assume that data and results coming from basic research can be ignored are also missing the point. Individualized treatment is not random treatment. It cannot be stressed enough that clinicians are also responsible for the problem of poor adherence. Even if many experienced clinicians have come to disregard this, every patient has the right to know why they are taking the therapy they are on or, indeed, why certain therapies are not an option. The more they understand their therapies, the better the long-term results.

HIV remains a dangerous opponent. Patients and clinicians must tackle it together.


Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999,  354:1112-5.

Brodt HR, Kamps BS, Gute P, et al. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997, 11:1731-8.

Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998, 351:543-9.

Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994, 343:871-81.

Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996, 348: 283-91.

Fischl MA, Parker CB, Pettinelli C, et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 1990; 323:1009-14.

Hammer SM, Katzenstein DA, Hughes MD et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996, 335:1081-90.

Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary. Lancet 2000, 355:2147-52.

Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995, 333:450-1.

Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-6.

Kirk O, Mocroft A, Katzenstein TL, et al. Changes in use of antiretroviral therapy in regions of Europe over time. AIDS 1998, 12: 2031-9.

Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000, 356:291-6.

Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996, 271:1582-6.

Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Med 2003;9:727-728.

Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic HIV infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990, 322:941-9.

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Filed under 6. ART 2011, 6.1. Perspective, Part 2 - Antiretroviral Therapy

6.2. Overview of Antiretroviral Agents

Christian Hoffmann –

Preliminary remark

As of now (March 2011) there are 30 individual or combination agents licensed for treatment of HIV infection. These drugs are derived from five different classes:

1. Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs)

2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

3. Protease inhibitors (PIs)

4. Entry inhibitors (coreceptor antagonists and fusion inhibitors)

5. Integrase inhibitors

The FDA in the US and the European EM(E)A do not always agree on the granting of brand names with the result that, in some cases, names differ from country to country. Sometimes a pharmaceutical company does not hold authorization for production worldwide. The NNRTI efavirenz, for example, is produced by BMS in Germany under the brand name Sustivaâ and in Austria by  MSD under the name of Stocrinâ. The situation is not likely to improve when patents and rights for some agents run out in industrial countries and several generics start arriving.

Moreover, definitions for indication areas vary widely. Some agents are specifically not licensed for primary (first line) therapy, such as entry inhibitors, the PI tipranavir and the NNRTI etravirine, as well as combination agents such as Atriplaâ. Other limitations concern pregnant women and children, which is specified in the appropriate chapter. More details can also be found in the chapter “Drugs” at the end of this book.

In the face of cost pressures suffered by the health insurance system, it is advisable for clinicians to adhere to the specific indication areas of the individual agents. Due to such a wide range of choice, this is possible in most cases, although not in all. Clinicians should have good reason when using an agent outside the stated indication area. A thorough documentation should be kept in the case of disagreement from payors.

In this chapter, individual agents listed by class are discussed with reference to their specific benefits and problems. Discussion on common primary therapy can be found in the chapter “What to start with?”. Other chapters are concerned with the adjustment of ART and therapy interruptions. Salvage therapy as well as new and experimental agents are discussed in other chapters.

Table 2.2. Overview of antiretroviral drugs.
Trade name


Drug Manufacturer
Nucleoside and Nucleotide Reverse-Transcriptase-Inhibitors (NRTIs)


Emtricitabine Gilead Sciences


Lamivudine ViiV Healthcare


Zidovudine ViiV Healthcare


Didanosine Bristol Myers-Squibb


Tenofovir Gilead Sciences


Stavudine Bristol Myers-Squibb


Abacavir ViiV Healthcare
Non-Nucleoside Reverse-Transcriptase-Inhibitors (NNRTIs)
Sustiva®, Stocrin®


Efavirenz BMS/MSD


Nevirapine Boehringer


Rilpivirine Janssen-Cilag


Etravirine Janssen-Cilag


Delavirdine ViiV Healthcare
Protease-Inhibitors (PIs)


Tipranavir Boehringer


Indinavir MSD


Saquinavir Roche


Lopinavir/Ritonavir Abbott


Ritonavir Abbott


Darunavir Janssen-Cilag


Atazanavir Bristol Myers-Squibb
Telzir®, Lexiva®


Fosamprenavir ViiV Healthcare


Nelfinavir Roche/ViiV Healthcare
Entry Inhibitors
Celsentri®, Selzentry®


Maraviroc ViiV Healthcare


Enfuvirtide Roche
Integrase Inhibitors


Raltegravir MSD
Combination Drugs




AZT+3TC ViiV Healthcare


TDF+FTC+RPV Gilead+Janssen-Cilag
Kivexa®, Epzicom®


3TC+ABC ViiV Healthcare


AZT+3TC+ABC ViiV Healthcare


TDF+FTC Gilead Sciences
* not yet approved in Europe.

Nucleoside Analogs (NRTIs)

Mechanism of action

Nucleoside analogs (“nukes”) are also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). Their target is the HIV enzyme reverse transcriptase. Acting as alternative substrates, they compete with physiological nucleosides, differing from them only by a minor modification in the ribose molecule. The incorporation of nucleoside analogs induces the abortion of DNA synthesis because phosphodiester bridges can no longer be built to stabilize the double strand.

Nucleoside analogs are pro-drugs. They are converted to the active metabolite only after endocytosis, whereby they are phosphorylated to triphosphate derivatives. Only this triphosphate is effective.

Nucleoside analogs were the first antiretroviral agents on the market. AZT (zidovudine, Retrovir®) was approved for the treatment of HIV infection in 1987. Once-daily dosing is sufficient for many nukes. Overall tolerability is fairly good. However, frequent complaints during the first weeks are fatigue, headache and gastrointestinal problems, which range from mild abdominal discomfort to nausea, vomiting and diarrhea. The gastrointestinal complaints are easily treated symptomatically (see chapter on “Management of Side Effects”).

Nucleoside analogs can cause a wide variety of long-term side effects, including myelotoxicity, lactate acidosis, polyneuropathy and pancreatitis. Many metabolic disorders, especially lipoatrophy, are also attributed to nucleoside analogs (Galli 2002). Long-term side effects that are probably related to mitochondrial toxicity were first described in 1999 (Brinkmann 1999). Mitochondrial function requires nucleosides. The metabolism of these important organelles is disrupted by the incorporation of false nucleosides leading to mitochondrial degeneration. More recent clinical and scientific data indicates that there are probably considerable differences between individual drugs with regard to mitochondrial toxicity. Agents like d4T or ddI are more toxic than abacavir or 3TC and are therefore not used in HIV treatment today andddC has disappeared entirely. For further details see chapter on “Mitochondrial Toxicity of Nucleoside Analogs”.

Nucleoside analogs are eliminated mainly by renal excretion and do not interact with drugs that are metabolized by hepatic enzymes. There is therefore little potential for interaction. However, ribavirin, used in the treatment of hepatitis C, can reduce intracellular phosphorylation of AZT or d4T (Piscitelli 2001). In patients with renal failure, dosages of nucleoside analogs have to be adjusted as opposed to protease inhibitors or NNRTIs. AZT and d4T are thymidine analogs, while FTC and 3TC are cytidine analogs. Combinations containing AZT plus d4T or FTC plus 3TC are therefore pointless since these drugs compete for the same attachment pocket. DdI is an inosine analog converted to dideoxyadenosine; abacavir is a guanosine analog. There is a high degree of cross-resistance between NRTIs (see chapter on “Resistance”).

Individual agents

Abacavir (ABC, Ziagen®) is a guanosine analog. Monotherapy studies showed this drug to lower viral load by approximately 1.4 logs within 4 weeks, but that resistance develops rapidly (Harrigan 2000). Abacavir is phosphorylated intracellularly to carbovir triphosphate, which has a long half-life (Harris 2002). In October 2004, following larger studies, abacavir was licensed for once-daily therapy (Clumeck 2004, Moyle 2005, Sosa 2005).

ABC+3TC is comparable in efficacy to either AZT+3TC (DeJesus 2004) or d4T+3TC (Podzamczer 2006). In combination with AZT+3TC (Trizivir®, see section on Triple Nukes), abacavir was however less effective than efavirenz (Gulick 2004) or indinavir (Staszewski 2001). Abacavir is also used to simplify ART. In randomized studies, a switch from a successful PI- or NNRTI-containing therapy to abacavir plus two NRTIs proved relatively safe (Clumeck 2001, Katlama 2003, Martinez 2003, Bonjoch 2005). However, there is an increased risk of virological failure, especially in extensively pretreated patients (Opravil 2002, Martinez 2003). Caution must also be taken in combination with TDF+3TC, under which resistances develop rapidly (see section on Triple Nukes).

With respect to mitochondrial toxicity, abacavir seems to compare favorably to other NRTIs. In comparison with d4T, the risk of lipoatrophy is lower (Podzamczer 2006). Moreover, switching from d4T to abacavir led to improvements in subjects with existing lipodystrophy (Carr 2002, John 2003, Moyle 2003, McComsey 2005). Improvement was associated with an increase in mitochondrial DNA as shown in in vitro studies (Hoy 2004, Martin 2004, McComsey 2004+2005).

One drawback to the use of abacavir is the risk of hypersensitivity reaction (HSR). HSR occurs in 7-11% of patients. On re-exposure after stopping ABC due to HSR, it can be fatal. Cases of severe HSR have been reported after only a single abacavir tablet (De la Rosa 2004) or after treatment interruption despite prior tolerability (El-Sahly 2004). Of note, a genetic predisposition exists. HSR appeared in 80% of cases with patients with the HLA B*5701 allele (Mallal 2002, Hetherington 2002). The predictive value of the HLA test was proven in the large PREDICT trial with approximately 2000 patients (Mallal 2008), and the assay is now obligatory prior to starting abacavir. However, clinical HSR cases without the HLA B*5701 allele have been observed on rare occasions.

Since the problem with HSR has largely been resolved,  abacavir has been discussed again  in 2008. Cohort studies have reported an association between recent use of abacavir and an increased risk of myocardial infarction (Sabin 2008, SMART 2008). These results, however, have met with some objections ( Brothers 2009). A recent meta-analysis of 26 randomized trials with almost 10.000 patients showed no increased risk under abacavir (Ding 2011). The opinion some experts hold that alternative regimens should be considered  for patients with underlying high cardiovascular disease risk, is no longer sustainable  (Behrens 2010).Today, abacavir is mainly used in the combination tablet Kivexaâ(see below). The individual substance Ziagenâ or even Trizivirâ (again see below) are of little significance today.

AZT (zidovudine, Retrovir®) was the first antiretroviral agent in 1987 to make it to market. Even very early studies that tested AZT monotherapy were able to show a significant survival benefit – at least in very immunocompromised patients (Fischl 1987). In contrast, two other early very large studies, ACTG 016 and ACTG 019, were not able to demonstrate significant survival benefit in asymptomatic patients, although the risk for progression was significantly reduced in both (Fischl 1990b, Volberding 1990). Even at that time, it started to become apparent that the success of AZT monotherapy was likely to be limited. The Concorde Study brought AZT into disrepute by showing that there was no long-term benefit of AZT treatment. The higher doses (1500 mg/day) led to considerable myelotoxicity (Fischl 1990). Myelotoxicity should also not be underestimated for the  current dosages of 500-600 mg/day and monitoring of the blood is obligatory. Long-term treatment almost always increases MCV (mean corpuscular volume of erythrocytes), which is to some extent suitable as a means of monitoring adherence.

AZT is very effective in combination with other ARV drugs. In the nineties, the combination of AZT and 3TC was one of the most frequently used backbones in HIV therapy. AZT has been tested in numerous clinical studies and offers more experience than any other agent (over 20 years).

In the last years AZT has came under pressure when,  it performed significantly worse than tenofovir in the Gilead 934 study. In this large-scale randomized study, ART-naïve patients were treated with efavirenz plus either AZT+3TC or TDF+FTC. In particular severe anemia was more frequent on AZT, leading to withdrawal in 5.5% of the cases (Gallant 2006). After 144 weeks, fewer patients on AZT had a viral load of less then 400 copies/ml than on TDF (58% vs 71%). This difference was due in large part to the fact that more patients on AZT withdrew due to adverse events (11% vs 5%). Apart from myelotoxicity, side effects leading to discontinuation were mainly gastrointestinal complaints such as nausea, usually occurring within the first few weeks of treatment. Moreover, a significant reduction in fat tissue of the extremities while on AZT was observed in this study (Arribas 2009).

Consequently, in many guidelines AZT is now no longer listed as a preferred first-line drug in treatment naïve patients. Another disadvantage is that AZT needs to be taken twice daily as opposed to most HIV compounds, thereby disqualifying it as being part of once-daily combinations. However, AZT currently remains a component of some  ART regimens and transmission prophylaxes as it proves to be valuable especially with regard to resistance. For example, a hypersensitivity to AZT is seen in viral isolates with mutations K65R or M184V. Lack of neurotoxicity and a good CNS penetration are additional advantages. It is also noteable that in the USA the patent for AZT has expired in 2005. The substance could soon be considerably cheaper.

ddC (zalcitabine, HIVID®) was the third NRTI to reach the market in 1992. Limited efficacy, unfavorable pharmacokinetics and side effects led to its withdrawal from the market in June 2006 – a novum in HIV therapy.

ddI (didanosine, Videx®) was, in 1991, the second NRTI to be licensed. Early studies showed improvement in survival rates of treatment-naive patients with AZT+ddI compared to AZT monotherapy. This effect was less marked in AZT-pretreated patients (Saravolatz 1996). Antiretroviral efficacy of ddI is comparable to AZT as part of triple combination therapy (Berenguer 2009, Crespo 2009). The introduction of acid-resistant tablets in 2000 replaced the chewable tablets used for many years and improved tolerability significantly. However, ddI is currently used only in specific situations (Molina 2005) mainly due to toxicity. Gastrointestinal complaints and polyneuropathy are the main side effects. Pancreatitis is more specific, occurring in up to 10%, and can be fatal in individual cases. This toxicity is probably dose-dependent (Jablonowski 1995). The cause for this is unclear, but could possibly be related to disorders of purine metabolism (Moyle 2004). Special caution should be given to combinations with ribavirin, d4T, hydroxyurea or tenofovir (Havlir 2001, Martinez 2004). Mitochondrial toxicity is greater than with other NRTIs (see chapter on “Mitochondrial Toxicity”).

Dosage needs to be adjusted according to the patient’s weight. If body weight is less than 60 kg, the dose should be reduced from 400 mg to 250 mg. Of note, ddI has to always be taken on an empty stomach.

d4T (stavudine, Zerit®) was the second thymidine analog to be introduced after AZT. Although better tolerated (less gastrointestinal complaints) and just as effective as AZT (Spruance 1997, Squires 2000), d4T is hardly ever used nowadays in western industrialized countries. This is mainly due to its long-term toxicities in comparison to other NRTIs, shown in various large randomized studies (Saag 2004).

Use of d4T is associated with lactic acidosis, hyperlactacidemia and Guillain-Barré-like syndromes (John 2001, Shah 2003), as well as for lipoatrophy (Mallal 2000, Mauss 2002).  Numerous studies have now been published in which substitution of d4T with other NRTIs, particularly abacavir or tenofovir, had positive effects on lipoatrophy and other metabolic disorders (Carr 2002, John 2003, Moyle 2003,  Libre 2006, Tebas 2009 ) Finally in March 2011 a red hand letter was distributed to physicians according to which d4T was only to be indicated if other antiretroviral drugs can not be applied. Duration was to be limited to the shortest possible time and whenever possible switched to other suitable therapy alternatives. Nothing further need to be said.

3TC (lamivudine, Epivir®) was licensed in Europe in August 1996 as the fifth NRTI. It is a well-tolerated cytidine analog and part of various combination preparations such as Combivir®, Kivexa® (Epzicom®) and Trizivir®. Its main disadvantage is its rapid development of resistance, and a single point mutation (M184V) is sufficient for compromising its effectiveness. Resistance is likely to develop after only a few weeks (Eron 1995). The full effect of 3TC only emerges in combination with other nucleoside analogs. Indeed, large studies such as NUCB 3002 or CAESAR showed a significant clinical benefit when 3TC was added to nucleoside therapy (Staszewski 1997). The M184V point mutation does have advantages: not only does it improve the susceptibility of certain AZT-resistant viruses in some patients but it also impairs viral fitness (Miller 2002). This was demonstrated in a study on monotherapy in  patients with the M184V mutation: maintaining 3TC monotherapy was associated with a lower increase in viral load and slower CD4 decline compared to completely stopping ART (see chapter on “Salvage”). Keeping 3TC as part of a combination despite proven resistance is therefore sensible in order to conserve the M184V mutation and thus reduce the replicative capacity of HIV, especially when not all the other agents in the regimen are active. The antiviral efficacy of 3TC equals that of its main competitor drug FTC (Rousseau 2003, Benson 2004). Once-daily dosing is possible although the half-life of 3TC is less than that of FTC (DeJesus 2004). As a side effect 3TC shows efficacy against hepatitis B viruses, useful in coinfected patients.

FTC (emtricitabine, Emtriva®) is a cytidine analog. It is biochemically very similar to 3TC, but has a longer half-life. Once-daily dosing is possible, and the drug also has efficacy against HBV. Tolerability is good, while the potential for interactions is minimal (Frampton 2005). FTC seems to have a low affinity for the mitochondrial polymerase so the risk of mitochondrial toxicity is likely to be relatively low. FTC was as effective as 3TC both as monotherapy as well as in combination with AZT (Rousseau 2003, Benson 2004). However, as with 3TC, efficacy is limited by the M184V point mutation. The drug was licensed in 2003 when randomized, double blind trial showed that FTC was clearly more effective and tolerable than d4T. The combination of TDF+FTC was superior to AZT+3TC in the large GS-934 study especially due to tolerability (Gallant 2006, Arribas 2008). Tolerability was probably in most part due to the second agent (AZT or d4T) and not FTC or 3TC. Post-approval, the ALIZE study confirmed the good long-term tolerability and efficacy of a once-daily combination of FTC+ddI plus efavirenz (Molina 2005).  FTC is currently an important component in combination therapy particularly as a fixed partner of tenofovir (Truvada®), with tenofovir and efavirenz (Atripla®) or with tenofovir and rilpivirine (Complera®). In contrast, the individual agent (Emtriva®) no longer plays a role. Due to the fact that no clinical differences have yet been established between 3TC and FTC, the choice between the two is usually determined by its co-medication (abacavir, tenofovir, AZT).

TDF (tenofovir, Viread®) acts as a false building block similar to nucleoside analogs, targeting the enzyme reverse transcriptase. However, in addition to the pentose and nucleic base, it is monophosphorylated and therefore referred to as a nucleotide analog. A more accurate description of the agent is tenofovir DF (disoproxil fumarate), which refers to the phosphonate form from which the phosphonate component is only removed by a serum esterase, and which is activated intracellularly in two phosphorylation steps (Robbins 1998).

Tenofovir is available as a single agent, but is most often administered in fixed-dose combinations within Truvada®, Atripla® and Complera®. In the GS-902 and -907 studies, in which tenofovir was added to an existing antiretroviral therapy, the viral load fell by approximately 0.6 logs after 48 weeks (Schooley 2002, Squires 2003). Tenofovir is very well tolerated. Side effects in these studies were comparable to the placebo arms. The 903 Study was a double-blind study in which ART-naive patients were given either tenofovir or d4T (both arms received 3TC and efavirenz). Results showed at least equivalent potency with a significantly reduced incidence of polyneuropathy and lipid changes compared to d4T (Gallant 2004). It has been shown that phosphorylated tenofovir has a low affinity for mitochondrial polymerase (Suo 1998). As a result of this convincing clinical data and its licensing in 2001, the drug is now very widely used in antiretroviral therapies. In the 934 study, TDF+FTC were significantly better than AZT+3TC (Gallant 2006, Arribas 2008), particularly due to improved tolerability. Furthermore, tenofovir can help improve lipoatrophy and dyslipidemia (Moyle 2006, Llibre 2006, Valdez 2008). Another advantage is its efficacy against the hepatitis B virus which resulted in the licensing of this drug for HBV monoinfection. Other areas of use are in vertical prevention and pre-exposure prophylaxis (refer to appropriate chapters).

The extensive use of tenofovir has revealed a few problems. The combination with ddI should be avoided for various reasons (see section on Inappropriate Drug Combinations). An unfavorable interaction with atazanavir exists that calls for being boosted with ritonavir (Taburet 2004). Efficacy may also be limited in some triple nuke regimens (see section on Triple Nukes).

However, the main problem today with tenofovir is its potential risk of nephrotoxicity (see chapter on “HIV and the Kidneys”). Nephrotoxicity is reflected by a mostly mild disturbance of renal function (Gallant 2005, Mauss 2005, Kirk 2010). Fortunately, severe dysfunctions are very rare (Gallant 2008). In a Swiss cohort trial, 46 out of 2592 patients (1.6%) had to discontinue tenofovir due to renal toxicity, on average within 442 days (Fux 2007). Renal failure can also be observed in the setting of Fanconi syndrome, a defect of the proximal tubular transport (Karras 2003, Schaaf 2003, Peyriere 2004). Patients with renal disease should either not be treated with tenofovir, or at least receive a lower dose (see chapter on “Drugs”). Elderly patients and patients with low body weight are particularly at risk (Crane 2006). However, it is so far impossible to predict who is at risk of developing renal dysfunction. According to current data, it is important to remain alert and to regularly check renal function of patients on tenofovir, especially of those on long-term therapy, especially because it is taken by such a large number of patients. For some time, tenofovir has also been associated with bone damage such as osteomalacia (see HIV and Rheumatology).

The choice of nuke backbones

Until now, all classical ART regimens have always contained two nucleoside or nucleotide analogs (a “nuke backbone”). This is mainly due to historical reasons. Nucleoside analogs were the first HIV drugs, and when PIs appeared years later, treatment with two nukes was standard. As knowledge has grown about the mitochondrial toxicity of some NRTIs, this concept is now being questioned by an increasing number of experts (see section on Nuke-Sparing). However, data on combinations without NRTIs are still limited, and there are currently no recommendations for such strategies. The most frequently used backbones are TDF+FTC, and with limitations, ABC+3TC. Both are available in fixed-dose combinations which can be taken once daily. AZT+3TC, the long-standing standard backbone in the nineties, is now considered an alternative.

Table 2.2. NRTI combinations.

















































+++ preferred backbones, ++ recommended as alternative, + other alternative, 0 insufficient data, – should be avoided. d4T is only indicated “if other antiretroviral drugs can not be applied.” (see above).


There is convincing data for the combination of TDF plus FTC (or initially 3TC). In the Gilead 903 Study, the combination TDF+3TC was not only as virologically effective as d4T+3TC, but was also much better tolerated (Gallant 2004). Since the introduction of FTC and the fixed-dose combination tablets of Truvada®, Atripla®, and, more recently, Complera®, tenofovir is almost always administered together with FTC and no longer with 3TC. Today TDF+FTC is the most frequently-used NRTI backbone. In the Gilead 934 Study (Gallant 2006), enrolling 509 ART-naive patients, TDF+FTC was tested against AZT+3TC in an open-label design (all patients also received efavirenz). At 48 weeks, a larger proportion of patients in the TDF+FTC arm reached less than 50 copies/ml (80% versus 70%). This was even true for patients with a higher baseline viral load. The significant differences were primarily related to the poorer tolerability of Combivir®, which often resulted in the discontinuation of therapy (9% versus 4%). Virological failure and resistance mutations were approximately equal in both arms and were infrequent. After 144 weeks, lipoatrophy was less frequent in the TDF+FTC arm (Arribas 2008). Providing no undesirable surprises with regard to nephrotoxicity in the long-term, TDF+FTC should remain the most frequently used backbone.


Another frequently used backbone is ABC+3TC, which is also available in a fixed-dose combination known either as Kivexa® or Epzicom®. The double-blind randomized CNA30024 Study showed the non-inferiority of ABC+3TC in comparison to Combivir® (DeJesus 2004). ABC+3TC even led to a significantly higher rise in CD4 T cells, although there was also a higher rate of allergies at 9% versus 3% (DeJesus 2004). The ZODIAC study also demonstrated good potency for ABC+3TC with efavirenz (Moyle 2004). In the ABCDE Study, ABC+3TC had the same efficacy as d4T+3TC, but had less toxicity (Podzamczer 2006).

Over the last few years, ABC+3TC has been compared to TDF+FTC in several randomized studies of therapy-naïve patients (Assert, ACTG 5202, HEAT), as well as in treatment-experienced patients (BICOMBO, STEAL) (see following Table).

Table 2.3. Randomized studies TDF+FTC (Truvada®, TVD) vs ABC+3TC (Kivexa®, KVX)
Study Setting, 3rd agent Major results
Therapy naive patients
HEAT(Smith 2009)

Double-blind (n=688)

plus LPV/r

Non-inferiority of KVX shown, AEs same in both arms
ACTG 5202(Sax 2009)

Double-blind (n=1858)

plus EFV or ATV/r

TVD better with high VL, more AEs on KVX
Assert(Post 2010, Stellbrink 20010)

Open (n=385)

plus EFV

TVD virologically better. On KVX overall more AEs, but less AEs of bone and kidney
Pretreated patients
STEAL(Martin 2009)

Open label (n=357)

VL <50

Same efficacy, but more AEs on KVX (i.e., cardiovascular, but low reduction of bone density)
BICOMBO(Martinez 2009)

Open label (n=333)

VL <200 >6 months

Non-inferiority of KVX not shown.More AEs on KVX
VL=viral load in number of copies/ml, AE=Adverse Events

The Table shows that data is not consistent. ABC+3TC was equivalent to TDF+FTC in HEAT and STEAL. In contrast, ACTG 5202, ASSERT and BICOMBO showed some differences to the disadvantage of ABC+3TC. Possibly the virological efficacy of TDF+FTC is better under certain conditions. Moreover, severe side effects are slightly more frequent under ABC+3TC. However, in studies like BICOMBO and ACTG 5202, HLA testing was not performed, standard nowadays, that significantly reduces abacavir HSR. It must be stressed that, all in all, results of TDF+FTC and ABC+3TC did not vary greatly despite the very different settings.


In the past  international guidelines recommended AZT+3TC as the standard backbone for first-line therapy. There is more experience with this combination than with any other. The resistance profile is favorable: the M184V mutation that frequently develops during 3TC treatment increases sensitivity to AZT. AZT+3TC are usually given as Combivir®. Although the licensing study for Combivir® showed no difference in toxicity (Eron 2000), in our experience the 300 mg AZT dose in Combivir® is too high for some patients (e.g., pregnant women) and can lead to anemia. In such cases, it is worth trying AZT+3TC as individual formulations, so that the dose of AZT can be reduced to 250 mg BID.

AZT+3TC have comparable efficacy to d4T+3TC  AZT+FTC (Benson 2004). The ACTG 384 Study showed superiority of AZT+3TC over d4T+ddI (Robbins 2003, Shafer 2003) which initially substantiated its status as the standard. This notion has however changed in the last years: Early results suggested a lower rate of lipoatrophy (Molina 1999). However, the development of lipoatrophy during AZT+3TC occurred only slightly later than with d4T+ddI. AZT+3TC was shown  to be less effective and less well-tolerated than TDF+FTC in the GS-934 study (Gallant 2006, Pozniak 2006). Another large ACTG-study also showed that it was less well-tolerated (Cambell 2011). Compared to ABC+3TC, immune reconstitution may be less impressive (DeJesus 2004). Facing these potential disadvantages and the fact that once daily dosing is not possible, many guidelines no longer recommend AZT+3TC as a preferred backbone in treatment-naïve patients.

ddI+3TC (FTC)

In many treatment guidelines, this combination is listed as an alternative for ART naïve patients. Of note, data is limited. According to some early duo-therapy trials, this combination is less effective than other backbones (Kuritzkes 1999). Newer studies suggest a comparable efficacy (and better tolerability) versus AZT+3TC (Berenguer 2008). However, looking at the long-term toxicity of ddI, we would only recommend ddI+3TC when important reasons argue against the use of TDF+FTC or ABC+3TC.

Poor and not-recommended backbones

It should be noted that the majority of the clinical trials cited above were conducted in treatment-naïve patients. In pretreated patients, other backbones may become necessary or meaningful due to resistance or lack of tolerability. But the following backbones should be avoided whenever possible:

Guidelines explicitly recommend avoiding the previously very popular combination of d4T+ddI. Mitochondrial toxicity is high with both individual agents, and it performs less well than AZT+3TC (Robbins 2003).  Considering the choice of NRTIs given today, its use is no longer  justified .

d4T+3TC is a combination recommended  for first-line therapy, like all other d4T-containing regimens. Studies such as ABCDE or GS-903 have shown that d4T+3TC causes notably more lipoatrophy than ABC+3TC or TDF+3TC (Gallant 2004, Podzamczer 2006).  There is no data or any argument for the use of d4T+FTC or d4T+TDF.

Increased gastrointestinal side effects and the necessity of taking ddI on an empty stomach (AZT is better tolerated taken with a meal) are facts that speak against the combination AZT+ddI. Due to its divergent resistance pathways AZT+TDF is not recommended for primary therapy and should be restricted to treatment experienced patients only.

The combination TDF+ddI is relatively toxic and over the years many studies have shown lower virologic and immunologic efficacy (see section on Inappropriate Initial Therapies). TDF+ABC are likely to be problematic due to rapid development of resistance. AZT+d4T and FTC+3TC are antagonistic (competitive, as noted above) and should never be employed.

Alternating backbones with regular changes from one backbone to another can currently not be recommended, although initial studies indicate that this strategy is at least not harmful (Molina 1999, Martinez-Picado 2003).


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Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002, 16:1257-63.

Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2304-15.

Shah SS, Rodriguez T, McGowan JP. Miller Fisher variant of Guillain-Barre syndrome associated with lactic acidosis and stavudine therapy. Clin Infect Dis 2003, 36:e131-3.

SMART. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008, 22:F17-F24.

Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir) through 48 weeks in the HEAT study. Abstract 774, 15th CROI 2008, Boston.

Sosa N, Hill-Zabala C, Dejesus E, et al. Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lami-vudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL). J AIDS 2005, 40:422-7.

Spruance SL, Pavia AT, Mellors JW, et al. Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double-blind, controlled trial. Ann Int Med 1997, 126:355-363.

Squires K, Pozniak AL, Pierone G, et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection. Ann Int Med 2003, 139: 313-320.

Staszewski S, Hill AM, Bartlett J, et al. Reductions in HIV-1 disease progression for zidovudine/lamivudine relative to control treatments: a meta-analysis of controlled trials. AIDS 1997, 11:477-483.

Staszewski S, Keiser P, Montaner J, et al. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral naïve HIV-infected adults: a randomized equivalence trial. JAMA 2001, 285: 1155-1163.

Stellbrink HJ, Moyle G, Orkin C, et al. Assessment of Safety and Efficacy of Abacavir/Lamivudine and tenofovir/Emtricitabine in Treatment-Naive HIV-1 Infected Subjects. ASSERT: 48-Week Result. Abstract PS10/01, 12th EACS 2009, Cologne

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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Mechanism of action and efficacy

NNRTIs were first described in 1990. As with the nucleoside analogs, the target enzyme is reverse transcriptase. However, NNRTIs bind directly and non-competitively to the enzyme at a position near to but distinct from the substrate binding site for nucleosides. The resulting complex blocks the catalyst-activated binding site of the reverse transcriptase. This in turn can bind fewer nucleosides, slowing down polymerization significantly. In contrast to NRTIs, NNRTIs do not require activation within the cell.

Three NNRTIs – nevirapine, delavirdine and efavirenz – were introduced between 1996 and 1998. Although studies such as ACTG 241 or INCAS had already clearly demonstrated the superiority of triple therapy compared to double nukes (D’Aquila 1996, Raboud 1999, Conway 2000), the acceptance and use of NNRTIs was rather hesitant and did not receive the media attention given to the PIs.

This was due to the early observation that functional monotherapy with NNRTIs, i.e., the mere addition of an NNRTI to a failing NRTI regimen, showed practically no effect. There were also initial difficulties in dealing with the development of problematic resistance: the risk of resistance is not only very high, but it can develop very rapidly. Once it occurs, it almost always indicates resistance to the entire class. Waiting too long when there is insufficient suppression of viral load is almost certain to lead to complete resistance to this class of drugs. One point mutation at position 103 (K103N) of the hydrophobic binding site is enough to eliminate the entire drug class. Resistance has now been described even in mothers who simply took a single dose of nevirapine as transmission prophylaxis (Eshleman 2002).

In large studies, the frequency of NNRTI mutations following a single perinatal nevirapine mono-prophylaxis was between 14% and a worrying 65% (Cunningham 2002, Jourdain 2004, Johnson 2005) which can impair the success of later NNRTI therapies (Lockman 2010). NNRTI resistance appear faster than you might expect! This is possibly due to the long half-life of NNRTIs (Muro 2005). Thus, NNRTIs should always be stopped some days prior to the other drugs if a break in therapy is planned (see chapter on “Treatment Interruption”). The rapid development of resistance is also reflected in the increasing number of primary transmitted resistance: in 2001/2002 almost 10% of all acute infections in Europe had NNRTI resistance (Wensing 2005). If there is resistance to one NNRTI, there is no need to start or continue treatment with an NNRTI –the immunological or virological status will not improve (Picketty 2004), because the ability of HIV to replicate is not reduced as much by NNRTI mutations as by some PI or NRTI mutations.

Despite the problems with resistance, both randomized and large cohort studies have demonstrated that NNRTIs are extremely effective when combined with nucleoside analogs. The immunologic and virologic potency of NNRTIs in treatment-naive patients is at least equivalent to that of PIs ( Torre 2001,  Robbins 2003, Soriano 2011). Studies such as ACTG 5142 or FIRST seem to support this superiority (MacArthur 2006, Riddler 2008). In contrast to PIs a clinical benefit with NNRTIs has not yet been proven as surrogate markers in trials have led to its approval. However, the efficacy of NNRTIs in treatment-experienced patients is probably weaker in comparison to PIs (Yazdanpanah 2004).

The simple dosing and the overall tolerability have enabled nevirapine and efavirenz to become important components of ART regimens, which are often ranked higher than those containing PIs. Over the last few years, many randomized studies have demonstrated that it is possible to switch from a PI to an NNRTI if good virological suppression has already been achieved. The efficacy was sometimes even better on NNRTIs than on the continued PI regimen (see chapter “When to Switch”).

Like efavirenz, nevirapine is metabolized by the cytochrome p450 system (Miller 1997). Nevirapine is an inducer, whereas efavirenz is an inducer and inhibitor of p450. In the combination of efavirenz plus either saquinavir or lopinavir the effects are so strong that dose adjustment is necessary.

So far, no study has provided definitive evidence that one NNRTI is more potent than another. Whereas delavirdine no longer has any significant role, due to various reasons (see below) and etravirine merely serves as a salvage substance, nevirapine and efavirenz have a similar standing in most countries (Mbuagbaw 2010). In the 2NN Study (The Double Non-Nucleoside Study), both agents were compared  in a large-scale randomized study (Van Leth 2004). A total of 1216 patients received a nuke backbone of d4T+3TC with either nevirapine 1 x 400 mg, nevirapine 2 x 200 mg, efavirenz 1 x 600 mg or efavirenz 1 x 800 mg plus nevirapine 1 x 400 mg. The only significant virological difference was an advantage of the efavirenz arm over the double NNRTI arm, mainly due to higher toxicity in the latter. In the nevirapine arm with 1 x 400 mg, severe hepatic side effects occurred more frequently than in the efavirenz arm; on the other hand, lipids were more favorably influenced in the nevirapine group. Sub-analyses of 2NN have shown that the hepatic toxicity associated with once-daily doses of nevirapine was observed in a single center in Thailand (Storfer 2005). In a randomized trial no increased risk for hepatotoxicity was observed in patients on once-daily nevirapine (Podzamczer 2008). In a subanalysis of the FIRST trial there were no differences with regard to efficacy between nevirapine and efavirenz (van den Berg 2008). In a small study more patients in ultrasensitive assays were under the detection level of 1 copy/ml under nevapirine than under efavirenz (Haïm-Boukobza 2011).

2NN, FIRST, as well as switch studies, such as the Spanish Nefa trial (Martinez 2003), demonstrate that the choice of NNRTI should be based mainly on the different side effect profiles (see below). Patient-specific factors should also be taken into account (Reviews: Sheran 2005, Mbuagbaw 2010).

Since 2008, etravirine, a second-generation NNRTI can be an option for patients with NNRTI resistance mutations from nevirapine or efavirenz. Another second-generation NNRTI, rilpivirine, was approved by the FDA in May 2011. The approval in Europe is expected for the end of this year.

Individual agents: Special features and problems

Nevirapine (NVP, Viramune®) was the first licensed NNRTI in 1997. The combination of nevirapine with AZT+ddI is probably the oldest HAART combination of all (D’Aquila 1996). In early randomized studies nevirapine performed comparably to indinavir (van Leeuwen 2003) and better than nelfinavir (Podzamczer 2002) The recently published ARTEN study showed  that the virological efficacy of nevirapine was comparable to boosted atazanavir (Soriano 2011) and in OCTANE-II similar to lopinavir/r (McIntyre 2010).

Over the long term nevirapine is usually well-tolerated. Studies such as Atlantic, 2NN or ARTEN compared favorable lipid changes (Van der Valk 2001, Van Leth 2004, Soriano 2009). In a small randomized trial lipid profiles improved when efavirenz was replaced by nevirapine (Parienti 2007). Whether these positive effects will have clinical relevance over time and really help to prevent cardiovascular events remains to be seen.

Nevirapine causes elevation of liver enzymes in up to 20%, which may occasionally be severe. Lead-in dosing is always required. During the first eight weeks on nevirapine, biweekly monitoring of transaminases is recommended. A rash develops in 15-20% and leads to discontinuation in up to 7% of patients (Miller 1997). Prophylactic administration of antihistamines or steroids does not prevent the rash (GESIDA 2004, Launay 2004). In the case of an isolated rash or isolated elevation of transaminases (up to five times the upper limit of normal), treatment can usually be continued but use caution when both occur simultaneously. It is recommended to stop treatment if a rash occurs together with even a slight elevation of transaminases (>2-fold ULN). It is important to note that hepatic toxicity may occur even after several months (Sulkowski 2002).

Patients with chronic hepatitis are at higher risk, as are women with low body weight (Sulkowski 2000, Sanne 2005, Kappelhoff 2005). An increased risk has also been reported for patients with good immune status. Women with CD4 T cell counts above 250/µl have a 12-fold elevated risk (11% versus 0.9%). In men there is an increased risk above 400 cells/µl (6.3% versus 1.2%). Although other studies failed to reveal an association between toxicity and immune status (Manfredi 2006, Wolf 2006,  Chu 2010), it is recommended not to use nevirapine in treatment naïve patients above these ranges. In contrast, in ART-experienced patients with higher CD4 T cell counts at the time of initiation of nevirapine the risk is not elevated (Mocroft 2007, De Lazzari 2008, Wit 2008). In August 2010 the EMEA altered their health warning in their publications – a switch to nevapirine is possible at a viral load of 50 copies/ml regardless of CD 4 cell count.

There is some evidence for an association between nevirapine-associated hypersensitivity and specific alleles at the HLA-DRB1 (Martin 2005) and polymorphisms in the p-glycoprotein drug transporter MDR1 gene (Haas 2006, Ritchie 2006). However, there is currently no test available which is able to predict hypersensitivity (Yuan 2011).

Gamma-glutamyl transpeptidase (GGT) elevations are very common, which may subject patients to false appearances of excess alcohol consumption.

The pharmacokinetics of nevirapine appears to allow once-daily dosing (Van Heeswijk 2000). Various studies such as 2NN, ARTEN or Atlantic have successfully used 400 mg once daily (van Leeuwen 2003, Van Leth 2004). Other studies also showed no difference in toxicity or regarding antiretroviral pretreatment (Calmy 2009). However, once-daily dosage of nevirapine has not yet been approved. In the VERxVe study nevapirine extended-release (NVP XR) showed good efficacy (Gathe 2010).  Launch is planned for the the middle of 2011.

Efavirenz (EFV, Sustiva®, Stocrin®) was the third NNRTI to be approved, and the first for which it could be shown that NNRTIs were at least as effective and maybe better than PIs in untreated or only slightly treatment-experienced patients. In particular, the 006 Study showed a superiority of efavirenz over indinavir (Staszewski 1999). Since then efavirenz has often been compared to other drugs and usually did well.In ACTG 5095, efavirenz in combination with AZT+3TC was better than abacavir (Gulick 2004); in ACTG 384 it was better than nelfinavir (Robbins 2003, Shafter 2003); and in AI424-034 and ACTG 5202 it was at least as effective as atazanavir and atazanavir/r respectively (Squires 2004, Daar 2011). In ACTG 5142, efavirenz appeared to be superior to lopinavir/r although resistance mutations were more frequently observed in the efavirenz arm (Riddler 2008).

In many guidelines, efavirenz is among the preferred drugs for treatment-naïve patients. However, there are some problems with its use: Mild CNS side effects are typical for efavirenz, which is recommended to be taken in the evening before going to sleep. Patients should be warned about these side effects, which usually include dizziness and numbness, but when taken before bed may also manifest as vivid dreams or even nightmares. In addition, patients should be warned about potentially hazardous tasks such as driving or operating machinery. The side effects probably correlate with high plasma levels (Marzolini 2001). Black African patients in particular seem to have a genetic predisposition (Haas 2004, Wyen 2008). Efavirenz disrupts sleep architecture (Gallego 2004). In one study, after four weeks of treatment with efavirenz, 66% of patients complained of dizziness, 48% of abnormal dreams, 37% of somnolence and 35% of insomnia (Fumaz 2002). Although these symptoms seem to resolve during the course of treatment, they may persist in about one fifth of patients (Lochet 2003). In such cases, efavirenz should be replaced if possible. A more recent study showed that CNS side effects can be reduced by a two week lead-in dosing, but this approach has not yet been validated (Gutiérrez-Valencia 2009).

However, lipids are not as favorably affected as with nevirapine (Parienti 2007). Gynecomastia is also seen on efavirenz, which is not only a psychological burden, but can be painful as well (Rahim 2004). In such cases, efavirenz should be replaced with nevirapine if possible. Efavirenz is teratogenic and contraindicated in pregnancy. It should be avoided in women of child-bearing age. In cases of pregnancy or trying to get pregnant, nevirapine should be favored. On the other hand, liver problems occur less frequently with efavirenz than with nevirapine. Due to the extensive half-life QD administration is safe and approved. Since 2007 efavirenz is available in the fixed-dose combination with tenofovir and FTC as Atripla®.

Table 2.4. Frequency of the most important side effects of nevirapine and efavirenz(numbers based on various studies referenced above).



CNS side effects



Severe CNS side effects

Very rare














Etravirine (ETV, Intelence®) is a diarylpyrimidine (DAPY) analog developed by Tibotec (Janssen-Cilag). This first second-generation NNRTI was approved in 2008 for antiretroviral treatment-experienced adult patients.

Etravirine works well against wild-type viruses, as well as resistant mutants, among them the classical NNRTI mutations such as K103N (Andries 2004). The genetic resistance barrier is higher than that of other NNRTIs. This appears to be because, by changing its confirmation, etravirine can bind very flexibly to the HIV-1 reverse transcriptase (Vingerhoets 2005). Mutations at the enzyme binding site therefore hardly affect the binding and therefore the potency of this NNRTI (Das 2004).

In Phase I/II studies, etravirine lowered viral load by an average of 1.99 logs in treatment-naïve patients after only one week (Gruzdev 2003) and by 0.89 logs in the presence of NNRTI mutations (Gazzard 2003). In C233, a large Phase II trial on 199 patients with NNRTI and PI mutations, who had previously been intensively treated, the viral load was significantly lower than the placebo arm after 48 weeks (TMC125 Writing Group 2007).

Another Phase II study (C227) brought a first setback. In this study etravirine was compared with an investigator-selected PI in NNRTI-resistant, PI-naïve patients. In an unplanned interim analysis, patients receiving etravirine demonstrated suboptimal virological responses relative to the control PI and the trial enrolment was stopped prematurely (Ruxrungtham 2008). Tibotec argued that in this study baseline resistance was higher than expected. The formulation of etravirine used then also showed poor bioavailability, which has been improved since (Kakuda 2008). Up to now there is no evidence of a correlation between pharmakinetical data and virlogical success (Kakuda 2010).

There are two large studies (DUET-1 and -2) leading to the approval of etravirine. In these double-blind, placebo-controlled, Phase III trials, patients on failing antiretroviral therapy with resistance to currently available NNRTIs and at least three primary PI mutations were randomly assigned to receive either etravirine or placebo, each given twice daily with darunavir/r, investigator-selected NRTIs, and optional T-20 (Lazzarin 2007, Madruga 2007).  After 96 weeks 57% of patients on etravirine achieved a viral load of less than 50 copies/ml compared to 36% on the placebo arm (Katlama 2010). However, the overall effect of etravirine decreased with an increasing number of NNRTI resistance mutations.  As with all substances etravirine needs a good active partner substances to develop its full efficacy (Tambuyzer 2010, Trottier 2010).

In most cases, etravirine is well-tolerated (Cohen 2009). In the DUET trials, tolerability was comparable to placebo. Only the typical NNRTI rash was observed more frequently (19% versus 11%) although they were mostly mild (Katlama 2009). In October 2009, FDA issued a warning on a limited number of cases of severe allergies (toxic epidermal necrolysis, Lyell’s syndrome, DRESS syndrome).A switch from efavirenz to etravirine can help to reduce the side effects on the CNS, however, patients who are tolerating efavirenz well see no advantage in the switach (Ngyuen 2011, Waters 2011).

There does not appear to be any relevant interaction with methadone or with other antiretroviral agents, with one exception: the level of etravirine is lowered significantly when combined with tipranavir (Kakuda 2006). Etravirine, at a dose of 800 mg (2 x 200 mg tablets BID), should be taken with a meal as this increases absorption.

Etravirine is an important and well-tolerated option for patients with NNRTI resistance. However, its efficacy is not unlimited. As with all other antiretroviral compounds, etravirine needs other active drugs. Current data suggest that etravirine should always be combined with a boosted PI, preferably darunavir.

Rilpivirine (RPV, Edurant®, formerly TMC 278) was approved by the FDA in May 2011. Approval for Europe is still pending. Like etravirine, it is also a DAPY NNRTI (Janssen 2005). Rilpivirine is effective against most NNRTI-resistant viruses. In three placebo-controlled dose-finding studies (up to 150 mg over 14 days) the agent was well tolerated (de Bethune 2005). An early Phase IIa study on therapy-naive patients receiving monotherapy for 7 days produced an average decrease in viral load of 1.2 logs. In addition, there was no dose-dependent effect between 25 and 150 mg (Goebel 2005). A considerable advantage of rilpivirine is its very long half-life (40 hours). In combination with lopinavir/r, its blood levels are significantly increased, necessitating dose adjustment (Hoetelmans 2005). When switching from efavirenz to rilpivirin lower levels have been observed in the beginning – its relevance, however, is still not clear (Crauwels 2011).

In an open randomized Phase IIb study, the antiviral effect of rilpivirine was comparable to efavirenz after 48 weeks, however with significantly less CNS side effects and less increase of lipids (Poznial 2010). The 25 mg doses are being tested against efavirenz in 1368 ART-naïve patients in two large-scale Phase III trials (ECHO and THRIVE). At 48 weeks a comparable effect with better tolerability was observed (Cohen 2010). However, resistances as well as virological failure was also observed more frequently under rilpivirine (9,0 versus 4,8 %). The QT prolongation under rilpivirine observed in the beginning, seems to be irrelevant (Vanveggel 2009) and teratogenic risk is small (Desmidt 2009). A parenteral nano-suspension is being investigated, in which ripilvirine levels are achieved via monthly injections, corresponding to a daily dose of 25 mg (Verloes 2008). Currently rilpivirine is also being tested as a fixed-dose combination substance with TDF+FTC. The European approval for this FDC pill (Complera®) which was already approved by the FDA in August 2011, is expected for 2012.

Delavirdine (DLV, Rescriptor®) was, in April 1997, the second NNRTI to be licensed by the FDA. Due to the pill burden and the required three times daily dosing, delavirdine is currently rarely prescribed. Delavirdine is not licensed in Europe where, in 1999, an application for licensure was rejected due to insufficient efficacy data. Although delavirdine may be as effective as other NNRTIs (Conway 2000), rash probably occurs more frequently (30%) than with other NNRTIs. Delavirdine increases plasma levels of various PIs, including saquinavir (Harris 2002). However, use of this as a strategy for boosting has not been widely accepted. Even in the US where it is approved, use (and so, helpful real life data) is limited.


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Protease Inhibitors (PIs)

Mechanism of action and efficacy

The HIV protease cuts the viral gag-pol polyprotein into functional subunits. If the protease is inhibited and proteolytic splicing prevented, non-infectious virus particles will result. With the knowledge of the molecular structure of the protease encoded by the virus, the first protease inhibitors were designed in the early nineties; these agents were modified in such a way that they fit exactly into the active site of the HIV protease (Youle 2007).

Since 1995, protease inhibitors have revolutionized the treatment of HIV infection. At least three large studies with clinical endpoints demonstrated the efficacy of indinavir, ritonavir and saquinavir (Hammer 1997, Cameron 1998, Stellbrink 2000). Although PIs have been criticized due to their sometimes high pill burden and side effects (see below), they remain an essential component of antiretroviral therapies. With growing knowledge of the mitochondrial toxicity of nucleoside analogs and through the introduction of easy-to-take PIs, this class of drugs is currently experiencing a renaissance – today, even PI-only regimens are being investigated.

At first, there was competition to establish which PI had superior efficacy. Current data suggest that the differences are not significant enough to completely compromise individual members of this class. Exceptions that have since been taken off the market are: the hard gel capsule saquinavir (Fortovase®) and ritonavir on its own as a PI. Boosted PI combinations are more effective than unboosted combinations (see below).

Apart from gastrointestinal side effects and high pill burden, all PIs used in long-term therapy show tolerability problems – to a greater or lesser extent, all are associated with lipodystrophy and dyslipidemia (Nolan 2003). Other problems include drug interactions, which can sometimes be substantial. Cardiac arrhythmias (Anson 2005) and sexual dysfunction have also been attributed to PIs (Schrooten 2001), although the data does not remain unchallenged (Lallemand 2002).

All PIs are inhibitors of the CYP3A4 system and interact with many other drugs (see chapter on “Drug Interactions”). Ritonavir is the strongest inhibitor, saquinavir probably the weakest. There is a high degree of cross-resistance between protease inhibitors, which was described even before PIs were put on the market (Condra 1995). With darunavir and tipranavir there are now two second-generation PIs on the market which are effective even in the presence of several resistance mutations (see below).

Why boost PIs?

Ritonavir is a very potent inhibitor of the isoenzyme 3A4, a subunit of the cytochrome P450 hepatic enzyme system. Inhibition of these gastrointestinal and hepatic enzymes allows the most important pharmacokinetic parameters of almost all PIs to be significantly increased or “boosted” (Kempf 1997): maximum concentration (Cmax), trough levels (Ctrough) and half-life. The interaction between ritonavir and the other PIs simplifies daily regimens by reducing the frequency and number of pills to be taken every day, in many cases independent of food intake. Some PIs can now be used in once-daily regimens.

Boosting with ritonavir is usually indicated by addition of an “/r” after the drug name. Resistance is only rarely observed on boosted PIs, at least in therapy–naïve patients, as the genetic barrier is high. This has been shown not only for lopinavir/r (Hammer 2006), but also for fosamprenavir/r (Eron 2006), atazanavir/r (Mallan 2008), saquinavir/r (Ananworanich 2006) and darunavir/r (Ortiz 2008). Patients with an elevated viral load should therefore receive boosted PIs at the start of therapy. Nelfinavir is the only PI for which boosting with ritonavir is not recommended as plasma levels do not rise significantly.

Boosting can be effective against resistant viral strains as a result of the elevated drug plasma levels (Condra 2000). However, a recently published randomized study evaluating TDM-guided dose escalation showed no benefit with this strategy (Demeter 2009). Ritonavir boosting is also associated with risks. There is a high degree of variability in plasma levels among individuals. As well as trough levels, peak levels are also elevated, which may lead to more side effects. If in doubt (reduced efficacy, more side effects), plasma levels should be measured in cases of boosting, especially in patients with severe hepatic disease, because the extent of interaction cannot be predetermined for individual cases. Dose adjustment is often necessary.

Table 2.5. Current doses of protease inhibitors with ritonavir boosting.

Dose (mg)



1 x 300/100

1 x 2

No limitation

2 x 600/100

2 x 2

No limitation

1 x 800/100

1 x 3

Only approved in PI-naïve patients

2 x 700/100

2 x 2

Should be used instead of amprenavir

1 x 1400/200

1 x 4

Approval only in US (PI-naïve patients)

2 x 800/100

2 x 3

Higher rate of nephrolithiasis (?)

2 x 400/100

2 x 2

The only fixed booster combination

1 x 800/200

1 x 4

PI-naive patients

2 x 1000/100

2 x 3

Officially approved for boosting

2 x 500/200

2 x 4

Only approved in treatment-experienced pts

*Number of pills including the ritonavir dose

Individual agents: Special features and problems

Amprenavir (APV, Agenerase®) was the fifth PI to enter the European market in June 2000. It was replaced by fosamprenavir in 2004 (Telzir® or Lexiva®, see below) and subsequently withdrawn from market.

Atazanavir (ATV, Reyataz®) was licensed in March 2004 as the first PI on the market for once daily administration. In treatment-naïve patients, atazanavir was compared to many other agents. In a Phase II study, potency was comparable to nelfinavir while tolerability of atazanavir was better (Sann 2003). Both boosted and unboosted atazanavir proved as effective as efavirenz (Squires 2004, Daar 2010) or nevirapine (Soriano 2011). The CASTLE study which compared atazanavir/r once-daily with lopinavir/r twice-daily in 883 treatment-naïve patients, proved that virologically atazanavir/r was at least as good or even better with more favorable lipid profiles and better gastrointestinal tolerability (Molina 2008+2010). In 2008 the results of the CASTLE study led to unlimited approval of atazanavir. Although several studies have shown no difference between boosted and unboosted atazanavir (Malan 2008, Squires 2009), boosting with ritonavir is recommended. Atazanavir is slightly less effective than lopinavir in treatment-experienced patients when it is not boosted (Cohen 2005). However, when boosted atazanavir is comparable to lopinavir, at least when PI resistance is limited (Johnson 2006).

In comparison to other PIs, atazanavir does not have a negative effect on lipid levels (Review: Carey 2010), its main advantage other than its once-daily dosing. Data from other studies are now available showing that lipids improve when nelfinavir or other PIs are replaced by atazanavir (Gatell 2007, Soriano 2008, Calzy 2009, Mallolas 2009). It also does not induce insulin resistance (Noor 2004). However, endothelial function which poses a risk factor for cardiovascular incidence caused by an increase in lipids, is not improved by atazanavir (Flammer 2009, Murphy 2010). Therefore, it is not yet clear, whether improved lipids on atazanavir actually lead to less myocardial infarctions. Whether improved lipid profiles show less lipodystrophy as suggested in smaller studies (Haerter 2004, Jemsek 2006, Stanley 2009) has still to be confirmed. Contrasting with earlier reports, more recent data suggest that boosting atazanavir with ritonavir seems to have some negative effects on lipid levels (Review: Carey 2010). Surprisingly one randomized study showed a slightly lower incidence of lipoatrophy in patients treated with atazanavir/r compared to unboosted atazanavir (McComsey 2009).

One problem with atazanavir is that more than half of patients experience elevated bilirubin levels, which can reach grade 3-4 in approximately one third of all cases (Squires 2004, Niel 2008, Soriano 2008). Some patients even develop jaundice. The mechanism for this resembles that of Gilbert’s Syndrome; there is reduced conjugation in the liver. A genetic predisposition has been identified (Rotger 2005). Although the hyperbilirubinemia is understood to be harmless and only few cases of serious hepatic disorders have been published to date (Eholie 2004), liver function should be monitored while on atazanavir. Treatment should be discontinued in cases of significantly elevated bilirubin (>5-6 times the upper limit of normal).

Unfavorable interactions occur particularly in combination with proton pump inhibitors (see chapter on “Drug Interactions”). Boosting is generally recommended, particularly for combinations that include NNRTIs or tenofovir, which significantly lower atazanavir levels (Le Tiec 2005).

The primary resistance mutation for this drug is I50L, which does not impair sensitivity to other PIs (Colonno 2003). On the other hand, there are a number of cross-resistant mutations and susceptibility to many virus isolates with moderate PI resistance is reduced (Schnell 2003).

Darunavir (DRV, Prezista®) is a nonpeptidic PI, originally developed by the Belgian company Tibotec (now Janssen-Cilag). Due to its impressive potency in the presence of PI-resistant mutants (Koh 2003), darunavir was initially an important drug for therapy experienced patients with limited options. In 2008 the license was extended to all HIV-infected patients requiring therapy (see below).

Two large Phase II studies, POWER-I (US) and -2 (Europe), brought darunavir to the forefront of attention and sped up the licensing for darunavir in the US in June 2006 and in Europe in February 2007 for therapy-experienced patients. The POWER studies included nearly 600 patients with extensive pretreatment (three classes and an average of 11 drugs) and high resistance (Clotet 2007). Several ritonavir-boosted darunavir doses were tested against a boosted comparison PI. Despite considerable resistance at baseline, in 46% of the patients in the 600 mg BID group plus 100 mg BID ritonavir, the viral load fell to less than 50 copies/ml after 48 weeks – a significantly improved result in comparison to the control PI (10%), and a success that had so far not been seen in this patient group with such limited options. Encouraging results in salvage treatment were also reported from the DUET trials, in which darunavir was combined with etravirine (see above).

In patients with moderate pre-treatment (naïve to lopinavir), darunavir/r was superior to lopinavir/r. In the TITAN study with 595 (lopinavir-naïve) patients, mainly pretreated with PIs, 71% showed a viral load of under 50 copies/ml at 48 weeks compared to 60% on lopinavir (Madruga 2007). Superiority was observed in all patient groups. Virologic failure and resistance against associated agents were significantly less on darunavir. Of note, efficacy was not compromised by the occurrence of PI resistant mutations (De Meyer 2008+2009).

In 2008, the license for darunavir was extended to treatment-naïve patients. The ARTEMIS trial demonstrated comparable efficacy of once daily darunavir/r compared to lopinavir/r in this patient population (Ortiz 2008, Mills 2009). Once-daily darunavir/r also showed potential in treatment-experienced patients with no darunavir resistance mutations (De Meyer 2008, Cahn 2010).

Darunavir is well tolerated. Gastrointestinal side effects are moderate and less severe than with other PIs (Clotet 2007, Madruga 2007). Dyslipidemia and raised liver enzymes do not appear to be significant. Rash, which may occur in up to 5-15% of patients, is usually mild. Relevant interactions occur with lopinavir causing a decrease of plasma levels of darunavir. This combination must be avoided. The same applies for sildenafil and estrogen.

The potency of darunavir is, of course, not unlimited. 11 mutations associated with darunavir resistance were identified in the POWER studies. These mutations are usually located at codons 32, 47, 50 and 87 (De Meyer 2006). With accumulation of at least three mutations, susceptibility to darunavir is reduced (Pozniak 2008). Darunavir and fosamprenavir in vitro susceptibility patterns are very similar. However, predicted incidence of clinically meaningful cross-resistance is low, due to differences in clinical cut-offs, which are higher for darunavir (Parkin 2008). Thus, pretreatment with amprenavir or fosamprenavir does not appear to compromise efficacy of darunavir. In view of the high resistance barrier, there are several trials currently testing darunavir as monotherapy (Katlama 2010, see below).

Fosamprenavir (Telzir®, USA: Lexiva®) as a calcium phosphate ester, has better solubility and absorption than its original version, now off the market, amprenavir. Fosamprenavir was licensed for treatment-naïve and -experienced patients in 2004. The recommended doses are either 1400 mg BID, 700 mg plus 100 mg ritonavir BID or 1400 mg plus 200 mg ritonavir once daily. Once-daily dosing is not recommended for treatment-experienced patients, and, like the unboosted dose, is not licensed in Europe. A recent trial suggested that for once-daily dosing, 100 mg ritonavir is sufficient (Hicks 2009).

Several large studies have compared fosamprenavir with other PIs. In the SOLO study with treatment-naïve patients, fosamprenavir boosted once-daily was about as effective as nelfinavir (Gathe 2004) and in the relatively small ALERT study as effective as atazanavir/r (Smith 2006). No resistance was found on boosted fosamprenavir even after 48 weeks (MacManus 2004). In the KLEAN study (Eron 2006), fosamprenavir/r twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and control of emergence of resistance as lopinavir/r, each in combination with ABC+3TC. In treatment-experienced patients in the CONTEXT study, fosamprenavir was not quite as effective as lopinavir/r although the difference was not significant (Elston 2004).

Fosamprenavir currently does not play an important role in HIV medicine. There is no convincing argument for its use. One advantage of the drug is that there are no restrictions with respect to food intake. It is important to note that efavirenz can significantly (probably with clinical relevance) lower plasma levels, as can nevirapine, which does not occur when fosamprenavir is boosted with ritonavir (Elston 2004).

Indinavir (IDV, Crixivan®) is one of the first PIs, initially very successful in large studies (Gulick 1997, Hammer 1997). Later, indinavir had mixed success, at least when unboosted: in the Atlantic Study, it was about as effective as nevirapine (Van Leeuwen 2003), but in the 006 Study it was clearly weaker than efavirenz (Staszewski 1999). There are numerous problems associated with indinavir. Firstly, it causes nephrolithiasis in 5-25% of patients (Meraviglia 2002) and thus requires good hydration (at least 1.5 liters daily). Unboosted indinavir must be taken three times daily on an empty stomach (Haas 2000). When boosted at 2 x 800/100 mg, indinavir/r side effects increase (Voigt 2002). In the MaxCmin1 Trial, the drop-out rate on indinavir was notably higher than among patients receiving saquinavir (Dragstedt 2003). Specific side effects associated with indinavir include mucocutaneous side effects reminiscent of retinoid therapy: alopecia, dry skin and lips, and ingrown nails. Many patients may also develop asymptomatic hyperbilirubinemia. Although it seems that the dose and toxicity can be reduced in most patients by boosting and monitoring plasma levels (Wasmuth 2007), indinavir is no longer among the regular choices for therapy.

Lopinavir/r (LPV, Kaletra®) was licensed in April 2001 and is the so far onlyPI with a fixed boosting dose of ritonavir. This increases concentrations of lopinavir by more than 100-fold (Sham 1998). In 2006, the old Kaletra® capsules were replaced by tablets, allowing a pill reduction (Gathe 2008). Lopinavir is still the most frequently prescribed PI worldwide and has also been licensed as once-daily since October 2009 after several studies had shown  its efficacy and tolerability (Molina 2007, Gathe 2009, Zajdenverg 2009, Gonzalez-Garcia 2010,). However, others have suggested a slightly reduced potency of once-daily dosing (Ortiz 2008, Flexner 2010). Lopinavir once-daily is only recommended, if the number of PI resistances is limited.

In treatment-naïve patients, lopinavir/r was significantly superior to an unboosted regimen with nelfinavir (Walmsley 2002). It has been regarded as the preferred PI for years. However, more recently, large randomized trials such as KLEAN, GEMINI, ARTEMIS and CASTLE have shown that there are no significant differences compared to boosted PIs such as fosamprenavir/r (Eron 2006), saquinavir/r (Walmsley 2009), or atazanavir/r (Molina 2008). In ACTG 5142, lopinavir/r was inferior to efavirenz (Riddler 2008), possibly due to lower tolerability.

In treatment-experienced patients, lopinavir/r showed slightly better results than boosted saquinavir (the old Fortovase® formulation) in an open-label randomized (MaxCmin2) trial on a heterogeneous population of treatment-experienced patients. This was particularly true for tolerability, but also with respect to treatment failure (Dragstedt 2005). On the other hand, in two large studies in PI-experienced patients, virologic efficacy of lopinavir/r was not significantly higher than that of boosted atazanavir (Johnson 2006) or fosamprenavir (Elston 2004) – although patient numbers in these studies were rather small. In comparison to darunavir, efficacy was even lower (Madruga 2007, De Meyer 2009).

Development of resistance with lopinavir/r first-line therapy is rare, but is theoretically possible (Kagan 2003, Conradie 2004, Friend 2004). Lopinavir/r has a high genetic barrier to resistance, and it is likely that at least 6-8 cumulative PI resistance mutations are necessary for treatment failure (Kempf 2002). That is why lopinavir is also considered for monotherapies (see below).

A significant problem of lopinavir are the gastrointestinal side effects (diarrhea, nausea) which are probably more frequent on a once-daily dosage (Johnson 2006). In addition, lipodystrophy and often considerable dyslipidemia, have been observed, probably more marked than with atazanavir (Molina 2008, Mallolas 2009), darunavir (Mills 2009) and saquinavir (Walmsley 2009), but not more so than with fosamprenavir (Eron 2006). A number of interactions should also be considered. The dose must be increased in combination with efavirenz and nevirapine, probably also with concurrent administration of fosamprenavir.

Nelfinavir (NFV, Viracept®) was the fourth PI on the market. The dose of five capsules BID is just as effective as three capsules TID. Boosting with ritonavir does not improve plasma levels.The most important side effect of nelfinavir is diarrhea, which may be considerable.

In comparison to NNRTIs or other PIs, nelfinavir is probably slightly less potent. This was demonstrated with nevirapine (Podzamczer 2002) and even more so with efavirenz (Albrecht 2001, Robbins 2003) and lopinavir/r (Walmsley 2002). A newer formulation (625 mg) that enables a reduction to two capsules BID is produced by ViiV Healthcare and is available in the US. In Europe, where Roche has the marketing rights, nelfinavir  no longer plays much of a role .

Ritonavir (RTV, Norvir®) was the first PI for which efficacy was proven on the basis of clinical endpoints (Cameron 1998). However, ritonavir is now obsolete as a single PI, since tolerability is poor (Katzenstein 2000). As gastrointestinal complaints and perioral paresthesias can be very disturbing, ritonavir is now only given to boost other PIs. The “baby dose” used for this purpose (100 mg BID) is better-tolerated.

Ritonavir inhibits its own metabolism via the cytochrome P450 pathway. The potent enzyme induction results in a high potential for interactions. Many drugs are contraindicated for concomitant administration with ritonavir. Metabolic disorders probably occur more frequently than with other PIs. Caution should be exercised in the presence of impaired liver function. It is important to inform patients that ritonavir capsules must be stored at cool temperatures, which can often be a problem when traveling. This is not necessary, however, for the new ritonavir tablets which came onto the market in early 2010.

Saquinavir (Invirase 500®), previously Invirase®, Fortovase®, was the first PI to be licensed for HIV therapy in December 1995, and is still today one of the few agents with efficacy based on clinical end points (Stellbrink 2000). Boosting with ritonavir raises the plasma level sufficiently, as does simultaneous food intake, so saquinavir should be taken with meals. Saquinavir is well-tolerated – there are hardly any serious side effects. The earlier hard gel (Invirase®) and soft gel (Fortovase®) capsules were replaced in 2005 by Invirase 500® tablets, which significantly reduced the number of pills to four a day (Bittner 2005). It is probable that much data from the Fortovase® capsules cannot be easily transferable to the tablets. Newer data from the randomized GEMINI trial compared ritonavir-boosted Invirase 500® tablets to lopinavir/r in 330 ART-naïve patients who all received TDF+FTC. There were no significant differences between arms with respect to efficacy at 48 weeks (Walmsley 2009). Some adverse effects such as lipid elevations, particular triglycerides, were less pronounced with saquinavir, as was diarrhea. However, discontinuation rates due to adverse events were comparable between arms. Saquinavir is another option for patients who need a boosted-PI regimen. However, even at the higher pill dosage, it is difficult to find an advantage over other PIs, such as atazanavir, darunavir or lopinavir.

Tipranavir (TPV, Aptivus®) is the first non-peptidic PI licensed in Europe in July 2005 for treatment-experienced patients. As oral bioavailability is only moderate, double the standard ritonavir boosting (McCallister 2004) is necessary, whereby 2 x 200 mg (BID) has to be used. The plasma levels can also be increased by a high fat meal.  Tipranavir shows good efficacy against PI-resistant viruses (Larder 2000). It even has a considerable effect in the presence of resistance mutations such as L33I/V/F, V82A/F/L/T and I84V. However, its efficacy is not limitless – with a combination of the above mutations, sensitivity declines significantly (Baxter 2006).

RESIST-1 (USA) and RESIST-2 (Europe) were two Phase III studies on 1483 intensively pretreated patients with a viral load of at least 1000 copies/ml and at least one primary PI mutation. All patients received either tipranavir/r or a comparison PI/r, each combined with an optimized therapy according to resistance testing. After 48 weeks, virological and immunological response to tipranavir was better than with the comparison PI (Hicks 2006).

A significant problem of tipranavir, apart from dyslipidemia (grade 3-4 increase in triglycerides: 22% versus 13% for the comparison PI), is an increase in transaminases. This is sometimes substantial (grade 3-4: 7% versus 1% in RESIST) and requires careful monitoring of all patients on tipranavir, especially those coinfected with hepatitis B or C. In treatment-naïve patients, tipranavir/r was less effective than lopinavir/r, mainly due to more adverse events leading to discontinuation (Cooper 2006). In addition, some unfavorable interactions also occur. Plasma levels of lopinavir, saquinavir, atazanavir and amprenavir fall significantly, so that double PI therapy with tipranavir is currently not under consideration. As the levels of AZT, abacavir and etravirine also drop, these combinations are not recommendable either. Use with delavirdine is contraindicated and ddI has to be taken with a two-hour time delay.

Taken together, tipranavir remains an important option in extensively treated patients harbouring PI-resistant viruses. Unfortunately, a study which directly compared tipranavir/r to darunavir/r was halted due to slow accrual. Cross-trial comparisons between these drugs should be discouraged as patient populations in the RESIST (tipranavir/r) studies differed considerably from those of the POWER (darunavir/r) trials.


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Entry inhibitors

Mode of action

There are three crucial steps for entry of HIV into the CD4 T cell:

1. Binding or attachment of HIV to the CD4 receptor (target of attachment inhibitors),

2. Binding to coreceptors (target of coreceptor antagonists),

3. Fusion of virus and cell (target of fusion inhibitors).

Figure 1: The three steps of HIV entry into the host cell. (courtesy of: Moore JP, Doms RW. The entry of entry inhibitors: a fusion of science and medicine. PNAS 2003, 100:10598-602).

Every step of HIV entry can theoretically be inhibited. All three drug classes, namely attachment inhibitors, coreceptor antagonists and fusion inhibitors are currently summarized as entry inhibitors. One important difference to other drug classes such as NRTIs, NNRTIs, PIs or integrase inhibitors is that entry inhibitors do not inhibit HIV intracellularly. They interfere early in the replication cycle of HIV. It is speculated that this will lead to a better tolerability of this class.

In May 2003 T-20 was licensed as the first entry inhibitor in Europe and the US. Maraviroc was the first CCR5 coreceptor antagonist and the first oral entry inhibitor in 2007. Numerous other drugs are in the pipeline, but most will not be available soon. T-20 and maraviroc will be discussed in this section, for other entry inhibitors refer to the next chapter, “ART 2011/2012”.

Co-receptor antagonists


In addition to CD4 receptors, HIV requires so-called co-receptors to enter the target cell. The two most important ones, CXCR4 and CCR5, were discovered in the mid- 1990s (Alkhatib 1996, Deng 1996, Doranz 1996). These receptors, of which there are probably more than 200 in total, are named after the natural chemokines that usually bind to them. Their nomenclature is derived from the amino acid sequence. For CCR5 receptors these are the CC-chemokine MIP and RANTES, for CXCR4 receptors it is the CXC-chemokine SDF-1.

HIV variants use either the CCR5 or the CXCR4 receptors for entry into the target cell. According to receptor tropism, HIV variants are termed R5-tropic if they use CCR5 as a co-receptor, whereas viruses with a preference for CXCR4 are termed X4-tropic viruses. R5 viruses predominantly infect macrophages (formerly, M-tropic). X4 viruses mainly infect T cells (formerly, T-tropic). Dual-tropic viruses are able to use both receptors. There also exist mixed populations of R5 and X4 viruses.

In most patients, R5 viruses are found in the early stages of infection. X4 viruses, which are probably able to infect a wider spectrum of cell types, usually occur in the later stages. The change in tropism is frequently associated with disease progression (Connor 1997, Scarlatti 1997). It is still not completely clear why this happens after several years of infection, although the tropism shift only needs a few small mutations. However, it is possible that X4 viruses are significantly more virulent, but because of their low glycosylation, more immunogenic. X4 viruses are neutralized better by the immune system and it is therefore likely that they only become apparent in the presence of a significant immune deficiency.

In treatment-naïve patients, R5 strains are found in 80-90%, compared to only 50-55% in patients with antiretroviral exposure (Hoffmann 2007). The most important predictor of R5 tropism seems to be a higher CD4 T cell count in both naive and antiretrovirally pretreated patients. A low HIV plasma viremia seems to be associated with R5 tropism only in untreated patients (Moyle 2005, Brumme 2005). In contrast, X4 viruses are almost exclusively found in advanced stages of the disease. When the CD4 T cell count is >500/µl, they are only found in 6%; at <25 CD4 T cells/µl, in more than 50% of patients (Brumme 2005). In addition, X4 viruses almost always occur in X4/R5-mixed populations and an exclusive X4 virus population is very rare.

In some individuals expression of CCR5 coreceptors on the cell surface is reduced. These individuals are usually healthy. The reduced expression of the receptor is usually due to a defective CCR5 allele that contains an internal 32-base pair deletion (delta 32 deletion). This deletion appears to protect homozygous individuals from sexual transmission of HIV-1. Heterozygous individuals are quite common (approximately 20%) in some populations. These individuals have a slower decrease in their CD4 T cell count and a longer AIDS-free survival than individuals with the wild type gene (Dean 1996, Liu 1996, Samson 1996). Thus, targeting the interaction between HIV-1 and the CCR-5 receptor appears to be an attractive therapeutic goal to prevent or slow disease progression.

In 2008 the case of a patient with acute myeloid leukemia and HIV-1 infection was published. This patient underwent stem cell transplantation from a donor who was homozygous for the CCR5 delta 32 deletion. The patient remained without viral rebound for many years after transplantation and discontinuation of ART. This outcome demonstrates the critical role CCR5 plays in maintaining HIV-1 infection (Hütter 2009, Allers 2011).

CCR5 antagonists should probably be given earlier on in the course of the disease. In the salvage situation, patients often harbour X4 viruses. The role of CCR5 antagonists might lie rather in the substitution of other antiretroviral agents in case of toxicity.

Testing for coreceptor usage (Tropism testing)

Since CCR5 blockers are effective only when a predominant R5 virus is present in the patient and coreceptor switch is not systematic, a baseline determination of the coreceptor usage of the virus is mandatory. Tropism testing prior to treatment avoids unnecessary costs and additional risks for the patient. Non-effectivity of CCR5 antagonists may cause regimen frailty and lead to resistance. This is why the development of CCR5 antagonists has brought along a completely new laboratory branch which focuses on predicting the coreceptors mainly or exclusively used by a viral population. More information can be found in the chapter “Resistance”.

Figure 2: Mode of action of the allosteric CCR5 antagonists maraviroc (and vicriviroc). By binding to a hydrophobic cavity formed between transmembrane helices in CCR5 near the membrane surface, the receptor molecule undergoes conformational changes. This inhibits the binding of viral gp120 to the receptor. R5A = CCR5 antagonist

Several commercial assays have been developed to determine HIV tropism phenotypically, such as Trofile® (Monogram Biosciences), Phenoscript® (VIRalliance) or XtrackC/PhenX-R® (inPheno). These assays amplify the HIV-1 envelope glycoprotein gene sequence from patient plasma samples to produce either replication-competent or replication-defective recombinant viruses. There are now several improved assays on the market. For example, the originally licensed Trofile® assay has been replaced by Trofile-ES®. This assay can detect smaller numbers of X4 virus, resistant to CCR5 inhibitors, when they constitute a minor subpopulation of virus within a swarm of CCR5-using virus. Several studies have illustrated the potential benefit of the use of the newer, more sensitive tests (Saag 2008, Su 2008).

Consequently, there is a need for the development of test methods which are easy and less time-consuming. Recently, the technically more simple and economic genotype tropism testing has been validated (Sierra 2007). Presently the focus of research is on the V3 loop of the envelope protein gp120, as this is the region where HIV binds to the coreceptor (Jensen 2003, Briz 2006). However, tropism does not only seem to be defined by the V3 loop sequence – virus isolates with identical V3 loops can differ in tropism (Huang 2006, Low 2007). Nevertheless, at present, genotypic tropism testing seems to be able to substitute the more complex and expensive phenotypic assay (Poveda 2009).

With genotypic testing, CCR5 antagonists may be suitable for many patients who have side effects on other agents, as long as the viral load is well suppressed. As mentioned above, phenotypic testing requires a viral load of at least 1000 copies/ml, whereas genotypic tests probably require less virus. At present, great efforts are being made in determining tropism from proviral DNA in patients with a low (even undetectable) viral load. This method investigates the genotype of HIV which is integrated in the genome of infected cells. First runs show that this is possible and effective (Soulie 2009).

The question of who is to pay for tropism testing has not been solved – the maraviroc manufacturer ViiV Healthcare refuses to take over the costs making it necessary to send individual requests directly to the health insurance.

Tropism shift and other consequences

During treatment failure of antiretroviral regimens containing CCR5 antagonists, many patients often show a selection shift to X4 viruses. This shift is mainly due to selections from preexisting pools (Westba 2006). In a pilot study in which patients with X4/R5 mixed populations received maraviroc, CD4 T cells were higher in comparison to placebo (Saag 2009). An X4 shift (induced HIV progression) while on CCR5 antagonists therefore seems very unlikely.

What other consequences could a CCR5 blockade have? Although individuals with a ∆32-gene defect for the CCR5 receptor are usually healthy, there are worries about negative effects of blocking these receptors, i.e., this chemokine receptor must exist for some reason.

Individuals with the ∆32 deletion  have been examined in numerous studies to see if they suffer more frequently from illnesses compared to patients without this gene defect. An increased appearance of West Nile viral infection (Glass 2006) or FSME (Kindberg 2008) has been greatly discussed, whereas the ∆32 deletion seems to be protective for rheumatism (Prahalad 2006). Presently the data is so heterogeneous and often contradictory, that it is difficult to speak of a distinct association of the gene defect with certain illnesses. However, it is advisable to monitor carefully, as experience with CCR5 antagonists has so far been limited.

Moreover, in theory, docking onto the receptor could cause an autoimmune reaction. However, this has not occurred in testing with monkeys (Peters 2005). Negative effects towards vaccinations are also being discussed (Roukens 2009). An analysis of the complete Phase I/II studies with maraviroc has shown no negative effects on immune function (Ayoub 2007). The initially disquieting reports of malignancies in a study with vicriviroc (Gulick 2007) has not been confirmed in any following studies.

Immune modulation with CCR5 antagonists?

A meta-analysis of all larger studies showed that an increase of CD4 T cells is greater on maraviroc than other agents (Wilkin 2008). This led to the supposition that CCR5 antagonists may be able to serve as immune modulators. Effects of an additional dosage in patients with poor immune constitution have not shown the results hoped for in studies so far (Lanzafame 2009, Stepanyuk 2009, Wilkin 2010). There are however indications of positive effects on immune activation (Funderberg 2009, Sauzullo 2010, Wilkin 2010+2011) and latent viral reservoir (Gutiérrez 2010). There is little experience outside experimental studies and the results are not yet confirmed.

Individual agents  (for not licensed agents, see chapter 3, “ART”)

Maraviroc (MVC, Celsentri® or Selzentry®) from Pfizer (now ViiV Healthcare) was the first drug in its class to be licenced for the treatment of HIV infection in September 2007. Maraviroc allosterically binds to CCR5. This means that it does not bind directly to the receptor but induces conformational changes within CCR5 that result in the inhibition of its binding to viral gp120. During maraviroc monotherapy, viral load declines by 1.6 logs after 10-15 days (Fätkenheuer 2005).

Two almost identical Phase III studies led to approval of the drug, namely MOTIVATE-1 (US, Canada) and -2 (Europe, Australia, US). A total of 1049 treatment-experienced patients with R5-only virus were enrolled in these trials (Gulick 2008, Fätkenheuer 2008). Patients had been treated with or had resistance to three antiretroviral drug classes and had a baseline viral load of more than 5000 copies/ml. Patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once-daily, maraviroc BID or placebo, each of which included OBT – substances such as darunavir, etravirine or raltegravir were not admittedAt 48 weeks in both studies more patients in the maraviroc arms were below 50 copies/ml (46% and 43% versus 17% with placebo). A treatment benefit of maraviroc over placebo was also shown in patients with a high viral load and multiple resistance (Fätkenheuer 2008). Results remained the same even after 96 weeks (Hardy 2010). Tolerability of maraviroc was excellent and did not differ from that of placebo. In addition, the shift to X4 viruses with no virological therapy success in half the patient population had no negative effects.

Maraviroc has also been tested in treatment naïve patients (Cooper 2010, Sierra-Madero 2010). In the MERIT study, a total of 721 patients randomly received AZT+3TC and either efavirenz or maraviroc BID (the arm with maraviroc QD was prematurely closed in 2006 due to lower efficacy). After 48 weeks, 65.3% of patients in the maraviroc arm reached a viral load below 50 copies/ml, compared with 69.3% in the efavirenz arm. Virological failure was more frequent on maraviroc (11.9% versus 4.2%). Although the CD4 T cell increases were significantly more pronounced on maraviroc, the study failed to show non-inferiority of maraviroc compared to efavirenz. Of note, there were significant differences seen between study populations in the northern versus southern hemisphere in this world wide trial. Response rates proved almost equal in northern hemisphere countries, but worse south of the equator. In addition, a retrospective analysis revealed that at least 4% of the patients in the maraviroc arm had experienced a tropism shift from R5 to dual tropic virus between screening and baseline. In these patients with dual tropic virus, response rates were very poor. Would a better and more sensitive test have been able to demonstrate a more relevant difference between maraviroc and efavirenz? A retrospective analysis using the enhanced Trofile assay, in which no differences were observed, seems to back this assumption (Cooper 2010). On the basis of this data the FDA extended the license for maraviroc to therapy-naïve patients in November 2009. However, the available data was not sufficient for EM(E)A to permit such an extension in indication.

As in the MOTIVATE studies, maraviroc’s tolerability was excellent in the MERIT study. The discontinuation rates due to adverse events were significantly lower than with efavirenz (4.2% versus 13.6%) and lipid profiles were better (MacInnes 2011). There seems to be no liver toxicity as seen with aplaviroc, another CCR5 antagonist whose development was halted in 2005, not even in those with existing liver damage (Abel 2009).

What about the efficacy of maraviroc in the presence of non-R5 viruses? In a double-blind randomized Phase II study on 113 patients the effect was, as expected, moderate. There was no antiviral effect compared to placebo. However, CD4 T cells improved significantly in those on maraviroc despite the lack of virologic efficacy (Saag 2009).

With regard to resistance, only limited data exist to date. Mutations in the gene regions coding for the V3 loop of the envelope protein gp120 may lead to complete resistance to maraviroc. This may occur by de novo acquisition of mutations allowing the virus to use the CXCR4 receptor or via “true” resistance. The latter may occur in viral isolates that remain R5 tropic. A shift to X4 tropism is not necessary as resistance may happen via an increased affinity of the viral envelope for unbound CCR5 molecules or through an ability of the viral envelope to use compound-occupied receptors for entry (Westby 2007, Lewis 2008). It seems that the resistance barrier for true maraviroc resistance in R5 viruses is high (Jubb 2009).

In practice it is important that the recommended dosage of maraviroc is adjusted to the concomitant therapy (Abel 2005). With boosted PIs (except for tipranavir) the usual dosage of 2×300 mg is halved, with efavirenz (or other enzyme inducers, such as rifampicin or carbamazepin) it is doubled. No adjustment is required with integrase inhibitors such as raltegravir and elvitegravir (Andrews 2010, Ramanathan 2010).


Abel S, Davis JD, Ridgway CE, Hamlin JC, Vourvahis M. Pharmacokinetics, safety and tolerability of a single oral dose of maraviroc in HIV-negative subjects with mild and moderate hepatic impairment. Antivir Ther 2009, 14:831-7.

Abel S, Russell D, Ridgway C, Muirhead G. Overview of the drug-drug interaction data for maraviroc. Abstract 76, 7th IWCPHT 2005, Quebec.

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Andrews E, Glue P, Fang J, Crownover P, Tressler R, Damle B. Assessment of the pharmacokinetics of co-administered maraviroc and raltegravir. Br J Clin Pharmacol. 2010, 69:51-7.

Ayoub A, van der Ryst E, Turner K, McHale M. A review of the markers of immune function during the maraviroc phase 1 and 2a studies. Abstract 509, 14th CROI 2007, Los Angeles.

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Fätkenheuer G, Nelson M, Lazzarin A. Subgroup analysis of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008, 359:1442-1455.

Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005, 11:1170-2.

Funderburg N, Kalinowska M, Eason J, et al. Differential effects of maraviroc (MVC) and efavirenz (EFV) on markers of immune activation (IA) and inflammation and their association with CD4 cell rises: a subanalysis of the MERIT study. Abstract H-1582, 49th ICAAC 2009, San Francisco.

Glass WG, McDermott DH, Lim JK, et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med 2006; 203:35-40.

Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously untreated patients with R5 HIV-1 infection. N Engl J Med 2008, 359:1429-1441.

Gulick RM, Su Z, Flexner C, et al. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-Infected, treatment-experienced patients: ACTG 5211. JID 2007;196:304-12.

Gutiérrez C, Diaz L, Hernández-Novoa B, et al. Effect of the intensification with a CCR5 antagonist on the decay of the HIV-1 Latent reservoir and residual viremia. Abstract 284, 17th CROI 2010, San Francisco.

Hardy D, Reynes J, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE Studies. Abstract 792, 15th CROI 2008, Boston.

Hardy WD, Gulick RM, Mayer H, et al. Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J AIDS 2010 Aug 11. [Epub ahead of print]

Huang W, Toma J, Fransen S, et al. Modulation of HIV-1 co-receptor tropism and susceptibility to co-receptor inhibitors by regions outside of the V3 Loop: Effect of gp41 amino acid substitutions. Abstract H-245, 46th ICAAC 2006, San Francisco.

Hütter G, Nowak D, Mossner M, et al.  Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009, 360:692-8.

Jensen MA, van’t Wout AB. Predicting HIV-1 coreceptor usage with sequence analysis. AIDS Rev 2003, 5:104-112.

Jubb B, Lewis M, Simpson P et al. CCR5-tropic resistance to maraviroc is uncommon even among patients on functional maraviroc monotherapy or with ongoing low-level replication. Abstract 639, 16th CROI 2009 Montréal.

Kindberg E, Mickiene A, Ax C, et al. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis. JID 2008;197:266-9.

Lanzafame M, Lattuada E, Vento S. Maraviroc and CD4+ cell count recovery in patients with virologic suppression and blunted CD4+ cell response. AIDS 2009, 23:869.

Lewis M, Mori J, Simpson P, et al. Changes in V3 loop sequence associated with failure of maraviroc treatment in patients enrolled in the MOTIVATE 1 and 2 Trials. Abstract 871, 15th CROI 2008, Boston.

Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996;86:367-77.

Low AJ, Dong W, Chan D, et al. Current V3 genotyping algorithms are inadequate for predicting X4 co-receptor usage in clinical isolates. AIDS 2007; 21.

MacInnes A, Lazzarin A, Di Perri G, et al. Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial. HIV Clin Trials 2011, 12:24-36.

Moyle GJ, Wildfire A, Mandalia S, et al. Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J Infect Dis 2005, 191:866-72.

Peters C, Kawabata T, Syntin P, et al. Assessment of immunotoxic potential of maraviroc in cynomolgus monkeys. Abstract 1100, 45th ICAAC 2005, Washington.

Poveda E, Seclén E, González Mdel M, et al. Design and validation of new genotypic tools for easy and reliable estimation of HIV tropism before using CCR5 antagonists. J Antimicrob Chemother 2009, 63:1006-10.

Prahalad S. Negative association between the chemokine receptor CCR5-Delta32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun 2006;7:264-8.

Rabkin CS, Yang Q, Goedert JJ, et al. Chemokine and chemokine receptor gene variants and risk of non-Hodgkin’s lymphoma in human immunodeficiency virus-1-infected individuals. Blood 1999, 93:1838-42.

Ramanathan S, Abel S, Tweedy S, West S, Hui J, Kearney BP. Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc. J AIDS 2010, 53:209-14.

Roukens AH, Visser LG, Kroon FP. A note of caution on yellow fever vaccination during maraviroc treatment: a hypothesis on a potential dangerous interaction. AIDS 2009, 23:542-3.

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Scarlatti G, Tresoldi E, Bjorndal A, et al. In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression. Nat Med 1997, 3:1259-65.

Sierra S, Kaiser R, Thielen A, Lengauer T. Genotypic coreceptor analysis. Eur J Med Res 2007, 12:453-62. Review.

Sierra-Madero J, Di Perri G, Wood R, et al. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. 4. HIV Clin Trials 2010, 11:125-32.

Soulié C, Fourati S, Lambert-Niclot S, et al. Factors associated with proviral DNA HIV-1 tropism in antiretroviral therapy-treated patients with fully suppressed plasma HIV viral load: implications for the clinical use of CCR5 antagonists. J Antimicrob Chemother 2010, 65:749-51.

Stepanyuk O, Chiang TS, Dever LL, et al. Impact of adding maraviroc to antiretroviral regimens in patients with full viral suppression but impaired CD4 recovery. AIDS 2009, 23:1911-3.

Su Z, Reeves JD, Krambrink A, et al. Response to vicriviroc (VCV) in HIV-infected treatment-experienced subjects using an enhanced Trofile HIV co-receptor tropism assay: reanalysis of ACTG 5211 results. Abstract H-895, 48th Annual ICAAC/IDSA 2008, Washington.

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Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 2006, 80:4909-20.

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Fusion inhibitors 

Fusion inhibitors prevent the final step of entry of HIV into the target cell. This fusion of virus and cell is complex and not completely understood. Simplified, it seems that binding to the CD4 and to the coreceptor induces conformational changes in the gp41, the transmembrane subunit of the viral envelope protein. In the course of these rearrangements, the N-terminal fusion peptide of gp41 translocates and inserts into the target cell membrane. A proposed extended conformation of the gp41 ectodomain, with its fusion peptide thus inserted and the transmembrane anchor still in the viral membrane, has been called the “pre-hairpin intermediate”. This is the target of various fusion inhibitors, including T-20 (Root 2001).

Individual agents

T-20 (Enfuvirtide, Fuzeon®) is the prototype of the fusion inhibitors. T-20 was licensed in Europe and the US in May 2003 for the treatment of HIV-1 infection in antiretroviral-experienced adults and children over 6 years of age. It is a relatively large peptide comprised of 36 amino acids, and therefore needs to be administered by subcutaneous injection. It binds to an intermediate structure of the HIV gp41 protein, which appears during fusion of HIV with the target cell.

Initially, HIV-infected patients were given T-20 monotherapy intravenously. Antiviral activity was dose-dependent, and at the higher dose of 100 mg BID, the viral load was reduced by almost 2 logs (Kilby 1998+2002). In early studies of the subcutaneous application, an effect on viral load was still evident in one third of patients after 48 weeks, but it became apparent that T-20 was of more benefit to those who received additional new drugs for their ART regimen.

Two Phase III studies led to the licensing of T-20. TORO 1 (T-20 versus Optimized Regimen Only) enrolled 491 extensively pretreated patients in North America and Brazil, most with multiresistant viruses. In TORO 2, 504 patients in Europe and Australia were enrolled. Patients in both studies on an optimized ART regimen either received 90 mg T-20 BID subcutaneously or none at all (Lalezari 2003, Lazzarin 2003). In TORO-1, the reduction in viral load was 0.94 logs better with T-20. In TORO-2 this difference was 0.78 logs (Nelson 2005). A strong impact on viral load was also seen in combination with tipranavir, darunavir, maraviroc or raltegravir. In all large studies evaluating these agents (RESIST, POWER, MOTIVATE, BENCHMRK), the additional use of T-20 was of significant benefit. If at least two active substances are not at hand, the option of T-20 should be discussed with the patient.

Small pilot studies such as INTENSE or INDEED suggest that T-20, given as “induction”, i.e., in the first weeks of a new salvage therapy lower the viral load more rapidly (Clotet 2008, Reynes 2007).

The success of T-20 therapy should be monitored early on, particularly in view of the cost. Patients without a decrease in viral load of at least one log after 8-12 weeks will not benefit and can be spared the required twice-daily injections. It is also not recommended to inject the full daily dose of T-20 once a day: although 180 mg QD has the same bioequivalence (as measured by AUC) to the standard 90 mg BID, at least one study has shown a trend towards a lesser decrease in viral load with the QD dose that was clearly associated with lower trough levels (Thompson 2006).

One observation in the TORO studies was the increased frequency of lymphadenopathy and bacterial pneumonia in those on T-20 (6.7/100 versus 0.6/100 patient years) (Trottier 2005). Septicemia also occurred more often on T-20, but the difference was not significant. The reason for the increased rate of infections remains unclear, but binding of T-20 to granulocytes has been suspected. Substantial side effects remain constant (98% in the TORO studies), and over the course of therapy, severe local skin reactions occur at the injection site. These can be particularly painful and can result in interruption of therapy: 4.4% of cases in the TORO studies. In our experience of everyday clinical treatment, therapy is interrupted more frequently due to these skin problems (see section on Side Effects). Unfortunately the development of a bioinjection system in which T-20 is pressed into the skin was halted (Harris 2006).

Resistance mutations develop relatively rapidly on T-20, but seem to reduce viral fitness (Lu 2002, Menzo 2004). Receptor tropism of the virus seems to be not significantly affected. There are some changes to a short sequence on the gp41 gene, causing reduced susceptibility to T-20, which is due to simple point mutations (Mink 2005). In contrast, viruses resistant to NRTIs, NNRTIs and PIs are susceptible to T-20 (Greenberg 2003). As it is is a relatively large peptide, it induces antibody production. This does not seem to impair efficacy (Walmsley 2003). More disturbing is the fact that in a large TDM study there was a very large interpatient variability and extremely low plasma levels were often found (Stocker 2006).

In summary, patients with a well-controlled viral load or who still have options with classical ART do not require T-20. For salvage therapy the drug seems to be very valuable in individual cases. However, T-20 probably has only a minor role to play in the future of HIV treatment. Many patients have already successfully replaced T-20 by newer oral antiretrovirals like raltegravir. Pilot studies provide evidence that this strategy is virologically safe (DeCastro 2009, Grant 2009, Santos 2009, Talbot 2009).

Increasing efficacy of ART and/or emptying latent reservoirs with T-20, as first reports suggested (Lehrmann 2005, Molto 2006), seems unlikely now (Gandhi 2010, Joy 2010). The price also remains an important aspect as ART costs can skyrocket with the addition of T-20, the company maintaining that it is one of the most complicated drugs it has ever manufactured.

References on fusion inhibitors and T-20

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Santos JR, Llibre JM, Ferrer E, et al. Efficacy and safety of switching from enfuvirtide to raltegravir in patients with virological suppression. HIV Clin Trials 2009, 10:432-8.

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Talbot A, Machouf N, Thomas R, et al. Switch from enfuvirtide to raltegravir in patients with undetectable viral load: efficacy and safety at 24 weeks in a Montreal cohort. J AIDS 2009, 51:362-4.

Thompson M, DeJesus E, Richmond G, et al. Pharmacokinetics, pharmacodynamics and safety of once-daily versus twice-daily dosing with enfuvirtide in HIV-infected subjects. AIDS 2006, 20:397-404.

Trottier B, Walmsley S, Reynes J, et al. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. JAIDS 2005, 40:413-21.

Walmsley S, Henry K, Katlama C, et al. Lack of influence of gp41 antibodies that cross-react with enfuvirtide on the efficacy and safety of enfuvirtide in TORO 1 and TORO 2 Phase III trials. Abstract 558, 10th CROI 2003, Boston.

Integrase inhibitors

Mode of action

Integrase, along with reverse transcriptase and protease, is one of the three key enzymes in the HIV replication cycle. It is involved in the integration of the viral DNA into the host genome and is essential for the replication of HIV (Nair 2002). It is of note that there is no integrase in human cells so that selective inhibition of this enzyme that does not induce side effects seems possible. Integrase inhibitors do not prevent entry of the virus into the cell. There are at least four important steps leading to the integration of viral DNA (review: Lataillade 2006). All these steps may be theoretically inhibited by integrase inhibitors.

Briefly, these steps are:

1. Binding of the integrase enzyme to viral DNA within the cytoplasm. This results in a stable viral DNA-integrase binding complex (pre-integration complex, PIC). This step can be inhibited by binding inhibitors such as pyrano-dipyrimides.

2. 3’ Processing. The integrase removes a dinucleotide at each end of the viral DNA producing new 3’ hydroxyl ends within the PIC. This step can be inhibited by 3’ processing inhibitors such as diketo acids.

3. Strand transfer. After the transport of the PIC from the cytoplasm through a nuclear pore into the cell’s nucleus, integrase binds to the host chromosomal DNA. By doing this, integrase mediates irreversible binding of viral and cellular DNA. This step can be inhibited by strand transfer inhibitors (STIs) such as raltegravir or elvitegravir.

4. Gap repair. The combination of viral and cellular DNA is a gapped intermediate product. The gap repair is done by host cell DNA repair enzymes. Integrase seems not to be necessary in this last step, which can be inhibited by gap repair inhibitors such as methylxanthines.

For almost a decade, the development of integrase inhibitors was slow. This was largely because of a lack of good lead compounds and reliable in vitro screening assays that incorporated each of the integration steps (Lataillade 2006). Only after 2000 has development progressed and the principle of strand transfer discovered (Hazuda 2000). Since 2005, numerous clinical studies have successfully evaluated integrase inhibitors (mainly strand transfer inhibitors). In December 2007, raltegravir was licensed as the first integrase inhibitor for the treatment of HIV-infected patients.

As with other antiretroviral drug classes, some questions remain unanswered. Although very well-tolerated during the first years of therapy, little is known about long-term toxicity. Genetic resistance barriers may also be an important issue. It seems relatively low with raltegravir. Increased viral suppression was observed with treatment-experienced patients on boosted PIs (viral load below the limit of detection) when switching to raltegravir, especially in those with existing resistance (Eron 2009). There is also evidence for cross-resistance. Future integrase inhibitors should bind differently to enzymes in the future. There is probably no need for “me-too” integrase inhibitors (Serrao 2009). Dolutegravir may meet these requirements (see next chapter). Problems also exist with the measurement of plasma levels (Acosta 2010). As soon as integrase inhibitor resistance develops, the agents should be stopped. This way, further resistance mutations (Wirden 2009) can be avoided as well as unnecessary costs.

Individual agents

Raltegravir (RAL, Isentress®) is a naphthyridine carboxamide derivative that inhibits the strand transfer step of integrase (see above). Raltegravir has a wide range of efficacy for R5 and X4 tropic viruses, as well as inhibiting the replication of HIV-2. During a 10-day monotherapy, viral load declined by 1.7-2.2 log (Markowitz 2006). In a Phase II study, 179 extensively pre-treated patients (median 10 years, in which approximately 30% of the patients had no treatment options) were tested. After 48 weeks, 64% of the patients on raltegravir had attained a viral load below 50 copies/ml, compared to only 9% in the placebo group. This was a truly exceptional result for a patient group with such an extensive treatment history (Grinsztejn 2007).

These data were confirmed by two large Phase III studies which led to approval of raltegravir. In BENCHMRK-1 and -2, a total of 699 intensively pretreated patients with triple-class resistance were randomized to raltegravir 400 mg BID or placebo, each combined with an optimized background therapy (Cooper 2008, Steigbigl 2008). After 16 weeks 79% (versus 43%) of patients showed a viral load below 400 copies/ml. Even in patients initially without an active substance in genotypic assays, the rate was as high as 57% (versus 10%). The effects were sustained beyond 144 weeks (Eron 2010).

Raltegravir has also been effective in treatment-naïve patients. The encouraging data from an early Phase II study (Markowitz 2007+2009) were confirmed by a large Phase III study in which 563 patients received either raltegravir or efavirenz (Lennox 2009): At week 48, rates of patients achieving undetectable plasma viremia (<50 copies/ml) were 86% and 82%, respectively. Patients taking raltegravir had a greater increase in CD4 T cell counts (189 versus 163, not significant). Tolerability was better and effects lasted for years (Lennox 2010, Rockstroh 2011). In September 2009, raltegravir was approved for first-line therapy.

Tolerability of raltegravir has so far been excellent. In BENCHMARK raltegravir was comparable to placebo. Apart from some anecdotal reports of rhabdomyolysis, hepatitis, rash and insomnia (Gray 2009, Santos 2009, Dori 2010, Tsukada 2010), frequently appearing side effects with raltegravir have not been seen. Assumptions of an increased tumor risk have been refuted after results of general assays were published in July 2007. Raltegravir seems to be safe, including in those with liver disease (Vispo 2010). Expected autoimmune diseases observed in animal testing have so far not been clinically confirmed (Beck-Engeser 2010).

The fact that viral load decreased significantly more rapidly in the first weeks in patients taking raltegravir compared to those taking efavirenz led to some speculations about a higher potency (Murray 2007). Several experimental studies are presently observing strategies aimed at achieving viral eradication with raltegravir intensification (see chapter on “Eradication”). However, some experts believe that the faster response on raltegravir-based regimens is not a matter of potency, but rather due to its unique effect of blocking integration of the HIV genome (Siliciano 2009).

What is known about resistance? There are at least two common resistance pathways, either via mutations Q148K/R/H or N155H. Both mutations are localized within the catalytic core of the integrase (Grinsztejn 2007, Malet 2008). A third pathway seems to be Y143 (Delelis 2010).

Resistance may occur quickly on a failing regimen. In the above-mentioned Phase II study virological failure occurred in 38/133 (29%) patients on raltegravir. In 34/38 patients, either the N155H or the Q148K/R/H mutation occurred after only 24 weeks (Grinsztejin 2007). In a study on combination with darunavir/r in treatmentnaïve patients, 5 out of 112 patients developed resistance mutations against raltegravir (Taiwo 2011). Thus, the resistance barrier of raltegravir seems not very high although it is higher than that for NNRTIs. A few days of monotherapy are not enough to select resistance mutations as is the case with nevirapine (Miller 2010). More probable is cross-resistance with elvitegravir (De Jesus 2007).

The randomized SWITCHMRK studies (Eron 2010) with more than 700 patients on a lopinavir/r-based ART with a viral load below 50/copies ml for at least three months,showed that this option may not always be safe. Switching to raltegravir showed a better lipid profile, but did not demonstrate non-inferiority with respect to HIV RNA <50 copies/ml at week 24 as compared to remaining on lopinavir/r. Again, these results provide evidence for a possibly lower resistance barrier of integrase inhibitors compared to boosted PIs. Even if the smaller Spanish SPIRAL study did not cofirm these results (Martinez 2010), switching from boosted PIs to these new substance groups should be considered with care. Switching from T-20 to raltegravir, however, is probably safe (De Castro 2009, Grant 2009, Santos 2009, Talbot 2009).

Only limited data exist in regard to interactions. However, raltegravir is not an inducer or an inhibitor of the cytochrome 450 enzyme system. Clinically relevant interactions are not expected ( Iwamoto 2008, Anderson 2008, Wenning 2008). During co-medication with rifampicin, levels of raltegravir may be reduced. In contrast, raltegravir plasma concentration increases with omeprazole coadministration in healthy subjects; this is likely secondary to an increase in bioavailability attributable to increased gastric pH (Iwamoto 2009).

Recommended dosage of raltegravir is 400 mg BID. Once daily doses is not possible, as the recently published QDMRK study has shown (Eron 2011). In patients with renal impairment, no dosage adjustment is required. There are no data for pediatric or pregnant patients.

Taken together, there is no doubt that raltegravir has become an important option for patients harbouring resistant viruses. Given its excellent efficacy and tolerability, application of raltegravir has been recently extended to treatment-naïve patients. A disadvantage is that raltegravir must be taken twice daily. More data is required for a wider application of raltegravir regarding long-term treatment, resistance and TDM.


Acosta E. Clinical pharmacokinetics and pharmacodynamics of integrase inhibitors. Abstract 115, 17th CROI 2010, San Francisco.

Anderson MS, Kakuda TN, Hanley W, et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother 2008, 52:4228-32.

Beck-Engeser GB, Eilat D, Harrer T, Jäck HM, Wabl M. Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir. PNAS 2009 Nov 18. [Epub ahead of print]

Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008, 359:355-65.

De Castro N, Braun J, Charreau I, et al. Switch from enfuvirtide to raltegravir in virologically suppressed multidrug-resistant HIV-1-infected patients: a randomized open-label trial. Clin Infect Dis 2009, 49:1259-67.

DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0158) use after virologic rebound on elvitegravir (EVT, GS 9137). Abstract TUPEB032, 4th IAS 2007, Sydney.

Delelis O, Thierry S, Subra F, et al. Impact of Y143 HIV-1 integrase mutations on resistance to raltegravir in vitro and in vivo. Antimicrob Agents Chemo-ther 2010, 54:491-501.

Dori L, Buonomini AR, Viscione M, Sarmati L, Andreoni M. A case of rhabdomiolysis associated with raltegravir use. AIDS 2010, 24:473-5.

Eron J, Cooper D, Steigbigel R, et al. Sustained Antiretroviral effect of raltegravir at week 156 in the BENCHMRK studies and exploratory analysis of late outcomes based on early virologic responses. Abstract 515, 17th CROI 2010, San Francisco.

Eron J, Rockstroh J, Reynes J, et al. QDMRK, a phase III study of the safety and efficacy of once daily vs twice daily ral in combination therapy for treatment-naïve HIV-infected patients. Abstract 150LB, 18th CROI 2011, Boston.

Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1+2): two multicentre, double-blind, randomised controlled trials. Lancet 2010, 375:396-407.

Grant PM, Palmer S, Bendavid E, et al. Switch from enfuvirtide to raltegravir in Virologically suppressed HIV-1 infected patients: effects on level of residual viremia and quality of life. J Clin Virol 2009, 46:305-8.

Gray J, Young B. Acute onset insomnia associated with the initiation of raltegravir: a report of two cases and literature review. AIDS Patient Care STDS 2009, 23:689-90.

Grinsztejn B, Nguyen BY, Katlama C, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 2007, 369:1261-9.

Harris M, Larsen G, Montaner J, et al. Outcomes of patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. Abstract 789, 15th CROI 2008.

Harris M, Larsen G, Montaner JS. Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen. AIDS 2008, 22:1224-1226.

Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287:646-50.

Iwamoto M, Kassahun K, Troyer MD, et al. Lack of a Pharmacokinetic Effect of Raltegravir on Midazolam: In Vitro/In Vivo Correlation. J Clin Pharmacol. 2007 Dec 12.

Iwamoto M, Wenning LA, Nguyen BY, et al. Effects of omeprazole on plasma levels of raltegravir. Clin Infect Dis 2009, 48: 489-492.

Iwamoto M, Wenning LA, Petry AS, et al. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2008, 52:4338-43.

Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 2006, 20:489-501.

Lennox JL, Dejesus E, Berger DS, et al. Raltegravir versus Efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J AIDS 2010, 55:39-48.

Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374:796-806

Luna MM, Llibre J, Larrousse M, et al. Immune activation markers during raltegravir intensification of a HAART regimen in subjects with persistent HIV-1 viral suppression. Abstract 574, 16th CROI 2009 Montréal.

Malet I, Delelis O, Valantin MA, et al. Mutations Associated with Failure of Raltegravir Treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 2008;

Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J AIDS 2006, 43:509-515.

Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J AIDS 2007, 46:125-33.

Markowitz M, Nguyen BY, Gotuzzo E, et al. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J AIDS 2009, 52:350-6.

Martínez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS 2010, 24:1697-707.

Miller M, Barnard R, Witmer M, et al. Short-term raltegravir monotherapy does not predispose patients to develop RAL resistance during subsequent combination therapy: analysis of samples from protocol 004. Abstract 557, 17th CROI 2010, San Francisco.

Murray JM, Emery S, Kelleher AD, et al. Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS 2007, 21:2315-21.

Nair V. HIV integrase as a target for antiviral chemotherapy. Rev Med Virol 2002, 12:179-93.

Rockstroh J, Lennox J, DeJesus E, et al. RAL demonstrates durable virologic suppression and superior immunologic response with a favorable meta-bolic profile through 3 years of treatment: 156-week results from STARTMRK. Abstract 542, 18th CROI 2011, Boston.

Santos JR, Llibre JM, Ferrer E, et al. Efficacy and safety of switching from enfuvirtide to raltegravir in patients with virological suppression. HIV Clin Trials 2009, 10:432-8.

Serrao E, Odde S, Ramkumar K, Neamati N. Raltegravir, elvitegravir, and metoogravir: the birth of “me-too” HIV-1 integrase inhibitors. Retrovirology 2009 Mar 5;6:25.

Siliciano R. New approaches for understanding and evaluating the efficacy of ARVs. Abstract 16, 16th CROI 2009 Montréal.

Steigbigel R, Cooper D, Eron J, et al. 96-week results from BENCHMRK1 and 2, phase III studies of raltegravir in patients failing ART with triple-class-resistant HIV. Abstract 571b, 16th CROI 2009 Montréal.

Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008, 359:339-354.

Taiwo B, Zheng S, Gallien S, et al. Results from a single arm study of DRV/r + RAL in treatment-naïve HIV-1-infected patients (ACTG A5262). Abstract 551, 18th CROI 2011, Boston.

Talbot A, Machouf N, Thomas R, et al. Switch from enfuvirtide to raltegravir in patients with undetectable viral load: efficacy and safety at 24 weeks in a Montreal cohort. J AIDS 2009, 51:362-4.

Tsukada K, Teruya K, Tasato D, et al.  Raltegravir-associated perihepatitis and peritonitis: a single case report. AIDS 2010, 24:160-1.

Vispo E, Mena A, Maida I, et al.  Hepatic safety profile of raltegravir in HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother 2010, 65:543-7.

Wenning LA, Friedman EJ, Kost JT, et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother 2008, 52:3253-8.

Wirden M, Simon A, Schneider L, et al. Raltegravir has no residual antiviral activity in vivo against HIV-1 with resistance-associated mutations to this drug. J Antimicrob Chemother. 2009, 64:1087-90.




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Table 2.2. Overview of antiretroviral drugs.

Trade name




Nucleosideand Nucleotide Reverse-Transcriptase-Inhibitors (NRTIs)




Gilead Sciences




ViiV HealthcareGSK




ViiV HealthcareGSK




Bristol Myers-SquibbMS




Gilead Sciences




Bristol Myers-SquibbMS




GSK ViiV Healthcare

Non-Nucleoside Reverse-Transcriptase-Inhibitors (NNRTIs)

Sustiva®(, Stocrin®)



















ViiV HealthcarePfizer

Protease-Inhibitors (PIs)

















Norvir® (als Booster)*











Bristol Myers-SquibbBMS

Telzir®(, Lexiva®)



ViiV HealthcareGSK




Roche/ViiV HealthcarePfizer


Celsentri®,  (Selzentry®)



PfizerViiV Healthcare





Integrase Inhibitors





Combination Drugs








ViiV HealthcareGSK

Complera®*Kivexa® (Epzicom®)












Kivexa®, Epzicom®



ViiV Healthcare




ViiV Healthcare




Gilead Sciences

Trade name





Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)




































Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Sustivaâor Stocrinâ




















Protease Inhibitors (PIs)




Boehringer Ingelheim
































Telzirâ or Lexivaâ










Entry Inhibitors

Celsentriâor Selzentryâ










Integrase Inhibitors






Combination drugs











Kivexaâ or Epzicomâ















* not yet approved in Europe. Therapy costs in Germany, red list as of March 2011. Some drugs have other trade names in different countries (in brackets outside Germany). * Indication of PIs including recommended Ritonavir boosting ( 1-400mg Norvir®. Price calculation according to monthly packages.for

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Filed under 6. ART 2011, 6.2. Overview of Antiretroviral Agents, Part 2 - Antiretroviral Therapy

6.3. Art 2011/2012: The Horizon and Beyond

– Christian Hoffmann –

Over the past few years, several important new drugs have been licenced, namely the PI darunavir, the NNRTIs etravirine and rilpivirine, the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc. Almost all HIV-infected patients can now be treated with a virologically successful regimen, even those with multiple resistance mutations. There are hardly anymore “untreatable” patients. However, despite this considerable progress, there is an urgent need for new drugs. This is not just true for patients with multiresistant viruses awaiting new treatment options. Significant problems related to long-term toxicity and adherence are anticipated for all therapies that will presumably need to span decades, as eradication of HIV is still out of reach. As a result, new drugs are needed that are easier to take, with high genetic barriers to development of resistance, and above all less toxic. To reach the goal of eradication, new drugs need to be more potent than those available today. The following overview of agents that could make it to the clinic based on current data (April 2011) does not claim to be complete.

New Pharmacoenhancers (PKEs)

Many antiretroviral agents, among them almost all PIs, but also some new drugs such as vicriviroc or elvitegravir, have to be boosted in order to enhance their pharmacokinetics. For more than a decade, ritonavir has been the only reliable option for boostering. At CROI in February 2009, new pharmacoenhancers were introduced for the first time that could challenge ritonavir’s booster monopoly. The advantages of these new agents inhibiting the CYP3A system is that they have no antiviral effect and thus cannot cause resistance. Obviously, there are no reports yet about long-term side effects and the effects of such a total inhibition of enzyme systems.

Cobicistat (GS-9350) is a PKE developed by Gilead, which showed similar booster effects to ritonavir in first clinical PK studies (German 2009). In a randomized Phase II trial with 79 ART-naive patients who had received atazanavir along with TDF+FTC, effects were comparable to ritonavir (Cohen 2011). Cobicistat has also been developed in a QUAD pill which contains the four Gilead agents tenofovir, FTC, the integrase inhibitor elvitegravir and cobicistat. In a first Phase II double-blind trial the QUAD pill was tested in 71 therapy-naïve patients with Atriplaâ. The results showed similar effects after 24 weeks (Cohen 2011). Cobicistat seems to be well-tolerated, however a slight increase of creatinine was noted. This may only be explained by a lessened tubular creatinine secretion and may not indicate an impairment of renal function. However, problems with regard to management of the creatinine levels under the QUAD pill may still occur, as it also contains the potentially nephrotoxic tenofovir. Nevertheless, Gilead, being experienced in matters concerning nephrotoxicity, is moving forward with Phase II trials.

SPI-452 is a PKE developed by Sequoia that does not have any anti-HIV effect (Gulik 2009). In a first clinical study, different doses plus various PIs were given to 58 healthy volunteers. Tolerance was good. The levels of darunavir (37-fold) and atazanavir (13-fold) significantly increased as well. The booster effect lasted for a long time. Sequioa will continue research with SPI-452 as an individual agent and in fixed combinations. Use with HCV protease inhibitors will also be investigated. A look at the website makes one wonder, as there seems to be no news since February 2009.

PF-03716539 is a PKE from Pfizer. Studies with healthy volunteers regarding its effects on midazolam, maraviroc and darunavir were concluded in October 2009. The results have not yet been officially released.

TMC-558445 manufactured by Tibotec pharmaceuticals is currently being tested in a phase-I study. Results are not available yet.

New formulations  

Currently available drugs are in further development, the most important goals being a reduction in pill burden, easier dosing and fewer side effects. Several such agents that have entered the market already include Invirase 500®, Truvada®, Kivexa® and Atripla® as well the new Norvir® tablets.

Viramuneâ(Extended-Release) is an improved version of the otherwise available nevirapine formulation (Battegay 2009). It allows a once-daily dosing of nevirapine in one pill. Presently, Boehringer is conducting several studies. First data of the VERxVE study were released in the end of 2010. In this study 1,011 treatment naïve patients were treated with either the standard nevirapine or the extended release formulation in addition to TDF+FTC. After 48 weeks, 81% of patients were under detection level in the once-daily-arm compared to 76% in the standard-arm (Gathe 2010). Licensing for viramune XR® has been applied for and is expected by the end of 2011.

Nelfinavir 625 mg – this newer formulation was approved in the US in April 2003. It reduces the nelfinavir dose to 2 tablets BID. One study has shown that this formulation is better tolerated, particularly with respect to gastrointestinal side effects – despite the fact that plasma levels are around 30% higher (Johnson 2003). In Europe, where nelfinavir is produced and sold by Roche instead of Pfizer, the 625 mg tabletwill not be available for the time being. .

Zerit PRC® (PRC = “prolonged release capsule” or XR = “extended release”) is a capsulated once-daily formulation of d4T (Baril 2002). d4T XR was approved in Europe in 2002, but never made it to market – apparently d4t is “out”.  There are attempts underway to improve d4T through minor modifications to its molecular structure. OBP-601 (4’-Ed4T) is a novel nucleoside analog with potent anti-HIV-1 activity and limited cellular toxicity with a unique in vitro resistance profile. The company BMS is apparently working on this substance under the name festinavir (Weber 2008).

Generics are not so difficult to produce as shown by experiences from Africa, India or Thailand. In many cases, bioequivalence has been demonstrated (Laurent 2004, Marier 2007). In developing countries many fixed drug combinations (FDC) are often used. The most frequently used FDC is d4T+3TC+nevirapine which exists as Triomune (Cipla), GPO-vir (GPO), Triviro LNS (Ranbaxy) or Nevilast (Genixpharma). FDCs also exist for AZT+3TC+nevirapine such as Duovir N (Cipla) or Zidovex-LN (Ranbaxy). Patent rights for generics have often been ignored making these preparations insignificant in industrial countries.


Baril JG, Pollard RB, Raffi FM, et al. Stavudine extended/prolonged release (XR/PRC) vs. stavudine immediate release in combination with lamivudine and efavirenz: 48 week efficacy and safety. Abstract LbPeB9014, 14th Int AIDS Conf 2002, Barcelona.

Battegay ME, Arasteh K, Plettenb erg A. Assessment of the steady-state PK parameters of two extended release (XR) nevirapine (NVP) tablets 400 mg and 300 mg QD compared with immediate release (IR) NVP tablets 200 mg BID in HIV-1-infected patients – the ERVIR study. Abstract PE 4.1/2, 12th EACS 2009, Cologne.

Cai Y, Klein C, Roggatz U, et al. Bioequivalence of pilot tablet formulations of ritonavir to the marketed soft gel capsule at a dose of 100 mg. Abstract 52LB, 14th CROI 2007, Los Angeles.

Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 2011, 25:F7-12.

Gathe J, Knecht G, Orrell C, et al. 48 week (Wk) efficacy, pharmacokinetics (PK) and safety of once a day (QD) 400 mg nevirapine (NVP) extended release formulation (XR) for treatment of antiretroviral (ARV) naive HIV-1 infected patients (Pts) [VERxVE]. Abstract H-1808, 50th ICAAC 2010, Boston.

German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J AIDS 2010, 55:323-9.

Gulnik S, Eissenstat M, Afonina E, et al. Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. Abstract 41, 16th CROI 2009, Montréal.

Johnson M, Nieto-Cisneros L, Horban A, et al. Viracept (Nelfinavir) 625 mg film-coated tablets: investigation of safety and gastrointestinal tolerability of this new formulation in comparison with 250 mg film-coated tablets (Viracept) in HIV patients. Abstract 548, 2nd IAS 2003, Paris.

Klein CE, Chiu YL, Causemaker SK, et al. Lopinavir/ritonavir (LPV/r) 100/25 mg tablet developed for pediatric use: bioequivalence to the LPV/r 200/50 mg tablet at a dose of 400/100 mg and predicted dosing regimens in children Abstract P4.1/01, 11th EACS 2007, Madrid.

Laurent C, Kouanfack C, Koulla-Shiro S, et al. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004, 364:29-34.

Marier JF, Dimarco M, Guilbaud R, et al. Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formula-tion versus coadministration of the individual products. J Clin Pharmacol 2007;47:1381-9.

Ramanathan S, Warren D, Wei L, Kearney B. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir.  Abstract A1-1301/34, 49th ICAAC 2009, San Francisco.

Weber J, Weberova J, Vazquez A, et al. Drug susceptibility profile of OBP-601, a novel NRTI, using a comprehensive panel of NRTI- or NNRTI-resistant viruses. Abstract 726b, 15th CROI 2008, Boston

New nucleoside analogs

Since the development of dexelvucitabine came to a halt, hopes are now limited that there will be new nucleoside analogs on the market in the near future. Developing NRTIs with strong potency against NRTI-resistant viruses thatat the same time showless mitochondrial toxicity appears to be difficult. It is unlikely that and of the following substanecd will ever make it to the market. Many of them have already disappeared.

Amdoxovir (DAPD) is a novel dioxolane guanosine NRTI which is converted in vivo to the highly efficient DXG. DAPD has good efficacy against viruses resistant to AZT/3TC and against hepatitis B virus (Corbett 2001). When patients showed changes of the ocular lenses during early clinical trials (Thompson 2003), development was halted in 2004 and Gilead withdrew its licensing agreement with two US universities. However, there is still hope for DAPD. Supported by RFS Pharma from Georgia (US), development is ongoing. In this program, DAPD is combined with AZT to use the distinct resistance profiles of both compounds. In the first double-blind, randomized study in 24 patients, the viral load declined by an impressive 1.97 logs after 10 days on 500 mg DAPD + 200 mg AZT BID. There are obviously synergistic effects (Murphy 2010) that can not be explained by interactions alone (Hurwitz 2010). The question will be how to avoid the toxicity of DAPD. Phase II studies are ongoing.

Apricitabine (ATC, AVX-754, formerly SPD-754) is a heterocyclic cytidine analog that was sold by Shire Biochem to Avexa in 2005. ATC chemically resembles 3TC but has in vitro activity against a broad spectrum of TAMs. Up to 5 nucleoside mutations do not significantly impair its activity (Gu 2006). However, susceptibility to ATC is reduced when the K65R is present (Frankel 2007). A first placebo-controlled study in 63 HIV-infected patients treated with ATC monotherapy showed decreases in viral load of between 1.2-1.4 logs depending on the dose – good potency for an NRTI (Cahn 2006). In 50 patients harbouring the M184V mutation there was a reduction of 0.7-0.9 log after three weeks on ATC (Cahn 2010). ATC-specific resistance mutations were not observed after 48 weeks and could not be selected during in vitro experiments (Oliveira 2009). Cephalgia and rhinitis are most frequent, otherwise tolerability of ATC seems to be good (Gaffney 2009). What about long-term toxicity? In monkeys, there were minor skin problems, usually hyperpigmentation, after 52 weeks of exposure. ATC was thus significantly less toxic than BCH-10652, which caused severe degenerative dermatopathy in all exposed monkeys (Locas 2004). 3TC and FTC significantly and competitively lower intracellular levels of ATC. Combination with other cytidine analogs is a problem. After negotiations with large pharmaceutical companies had failed in May 2010, further development was discontinued and it is questionable if it will be resumed.

Dioxolanthymidine (DOT) is a new thymidine analog – one of the few new agents in this subgroup. Dioxolane appeared to be relatively good in preclinical trials (Chung 2005, Liang 2006). Presently, prodrugs are being tested, however, clinical studies have yet to be conducted (Liang 2009).

EFda or 4-ethynol-2-fluor-deoxyadenosine seems to be one of the most effective NRTIs according to the results of animal testing on monkeys. The SIV virus load decreased after 7 days by 2-3 logs (Parniak 2009). It is also being evaluated as a potential microbicide.

Elvucitabine (ACH-126,443) is a cytidine analog developed by Achillion Pharmaceuticals. It is an enantiomer of dexelvucitabine and is also effective against HBV. In vitro studies show potency even in the presence of numerous resistance mutations (Fabrycki 2003). It is also of interest as it seems to have an extremely long half-life of up to 150 hours – this may allow once-weekly dosing (Colucci 2005).

A small, double-blind study showed a reduction in viral load of between 0.7 and 0.8 logs after 28 days in HIVpatients with the M184V mutation. However, this study had to be prematurely terminated, as 6/56 patients developed leucopenia or rash on a dose of 100 mg (Dunkle 2003). It seems that mitochondrial toxicity is lower than that of dexelvucitabine. On the other hand, this lower toxicity may also lower the efficiency of incorporation by drug-resistant forms of HIV-1 RT (Murakami 2004). Less toxicity at the expense of less efficacy? In a smaller Phase II study in 77 therapy naïve patients (with efavirenz and tenofovir), elvucitabine was comparable to 3TC at 96 weeks (DeJesus 2010). There appear to be problems in interactions with ritonavir, which may be due to ritonavir inhibiting an efflux gut transporter with activity present at various levels in subjects (Colucci 2009).

Fosalvudine is an NRTI by the company Heidelberg Pharma, which is a prodrug of the fluorothymidine alovudine. The active part is released only after enzymatic cleavage in the tissue. It is hoped that the toxicity commonly seen with flurothymidines can thus be reduced. In a Phase II trial with 43 ART-naïve HIV+ patients, fosalvudine was well-tolerated and after 2 weeks of monotherapy with 5-40 mg viral load decreased by up to 1 log (Cahn 2007). Trials with pretreated patients are being conducted in Russia as well as in Argentina. Animal testing on rats, however, indicate high mitochondrial toxicity (Vennhoff 2009). Further development is questionable.

Fozivudine is another NRTI developed by Heidelberg Pharma according to the “enhanced pro-drug-principle”. In Phase I/II trials (Bogner 1997, Girard 2000), fozivudine was well-tolerated, but only moderately effective – after 4 weeks, a decrease in viral load at the highest doses of approximately 0.7 logs was reached (Girard 2000). According to the company’s website, they are looking for partners to be able to conduct further trials. It has been silent for a while – no one seems to be very interested in a new AZT.

GS-7340 is a derivative of tenofovir which enables higher tenofovir concentrations in peripheral blood mononuclear cells. GS-7340 has been tested in different doses against tenofovir in 30 HIV-infected patients. After 2 weeks viral load decreased to 1,71 logs in comparison to 0,94 logs. It seems that a very promising tenofovir backup is developing here with better efficacy at an altogether lower systematic tenofovir exposure (Markowitz 2011). However, due to the success of tenofovir, the company will be in no hurry to develop a competition all too quickly.

Phosphazide (Nicavir) is a nucleoside analog that was developed (and is marketed) in Russia, which is very similar to AZT (Skoblov 2003). After 12 weeks of phosphazide monotherapy (400 mg), viral load in a small group of patients dropped by median 0.7 logs. Since phosphazide is a prodrug of AZT, it requires an additional activation step. The D67N mutation seems to reduce efficacy (Machado 1999). A small study has shown potency in combination with ddI and nevirapine (Kravtchenko 2000), another with ddI and saquinavir (Sitdykova 2003). It is still hard to see the advantage over AZT – although better tolerability was presumed, this has not been shown.

Racivir is a cytidine analog produced by Pharmasset. It is a mixture of FTC and its enantiomer. Possibly, both enantiomers have different resistance profiles so that, theoretically, the development of resistance is impeded (Hurwitz 2005). It has shown good antiviral activity in combination with d4T and efavirenz after two weeks (Herzmann 2005). In a double blind randomized study in 42 patients harbouring the M184V mutation, viral load declined by 0.4 logs after 28 days (Cahn 2007). There has been no news since then. There seems to be little interest for larger companies to further develop racivir.

Stampidine is a nucleoside analog developed by the Parker Hughes Institute. It resembles d4T and is apparently 100 times more potent than AZT in vitro (Uckun 2002). It also has activity against HIV mutants with up to 5 TAMs (Uckun 2006). It has been discussed also as a potential microbicide (D’Cruz 2004).

Out of sight, out of mind: the following NRTIs are not being pursued:

  • Adefovir dipivoxil (bis-POM PMEA) from Gilead, low activity against HIV, nephrotoxicity, has an indication in hepatitis B
  • Dexelvucitabine (DFC or Reverset) from Incyte, stopped in 2006 due to several cases of pancreatitis
  • dOTC from Biochem Pharma, stopped due to toxicity in monkeys
  • FddA (Lodenosine) from US Bioscience, stopped in 1999 due to severe liver/kidney damage
  • KP-1461 from Koronis, stopped in June 2008 due to no efficacy
  • Lobucavir from BMS, stopped due to carcinogenicity
  • MIV-210 from Medivir/Tibotec, currently being developed for HBV
  • MIV-310 (alovudine, FLT) from Boehringer Ingelheim, stopped in March 2005 due to a disappointing Phase II study
  • SPD-756 (BCH-13520) and SPD-761    


Bogner JR, Roecken M, Herrmann DB, Boerner D, Kaufmann B, Gurtler L, Plewig G, Goebel FD. Phase I/II trial with fozivudine tidoxil (BM 21.1290): a 7 day randomized, placebo-controlled dose-escalating trial. Antivir Ther 1997, 2:257-64.

Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 2006, 20:1261-8.

Cahn P, Schürmann D, Reuss F, et al. A phase-II study of 14 days monotherapy with the nucleoside-analogue Fosalvudine Tidoxil in treatment-naïve HIV-1 infected adults. WEPEB114LB, 4th IAS 2007, Sydney.

Cahn P, Sosa N, Wiznia A, et al. Racivir demonstrates safety and efficacy in patients harbouring HIV with the M184V mutation and > 3 TAM. Abstract 488, 14th CROI 2007, Los Angeles.

Cahn P, Altclas J, Martins M, et al. Antiviral activity of apricitabine in treatment-experienced HIV-1-infected patients with M184V who are failing combina-tion therapy. HIV Med 2010 Nov 3. [Epub ahead of print]

Chung KC, Yadav V, Rapp K, Chong Y, Schinazi R. Dioxolane thymine nucleoside is active against a variety of NRTI-resistant mutants. Abstract 554, 12th CROI 2005, Boston.

Cihlar T, Laflamme G, Fisher R, et al. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother 2009, 53:150-6.

Cihlar T, Ray AS, Boojamra CG, et al. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother 2008;52:655-65.

Colucci P, Pottage J, Robison H, et al. The different clinical pharmacology of elvucitabine (beta-L-Fd4C) enables the drug to be given in a safe and effective manner with innovative drug dosing. Abstract LB-27, 45th ICAAC 2005, Washington.

Colucci P, Pottage JC, Robison H, et al. Multiple-dose pharmacokinetic behavior of elvucitabine, a nucleoside reverse transcriptase inhibitor, adminis-tered over 21 days with lopinavir-ritonavir in human immunodeficiency virus type 1-infected subjects. Antimicrob Agents Chemother 2009, 53:662-9.

Corbett AH, Rublein JC. DAPD. Curr Opin Investig Drugs 2001, 2:348-53.

D’Cruz OJ, Uckun FM. Stampidine is a potential nonspermicidal broad-spectrum anti-HIV microbicide. Fertil Steril 2004, 1:831-41.

DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with a unique pharmacokinetic profile. Abstract H-892, 48th ICAAC 2008, 2008.

DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs lamivudine with tenofovir and efavirenz in antiretroviral-treatment-naïve HIV-1 infected patients: 96 week final results. Abstract 511, 17th CROI 2010, San Francisco.

Dunkle LM, Gathe JC, Pedevillano DE, et al. Elvucitabine: potent antiviral activity demonstrated in multidrug-resistant HIV infection. Antiviral Therapy 2003, 8:S5.

Fabrycki J, Zhoa Y, Wearne J, et al. In vitro induction of HIV variants with reduced susceptibility to elvucitabine (ACH-126,443,beta-L-Fd4C). Antiviral Therapy 2003, 8:S8.

Frankel F, Xu H, Coates J, Wainberg M. In vitro investigation of the resistance profile of apricitabine. Abstract 581, 14th CROI 2007, LA.

Gaffney MM, Belliveau PP, Spooner LM. Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infection. Ann Pharmacother 2009, 43:1676-83

Girard PM, Pegram PS, Diquet B, et al. Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection: pharmacokinetics, tolerability, and efficacy. J AIDS 2000, 23:227-35.

Gu Z, Allard B, de Muys JM, et al. In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcrip-tase inhibitor for treatment of human immunodeficiency virus infection. Antimicrob Agents Chemother 2006, 50:625-31.

Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res 2005, 67:1-9.

Herzmann C, Arasteh K, Murphy RL, et al. Safety, pharmacokinetics, and efficacy of (+/-)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine with efavirenz and stavudine in antiretroviral-naive HIV-infected patients. Antimicrob Agents Chemother 2005, 49:2828-33.

Hurwitz SJ, Asif G, Fromentin E, Tharnish PM, Schinazi RF. Lack of pharmacokinetic interaction between amdoxovir and reduced- and standard-dose zidovudine in HIV-1-infected individuals. Antimicrob Agents Chemother 2010, 54:1248-55.

Hurwitz SJ, Otto MJ, Schinazi RF. Comparative pharmacokinetics of Racivir, (+/-)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans. Antivir Chem Chemother 2005, 16:117-27.

Kravtchenko AV, Salamov GG, Serebrovskaya LV, et al. The first experience of HAART with phosphazid + didanosine + nevirapine in HIV-infected patients in Russia. Abstract 3, 5th Int Conf Drug Therapy 2000, Glasgow, Scotland.

Liang Y, Narayanasamy J, Schinazi RF, Chu CK. Phosphoramidate and phosphate prodrugs of (-)-beta-d-(2R,4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies. Bioorg Med Chem 2006, 14:2178-89.

Liang Y, Sharon A, Grier JP, et al. 5′-O-Aliphatic and amino acid ester prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine (DOT): synthesis, anti-HIV activity, cytotoxicity and stability studies. Bioorg Med Chem 2009, 17:1404-9.

Locas C, Ching S, Damment S. Safety profile of SPD754 in cynomolgus monkeys treated for 52 weeks, Abstract 527, 11th CROI 2004, San Francisco.

Machado J, Tsoukas C, Salomon H, et al. Antiviral activity and resistance profile of phosphazid – a novel prodrug of AZT. Abstract 594, 6th CROI 1999, Chicago.

Markowitz M, Zolopa A, Ruane P, et al. GS-7340 Demonstrates Greater Declines in HIV-1 RNA than TDF during 14 Days of Monotherapy in HIV-1-infected Subjects. Abstract 152LB, 18th CROI 2011, Boston.

Murakami E, Ray AS, Schinazi RF, Anderson KS. Investigating the effects of stereochemistry on incorporation and removal of 5-fluorocytidine analogs by mitochondrial DNA polymerase gamma: comparison of D- and L-D4FC-TP. Antiviral Res 2004, 62:57-64.

Murphy RL, Kivel NM, Zala C, et al. Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals. Antivir Ther 2010, 15:185-92.

Oliveira M, Moisi D, Spira B, Cox S, Brenner BG, Wainberg MA. Apricitabine does not select additional drug resistance mutations in tissue culture in human immunodeficiency virus type 1 variants containing K65R, M184V, or M184V plus thymidine analogue mutations. Antimicrob Agents Chemother 2009, 53:1683-5.

Parniak MA, Murphey-Corb M, Nyaundi J, et al. Highly potent in vivo activity of QD administration of 4′-ethynyl-2-fluoro-deoxyadenosine in SIV-infected rhesus macaques. Abstract H-926/409. 49th ICAAC 2009.

Ray AS, Vela JE, Boojamra CG, et al. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob Agents Chemother 2008, 52:648-54.

Sitdykova YR, Serebrovskaya LV, Kravchenko AV. Immune reconstitution on treatment of HIV-infected patients with phosphazid, didanosine and saquinavir/ritonavir once daily in russia. Abstract 2.7/1. 9th EACS 2003, Warsaw, Poland.

Skoblov Y, Karpenko I, Shirokova E, et al. Intracellular metabolism and pharmacokinetics of 5´-hydrogenphosphonate of 3´-azido-2´,3´-dideoxythymidine, a prodrug of 3´-azido-2´,3´-dideoxythymidine. Antiviral Res 2004;63:107-13.

Thompson M, Richmond G, Kessler M, et al. Preliminary results of dosing of amdoxovir in treatment-experienced patients. Abstract 554, 10th CROI 2003, Boston.

Uckun FM, Pendergrass S, Venkatachalam TK, Qazi S, Richman D. Stampidine is a potent inhibitor of zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical HIV type 1 isolates with thymidine analog mutations. Antimicrob Agents Chemother 2002, 46:3613-3616.

Uckun FM, Venkatachalam TK, Qazi S. Potency of stampidine against multi-nucleoside reverse transcriptase inhibitor resistant human immunodefi-ciency viruses. Arzneimittelforschung 2006, 56:193-203.

Venhoff AC, Lebrecht D, Reuss FU, et al. Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcrip-tase inhibitor prodrug. Antimicrob Agents Chemother 2009, 53:2748-51.


In 2008, etravirine was the first second-generation NNRTI to be licenced. Encouraged by this success, many pharmaceutical companies have NNRTIs in their pipeline again.

GSK-2248761 (GSK 761, formerly IDX-899) is an NNRTI developed by ViiV Healthcare. The resistance profile in vitro has no cross-resistance with efavirenz (Richman 2008). In vivo the viral load decreased by 1.8 logs at 8 days (Zala 2008). The half-life is long (Zhou 2009).  Early 2011, the FDA interrupted ongoing clinical studies after cerebral seizures had been observed. Further development is questionable, despite assertions by ViiV that the issue is not yet closed.

Lersivirin (UK 453,061) is another new NNRTI by ViiV Healthcare with good efficacy against classic NNRTI resistances (Corbeau 2010). Healthy volunteers had tolerated the substance well over 28 days (Davis 2010). In HIV-infected patients, a decrease of viral load up to 2,0 logs was observed under 10-750 mg after 7 days of monotherapy (Fätkenheuer 2009).

RDEA806 is an NNRTI by Ardea Bioscience. The resistance barrier is very high and the potential for interaction low (Hamatake 2007). Monotherapy trials with HIV-infected patients showed a reduction of over 1.8 logs at 7 days with excellent tolerability (Moyle 2010). The data seem promising enough to start Phase IIb trials. However, the company’s website is strangely blank on the topic.

Out of sight, out of mind, the following NNRTIs are no longer being developed:

  • Atevirdine – Upjohn is concentration on delavirdin (a good idea?)
    • BIRL355BS from Boehringer Ingelheim, in 2007 due to toxicity/metabolites
    • Calanolide A from Sarawak due to poor efficacy
    • Capravirin (AG1549) from Pfizer, limited activity
    • DPC 083 (BMS-561390), May 2003, poor PK/secure data
      • DPC 961 due to suicidal thoughts in healthy volunteers; DPC 963
      • Emivirine (EMV, MKC-442, coactinone) from Triangle, due to limited activity
      • GW420867X from GSK, due to being too much of a me-too drug
      • GW8248 and GW5624 from GSK, due to poor bioavailability
      • HBY-097 from Hoechst-Bayer, due to unfavorable side effects
      • Loviride,  Janssen pharmaceuticals, due to limited activity in the  CAESAR-study
        • MIV-150 from Medivir/Chiron, due to poor bioavailability, is now being developed as a microbicide
        • PNU 142721, Pharmacia & Upjohn, too similar to efavirenz  (Me-too)
          • TMC120 (dapivirine) from Tibotec, due to poor oral bioavailability, now being studied as a microbicide


Cohen C, Molina JM, Cahn P et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised phase III trials comparing TMC278 versus efavirenz in treatment-naïve HIV-1-infected patients. Abstract THLBB206, 18th IAC 2010, Vienna.

Corbau R, Mori J, Phillips C, et al. Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2010, 54:4451-63.

Crauwels H, Vingerhoets J, Ryan R. Pharmacokinetic parameters of once-daily TMC278 following administration of EFV in healthy volunteers. Abstract 630, 18th CROI 2011, Boston.

Davis J, Hackman F, Ndongo MN, et al. Safety and tolerability of lersivirine, a nonnucleoside reverse transcriptase inhibitor, during a 28-day, randomized, placebo-controlled, Phase I clinical study in healthy male volunteers. Clin Ther 2010, 32:1889-95.

Desmidt M, Willems B, Dom P, et al. Absence of a teratogenic potential from a novel next-generation NNRTI, TMC278. Abstract PE7.1/4, 12th EACS 2009, Cologne.

Fätkenheuer G, Staszewski S, Plettenberg A, et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV infected patients. Abstract WESS202, 4th IAS 2007, Sydney.

Goebel F, Yakovlev A, Pozniak A, et al. TMC278: Potent anti-HIV activity in ART-naive patients. Abstract 160, 12th CROI 2005, Boston.

Hamatake R, Zhang Z, Xu W, et al. RDEA806, a potent NNRTI with a high genetic barrier to resistance. Abstract 1662, 47th ICAAC 2007, Chicago.

Hoetelmans R, van Heeswijk R, Kestens D, et al. Pharmacokinetic interaction between TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), and lopinavir/ritonavir (LPV/r) in healthy volunteers. Abstract PE4.3/1, 10th EACS 2005, Dublin.

Janssen PA, Lewi PJ, Arnold E, et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 2005, 48:1901-9.

Langdon G, Davis J, Layton G, et al. Pharmacokinetic interaction of the next generation NNRTI UK-453,061 with other antiretrovirals and assessment of safety and tolerability in healthy male subjects.  Abstract 763, 15th CROI 2008, Boston.

Moyle G, Boffito M, Manhard K, et al. Antiviral activity of RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor in treatment naive HIV patients. Abstract THAB0403, XVII IAC 2008, Mexico City.

Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC 278 demonstrates potent and sustained efficacy in ART naive patients. Abstract LB144 LB, 14th CROI 2007. Los Angeles.

Richman D, Jakubik J, Chapron C, et al. Genotypic resistance and phenotypic cross-resistance profile in vitro for a novel NNRTI: IDX899. Abstract 729, 15th CROI 2008, Boston.

Vanveggel S, Buelens A, Crauwels H, et al. TMC278 25mg QD has no effect on corrected QT interval in a study in HIV-negative volunteers. Abstract PE7.1/2, 12th EACS 2009, Cologne.

Verloes R, van’t Klooster G, Baert L, et al. TMC278 long acting – a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers. Abstract TUPE0042, 17th IAC 2008, Mexico City.

Zala C, Murphy R, Zhou XJ, et al. IDX899, a novel HIV-1 NNRTI with high barrier to resistance, provides suppression of HIV viral load in treatment-naive HIV-1-infected subjects. Abstract THAB0402, XVII IAC 2008, Mexico City.

Zhou XJ, Pietropaolo K, Damphousse D, et al. Single-dose escalation and multiple-dose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor, in healthy subjects. Antimicrob Agents Chemother 2009, 53:1739-46.

New protease inhibitors (PIs)

Even among PIs, many agents have been lost along the way. Following the licensing of darunavir, not much can be expected from PIs in the near- to mid-term. This may also be due to the high bar on new PIs in view of the existing results within this group (Review: Pokorná 2009).

DG17 is a prodrug of DG35 and has been under clinical testing for some time. A recent study showed a clear boosting effect with ritonavir and significant pharmacoenhancement reliving further clinical development of the drug (Cherry 2008).

PL-100 (MK8122) is a PI from the Canadian company Ambrilia Biopharma cooperating with Merck. The prodrug PPL-100 is metabolized to the active agent PL-100 which is believed to act against a broad range of PI-resistant viruses (Dandache 2007). PK data on healthy individuals look good. Moreover, the long half-life of 30-37 hours is of note. However, in 2008, clinical development was halted as Merck wants to concentrate more on prodrugs.

SM-309515 is a new PI from Sumitomo Pharmaceuticals and has apparently entered Phase I studies. Earlier versions failed due to the short half-life, and attempts are now being made to improve this (Mimoto 2008). The drug remained effective against mutations such as S37N, I47V, R57K, and I84V. Ritonavir boosting is now being tested in humans.

SPI-256 from Sequioa Pharmaceuticals is effective in vitro against PI-resistant isolates (Gulnik 2006). Healthy individuals have tolerated it well.

TMC-310911 is a new PI from Tibotec which is currently being examined with the booster-drug TMC-558445 in a Phase I-study. Data is not yet available.

Out of sight, out of mind the following PIs are no longer being developed:

  • AG-001859 – from Pfizer
  • Brecanavir – from GSK stopped in 2006 due to poor PKdata
  • DPC 684/681 –  narrow therapeutic range due to cardiotoxicity
  • GS 9005 – previously GS 4338, from Gilead
  • JE-2147, AKA AG1776, KNI-764 – from Pfizer, no news since 1999
  • KNI-272, Kynostatin – due to poor PK data
  • Mozenavir, DMP-450 – from Gilead, me-too drug, not offering anything new or better
  • RO033-4649 – from Roche, probably too similar to saquinavir
  • SC-52151 and SC-55389A – poor bioavailability
  • TMC-126 – Tibotec concentrated on TMC-114 (darunavir)


Cherry CL, Hoy JF, Rowe JS, Krum H, Mills J, Lewin SR. Phase 1 single dose studies to optimize the pharmacokinetics of DG17, a novel HIV-protease inhibitor pro-drug, using sodium bicarbonate and ritonavir. Curr HIV Res 2008, 6:272-5.

Dandache S, Sevigny G, Yelle J, et al. In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2007;51:4036-43.

Gulnik S, Afonina E, Eissenstat M, Parkin N, Japour A, Erickson J. SPI-256, a highly potent HIV protease inhibitor with broad activity against MDR strains. Abstract 501, 13th CROI 2006, Denver.

Hammond J, Jackson L, Graham J, et al. Antiviral activity and resistance profile of AG-001859, a novel HIV-1 protease inhibitor with potent activity against protease inhibitor-resistant strains of HIV. Antiviral Therapy 2004; 9:S17.

Mimoto T, Nojima S, Terashima K. Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure. Bioorg Med Chem 2008, 16:1299-308.

Pokorná J, Machala L, Řezáčová P Konvalinka J. Current and Novel Inhibitors of HIV Protease. Viruses 2009, 1:1209-1239.

Wu JJ, Stranix B, Milot G, et al. PL-100, a next generation protease inhibitor against drug-resistant HIV: in vitro and in vivo metabolism. Abstract H-253, 46th ICAAC 2006, San Francisco.

New entry inhibitors

With T-20 and maraviroc two entry inhibitors have already been licenced (see Chapter 2). Even if the antiviral effects of the drugs are not overwhelming, the concept is intriguing and entry inhibitors could open up new possibilities for the treatment of HIV infection in the coming years. On the other hand, a lot of the data does not go beyond basic science at this stage and many of the drugs discussed below may eventually disappear. Most significantly, coreceptor antagonists have had to bear several bitter setbacks.

New attachment inhibitors

Attachment of the viral glycoprotein gp120 to the CD4 receptor is the first step in the entry of HIV into the target cell. In theory, this step can be inhibited at least by two different mechanisms, namely blocking either gp120 or CD4. Both modes of action are currently under investigaton. Consequently, attachment inhibitors are very heterogeneous, so it is not possible to speak of a single drug class.

Since the beginning of the nineties, there have been a number of investigations into soluble CD4 molecules that prevent the attachment of HIV to the CD4 cell (Daar 1990, Schooley 1990). But, after disappointing results (probably due to the very short half-life of soluble CD4), this approach was abandoned for several years. With the growing knowledge of the mechanism of HIV entry into the cell, as well as following the success of T-20 as the first entry inhibitor, the development of attachment inhibitors has been reinvigorated. However, most drugs are not yet far advanced, often have problematic PK data and are therefore still in the proof-of-concept stage.

BMS-663068 is an attachment inhibitor from BMS. As a small molecule it binds very specifically and reversibly to HIV gp120 and thereby prevents attachment of HIV to the CD4 cell Thus, it does not bind to CD4 like ibalizumab (see below). The substance drew a lot of attention in the CROI study (Nettles 2011). 50 treatment naïve patients received different doses once or twice daily over 8 days. Viral load decreased by 1,2 and 1,8 logs – the maximum reduction in both arms was achieved a few days after treatment had concluded. Unfortunately no doses related dependence was observed and interindividual bioavailability was high. Headaches (44%) and rash (16%, mostly mild) were most frequent. Nevertheless, it is considered a promising revival of a new substance group. BMS-663068 is a prodrug of BMS-62659, with a broad range of efficacy against several HIV isolates (Nowicka-Sans 2011). It is the replacement for BMS-488043, stopped in 2004 after first clinical data were released (Hanna 2004). resistance occurs quickly as the binding site of gp120 is one of the most variable gene regions of all (Madani 2010).

Ibalizumab (formerly TNX-355 or HU5A8) is a monoclonal antibody that binds to the CD4 receptor preventing entry of HIV. The mechanism of action has not been clearly described. In contrast to other attachment inhibitors, ibalizumab does not seem to prevent binding of gp120 to CD4, but rather through conformational changes and thereby the binding of gp120 to CXCR4. Some experts therefore describe it as a coreceptor antagonist. It can be administered intravenously. Following the initial early data (Jacobsen 2004+2009, Kuritzkes 2004), data from a placebo-controlled Phase II trial were very encouraging (Norris 2006). In this study, extensively pretreated patients received ibalizumab as an infusion every two weeks for a year in two different doses (10 mg/kg or 15 mg/kg) or placebo in addition to an optimized ART regime. This study showed a long-lasting decrase in viral load of approximately one log after 48 weeks in both arms.

According to these data, ibalizumab appears to be one of the more promising agents in HIV medicine. There seems to be an inverse correlation between the sensitivity for ibalizumab and soluble CD4, which does not work on its own, as shown above (Duensing 2006). Resistances cause a higher sensitivity towards soluble CD4 and the gp120 antibody VC01, which is why attempts are made to administer ibalzumab in a cocktail of CD4 and VC01 (Pace 2011). First data on resistances have been published recently (Toma 2011). However, one issue will be whether binding to CD4 will affect the functionality of the CD4 T cells. There have been no negative affects reported so far and it seems that the binding site for ibalizumab to CD4 receptors is localized differently from the molecules. The CD4 T cells may be able to employ its normal functions, even if ibalizumab occupies the HIV binding site.

Origially ibalizumab was developed by Tanox Biosystems (Houston, Texas) and later taken over by the biotechnology company Genentech in 2007. In mid-2007 Genentech sold the license for ibalizumab to TaiMed Biologics, a Taiwanese biotech company – they are presently planning Phase IIb trials in Europe and the USA. The continuing research with this agent can be ascribed to the dedication of David Ho, Taiwanese himself and director of the Aaron Diamond AIDS Research Center. They have started to work on a subcutaneous version that quite possibly will take longer to develop.


Daar ES, Li XL, Moudgil T, Ho DD. High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci U S A 1990, 87:6574-6578.

Duensing T, Fung M, Lewis S, Weinheimer S. In vitro characterization of HIV isolated from patients treated with the entry inhibitor TNX-355. Abstract 158 LB,  13th CROI 2006, Denver.

Hanna G, Lalezari L, Hellinger J, et al. Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. Abstract 141, 11th CROI, 2004, San Francisco.

Jacobson JM, Kuritzkes DR, Godofsky E, et al. Phase 1b study of the anti-CD4 monoclonal antibody TNX-355 in HIV-infected subjects: safety and antiretroviral activity of multiple doses. Abstract 536, 11th CROI 2004, San Francisco.

Jacobson JM, Kuritzkes DR, Godofsky E, et al. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother 2009, 53:450-7.

Kuritzkes DR, Jacobson J, Powderly WG, et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004, 189:286-91.

Madani N, Princiotto A, Schön A, et al. Binding requirements for the entry inhibitor BMS-806. Abstract 65, 17th CROI 2010, San Francisco.Norris D, Morales J, Godofsky E, et al. TNX-355, in combination with optimized background regimen, achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks. Abstr. ThLB0218, XVI IAC 2006, Toronto.

Nettles R, Schürmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: A potentially first-in-class oral HIV attachment inhibitor. Abstract 49, 18th CROI 2011, Boston.

Norris D, Morales J, Godofsky E, et al. TNX-355, in combination with optimized background regimen, achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks. Abstr. ThLB0218, XVI IAC 2006, Toronto

Nowicka-Sans B, Gong YF, Ho HT, et al. Antiviral Activity of a New Small Molecule HIV-1 Attachment Inhibitor, BMS-626529, the Parent of BMS-663068. Abstract 518, 18th CROI 2011, Boston.

Pace G, Fordyce M, Franco D. Anti-CD4 monoclonal antibody ibalizumab exhibits exceptional breadth and potency against HIV, which adopts a unique pathway to resistance. Abstract 585, 18th CROI 2011, Boston.

Schooley RT, Merigan TC, Gaut P, et al. Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med. 1990, 112:247-253.

Toma J, Weinheimer SP, Stawiski E, et al. Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody ibalizumab. J Virol 2011, 85:3872-80.

New co-receptor antagonists

In addition to CD4 receptors, HIV also requires so-called co-receptors to enter the target cell. The two most important ones, CXCR4 and CCR5, were discovered in the mid-90s (see Chapter 2). Both receptors can be blocked (antagonized). In 2007, maraviroc was licenced as the first CCR5 antagonist. These small molecules are given orally and bind allosterically to the receptor. Beside these allosteric inhibitors there are monoclonal antibodies binding directly to the receptor. Below we will discuss those agents with published data.

New CCR5 antagonists (small molecules)

Vicriviroc (SCH-D, or 417690) is or was a CCR5 antagonist from Schering-Plough. Clinical development of this promising substance was halted in July 2010    after a pooled analysis of two Phase III trials, VICTOR E3 and E4 (Gathe 2010). A total of 721 pretreated patients received 30 mg vicriviroc or placebo in an optimized therapy containing mainly darunavir/r and/or raltegravir. No difference was observed between vicriviroc and placebo after 48 weeks (64% versus 62% below 50 copies/ml). Despite obvious differences in patients who were down to a maximum of two active drugs (70% versus 55%) the company decided to stop development of vicriviroc. Why this is mentioned here? Because this example clearly shows the problems new agents will face in the future. With the improvement of therapies over time, it is becoming more and more difficult to show effects – background therapies have become “too” good.

Cenicrivoc (TBR-652 or formerly TAK-652) is a new orally available CCR5 antagonist by the Japanese company Takeda, that has now been bought by Tobira. Laboratory data demonstrated that several mutations in the V3 region (and in the env gene) must exist for complete resistance towards TAK-652. Tropism does not seem to change when resistance happens (Baba 2007). Oral bioavailability is good and with 35-40 hours half-life a once daily dosage is possible. The oral availability is improved with food intake. TBR-652 also seems to be effective against CCR2, a receptor seated on moncytes, dendritic and memory T cells. Despite this, there are no concerns regarding its safety and the substance has shown good tolerability in healthy volunteers (Palleja 2009). In a first double-blind study of 10 days monotherapy and different doses in 54 patients, the viral load decreased by a maximum of 1.5-1.8 logs (Lalezari 2011, Marier 2011).

INCB9471 is an orally available CCR5 antagonist by the company Incyte. In a small study with 21 HIV-infected patients, who had received it or placebo over 14 days (Cohen 2007), the lowest viral load reduction was reached at -1.82 logs at 16 days. Due to the long half-life of 60 hours, effects continued until day 20, 6 days after therapy was stopped. Incyte stopped working on the agent in March 2008 to be able to focus on other products – they are looking for a buyer, and further development may be questionable.

PF-232798 is an orally available CCR5 antagonist by Pfizer (now ViiV Healthcare) and probably a maraviroc backup. It has a long half-life and can probably be administered once daily. In vitro it reacts well to maraviroc resistance. In healthy volunteers, it was well tolerated (Dorr 2008).

SCH-532706 is a new CCR5 antagonist from Schering. At first sight, there seems to be no advantage of this agent over vicriviroc. A total of 12 patients receiving 60 mg SCH-532706 (with 100 mg ritonavir) showed a reduction of viral load of up to 1.62 logs at 15 days (Pett 2009). A once-daily administration seems possible. There may be a positive effect on immune activation (Pett 2010) – however, it seems unlikely that this substance will be further pursued after the end of vicriviroc.

Other innovative CCR5 blockers

HGS004 (CCR5mAb004) developed by Human Genome Sciences is a monoclonal antibody showing a high resistance barrier in vitro (Giguel 2006). The half-life is approximately 5-8 days, and 80% of the receptors are occupied over a period of up to 4 weeks after a single dose. In an initial trial, 54 ART-naïve patients received a single infusion between 0.4 and 40 mg/kg HGS004 or placebo (Lalezari 2008). More than half the patients in the higher dose arms showed a reduction of at least one log at 14 days. Possibly, the company has now turned their attention to HGS101 which is even more effective in vitro and in addition effective against maraviroc resistances (Latinovic 2011).

PRO 140 is a monoclonal antibody by the company Progenics, directed against human CCR5 receptors (Trkola 2001). It is not a chemokine derivative like maraviroc or vicriviroc and even seems to have a synergistic effect (Murga 2006). The resistance barrier is probably high (Jacobsen 2010). PRO 140 must be administered parenterally. The normal function of CCR5 receptors should not be interfered with, at least not in the required dosages for inhibition of HIV replication (Gardner 2003). Healthy patients showed excellent tolerability to intravenous single administration of the drug and dose-dependent concentrations were measured (Olson 2005). What was particularly surprising was the extended effect – CCR5 receptors were occupied for up to 60 days and more (Olson 2006). In a trial with 39 HIV-infected patients treated with intravenous single doses of between 0.5 and 5.0 mg/kg, viral load decreased with the highest doses by 1.83 logs with a nadir at day 10 (Jacobson 2008). A higher dosage does not seem to achieve more (Jacobsen 2010). Comparable effects are reached with weekly subcutaneous administration (Jacobson 2010). If the so far excellent tolerability of PRO 140 is confirmed, it may develop to become  the first therapy on a weekly  basis.

ESN-196 is a pilot agent developed by Euroscreen, which does not block the coreceptor, but is agonistic, like the chemokine RANTES, causing internalization of the receptor (Ferain 2008). This CCR5 agonist reduces the receptor density on the cell surface. Therefore, it is as effective as maraviroc in vitro. As an agent with an extended effect, it could become an alternative, even with CCR5A resistant viruses, if proven safe in clinical trials.

Aprepitant (Emend®) is approved as a neurokinin-1 receptor antagonist and as an antiemetic in patients receiving highly emetogenous chemotherapy. It apparently has an effect on R5-tropic viruses caused by a down-regulation of the CCR5 receptors. Lab data showed dose-dependent effects on HIV replication (Wang 2007, Manak 20010). It is alleged that studies with HIV-infected patients are being run.

CXCR4 antagonists

In the early stages of infection, the R5 virus is found in most patients; X4 virus appears at later stages. X4 viruses are found in approximately 50% of cases in intensely pre-treated patients (Hoffmann 2007). This is why theoretically the blocking of CXCR4 receptors seems so attractive, as those patients with limited options would benefit most from it. The combination with CCR5 antagonists seems to be an interesting option. However, the development of CXCR4 antagonists is less advanced than that of the CCR5 antagonists (Khan 2007). This is mainly because theoretically, less clinical consequences are feared with the CCR5 blockade – individuals with a CCR5 genetic defect are healthy. In contrast, an inherent and mostly harmless defect with CXCR4 in humans has not been recorded. CXCR4 blockade had severe consequences in animal testing, for example in angiogenetic haematopoiesis or brain development (Tachibana 1998, Nagasawa 1998, Zou 1998). Years of basic research will certainly be necessary until large clinical studies can be attempted. Nevertheless, several chemically-different substances are in preclinical testing (Jenkinson 2010, Miller 2010, Skerl 2010, Steen 2010, Thakkar 2010). Despite the hurdles, CXCR4 antagonists seems to be a promising class. Research has shown an interesting side-effect that some agents are able to mobilize stem cells. This is why one of the pilot drugs, AMD 3100, presently under the name plexifor, is being further developed as a growth factor for leukocytes as well as a G-CSF alternative (Uy 2008). Such an effect, however, is obviously not desired in permanent HIV therapy. CXCR4 antagonists are also being discussed with regard to lupus erythematodes (Chong 2009).

AMD 11070 is a CXCR4 antagonist developed by AnorMED. Healthy volunteers showed excellent tolerability with AMD 070, but often developed leukocytosis (Stone 2004). The efficacy in HIV-infected patients with dual-tropic viruses was validated in two pilot studies (Moyle 2007, Saag 2007). The viral load decreased by at least one log in 7/15 patients on 10 days of monotherapy. However, in 2007, development was preliminarily stopped because of a liver toxicity. Binding to the X4 receptor is localized differently than the precursor agent AMD 3100, so there may be some scope for the development of new, more potent and less toxic CXCR4 antagonists (Wong 2007) – at least a start was made with AMD 11070 and evidence of efficacy was found. Presently AMD 3465 seems to be another possibility (Bodart 2009).

KRH-3955 and KRH-3140 are two new CXCR4 antagonists that have proven effective in mouse models (Tanaka 2006). According to preclinical data, KRH-3955 seems especially promising (Murakami 2009) and bioavailability is good (in dogs). Likewise, POL3026 is still preclinical and may help inhibit selected X4 shifts while on CCR5 antagonists (Moncunill 2008).


Baba M, Miyake H, Wang X, Okamoto M, Takashima K. Isolation and characterization of human immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob Agents Chemother 2007;51:707-15.

Bodart V, Anastassov V, Darkes MC, et al. Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4. Biochem Pharmacol 2009, 78:993-1000.

Chong BF, Mohan C. Targeting the CXCR4/CXCL12 axis in systemic lupus erythematosus. Expert Opin Ther Targets 2009, 13:1147-53.

Cohen C, DeJesus E, Mills A, et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. Abstract TUAB106, 4th IAS 2007, Sydney.

Dorr P, Westby M, McFadyen L, et al. PF-232798, a Second Generation Oral CCR5 Antagonist. Abstract 737, 15th CROI 2008, Boston.

Ferain O, Schols D, Bernard J, et al. ESN-196, a novel, small-molecule CCR5 agonist inhibits R5 HIV infection. Abstract 738, 15th CROI 2008, Boston.

Gardner J, Cohen M, Rosenfield SI, Nagashima KA, Maddon PJ, Olson WC. Immunotoxicology of PRO 140: a humanized anti-CCR5 monoclonal antibody for HIV-1 therapy. Abstract 876, Abstract 444, 43rd ICAAC 2003, Chicago.

Gathe J, R Diaz R, Fätkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. Abstract 54LB, 17th CROI 2010, San Francisco.

Giguel F, Beebe L, Migone TS, Kuritzkes D. The anti-CCR5 mAb004 inhibits hiv-1 replication synergistically in combination with other antiretroviral agents but does not select for resistance during in vitro passage. Abstract 505, 13th CROI 2006, Denver.

Hoffmann C. The epidemiology of HIV coreceptor tropism. Eur J Med Res 2007;12:385-90.

Jacobson J, Thompson M, Fischl M, et al. Phase 2a study of PRO 140 in HIV-infected adults. Abstract HG-1220, 49th ICAAC 2009, San Francisco.

Jacobson JM, Lalezari JP, Thompson MA, et al. Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults. Antimicrob Agents Chemother 2010, 54:4137-42.

Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis 2008, 198:1345-52.

Jacobson JM, Thompson MA, Lalezari JP, et al. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a  CCR5 monoclonal antibody. J Infect Dis 2010, 201:1481-7.

Jenkinson S, Thomson M, McCoy D, et al. Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent noncompetitive CXCR4 receptor antagonist. Antimicrob Agents Chemother 2010, 54:817-24.

Khan A, Greenman J, Archibald SJ. Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates. Curr Med Chem 2007;14:2257-77.

Lalezari J, Gathe J, Brinson C, et al. Safety, Efficacy, and Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected, Treatment-Experienced, CCR5 Antagonist-Naïve Subjects. J AIDS 2011 Feb 11. [Epub ahead of print]

Lalezari J, Yadavalli GK, Para M, et al. Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients. J Infect Dis 2008, 197:721-7.

Latinovic O, Reitz M, Le NM, Foulke JS, et al. CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells. Virology 2011, 411:32-40.

Manak M, Moshkoff D, Nguyen L, et al. Anti-HIV activity of aprepitant and synergistic interactions with other ARVs. Abstr. 750, 15th CROI 2008, Boston.

Marier JF, Trinh M, Pheng LH, Palleja SM, Martin DE. Pharmacokinetics and Pharmacodynamics of TBR-652, a Novel CCR5 Antagonist, in HIV-1-Infected, Antiretroviral Treatment-Experienced and CCR5 Antagonist-Naïve Patients. Antimicrob Agents Chemother 2011 Apr 12. [Epub ahead of print]

Moncunill G, Armand-Ugon M, Clotet I, et al. Anti-HIV Activity and Resistance Profile of the CXCR4 Antagonist POL3026. Mol Pharmacol 2008.

Moyle G, DeJesus E, Boffito M, et al. CXCR4 antagonism: proof of activity with AMD 11070. Abstract 511, 14th CROI 2007, Los Angeles.

Murakami T, Kumakura S, Yamazaki T, et al. The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100. Antimicrob Agents Chemother 2009, 53:2940-8.

Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2006, 50:3289-96.

Nagasawa T, Tachibana K, Kishimoto T. A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Semin Immunol 1998, 10:179-85.

Olson W, Doshan H, Zhan C et al. First-in-humans trial of PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy. Abstract WePe6.2C04, 3rd IAS 2005, Rio de Janeiro.

Olson WC, Doshan H, Zhan C. Prolonged coating of CCR5 lymphocytes by PRO 140, a humanized CCR5 monoclonal antibody for HIV-1 therapy. Abstract 515, 13th CROI 2006, Denver.

Palleja S, Cohen C, J Gathe J, et al. Safety and efficacy of TBR 652, a chemokine receptor 5 (CCR5) antagonist, in HIV 1-infected, antiretroviral (ARV) treatment-experienced, CCR5 antagonist–naïve patients. Abstract 53, 17th CROI 2010, San Francisco.

Pett SL, McCarthy MC, Cooper DA, et al.  A phase I study to explore the activity and safety of SCH532706, a small molecule chemokine receptor-5 antagonist in HIV type-1-infected patients. Antivir Ther 2009, 14:111-5.

Pett SL, Zaunders J, Bailey M, et al. A novel chemokine-receptor-5 (CCR5) blocker, SCH532706, has differential effects on CCR5+CD4+ and CCR5+CD8+ T cell numbers in chronic HIV infection. AIDS Res Hum Retroviruses 2010, 26:653-61.

Saag M, Rosenkranz S, Becker S, et al. Proof of concept of ARV activity of AMD 11070 (an orally administered CXCR4 entry inhibitor): results of the first dosing cohort A studied in ACTG protocol A5210). Abstract 512, 14th CROI 2007, Los Angeles.

Skerlj RT, Bridger GJ, Kaller A, et al. Discovery of Novel Small Molecule Orally Bioavailable C-X-C Chemokine Receptor 4 Antagonists That Are Potent Inhibitors of T-Tropic (X4) HIV-1 Replication. J Med Chem. 2010 Mar 19. [Epub ahead of print]

Steen A, Schwartz TW, Rosenkilde MM. Targeting CXCR4 in HIV Cell-Entry Inhibition. Mini Rev Med Chem. 2010 Jan 21. [Epub ahead of print]

Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998, 393:591-4.

Tanaka Y, Okuma K, Tanaka R, et al. Development of novel orally bioavailable CXCR4 antagonist, KRH-3955 and KRH-3140: binding specificity, pharmacokinetics and anti-HIV activity in vivo and in vitro. Abstract 49 LB, 13th CROI 2006, Denver.

Thakkar N, Pirrone V, Passic S, et al. Persistent interactions between the biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother. 2010 Mar 15. [Epub ahead of print]

Trkola A, Ketas TJ, Nagashima KA, et al. Potent, broad-spectrum inhibition of HIV type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 2001, 75:579-88.

Tsibris AM, Paredes R, Chadburn A, et al. Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211. Clin Infect Dis 2009, 48:642-9.

Tsibris AM, Sagar M, Su Z, et al. Emergence in vivo of vicriviroc resistance in HIV-1 subtype C: role of V3 loop and susceptibility to other CCR5 antagonists. Abstract 870, 15th CROI 2008, Boston.

Uy GL, Rettig MP, Cashen AF. Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther 2008, 8:1797-804.

Wang X, Douglas SD, Lai JP, Tuluc F, Tebas P, Ho WZ. Neurokinin-1 receptor antagonist (aprepitant) inhibits drug-resistant HIV-1 infection of macrophages in vitro. J Neuroimmune Pharmacol 2007;2:42-8.

Wong R, Bodard V, Metz M, et al. Understanding the interactions between CXCR4 and AMD 11070, a first-in-class small-molecule antagonist of the HIV coreceptor. Abstract 495, 14th CROI 2007, Los Angeles.

Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998, 393:595-599.

New fusion inhibitors

Although the fusion inhibitor (FI) T-20 was the first entry inhibitor, there has been little development in this field (Review: Eggink 2010). Subcutaneous injection required for many FIs is unappealing for patients and clinicians. It still needs to be demonstrated, whether small molecule FIs, a new group of FIs with oral bioavailability, are effective (Jiang 2004,+ 2005). Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor may dramatically increase its antiviral potency (Ingallinella 2009).

Sifuvirtide is an FI developed in China. In animal testing with monkeys a longer half-life (39 hours) and a higher affinity towards gp41 rather than towards T-20 was observed (Dai 2005). Sifuvirtide was well-tolerated in healthy patients (He 2008) and interesting synergetic effects were reported with T-20 (Pan 2009). However, there seem to be some cross-resistances (Liu 2010).

SP01A from Samaritan Pharmaceuticals is especially interesting because its effects are different from other entry inhibitors. As a procaine hydrochloride, SP01A reduces the expression of key enzyme HMG-CoA reductase, removes cholesterol from the cell membrane and seems to inhibit, not only in vitro, the fusion of virus and cell. The efficacy of this agent, which has been repeatedly tested in HIV+ patients for years, has been shown in three Phase II trials so far. Results were moderate, showing that only 50% of patients have a reduction of viral load at the highest doses of 800 mg. After 10 days of monotherapy, viral load fell by 0.4 logs and after 28 days by 0.5 logs. These results were published in July 2007 on the company’s website (

TR-999 and TR-1144 are two new generation fusion inhibitors, developed by Trimeris in cooperation with Roche (Delmedico 2006). According to studies in monkeys, the potency, duration of action and pharmacokinetics of these peptides are much improved in comparison to T-20. Although administration is still by injection, it may be possible to limit this to once a week. They have only been involved in one clinical trial since 2007, with data due in 2008. There has been no update on their website.

Virip blocks entry of HIV-1 into the cell by interacting with the gp41 fusion peptides. It is also called an anchor inhibitor. Researchers from Ulm, Germany, discovered the peptide in hemofiltrate, the liquid that is filtered out of the blood of dialysis patients, when replacing it with electrolytic solution. Thus virip is a “natural” entry-inhibitor whose antiretroviral activities can significantly be increased by slight modifications or replacement of some amino acids (Munch 2007). In a first study with HIV-infected patients, continuous infusion with the highest dosage led to a reduction of approximately 1 log at 10 days (Forsmann 2010). Tolerability was good and a subcutaneous application is presently being evaluated.

Out of sight, out of mind, entry inhibitors not moving forward:

  • AMD 3100 (CXCR4A) from AnorMed, due to cardiotoxicity
  • Aplaviroc, (CCR5A), from GSK, due to hepatotoxicity
  • BMS 806, BMS-488043  an attachment inhibitor, due to poor PK data
  • FP-21399 (FI) from Lexigen/Merck, due to low potency
  • PRO 542, an attachment inhibitor from Progenics, to focus on PRO 140
  • SCH-C (CCR5A) from Schering-Plough, due to cardiac arrhythmia
  • T-1249  and T-649 (FIs) from Roche/Trimeris, due to little prospect of success
  • TAK-779, TAK-220 (CCR5A) from Takeda, replaced by TAK-652


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Delmedico M, Bray B, Cammack N, et al. Next generation HIV peptide fusion inhibitor candidates achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic properties. Abstract 48, 13th CROI 2006, Denver.

Eggink D, Berkhout B, Sanders RW. Inhibition of HIV-1 by fusion inhibitors. Curr Pharm Des 2010, 16:3716-28.

Forssmann WG, The YH, Stoll M, et al. Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci Transl Med 2010, 2:63re3.

He Y, Xiao Y, Song H, et al. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 2008, 283:11126-34.

Ingallinella P, Bianchi E, Ladwa NA, et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency. Proc Natl Acad Sci U S A 2009 Mar 18.

Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother 2004, 48:4349-59.

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Liu Z, Shan M, Li L, et al. In vitro selection and characterization of HIV-1 variants with increased resistance to sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem 2011, 286:3277-87.

Munch J, Standker L, Adermann K, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide. Cell 2007;129:263-75.

Pan C, Lu H, Qi Z, Jiang S. Synergistic efficacy of combination of enfuvirtide and sifuvirtide, the first- and next-generation HIV-fusion inhibitors. AIDS. 2009 Feb 24.

New integrase inhibitors

The integration of viral DNA, enabled by the HIV enzyme integrase into the host DNA, is a major step for the replication cycle of HIV. In 2007, raltegravir, the first integrase inhibitor for treatment of HIV infection, was licenced (see Chapter 2). On account of its great success, it can be expected that clinical research will focus on this class for the next few years. One major problem seems to be cross-resistance, which makes it necessary to find new integrase inhibitors that will interact differently to the enzyme than raltegravir – me-too integrase inhibitors that are marginally different in their efficacy and pharmacokinetics are not needed (Serrao 2009).

Dolutegravir (GSK-1349572 or DTG)  is a new integrase inhibitor which initially emerged via Shinogi cooperating with GSK and is now being developed by ViiV Healthcare. As an integrase inhibitor of the second generation it shows improvements, especially with regard to pharmacokinetics (once daily unboosted administration will be possible) and resistance profile. In a Phase IIa study with 35 patients, a reduction of 2.5 logs to below 50 mg/ml was observed and 70% achieved a viral load below 50 (Lalezari 2009). In SPRING-1, a Phase IIb study, 200 treatment naïve patients received different doses of either dolutegravir (10,25 or 50 mg) or efavirenz in addition to 2 NRTIs (Arribas 2010). After an interim analysis at week 16, 90-96% of patients were under detection level of 50 copies/ml in the dolutegravir-arm compared to 60% in the efavirenz-arm. Tolerability was very convincing in SPRING-1 and in all other studies so far (Lou 2009). Cross-resistance with other integrase inhibitors do not seem to be a problem (Underwood 2009, Seki 2010). An important resistance appears to exist with T124A,  as well as mutations typical for raltegravir with Codon 148. Efficacy seems to decline with the existence of further mutations (Garrido 2011). Preliminary clinical data of the VIKING-study show, that higher dosage may help to overcome raltegravir resistances. In VIKING II, 13 out of 24 patients with raltegravir resistances reached a viral load of 400 copies/ml under 10 days monotherapy with 100 mg dolutegravir. The results were better than in VIKING I with 50 mg dolutegravir (Eron 2011). There are no interactions with boosted PIs. However, etravirine reduces the GSK-1349572 levels significantly (Song 2011). This also applies for antacids and it is recommended not to administer them simultaneously (Patel 2011). Dolutegravir is currently being tested in the 50 mg dosage in combination with ABC+3TC. Several studies are ongoing. Taken together, dolutegravir seems to be one of the agents that will make it to the market over the next few years.

Elvitegravir (GS-9137, formerly JTK-303) is an integrase inhibitor developed by Gilead, with a biochemical similarity to chinolone antibiotics (Sato 2006). Like raltegravir, elvitegravir inhibits the strand transfer. Individual doses were orally bioavailable, safe and well tolerated (Kawaguchi 2006). In a study with 40 patients (ART-naïve and pre-treated), viral load decreased by 2 logs at 10 days of monotherapy (DeJesus 2006). A disadvantage is that elvitegravir must be boosted with 100 mg ritonavir (Kearney 2006), but on the other hand a single administration per day seems possible.

A Phase II study, in which 28 patients received either three boosted doses (20, 50 and 125 mg) of elvitegravir or of a new ritonavir-boosted PI, was well-tolerated (Zolopa 2010). One 20 mg arm was prematurely stopped due to a high failure rate, but in the higher dose arms more patients showed a viral load below 50 copies/ml (approximately 40% versus 30%) after 16 weeks. One must be warned against premature comparisons with data from raltegravir, as this study was differently designed – it was compared to an active PI and not a placebo (Zolopa 2010). Like with raltegravir, tolerance was excellent. The dose for future studies is 125 mg.

In vitro resistance mutations can be selected with elvitegravir, too, and there seems to be at least two resistance pathways at T661 or E92Q  (Shimura 2008). Especially E92Q requires a high resistance (36-fold). In the case of Y143, a raltegravir resistance, efficacy seems to persist (Métifiot 2011).  Resistance of elvitegravir and raltegravir overlap to a great extent, thus cross-resistance seems possible (Kodama 2006). No virological response was observed in a small clinical study with patients who changed from elvitegravir to raltegravir (DeJesus 2007).

Major interactions with elvitegravir are not expected, at least not with NRTIs, darunavir, tipranavir, fosamprenavir or etravirine. However, the doses of maraviroc must be halved (Mathias 2007, Ramanathan 2008).

To avoid dependancy on ritonavir as a booster agent, Gilead is presently investigating combinations of elvitegravir with cobicistat (GS-9350), a new pharmacoenhancer (PKE). Encouraging PK data were obtained from healthy volunteers (German 2010), and they are now developing a QUAD pill consisting of a combination of tenofovir, FTC, cobicistat and elvitegravir. In a first Phase II trial, the QUAD pill was tested on therapy-naïve patients double-blind versus Atripla® with comparable effects after 24 weeks (Cohen 2010).

GSK-774 is probably a backup for dolutegravir, but not less effective. In a first double-blind randomized study with 48 volunteers the substance showed good tolerability over 14 days. Under the 13 HIV-infected patients the viral load was reduced by 2.6 logs (Min 2009).

Out of sight, out of mind, recently stopped integrase inhibitors:

  • BMS-707035, probably no advantage over raltegravir
  • GSK-364735, due to liver toxicity in monkeys, stopped in Phase I in 2007
  • S-1360 (Shionogi/GSK), stopped in 2005 due to toxicity
  • L-870810 (Merck), due to liver toxicity seen in dogs


Arribas J, Lazzarin A, Raffi F, et al. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral-naive adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). Abstract THLBB205, XVIII IAC 2010, Vienna.

Bar-Magen T, Sloan RD, Donahue DA, et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol 2010, 84:9210-6.

Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS 2011, 25:F7-12.

DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J AIDS 2006, 43:1-5.

DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0158) use after virologic rebound on elvitegravir (EVT, GS 9137). Abstract TUPEB032, 4th IAS 2007, Sydney.

Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. Abstract 151LB, 18th CROI 2011, Boston.

Garrido C, Soriano V, Geretti AM, et al. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients – Impact of HIV subtypes and prior raltegravir experience. Antiviral Res 2011, 90:164-167.

German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J AIDS 2010, 55:323-9.

Goethals O, Vos A, Van Ginderen M, et al. Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles. Virology 2010, 402:338-46.

Kawaguchi I, Ishikawa T, Ishibashi M, Irie S, Kakee A. Safety and pharmacokinetics of single oral dose of JTK-303/GS 9137, a novel HIV integrase inhibitor, in HIV healthy volunteers. Abstract 580, 13th CROI 2006, Denver.

Kearney B, Mathias A, Zhong L, et al. Pharmacokinetics/pharmacodynamics of GS-9137 an HIV integrase inhibitor in treatment-naive and experienced patients. Abstract 73, 7th Int Workshop Clin Pharm HIV Therapy 2006, Lisbon, Portugal.

Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a novel HIV integrase inhibitor JTK-303/GS-9137. Abstract H-254, 46th ICAAC 2006, San Francisco.

Lalezari J, Sloan L, DeJesus E, et al. Potent antiviral activity of S/GSK1349572, a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients. Abstract TUAB105, 5th IAS 2009, Cape Town.

Lou Y, Min S, Chen S, et al. Meta-analysis of safety for short-term dosing of an HIV integrase inhibitor, S/GSK1349572, from seven clinical studies. Abstract H-931/414, 49th ICAAC 2009, San Francisco.

Mathias A, Hinkle J, Enejosa J, et al. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Tipranavir/r. Abstract TUPDB06, 4th IAS 2007, Sydney.

Mathias A, Shen G, Enejosa J, et al. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Darunavir/r. Abstract TUPDB03, 4th IAS 2007, Sydney.

Mathias AA, West S, Hui J, Kearney BP. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther 2009, 85:64-70.

Métifiot M, Vandegraaff N, Maddali K, et al. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 2011 Apr 18. [Epub ahead of print]

Min S, DeJesus E, McCurdy L, et al. Pharmacokinetics (PK) and safety in healthy and HIV-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor. Abstract H-1228, 49th ICAAC 2009, San Francisco.

Patel P, Song I, Borland J, et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother 2011 Apr 28. [Epub ahead of print]

Ramanathan S, Kakuda TN, Mack R, West S, Kearney BP. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther 2008, 13:1011-7.

Ramanathan S, Mathias AA, Shen G, et al. Lack of clinically relevant drug-drug interaction between ritonavir-boosted GS-9137 (elvitegravir) and fosamprenavir/r. Abstract WEPEB014, 4th IAS 2007, Sydney.

Ramanathan S, Shen G, Hinkle J, Enejosa J, Kearney BP. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J AIDS 2007;46:160-6.

Ramanathan S, West S, Abel S, et al. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir plus maraviroc. Abstract H-1425, 47th ICAAC 2007, Chicago.

Sato M, Motomura T, Aramaki H, et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 2006, 49:1506-8.

Seki T, Kobayashi M, Wakasa-Morimoto C, et al. S/GSK1349572 is a potent next generation HIV Integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones. Abstract 555, 17th CROI 2010, San Francisco.

Serrao E, Odde S, Ramkumar K, Neamati N. Raltegravir, elvitegravir, and metoogravir: the birth of “me-too” HIV-1 integrase inhibitors. Retrovirology. 2009 Mar 5;6:25.

Shimura K, Kodama E, Sakagami Y, et al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008;82:764-74.

Song I, Borland J, Chen S, et al. Effect of Atazanavir and Atazanavir/Ritonavir on the Pharmacokinetics of the Next-Generation HIV Integrase Inhibitor, S/GSK1349572. Br J Clin Pharmacol. 2011 Feb 22. [Epub ahead of print]

Song I, Borland J, Min S, et al.  The effect of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother 2011 May 9. [Epub ahead of print]

Song I, Min S, Borland J, et al. The effect of ritonavir-boosted protease inhibitors (PIs) on the HIV integrase inhibitor, S/GSK1349572, in healthy subjects. Abstract A1-1304/37, 49th ICAAC 2009, San Francisco.

Song I, Patel A, Min S, et al. Evaluation of antacid and multivitamin (MVI) effects on S/GSK1349572 pharmacokinetics (PK) in healthy subjects. Abstract A1-1305/38, 49th ICAAC 2009, San Francisco.

Underwood M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. Abstract WEPEA098, 5th IAS 2009, Cape Town.

Van Wesenbeeck L, Rondelez E, Feyaerts M, et al. Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Antimicrob Agents Chemother 2011, 55:321-5.

Zolopa AR, Berger DS, Lampiris H, et al. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV Type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis 2010, 201:814-22.

New maturation inhibitors

The so-called maturation inhibitors inhibit HIV replication in a very late phase of the HIV reproduction cycle, i.e., at the budding or maturation of new virions. As is the case for integrase inhibitors, 2005 can be seen as the introductory year: this was the first time an agent was shown to have an antiviral effect on HIV-infected patients. Maturation inhibitors are, without a doubt, an interesting class of new drugs. Whether any of the agents will make it as far the clinic remains uncertain, as several problems have surfaced during the development of the prototype, bevirimat.

Bevirimat (MPC-4326, formerly PA-457) is a derivative of betulinic acid, which is isolated as triterpene carbonic acid from birch bark. It was produced by Panacos, which was sold to Myriad Pharmaceuticals. Bevirimat inhibits budding or maturation of new virions (Li 2003) by inhibiting the transition of the capsid precursor (p25) into the mature capsid protein (p24). This prevents the production of infectious viruses. Its long half-life allows once daily dosing (Martin 2007, Smith 2007). Tolerability of bevirimat which up to now has been tested in more than 650 patients has been good, including in the presence of atazanavir (Martin 2008). However, interactions seem to exist with darunavir (reduces bevirimat levels) and raltegravir (raltegravir levels increase) (Beelen 2010).

Data of a placebo-controlled Phase IIa trial was published in autumn 2005, in which patients received an oral once daily monotherapy of bevirimat for 10 days (Beatty 2005). In the highest dose group (200 mg) viral load decreased by 1.03 logs (median); in the 100 mg group it was just 0.48 logs. However, some patients showed no effect on the viral load, which can be ascribed to “natural” polymorphisms in the gag gene (van Baelen 2009, Lu 2011). Patients harbouring viruses with no gag polymorphisms (mutations) on the positions Q369, V370 or T371 before therapy, responded better to bevirimat. In a more recent monotherapy study with 32 patients receiving higher dosage, a reduction of viral load of 0.54 and 0.7 logs respectively, was observed with 200 or 300 mg after 14 days. Without the polymorphism, effects were greater than the one log level, those with the polymorphism had a drop of only 0.2 logs (Bloch 2009). Only about 50-70% of all individuals tested, seemed to be without gag polymorphisms. There appears to be no difference between treatment-naïve and pre-treated patients, nor is there any influence due to the degree of the underlying immunodeficiency (Margot 2009, Knapp 2009, Seclén 2010). However, there seems to be a strong correlation with PI resistance (Verheyen 2010).

This shows clearly the need for tests on these gag polymorphisms before starting therapy with bevirimat and possibly with other maturation inhibitors – not unlike the tropism test with CCR5 antagonists. In June 2010, Myriad announced that they would not continue to develop bevirimat – it remains unclear how and if development will proceed.

PA1050040 is similar to bevirimat, working in the same way, but seems to be effective against bevirimat-resistant viruses (with L363M). PK data appear to be better, while the potential for interactions is less. According to Panacos, a Phase I study has been initialized (Kilgore 2007).

UK-201844 is a maturation inhibitor developed by Pfizer. It was detected after screening over a million agents (Blair 2007). The method of efficacy seems to lie in the interaction with gp160 processing resulting in the production of non-infectious viruses.

BIT-225 by the Australian company Biotron is a specific HIV replication inhibitor in macrophages, but not in T cells (Khoury 2007). It works with a different mechanism than the Vpu ion channel inhibitor and inhibits the release of viral particles from macrophages. BIT-225 could play a role in eradication from latent cell reservoirs. According to Biotron, a successful Phase I study ended in September 2007, showing no relevant toxicity with 40 healthy volunteers receiving doses of 35-400 mg and providing acceptable PK data.

MPC–9055 is, like bevirimat, a maturation inhibitor by Myriad Pharmaceuticals in Salt Lake City. The agent demonstrated good tolerance and acceptable pharmacokinetics with 55 healthy volunteers (Beelen 2009). After the end of bevirimat, develpmet of MPC-9055 seems unlikely.


Beatty G, Jacobson J, Lalezari J, et al. Safety and Antiviral Activity of PA-457, the First-In-Class Maturation Inhibitor, in a 10-Day Monotherapy Study in HIV-1 Infected Patients. Abstract Abstract H-416D, 45th ICAAC 2005, Washington.

Beelen A, Balch A, Swabb E. MPC-4326 drug-drug interaction profile. Abstract 615, 17th CROI 2010, San Francisco.

Beelen A, Otto J, Fidler M, et al. Phase 1, single ascending oral dose study of the safety, tolerability, and pharmacokinetics of a novel HIV-1 maturation inhibitor in HIV- healthy volunteers. Abstract 570, 16th CROI 2009, Montréal.

Blair W, Cao J, Jackson L, et al. Execution of a high throughput HIV-1 replication screen and the identification of a novel small molecule inhibitor that targets HIV-1 envelop maturation. Abstract 50LB, 13th CROI 2006, Denver.

Bloch M, Bodsworth N, Fidler M, et al. Efficacy, safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. Abstract H-1230, 49th ICAAC 2009, San Francisco.

Khoury G, Ewart G, Luscombe C, et al. The antiretroviral efficacy of a novel compound BIT225: inhibition of HIV-1 release from human macrophage reservoirs. Abstract MOPDX06, 4th IAS 2007, Sydney.

Kilgore N, Reddick M, Zuiderhof M, et al. Characterization of PA1050040, a second generation HIV-1 maturation inhibitor. Abstract MOPDX05, 4th IAS 2007, Sydney.

Knapp D, Huang S, Harrigan R. Stable prevalence of bevirimat-related HIV gag polymorphisms both before and after HAART exposure. Abstract 636, 16th CROI 2009, Montréal.

Lalezari J, Richmond G, Thompson M, et al. Pharmacokinetics and safety of a novel 100 mg tablet formulation of MPC-4326 in subjects with HIV-1 infection. Abstract H-1309/42, 49th ICAAC 2009, San Francisco.

Li F, Goila-Gaur R, Salzwedel K, et al. PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Natl Acad Sci U S A 2003, 100:13555-60.

Lu W, Salzwedel K, Wang D, Chakravarty S, Freed EO, Wild CT, Li F.A Single Polymorphism in HIV-1 Subtype C SP1 is Sufficient to Confer Natural Resistance to the Maturation Inhibitor, Bevirimat. Antimicrob Agents Chemother. 2011 Apr 18. [Epub ahead of print]

Margot N, Gibbs C, Miller M. Phenotypic susceptibility to bevirimat among HIV-infected patient isolates without prior exposure to bevirimat. Abstract 637, 16th CROI 2009´, Montréal.

Martin DE, Blum R, Wilton J, et al. Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers. Antimicrob Agents Chemother 2007;51:3063-6.

Martin DE, Galbraith H, Schettler J, Ellis C, Doto J. Pharmacokinetic properties and tolerability of bevirimat and atazanavir in healthy volunteers: an open-label, parallel-group study. Clin Ther 2008, 30:1794-805.

Salzwedel K, Martin DE, Sakalian M. Maturation inhibitors: a new therapeutic class targets the virus structure. AIDS Rev 2007;9:162-72.

Seclén E, González Mdel M, Corral A, et al. High prevalence of natural polymorphisms in Gag (CA-SP1) associated with reduced response to Bevirimat, an HIV-1 maturation inhibitor. AIDS 2010, 24:467-9.

Smith PF, Ogundele A, Forrest A, et al. Phase I and II study of the safety, virologic effect, and PKs/pharmacodynamics of single-dose 3-o-(3´,3´-dimethylsuccinyl)betulinic acid (bevirimat) against HIV infection. Antim Ag Chemoth 2007;51:3574-81.

Van Baelen K, Salzwedel K, Rondelez E, et al. HIV-1 Susceptibility to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag SP1. Antimicrob Agents Chemother. 2009 Feb 17.

Verheyen J, Verhofstede C, Knops E, et al. High prevalence of bevirimat resistance mutations in protease inhibitor-resistant HIV isolates. AIDS 2010, 24:669-73.


In recent years, in addition to ART, immunomodulatory treatment strategies have been investigated. Although repeatedly discussed as an alternative or supplemet, these therapies still lack proof of clinical benefit. The most recent example is the failure of the two large IL-2-studies (see below). Some approaches are nevertheless addressed here briefly (in alphabetic order) below.

Cyclosporin A (Sandimmune®) – Immune activation may lead to increased HIV replication, and a treatment hypothesis has been to suppress the immune system in an attempt to slow down viral replication. This is the rationale behind studies investigating the use of cyclosporin A, a drug which is normally used for prophylaxis of transplant rejection after allogenic organ transplantation. However, results of clinical trials have been disappointing. Cyclosporin A had no effect on CD4 or CD8 count, nor on expression of activation markers (Calabrese 2002, Lederman 2006). This was not only the case in chronically but also in acutely infected patients (Miro 2009, Markowitz 2010). Cyclosporin A therefore probably has a limited future in the therapy of HIV infection.

G-CSF (granulocyte colony-stimulating factor) is available as filgastrim (Neupogen®), lenogastrim (Granocyte®) and most recently as the less expensive biosimilars. It is also licensed for permanent neutropenia in advanced HIV infection to avoid bacterial infection. In a randomized study with 258 HIV+ patients with CD4 T cells under 200/µl, the rate of severe neutropenia was 2% versus 22% in the control group after 24 weeks (Kuritzkes 1998). Incidence of bacterial infection was reduced by 31% and the number of inpatient days by 45%. No effects on viral load were detected. Patients with CMV retinitis showed a large survival benefit on G-CSF (Davidson 2002). Although severe neutropenia has become rare on ART, G-CSF can be useful today, especially in chemotherapy, with interferon or other myelo-suppressive drugs such as valgancyclovir.

GM-CSF (granulocyte macrophage colony-stimulating factor) is available as molgramostim (Leucomax®) or sargramostim (Prokine®). Three double-blind, randomized studies showed a slight effect on viral load (Angel 2000, Skowron 1999, Brites 2000). However, in one study in patients with uncontrolled infection, there was a slight increase of viremia (Jacobsen 2003). GM-CSF seems to prevent significant loss of CD4 T cells during treatment interruptions (Fagard 2003). Given the side effects and significant cost of GM-CSF, it cannot be recommended outside of clinical studies. GM-CSF is not licensed in Europe.

Hydroxyurea (HU, Litalir®)) is an old chemotherapeutic agent with relatively low toxicity still being used today in hematology (mostly in chronic myelogenous leukemia). It inhibits DNA synthesis via the ribonucleotide reductase, and leads to an intracellular shortage of deoxynucleotide triphosphates. A synergistic effect on HIV replication in combination with ddI was demonstrated in 1994 (Lori 1994). A Swiss study, in which 144 patients were treated with hydroxyurea (HU) or placebo in addition to d4T+ddI, attracted attention in 1998 (Rutschmann 1998). After 12 weeks, 54% (versus 28% in the placebo group) demonstrated a viral load below 200 copies/ml. Was this the discovery of a new cheaper option for HIV treatment? Hydroxyurea became even more fashionable after publication of the “Berlin Patient”, a patient who had been treated with hydroxyurea in addition to indinavir and ddI during acute infection, had stopped all therapy after a few months and subsequently showed no detectable plasma viremia (Lisziewicz 1999). Was this unexpected outcome due to hydroxyurea? Several smaller studies from the US and Argentina seemed to confirm these positive results. Many treating physicians added the drug to ART and many started to dream of a cheap combination of ddI+HU for Africa. These initial hopes subsided rapidly. In particular, the combination with ddI and d4T in particular is toxic: severe polyneuropathy (Moore 2000) and fatal pancreatitis were reported (Havlir 2001). Three randomized studies failed to show any effect, except for high rates of toxicity (Blanckenberg 2004, Stebbing 2004, Swindels 2005). Even in patients with acute HIV infection there was no effect. Thus, further Berlin patients could not be “reproduced” (Zala 2002). Hydroxyurea should not be used in antiretroviral therapy.

Interferons have an antiretroviral effect which has been known for years (Mildvan 1996). The antiviral effect of 3 million IU daily or under pegylated interferon weekly  is about 0.5-1 log (Haas 2000, Hatzakis 2001, Asmuth 2010). Higher dosing may increase this effect (Hatzakis 2001). We have seen patients coinfected with HIV/HCV, who achieved an undetectable HIV RNA during hepatitis C therapy with interferon and ribavirine only. However, an in-depth investigation of the antiviral activity of interferon was not conducted, because of the subcutaneous delivery route and its not insignificant side effects. Whether pegylation of interferone will change circumstances, remains uncertain.

Interleukin-2 (IL-2, aldesleukin, Proleukin®) is a cytokine produced by activated T cells which induces proliferation and cytokine production in T cells, B cells and NK cells. It has been employed in oncology for years and is now usually administered subcutaneously. The most important effect of IL-2 in HIV medicine is the increase in CD4 and CD8 T cells, which may be quite impressive in individual cases. CD45RO memory cells initially increase, followed by naive CD45RA T cells (Chun 1999, Carcelain 2003). This effect is mainly due to a reduced T cell turnover (Kovacz 2005, Sereti 2005, Vento 2006).

The question, whether the CD4 T cells generated by IL-2 were would lead to a clinical benefit, was answered by two large randomized studies, ESPRIT and SILCAAT in 2009 (Abrams 2009). In the ESPRIT study, 4131 patients with at least 300 CD4 T cells/µl were treated with and without IL-2 in addition to ART. SILCAAT had a similar concept, but enrolled 1695 patients with 50-299 CD4 T cells/µl. The results were very disappointing. Although supplementation of ART with IL-2 resulted in a statistically significant increase in CD4 T cell count (ESPRIT: +160, SILCAAT: +59 CD4 T cells/µl), it did not lead to a clinical benefit. Despite improved CD4 T cells under IL-2, patients did not develop less opportunistic infections and mortality was not reduced. Moreover, serious adverse events (including fever, malaise, injection site reactions and deep-vein thrombosis) were more likely to occur among patients receiving IL-2 in the ESPRIT study. Another randomized study (STALWART) provided similar results (Tavel 2011).  Conclusion: SILCAAT, ESPRIT and STALWART have shown that IL-2 as a supplementary therapy in HIV-infected patients is no longer viable, even in patients without immunological response on ART.

Interleukin-7 seems to be more promising. This cytokine plays a fundamental role in T cell homeostasis and is implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes (Review: Chahroudi 2010). Two small randomized placebo-controlled pilot trials with 6 and 16 HIV+ patients, respectively, demonstrated a good increase of CD4 T cells with different subcutaneous doses. The tolerability was good and side effects typical for interleukin-2 were not observed (Levy 2009, Sereti 2009). If these results are confirmed, interleukin-7 may become a good option for patients whose immune constitution remains poor despite good viral load suppression on ART. It remains to be seen how things will develop after the end of interleukin-2.

Interleukin-12 stimulates T lymphocytes and NK cells to generate a Th1-type immune response. In a randomized Phase I study with rhIL-12 100 ng/kg 2 x week, the drug was well tolerated but had no effect on lymphocyte subpopulations, antigen-specific immune response or viral load (Jacobson 2002). Further development is therefore uncertain. The same would appear to be true for interleukin-10 (Angel 2000) or interleukin-15 (Ahmad 2005). In the age of highly effective antiretroviral therapies, such experimental therapies have to meet ever-increasing standards.

Corticosteroids have been pushed by some HIV clinicians. However, such treatment does not stand the test of controlled studies. In a placebo-controlled study with 0.5 mg prednisone/kg over 8 weeks, there were no effects on CD4 T cells or viral load (McComsey 2001). In ACTG 349, 24 patients were treated with 40 mg prednisone daily or not in a double-blind randomized design (Wallis 2003). After 8 weeks, there was a trend towards higher levels of CD4 T cells in the prednisone arm, but there were no effects on activation markers or apoptosis. Two patients on prednisone developed necrosis of the femoral head. This study should advise caution before considering steroids for immunological reasons.

Murabutide is a synthetic muramyldipeptide with a variety of effects on the immune system. It can raise unspecific resistance to infection, induce anti-inflammatory cytokines and growth factors, and strengthen the antiviral effects of cytokines such as IL-2 or interferon. In HIV+ patients, a team in France has used it mainly as an immune modulator, although only in small studies, and at the most, with moderate effect (Bahr 2003).

Mycophenol (Cellcept®) has a theoretical concept similar to that of hydroxyurea and cyclosporin A. Mycophenol inhibits inosine monophosphate (IMP) dehydrogenase and is normally used for prophylaxis of acute transplant rejection in patients with allogenic kidney, heart or liver transplantations, as well as for some autoimmune diseases. Inhibition of lymphocyte proliferation and the subsequent reduction of target cells should theoretically inhibit replication of HIV. Initial reports seem to demonstrate an effect on viral load at least in some patients (Margolis 2002, Press 2002). Whether this will be confirmed by randomized trials seems uncertain. Current data suggest that this is unlikely (Sankatsing 2004, Margolis 2006).

Remune®, the prototype of therapeutic vaccination, has gone from disaster to disaster. Developed by a team headed by the since-deceased Jonas Salk, Remune® was a therapeutic vaccine comprised of an envelope-depleted (gp120) virus which, although indeed immunogenic, does not seem to provide any clinical benefit (i.e., prolongation of life and delay of disease progression). A large trial was interrupted prematurely in May 1999. More than 2500 patients had taken part for a mean of 89 weeks in this study, which was designed to evaluate the addition of Remune® to ART. As well as the lack of clinical benefit, not even advantages with respect to CD4 T cell counts or viral loads could be shown (Kahn 2000).

THC, cannabinoids have no anti-HIV effect. A controlled, randomized study, in which patients could either smoke marijuana or receive THC (dronabinol, Marinol®) or placebo in addition to ART, showed no effects on lymphocyte subpopulations, lymphocyte function or viral load after three weeks (Bredt 2002). THC, which is metabolized via the cytochrome P450 system, had no detrimental effects on PI plasma levels (Abrams 2003). More recently, a randomized study showed that smoked cannabis was well-tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings were comparable to oral drugs used for chronic neuropathic pain (Abrams 2007).


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Filed under 6. ART 2011, 6.3. ART 2011/2012: The Horizon and Beyond, Part 2 - Antiretroviral Therapy

6.4. Goals and Principles of Therapy

– Christian Hoffmann –

With current antiretroviral therapies, eradication of HIV is not possible. The ultimate goal in HIV medicine – a cure – is not a realistic scenario in the immediate future. Patients and physicians probably have to deal with lifelong treatment. Lifelong, meaning for decades, as experts anticipate a normal life expectancy for HIV-infected patients (Hill 2010). The goal of ART in 2011 is to prolong the patient’s life and maintain the best possible quality of health and life.

In the fine-tuning of monthly evaluations – including CD4 T cell count, viral load, routine laboratory, genotypic and phenotypic resistance and/or tropism testing and drug plasma levels, it may be useful to reflect upon the goal. Patients and physicians should not lose sight of the big picture. Even if a high CD4 T cell count and a low viral load are useful therapeutic goals, the patient’s condition is at least as significant as the laboratory results. Patients, too, can often lose focus. The response to the doctor’s query: “How are you?” is often accompanied by a glance toward the CD4 T count result on the chart: “That’s what I’d like you to tell me!”. Treatment aimed only at improving laboratory values with little emphasis on the physical and mental well being of the patient cannot be successful in the long-term.

Success and failure of treatment

Both success and failure of treatment can be evaluated using different criteria – virologic, immunologic or clinical. Of these, the first indicator is virologic (change in viral load). This is followed, often a little later, by immunologic markers (rise or fall in CD4 T cell count). Clinical outcome usually only becomes apparent much later – first the lab values deteriorate, then the patient; or vice-versa, as lab values get better, the patient generally follows. The clinical success of ART for asymptomatic patients is often not perceived, although the risk of opportunistic infections is reduced to half after only three months on ART (Ledergerber 1999) – the individual patient may not realize what was avoided by starting therapy.

Virological treatment success and failure

Virological treatment success is usually understood as being the reduction of viral load to below the level of detection (usually 50 copies/ml). This is based on the understanding that, the more rapid and greater the decrease in viral load, the longer the therapeutic effect (Kempf 1998, Powderly 1999). In the INCAS Trial, the relative risk of treatment failure (defined here as an increase to above 5000 copies/ml) in patients who had reached a viral load below 20 copies/ml was 20 times lower than in those who never reached a level under 400 copies/ml (Raboud 1998). If this still matters in the era of newer antiretroviral therapies is not clear.

On ART, viral load declines in two phases (see chapter on “Monitoring”). An initial, very rapid decrease in the first few weeks is followed by a slower phase, in which plasma viremia declines slowly. A decay to below the level of detection should be reached after 3-4 months; in cases of very high baseline viral load it may take longer. However, a viral load above the level of detection after six months of treatment is almost always considered a failure. The same is true if a rebound in viral load is confirmed, usually 2 weeks later. Consideration then needs to be given to factors that will improve therapy (drug levels,resistance, compliance, etc).

Virological treatment failure can be recognized quite early – therefore, initial monitoring after four weeks is useful not only to the patient for psychological reasons (“less virus, more CD4 cells”). But it is also an important indication for the continued success of treatment. If the viral load is not below 5000 copies after four weeks of ART, later treatment failure is likely (Maggiolo 2000). If the patient’s viral load is not below 500 copies/ml or at least one log below baseline, the rate of having a viral load of 500 copies/ml at week 24 is only 9% (Demeter 2001). According to one prospective study, virologic response can be anticipated  after 48 weeks or even  only 7 days (Haubrich 2007). However, such early controls of plasma viremia are not routine.

The cut-off point of 50 copies/ml is somewhat arbitrary. It is based on the currently available assays for measurement of viral load. Whether 60 copies/ml are indeed worse than 30 copies/ml and indicate a lower success of treatment has yet to be proven. There are however indications that even patients with a low viral load of below 50 copies/ml can experience a viral load rebound caused by differences (Geretti 2010).

At such low levels, methodological inaccuracies must also be taken into account. A single viral load rebound (blip) to low levels (up to 1000 copies/ml) is often irrelevant (see below). Blips need to be distinguished from low, repetitive, measurable plasma viremia (50-400 copies/ml), in which the risk of resistance has been shown to be much higher – in one study it was 43% (Nettlers 2004). The risk of a viral load rebound and even mortality with persistently low viral load is higher compared to blips (Hull 2010).

A viral load “below the level of detection” of 50 copies/ml means just that – no more, no less. Numerous studies indicate that replication and therefore development of resistance can continue even with an undetectable viral load. 50 copies/ml indicate that 5 liters of blood contain 250,000 virions; in addition, even more actively replicating viruses are present in the lymphatic organs. Thus, theoretically, a measurable viremia, even at very low levels, may possibly translate to a higher risk of resistance in the long-term. Perhaps there is indeed a relevant difference between 100 and 10 copies/ml with regard to the risk of developing resistance. But we just do not know yet.

Risk factors for virological failure are pretreatment with antiretroviral agents (existing resistance mutations) and low adherence (Deeks 2000). Whether the level of the CD4 T cell counts or of the plasma viremia at the time of treatment initiation play a role in treatment-naïve patients has not been conclusively proven. Many cohort studies failed to demonstrate an association (Cozzi-Lepri 2001, Phillips 2001, Le Moing 2002) (see chapter on “When to Start ART”).

It seems that many other risk factors associated with virological failure or response are not known. A new area in this setting is pharmacogenetic research focusing on how genes influence an individual response to drugs. Investigators have begun to identify associations among human genetic variants, predisposition to HIV drug toxicities, and likelihood of virologic response. These include associations among abacavir hypersensitivity reactions, HLA type, and enzyme polymorphisms (Haas 2006). Pharmacogenomic testing will ultimately benefit persons living with HIV through individualized drug prescribing.

More good news is that morbidity and mortality may be lowered significantly even if the viral load is not decreased below the level of detection (Mezzaroma 1999, Deeks 2000, Grabar 2000). Patients often remain immunologically stable for relatively long periods of time, even with insufficient viral suppression. A large cohort study has shown that CD4T cells do not drop as long as the viral load remains below 10,000 copies/ml or at least 1.5 logs below the individual set point (Lederberger 2004). However, with the introduction of new drug classes much more is possible now than in the 90s. In the era of darunavir, etravirine, maraviroc and raltegravir, virological success (achieving a non-detectable viremia) is possible more often than not.

How long does virological treatment success last?

Little is known about how long treatments remain effective. The belief that treatment success is limited to only a few years is widespread. It originated during the early years of ART. Many patients at the time were still inadequately treated or had been pretreated with mono- or dual-therapy, and had thus developed extensive resistance. In such patients, the effect of treatment was often limited, as even a single point mutation was often enough to topple a whole regimen. Today, especially in therapy-naïve patients without pre-existing mutations, the risk of treatment failure is much less.

After thirteen or fourteen years using combination ART, a very high number of patients still have viral loads below the level of detection. This is particularly true for patients who were adequately treated from the start, as judged by today’s standards (starting with triple therapy and/or rapid switching of several drugs). One of the few trials with a longer follow-up period studied 336 antiretroviral-naive patients who had reached a viral load below 50 copies/ml within 24 weeks (Phillips 2001). After 3.3 years, the risk of viral rebound seemed at first glance to be relatively high at 25.3%. More detailed analysis showed that a large proportion of the patients experiencing viral rebound had actually interrupted ART. True virological failure was only seen in 14 patients, which corresponds to a risk of 5.2% after 3.3 years. Most importantly, the risk of virological failure decreased significantly with time.

This is supported by cohort studies showing that the rates of virological failure, due to resistance have markedly declined in recent years (Lohse 2005, Lampe 2006). Antiretroviral therapies and treating physicians are getting better and better. As demonstrated by a large cohort study in Europe in 1995-96, 58% achieved HIV-1 RNA of 500 copies/ml or less by 6 months, compared with 83% in 2002-03 (May 2006). Nowadays, most patients have a constant viral load below 50 copies/ml (Ledergerber 2010). In many centers today, at least 90% of patients on ART have an undetectable plasma viremia. The cohort in Bonn is a good example. In 2007, only 57 out of 560 (10%) patients on ART showed detectable viremia. In 32 of these patients, adherence problems were a major cause and only 9% had a multiresistant virus (Klein 2009).

These studies clearly show that, providing treatment is not interrupted, viral load can remain below the level of detection for many years, perhaps decades.

Blips – do they mean virological failure?

Blips are understood to be transient and mostly small increases in viral load, provided the viral load before and after the blip was below 50 copies/ml. At least three measurements of viral load are therefore required to be able to identify a blip. Blips are a frequent phenomenon of patients on ART and are observed in 20-40% (Sungkanuparph 2005). Blips often worry both patients and clinicians: Is this a sign for treatment failure?

Although a few studies indicate that this is not the case in the medium-term (Havlir 2001, Moore 2002, Sklar 2002, Mira 2003, Sungkanuparph 2005), little is known about the causes of blips. For example,there has been no consistent data about association between compliance and blip frequency. While some studies did not find any association (Di Mascio 2003, Miller 2004), others did (Podsadecki 2007).

It is possible that blips are the result of immunological mechanisms. The earlier patients are treated in the course of infection, i.e. the higher the CD4 T cell count at therapy initiation, the more seldom blips seem to occur (Di Mascio 2003+2004, Sungkanuparph 2005). There does not appear to be any association with particular antiretroviral combinations – in a large cohort study (Sungkanuparph 2005), the frequency of blips on an NNRTI regimen was 34% and 33% on a PI regimen,  even the amount of the blips were equivalent (median 140 and 144 copies/ml, respectively). In both groups, the risk of virological failure at 2 years was approximately 8%. One important observation of this trial was, that blips did not increase the risk of treatment failure, not even on NNRTIs, which was anticipated, due to the rapid development of resistances to NNRTIs. Another team has since confirmed these results (Martinez 2005).

But, what do blips actually mean? At the beginning of 2005, a study team led by Bob Siliciano set out to determine this. In a labor-intensive study (Nettles 2005), 10 stalwart patients who had had a viral load of less than 50 copies/ml for at least six months, had blood samples taken every 2-3 days over a period of 3-4 months. The obvious result: the more you look, the more you find. During the observation time, at least one transient increase in the viral load was measurable above 50 copies/ml in nine of the ten patients. Each blip was moderate, with a median value of 79 copies/ml, ranging from 51 to 201 copies/ml. The blips were not associated with either specific clinical data, low plasma levels, or resistance. This observation led the authors to believe that blips (with low, measurable values) mainly represent biological or statistical exceptions and are not involved with treatment failure. In an estimated steady state level of viral load at around 20 copies/ml, the values are distributed randomly. However, 96% of the randomly distributed measurements were less than 200 copies/ml. There seems to be an association between the level of the blip and virological failure. This was also shown in one other study (Garcia-Gasco 2008).

It should be noted that other factors may also be responsible for intermittent viremia. Sporadic immune activation during concomitant infections may elevate the level of chronically infected cells and replenish viral reservoirs, including the latent cell reservoir, providing a mechanism for recurrent viral blips and low levels of viremia while on ART (Jones 2007). In one large retrospective analysis, 26% of blips were caused by intercurrent infections (Easterbrook 2002). For example, syphilis can cause a significant increase in viral load and reduction of CD4 T cells (Buchacz 2004). Viral load can also increase temporarily after immunizations (Kolber 2002).

Based on available data, blips do not necessitate an immediate change of ART. However, caution should be applied for higher blips (>200-500 copies/ml). It should be stressed that blips need to be distinguished from low, repetitive, measurable plasma viremias, in which the risk of resistance has been shown to be much higher (Gunthard 1998, Nettlers 2004, Hull 2010). Blips should raise the opportunity to talk to the patient about compliance. It can not be discussed often enough. Does the patient take his or her drugs regularly or are doses occasionally missed? Are the dosing directions (on an empty stomach or with a meal) followed correctly? All these points should be considered before changing therapy prematurely. Each new therapy can cause new problems. Therefore, every suspected increase in the viral load should be controlled within a short interval, before the treatment is changed.

Immunological treatment failure and success

Immunological treatment success is generally defined as an increase in the CD4 T cell count. A more precise definition for immunological treatment success does not currently exist. Depending on the study, increases of 50, 100 or 200 CD4 T cells/µl or increases to above 200 or 500 CD4 T cells/µl are  evaluated as a success. Failure is usually described in a missing increase or reduction of CD4 T cell count in patients receiving ART.

It is difficult to individually predict the immunological success of therapy for patients on ART, as it varies significantly from one person to another. As with the decrease in viral load, the increase in CD4 count also seems to have two phases. After a first, usually rapid increase over the first three to four months, further increases are considerably less pronounced. In a prospective study involving some 1000 patients, the CD4 count increased during the first three months by a median of 21.2 CD4 T cells/µl per month; in the following months the increase was only 5.5 CD4 T cells/µl (Le Moing 2002). In EuroSIDA, the greatest mean yearly increase in CD4 count of 100 cells/µl was seen in the year after starting ART. Significant, but lower, yearly increases in CD4 count, around 50 cells/µl, were seen even at 5 years after starting ART in patients whose current CD4 count was less than 500 cells/µl (Mocroft 2007).

It is still under debate, whether the immune system is restored continuously after a long period of viral load suppression or, whether a plateau is possibly reached after three to four years beyond which there is no further improvement (Smith 2004, Viard 2004, Mocroft 2007, Lok 2010). In our experience, both are possible. There are patients showing immunological improvement even after 6-8 years after initiation and there are patients in which CD4 T cells remain stable at a low level. The lower the CD4 count at baseline, the less likely it is to normalize completely (Valdez 2002, Kaufmann 2003+2005, Robbins 2009). The immune system often does not recover completely. In the Swiss Cohort, only 39% of 2,235 patients who had begun ART in 1996-97 reached a CD4 T cell count above 500/µl (Kaufmann 2003). However, it appears that the increase within the first 3-6 months provides certain clues as to how well the immune system will be restored (Kaufmann 2005). Negative consequences of a low CD4 cell count at the time of ART initiation are often present for a long time. In one study, 25% of patients who started an ART at lower levels of CD4 T cell count, did not  reach normal levels of 500 CD4 T cells, even after a decade of otherwise effective ART with good viral suppression (Kelley 2009, Lok 2010).

Immunological treatment success is not necessarily linked to maximal viral suppression; even partial suppression can result in improved CD4 T cell count (Kaufmann 1998, Mezzaroma 1999, Ledergerber 2004). The initial level of viral load is also not significant; It sems to be important that the viral load remains lower than before treatment (Deeks 2002, Ledergerber 2004). In view of the numerous factors that occur independent of ARTwhich are able to influence therapy success and individual regeneration capacity (see below), it is mostly not wiseto call on the CD4 T cell count alone as the deciding criterion for the success of ART. Virological success is more appropriate for judging the efficacy of specific regimens. Once CD4 T cells have normalized and plasma viremia remains undetectable, it is unlikely that they will significantly change (Phillips 2002). In such cases, immunological treatment success does not require constant monitoring.

Discordant response

Failure to achieve therapeutic goals – in terms of immunologic and virologic success – is referred to as a discordant response. The frequencies of such discordant responses in adults are outlined in Table 4.1.

Table 4.1. Prospective cohort studies, treatment response*.
Response to ART

Grabar 2000
n = 2,236

Moore 2005
n = 1,527

Tan 2007

n = 404

Virological and immunological




Discordant: only immunological




Discordant: only virological




No treatment response




*Immunological response was defined as a rise in CD4 T cells >50/µl after 6 months (Grabar 2000) or at least >100/µl during follow-up (Moore 2005, Tan 2007). Virological response: <1000 copies/ml  (Grabar 2000) or <500 copies/ml  (Moore 2005) <50 copies (Tan 2007)

Therapies can be virologically successful without immunological improvement; despite undetectable viral load, CD4 T cell counts remain low (Piketty 1998, Grabar 2000, Moore 2005, Tan 2007). Conversely, ART may be extremely effective immunologically and induce significant increases in the CD4 count, while viral load remains detectable. Although therapies have constantly improved, discordant responses appear in one fourth of all treatment-naïve patients. Especially in patient groups showing virological success but little immunological improvement, it is often not clear how to continue therapy. Mortality seems to be slightly higher in this patient group, but has not been related to AIDS diseases (Gilson 2010).

The risk factors for a lack of immunologic response can often not be influenced and are also heterogenic (Review: Aiuti 2006). Low CD4 counts at baseline, as well as a low viral load at treatment initiation are only two factors (Florence 2003, Kaufmann 2005, Moore 2005, Wolbers 2007, Kelley 2009). Age may also play a role. In older patients, immunologic response is often only moderate in comparison to virologic response. This may be mainly due to thymic degeneration (Lederman 2000, Grabar 2004). Various studies have demonstrated that the probability of not achieving a rise in CD4 count increases with patient age and with progressive decrease in thymus size as detected by CT (Goetz 2001, Marimoutou 2001, Piketty 2001, Teixera 2001, Viard 2001, Wolbers 2007). Patients, who are intravenous drug users, also have relatively poor increases in CD4 T cells compared to other patients (Dragstedt 2004). In the SWISS cohort, increase of CD4 T cells were more pronounced in female patients (Wolbers 2007).

Other possible causes for a lack of immunological response, despite good viral suppression, may be immuno- or myelosuppressive concomitant therapies. We have seen patients remaining on less than 50 CD4 T cells/µl for more than a decade, despite virological suppression. A significant immune reconstitution only set in after removing prophylaxis with ganciclovir or cotrimoxazole. Other causes may be autoimmune diseases (morbus crohn, lupus erythematodes) or liver cirrhosis.

However, there is some evidence that certain antiretroviral regimens have unfavorable effects on immune reconstitution. Significant drops in CD4 T cell count were observed in patients with a suppressed viremia, who switched to a simplified regimen of TDF+ddI plus nevirapine (Negredo 2004). The reason for this is still not understood, but seems to be related to negative interactions between ddI and tenofovir. Where possible, this combination should be avoided, especially in primary therapy. In two other studies, the CD4 T cell increase with abacavir+3TC or TDF+FTC was significantly better than with AZT+3TC (all combined with efavirenz), despite comparable virological success. This may be related to the myelotoxicity of AZT (DeJesus 2004, Pozniak 2006). In the Swiss cohort, patients on an AZT-containing regimen had 60 CD4 T cells less than patients without AZT over a period of two years (Huttner 2007). Whether it makes sense for patients showing poor immunologic success to switch to AZT-free regimens is questionable. There is no difference between NNRTIs and PIs regarding immune reconstitution and a switch is ineffective (Torti 2011).

What about new substances? Observations of a meta-analysis, which showed that an increase of CD4 T cells on maraviroc was overall better than with other agents, led to several other studies. In these studies patients with poor immune reconstitution received an additional dose of maraviroc. The results were disappointing (Lanzafame 2009, Stepanyuk 2009, Wilkin 2010). The same applies to raltegravir (Hatano 2010) and T-20 (Joly 2010), none of them showing any effects on immune reconstitution.

Some reports show that the thymic function and corresponding immune reconstitution can be stimulated by growth hormone (Tesselaar 2008, Napolitano 2008). Such approaches are still experimental and not recommended as routine. Whether higher CD4 T cell counts have clinical benefits or not, remains unknown. However, the example with interleukin-2 (see section on immune therapy) may call for caution, as in this case higher CD4 T cell counts had no positive effect on the frequency of opportunistic infections.

Practical considerations in dealing with viral load and CD4 count

  • Viral load (VL) is the most important parameter in treatment monitoring.
  • If possible use only one type of assay (in the same lab) – bear in mind that there is considerable methodological variability (up to half a log).
  • Virological success should be monitored one month after initiation or modification of ART.
  • VL should be below 50 copies/ml after 3-4 months (in those with high initial viral load, after 6 months at the latest) – if it has not responded, look for why.
  • The greater the decrease in viral load, the more durable the response to ART.
  • Transient, low-level increases in VL (blips) are usually insignificant – but VL should be monitored at short intervals (e.g., 4-6 weeks after such blips).
  • The older the patient, the likelier a discordant response (low VL with no significant increase in CD4 count).
  • In contrast to VL, increase in CD4 T cells, i.e., immunological success, is difficult to influence.
  • CD4 T cells are probably more predictive of the individual risk for AIDS.
  • Once CD4 T cell count is good, it requires less frequent monitoring. With higher CD4 counts, values may vary considerably from one measurement to the next (which may mislead the patient to either a false sense of euphoria or unnecessary concern).

Clinical treatment success and failure

Clinical treatment success is dependent on virologic and immunologic therapeutic success. In individual patients, clinical response is not always easy to assess. After all, there is no way to show what might have occurred, if treatment had not been started. As an asymptomatic patient cannot feel much better, it may be difficult to find good arguments to continue treatment in the presence of side effects, which, at least temporarily, may affect the quality of life.

Clinical success is almost always evaluated via clinical endpoints (AIDS-defining illnesses, death), although the improvement on ART in a patient with considerable constitutional symptoms should also be seen as clinical success. With regard to risk of disease progression, the immunologic response is at least as important as the virologic response. However, the extent of virologic success is of great significance. In the Swiss Cohort, out of those with a constantly undetectable viral load, the proportion of patients, who went on to develop AIDS or die was 6.6% after 30 months. In contrast, this proportion was 9.0% in patients with viral rebound and up to 20.1% if the viral load was never suppressed to undetectable levels (Ledergerber 1999). The importance of complete and sustained virological treatment success for clinical benefit has also been reported from other cohorts (Thiebaud 2000, Lohse 2006).

Table 4.2. Risk of progression, as defined by immunologic and virologic treatment response (See previous table caption for definitions). 95% confidence intervals in parentheses

Grabar 2000

Piketty 2001

Moore 2005

Baseline CD4 T cells (median)




Response to ART
Virologic and immunologic




Immunologic response only

1.6 (1.0-2.5)

6.5 (1.2-35.8)

1.9 (1.1-3.0)

Virologic response only

2.0 (1.3-3.1)

9.7 (1.6-58.4)

2.5 (1.5-4.0)

No treatment response

3.4 (2.3-5.0)

51.0 (11.3-229.8)

3.5 (2.3-5.3)

Clinical endpoints: progression/death  (Grabar 2000, Piketty 2001), death (Moore 2005).

Clinical failure is usually defined as the development of an AIDS-associated condition or death. However, illness is not always indicative of clinical treatment failure. This is particularly true for the immune reconstitution inflammatory syndrome (IRIS), where a pre-existing, subclinical infection becomes apparent during the first weeks after initiation of antiretroviral therapy (see chapter on “AIDS”). An OI with increased CD4 T cells does not necessarily mean that the ART has failed, but that the immune system is resuming its work, to put it in simple terms. On the other hand, if a patient develops serious side effects or dies, this should clearly be evaluated as a clinical failure. Fortunately, this is rare. Other causes must also be considered.

Many serious and life-threatening events that affect HIV-infected patients on ART today are neither associated with ART nor AIDS, but related to hepatic or cardiovascular complications (Reisler 2003). The following table shows the diseases leading to death in patients in France in the years 2000 and 2005. According to this analysis, only every third patient actually dies of AIDS. Other diseases such as tumors or (mostly hepatic) liver diseases are becoming more important.

Table 4.3. Causes of death in HIV-infected patients in France (Lewden 2008).

2000  (n=964)

2005  (n=1042)

AIDS-defining events



Non-AIDS-defining cancers



Liver diseases



Cardiovascular diseases






What can be achieved today?

Every HIV clinician sees the remarkable strides made possible by ART reflected in his or her own patients (see example below). In many areas, the incidence of AIDS has been reduced to less than a tenth of what it was at its height (Mocroft 2000). Some illnesses that occur only with severe immunodeficiency are rarely seen today. CMV retinitis or MAC disease have become unusual. AIDS cases in Western countries occur mainly in patients who are not being treated with antiretroviral therapy – usually because they are unaware of their infection or do not want to acknowledge it. These so-called late presenters now make up a large proportion of the cases of AIDS (see below). In patients who are continuously followed in specialized centers, AIDS has become a rare occurrence.The mortality rate has continued to decline over time (Mocroft 2002). According to a large study from Denmark, the estimated median survival is more than 35 years for a young person diagnosed with HIV infection in the late HAART era (Lohse 2007). In the US, median life expectancy after diagnosis HIV increased from 10.5 to 22.5 years between 1996 and 2005 (Harrison 2010). In ART-CC, a collaboration of several large cohorts, life expectancy of a 20 year old HIV+ patient increased from 36.1 to 49.4 years between 1996-1999 and 2003-2005 (ART-CC 2008). Life-expectancy of HIV-infected patients is constantly approaching that of the general population (Lodwick 2010, van Sighe 2010, Hill 2010). However, all analyses show that a large gap still exists between certain patient groups compared to the general population. This applies not only to patients with hepatitis coinfection or active drug consumption, but also to black patients or patients with low CD4 T cell count when starting ART (Lohse 2007, ART-CC 2008, Harrison 2010).

Table 4.4. Patient (female, 41 yrs old) showing advances due to ART*.

CD4 T cells

Viral load

Feb 95 AZT+ddC

23 (4%)


Nov 96 AIDS: Toxoplasmosis, MAC, Candida esophagitis

12 (1%)


Feb 97 d4T+3TC+SQV

35 (8%)


Jun 97 Stopped HAART due to polyneuropathy
July 97 AZT+3TC+IDV

17 (4%)


Mar 98

147 (22%)


Mar 99 AZT+3TC+IDV/r+NVP

558 (24%)


Mar 00

942 (31%)


Apr 05 AZT+3TC+LPV/r+NVP

744 (30%)



861 (24%)


*Excellent immune reconstitution despite initial severe immunodeficiency and several AIDS-defining illnesses. All prophylaxes (MAC, toxoplasmosis, PCP) have now been discontinued.

The effect of antiretroviral therapy is already noticeable at an early stage in the course of infection. In a recent analysis of several cohorts of seroconverters, the mortality rate of HIV-infected patients was not higher than that of the general population in the first five years after infection, with the exception of patients, who had been infected by intravenuous drug consumption (Porter 2008). Compared to the years prior to 1996, mortality rate of seroconverters had dropped from 42.7/1000 patient years to 8.5/1000 patient years between 2004 and 2006 (Porter 2008). Data from prospective controlled studies on this dramatic change is still limited, as there have not been many randomized trials with clinical endpoints (Hammer 1997, Cameron 1998, Stellbrink 2000).

The results seen in these studies, due to their design, led to licensing of the PIs. In a multi-center trial, 1090 clinically advanced patients received ritonavir liquid formulation or placebo in addition to their ongoing treatment. The probability of AIDS and death at follow-up of 29 weeks was 21.9% in the ritonavir arm and nearly double (37.5%) in the placebo arm (Cameron 1998).

Studies of mono- or dual therapy are no longer considered ethically justifiable and the number of clinical endpoints that occur is fortunately now extremely low. As a result, the duration of any contemporary study to prove clinical benefit of one combination over another would have to be extended over a long period of time. Unrealistically large study populations would also now be required given the extremely low probability of progression – only rarely will such investigations be undertaken in the future (Raffi 2001). One of the few trials which could confirm the benefits of ART on clinical endpoints, was the SMART trial (see section on Treatment Interruption below).

This is why data from large cohorts such as EuroSIDA, the Swiss Cohort and the US HOPS Cohort is usually used to demonstrate the benefit of ART (Table 4.5). The Swiss Cohort showed that the effect of ART increases over time – after more than two years on ART, the risk of disease progression was only 4% of the risk without ART (Sterne 2005). However, numerous cohort studies (with more than 20,000 patients) have shown that during recent years there has been no further decline in AIDS and mortality rates. Like in 1997, the risk of AIDS remained relatively stable at 6% in 2003. It seems that, in many patients, ART is simply begun too late. Over the last few years, almost half of the patients initiating therapy had a CD4 T cell count of less than 200 cells/µl (May 2006).

The effect on AIDS-defining diseases appears to be different. The most obvious is the decline in the incidence of viral OIs, although this is not as pronounced for fungal infections (D’Arminio 2005).

Table 4.5. Decline in morbidity and mortality in large cohorts.
  Where (n) Patients (Period)


(/100 PY)


(/100 PY)

Palella1998 USA (1255) <100 CD4+T cells/µl(1/1994-6/1997)

29.4 ® 8.8

21.9 ® 3.7*

Ledergerber 1999 Switzerland (2410) 6 months before versus 3 months after HAART (9/1995-12/1997)


15.1 ® 7.7

Mocroft2000 Europe (7331) All (1994-1998)


30.7 ® 2.5

Mocroft2002 Europe (8556) All (1994-2001)

15.6 ® 2.7


D’Arminio 2005 Worldwide (12,574) The first 3 months after versus 3 years after HAART


12.9 ® 1.3

D:A:D 2010 Worldwide(33,308) All (99-07)



* MAC, PCP, CMV. Mortality/Morbidity each per 100 py  = patient years

With regard to opportunistic infections and malignancies, the effect of ART is equally as apparent on their clinical course as it is on their incidence. Illnesses such as cryptosporidiosis or PML can be cured, while Kaposi’s sarcoma can resolve completely without specific therapy. Prophylaxis of pneumocystis pneumonia, toxoplasmic encephalitis, CMV, or MAC infection can usually be safely withdrawn at the adequate CD4 counts. These effects are discussed in more detail in the corresponding chapters.

Treatment goal – eradication

In a chapter on the goals of therapy, one must discuss the cure. Only by addressing this will we finally achieve it. After the success of the last twenty years that has enabled many patients to control the infection for decades, many clinicians share the opinion that a cure has to be the major goal for the future.

The case of a patient from Berlin, published in 2008, shows that a cure is at least theoretically possible. This patient had suffered from acute myeloid leukemia and underwent allogeneic stem cell transplantation. The healthy stem cell donor was homozygote for the ∆32 mutation – after the transplant the viral load of this patient (which was very high before ART initiation) remained below the limit of detection without ART for years (Hütter 2009, Allers 2011). The virus was undetectable in the blood, in the lymph nodes and in the intestinal mucosa. The media hysteria following this publication made patients believe in a cure and physicians were put in the undesirable position of having to dash these freshly raised hopes. An allogeneic stem cell transplant is not only complicated and expensive, but also highly risky (mortality up to 30%), making this approach not very practical, although it was interesting for academic purposes. One cannot say for sure that this patient from Berlin is permanently cured and in no need of further treatment with ART but the case does raise hopes for the future.

What is the cure?

An important question is whether eradication is necessary for a cure. Must all virus be removed from the body? A cure could also mean that the body is able to control HIV without help of medication – i.e., in some viral infections, like herpes, low viral levels persist for a lifetime. This is why a difference is being made today between a sterilizing cure and functional cure (Reviews: Richman 2009, Lewin 2011).

Table 4.6. A case of an “elite controller“.
Date ART

CD4 cells/µl

HIV RNA copies/ml

04/03 Acute HIV infection (seroconversion)

203 (8%)

>1 million

04/03 Start with ART (AZT+3TC+IDV/r)

412 (12%)

>1 million

01/04 ART stopped after 8 months

838 (52%)



467 (46%)



1288 (51%)


03/11 Seven years without ART

822 (39%)


Comment: Whether ART during acute infection had a positive effect remains unclear. Such a favorable course is also possible without intervention.

Some patients have already reached functional cure. These so-called elite controllers, some found in any large HIV center, have normal CD4 T cells for many years and even more impressive, a viral load below the limit of detection without being on therapy (Table 4.6). Only when investigating with ultrasensitive methods or examining the lymph nodes can a relatively tiny amount of virus be found. Co-receptor defects explain only a few of the cases. But what is it that makes HIV-specific immune response in these patients so effective, what causes the virus to be so unfit, what are the underlying genetic modifications? These are some questions being pursued by many leading research teams.

The problem with latent reservoirs

At this point in time, eradication of HIV, the removal of all HIV from the body, is unrealistic. The main reason is that latently HIV-infected cells comprise a lifelong reservoir (Saksena 2003). Even after years of sufficient suppression, viral transcription is still  detected (Finzi 1999, Furtado 1999, Zhang 1999, Sharkey 2000). This is particularly true in blood cells, but also in the lymph nodes and in sperm (Lafeuillade 2001, Nunnari 2002). Replication also takes place in cells of the gastrointestinal tract, even if no viruses are detected in the blood. In addition, latently infected reservoirs consist of very heterogenic cell populations and their stability is probably independent of residual virus replication.

Theoretically, how long does it take until the last latently infected cells are removed? A half-life of 44.2 months for the latently-infected cell reservoir was measured in a study with 62 patients, whose viral load had been successfully suppressed on ART for a period of seven years (Siliciano 2003). The calculated time to eradication of these reservoirs was 73.4 years. Even in patients with no measurable blips during at least three years of stable ART and with a tendency for a more rapid decrease of viral load, the time to eradication was still 51.2 years. Virus in resting CD4 memory cells with minimal evolution persists, even after close to 9 years on ART (Nottet 2009).

Intensification trials

Presently many studies are investigating whether the viral decay rates can be improved or whether any change at all can be effected by intensifying therapy. Different strategies are being followed, such as additional administration of integrase or entry inhibitors, but also of other substances which may help to empty the latent reservoirs. These studies are discussed below:

Mega-HAART, entry inhibitors: In a trial with patients with good viral suppression and additional PIs or NNRTIs in their ART, an ultrasensitive single copy assay showed no further reduction of viral load by intensification (Dinoso 2009). The level of viral load depends not so much on the applied regime, but on on the pre-therapeutical setpoint (Maldarelli 2007). Additional administration of the entry inhibitor T-20 did not show any effects either (Ghandi 2010). Resting T cells are also not achieved with T-20 nor with a combination with valproic acid (Archin 2010). Maraviroc, as a potential immune-modulating CCR5 antagonist, was also investigated as an intensification strategy. A small study showed possible, moderate effects on the latent reservoirs (Gutiérrez 2010) and other studies showed effects on immune activation (Sauzullo 2010, Wilkin 2010). One study with acutely infected patients showed hardly any effects either on virologic or immunologic parameters (Evering 2010).  Another carefully designed study with 40 patients with acute HIV-infection, compared a five-fold ART plus raltegravir + maraviroc with a classic three-drug therapy. Results showed no advantages of the intensive therapy, neither regarding residual viremia, nor regarding the degree of immune reconstitution or immune activation (Markowitz 2011). Obviously. t is not a question of amount.

Raltegravir: Hopes for additional effects with raltegravir were raised by a study in which treatment-naive patients on a raltegravir regimen achieved a viral load below the limit of detection significantly more rapidly than those on efavirenz (Murray 2007). At least two prospective studies in which raltegravir was added to an existing ART showed no additional antiviral effect by means of ultrasensitive viral load assays (Gandhi 2009, MacMahon 2010). Immune activation was also not influenced by raltegravir (Luna 2009, Massanella 2011). Results are contradictory regarding the question of whether proviral DNA decreases more rapidly. While two small studies showed positive effects (Arponen 2008, Reigadas 2010), at least three larger studies did not confirm these results (Buzon 2010, de Laugerre 2010, Hatano 2010). Several studies showed an increase of episomal DNA while on raltegravir. This DNA, also referred to as 2-long terminal repeat (2-LTR) circular, develops when integrase inhibitors block the DNA integration process into the chromatin. Evidence of this episomal DNA (2-LTR circles) in approximately 30% of patients receiving raltegravir plus effective ART, shows that an active viral increase was stopped (Reigadas 2010, Buzon 2010). Another study demonstrated that resting CD4 T cells were not achieved with raltegravir or with a combination with valproic acid (Archin 2010) (see below). Specific sites, such as CNS or gut are not influenced (Yukl 2010, Yilmaz 2011).

Other agents as reservoir eradicators: Several attempts to empty viral reservoirs using different methods (IL-2, hydroxyurea or OKT), have not been successful (Kulkosky 2002, Pomerantz 2002). A pilot study on valproic acid, an epileptic drug, caused a stir in the summer of 2005. Implemented as an inhibitor of histon deacetylase 1 (HDAC), it suggested a clearance of HIV from resting T cells (Lehrmann 2005). In three out of four patients the number of infected resting CD4 T cells decreased significantly and half life was reduced to 2-3 months compared to other studies showing a longer half life of 44 months on ART (Siciliano 2003). Other smaller follow up studies (Steel 2006, Siliciano 2007, Archin 2010) did not confirm these results. More recently, a randomized crossover study finally put an end to the discussion about valproic acid, showing no effect at all in 56 patients (Routy 2010). Despite this, other new and more potent HDAC inhibitors are being investigated (Edelstein 2009, Matalon 2010) and approaches with immunoglobulin are repeatedly proposed (Lindkvist 2009).

Summary: It is very doubtful that an eradication is possible with the available regimens (Shen 2008, Lewin 2011). Intensification or extension to a four- or five-fold therapy amounts to nothing. Strategies, which directly attack latently infected cells are more promising. However, latently infected cells differ minutely from non-infected cells, which can not be easily discerned by the methods available in most clinics and they are also non-specific. Washing out the reservoirs or eliminating all the infected memory cells has either been unsuccessful or too toxic. Removing the HIV genome from infected cells with special recombinases has been successful in the laboratory; but there is still a long way to go before this can be used in the clinic (Sarkar 2007). Considering the complexity of the immune system, which is still not completely understood, a cure probably lies in the distant future.


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Hunt P, Shulman N, Hayes T, et al. Immunomodulatory effects of MVC intensification in HIV-infected individuals with incomplete CD4+ T cell recovery during suppressive ART. Abstract 153LB, 18th CROI 2011, Boston.

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Filed under 6. ART 2011, 6.4. Goals and Principles of Therapy, Part 2 - Antiretroviral Therapy

6.5. When to Start ART

– Christian Hoffmann –

“It’s the most important question in HIV therapy” (A. Fauci)

The indication for antiretroviral therapy is based on clinical assessment, CD4 T cell count and viral load. These three important factors determine whether therapy should be started or if it should be deferred. At first glance, it appears straightforward, the lower the CD4 count and the higher the viral load, the higher the risk of AIDS (Mellors 1997, Lyles 2000) and the more urgent the indication for treatment.

Nevertheless, the best time for initiation of therapy remains the subject of controversial debate. The risk of AIDS must be weighed against the risks of long-term toxicity and viral resistance. In Table 5.1, the current guidelines in the US, Europe, Britain and Germany on starting therapy are summarized. Significant differences can be seen especially in patients with high CD4 T cells.

Table 5.1. Recommendations  from various guidelines on when to initiate therapy

CD4 T cells/µl

Initiation of HAART is…

All values

“Recommended” (DHHS, GA, EACS)


“Recommended” (DHHS, GA, EACS)


“Recommended (DHSS, GA, EACS)


“Recommended” (DHSS)“Generally advisable” with additional criteria*, otherwise ”acceptable” (GA)“recommended at viral load above 100,000, coinfection, age > 50, high risk of cardiovascular/malignant diseases” (EACS)


“Moderately recommended” or “optional”, controversial (DHSS)“Acceptable” with additional criteria, otherwise “Generally not recommended” (GA)“Generally procrastinated”, but “May be offered if one of the points listed in 350-500 apply” (EACS)
DHHS: US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. January 2011.
GA: Deutsch-Österreichische Leitlinien zur Therapie der HIV-Infektion. March 2010.  Additional criteria refer to viral load above 100,000 copies/ml, HCV- or HBV-infection, age over 50 years, Framingham-Score above 20%/10 years and rapidly decreasing CD4 T cell count.
EACS: European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV-infected adults in Europe.November 2009.

The practice of treatment is ever changing. In Europe, the median CD4 T cell count at initiation of ART was 200 CD4 T cells/µl during the first years of this decade, after being 270/µl in 1998 (May 2006). But in more recent years, the pendulum is swinging back. With regard to new drugs which are more potent and better to tolerate, there is a strong trend towards earlier treatment initiation.

At least all international guidelines agree that all symptomatic patients as well as patients with less than 200 CD4 T cells/µl should be treated. Since 2007/2008, most guidelines have determined a CD4 T cell count of <350 CD4/µl, instead of 200 CD4/µl as a definitive threshold for initiation of ART. In the US, it has recently increased to 500 CD4/µl. Lack of randomized studies forces all guidelines to partially rely on cohort studies, meta-analyses and evaluation of larger databases. Such data is problematic, however, as important aspects such as compliance or prior treatment regimens are not captured, and very heterogeneous patient populations are included.

A recent Cochrane analysis concluded that evidence for initiating ART at CD4 levels higher than 200 or 250 cells/μl to reduce mortality rates in asymptomatic patients is of moderate quality. Guidelines merely provide points of reference and are not set in stone. Decisions must be made on a case-by-case basis, even if some health insurance providers tend to ignore this and use guidelines to their advantage. In some situations, therapy may be started earlier than recommended in the guidelines; in other cases, therapy might (or even should) be deferred. And last but not least, the patient should be ready to start ART. Experience as well as some intuition of the treating physician is mandatory.

How high is the individual risk of progression?

The following table lists the (selected) risks of developing AIDS within six months, as identified in 3326 patients from the pre-HAART era (Phillips 2004). The range of the individual risk of progression, calculated by using CD4 T cells, viral load and age only, varies widely – from 0 to almost 50%. This may also demonstrate how helpful these surrogate markers can be.

Table 5.2. Predicted six-month percentage risk of developing AIDS, according to age, viral load and CD4 T cell count (data from the pre-HAART era).

100 CD4/µl

200 CD4/µl

350 CD4/µl

35 years
    Viral load 10,000 copies/ml




    Viral load 100,000 copies/ml




55 years
    Viral load 10,000 copies/ml




    Viral load 100,000 copies/ml




VL = Viral load. (From: Phillips A, CASCADE Collaboration. AIDS 2004, 18:51-8.)

But even after initiation of ART individual risk may vary considerably. Table 5.3 shows individual risks after initiation of ART for different age groups. These data were derived from 12 cohorts in Europe and North America, in which more than 20,000 patients started antiretroviral therapy between 1995 and 2003 (May 2007). It is of note that the data apply only to asymptomatic patients without intravenous drug use (IVDU). In patients with AIDS and in IVDUs, progression risks can be much higher. On the other hand, it seems possible that these data overestimate the individual risk as risk may be lower with the newer drug combinations. Moreover, treatment interruptions were not taken into account (every patient who started with ART was regarded to be treated continuously). This fact may also have led to an overestimation of the risk of progression. Thus the values in Table 5.3 are only rough estimates and should be interpreted with caution. However, they could be helpful in any discussion with the patient, of course without browbeating or scaring them with statistics.

One important caveat of cohort studies is the fact that the individual treatment success of the patient is not taken into account. This was shown by an analysis of 13 cohort studies from Europe and North America including 9,323 adult treatment-naive patients who started ART with a combination of at least three drugs. At 6 months after starting ART, the current CD4 T cell count and viral load, but not values at baseline, were strongly associated with subsequent disease progression (Chene 2003).

Table 5.3. Probability (%) of experiencing a new AIDS-defining disease or death by the end of 1 year (5 years) after the patient starts ART. Only valid for patients without previous AIDS and non-IVDUs.

<25 CD4

25-49 CD4

50-99 CD4

100-199 CD4

200-350 CD4

>350 CD4

16-29 years
    VL <100.000

10 (19)

8 (17)

7 (16)

5 (11)

2 (7)

2 (6)

    VL >100.000

12 (23)

10 (21)

9 (19)

6 (13)

3 (8)

2 (7)

30-39 years
    VL <100.000

12 (22)

10 (19)

8 (18)

5 (12)

3 (8)

2 (6)

    VL >100.000

14 (26)

12 (23)

10 (22)

6 (15)

3 (10)

2 (8)

40-49 years
    VL <100.000

13 (25)

11 (22)

10 (20)

6 (14)

3 (9)

2 (7)

    VL >100.000

16 (29)

13 (26)

12 (24)

7 (17)


3 (9)

>50 years
    VL <100.000

16 (29)

13 (26)

12 (24)

7 (17)

4 (11)

3 (9)

    VL >100.000

19 (35)

16 (31)

14 (29)

9 (21)

5 (13)

3 (11)

From VL are copies/mL, CD4 cells/ml.

To evaluate the individual risk for a treatment-naïve patient, one can check (May 2007). Only a few parameters are needed. It is also possible to calculate the risk after 6 months on ART.

Practical experiences

Even if the indication for ART seems obvious, it should be clarified whether the patient is indeed prepared to start treatment (treatment readiness). The problem is not necessarily the initiation of ART, but the longer-term maintenance. The decision to initiate treatment is often made prematurely. It is usually unwise to prescribe antiretroviral medication to a patient in the very first consultation. One should first attain an overall picture of the patient, and try to get to know something about lifestyle and motives – why they have come to see a doctor and what they expect.

In some cases, patients put themselves under pressure unnecessarily, or allow others to pressure them. A single low CD4 count, a prolonged case of flu seeming to indicate a weakened immune system (“I never had anything like this before”), springtime lethargy, new study results, a promising new drug in the newspaper (“I’ve heard a lot about the new entry inhibitors”), a friend/partner who has started therapy – none of these are therapeutic indications. It is often particularly difficult to inform people from other cultures that not every person with an HIV infection needs immediate therapy.

On the other hand, the patient’s wish to start a therapy should be respected. If after a detailed discussion a well-informed patient wants to begin treatment, even though the results justify waiting, ART should not be withheld. For many patients, treatment can be a psychological support. Not everybody can sleep peacefully at night knowing that inside them a hundred million new viruses are being produced every day and a huge number of helper cells are being destroyed.

However, if a vacation is planned, it is better to delay therapy, so that treatment response and side effects can be adequately monitored. On the other hand, patients may sometimes find one reason after another (stress at work, exams, change of job, etc.) to delay initiation of treatment. Many patients are afraid of AIDS, but often just as afraid of ART (“the pills are the beginning of the end!”). They may have irrational or simply false expectations of ART and its consequences – starting therapy does not mean that one will be subjected to daily infusions and no longer able to work. Therapy should be explained to every patient from the outset. It is also useful to define individual threshold values for the commencement of therapy with patients early on, so that therapy is started only when these levels are reached. In our experience, patients are more motivated by this approach.

As a rule, as much time as is needed should be taken for the decision to start therapy. A well-informed patient will adhere better. We recommend that patients come for several consultations to get prepared for treatment. There are two exceptions: acute HIV-infection (see chapter on “Acute Infection”) and severe immunodeficiency. However, even in the presence of most AIDS-defining conditions, the acute disease should often be treated first before initiating ART, as the potential for complications with PCP, toxoplasmosis or CMV therapies unnecessarily jeopardize treatment options. In asymptomatic patients with very low CD4 T cells, it makes sense to start first with a PCP prophylaxis. Over the next few days, one can perform an exam (X-ray, ultrasound, fundoscopy, etc) and check the patient’s readiness. Does the patient come back? Are they really motivated?

We also tend to start ART earlier in older patients (>50 years). The regenerative capacity of the immune system in older patients is significantly reduced (Ledermann 2002, Grabar 2004). More importantly, the risk of developing opportunistic infections also depends on age (Phillips 2004). Another example from the CASCADE Study (Table 5.2) exemplifies this: a 25 year-old patient with 100 CD4 T cells/µl and a viral load of 100,000 copies/ml, has a risk of approximately 10% for developing AIDS within six months – for a 55 year-old this level of risk is reached at 150 CD4 T cells/µl and a viral load of 30,000 copies/ml. In Table 5.3 there is a strong association between age and progression.

By now, several guidelines have taken age considerations into account and state that therapy be offered to patients older than 50 years even if high CD4 T cells are high. Guidelines also recommend initiation of therapy in cases of hepatitis coinfection, HIV-associated nephropathy, but also cardiovascular risks and malignant diseases.

Practical tips for initiation of ART

Below 200 CD4 T cells/µl or an AIDS-defining event

  • Start immediately with ART. Do not wait until acute OI therapy is finished
  • Take time to get acquainted with the patient (What took him so long to start treatment?), undergo diagnostic procedures, give proper counselling and start treatment with prophylaxes in advance

Between 200 and 350 CD4 T cells/µl

  • More time can be spent getting to know each other and planning
  • Address fears and anxieties before starting therapy
  • Try not start with therapy before a holiday or other big event, but do not let the patient put off therapy forever

Above 350 CD4 T cells/µl

  • Here again talk about ART at an early stage, so the patient knows what to expect
  • Define thresholds below which ART can be initiated (follow present guidelines of 350µ)
  • Do not only consider the absolute CD4 T cells, but observe other individual factors: Coinfection? Age? Malignancy? Pregnancy? If so, start earlier!
  • Respect the patient’s wish for time of therapy initiation
  • Check to see if the patient is suitable for a clinical trial

It is also important to consider the percentage value along with the absolute value of the CD4 T cell count. In particular, when the CD4 T cell count is high and the immune status appears good, the CD4 percentage is the most important parameter for predicting the risk of developing AIDS. In one study, the risk of progression for patients with more than 350 CD4 T cells/µl was increased approximately four-fold if the percentage of CD4 T cells was below 17% (Hulgan 2005).

Finally, it should not be forgotten that the whole discussion is based on “minimum” figures, as CD4 T cells are actually surrogate markers. As a surrogate, they are a substitute for clinical endpoints. They are only a rough expression of the clinical reality. Although they usually do this very well, and even though the CD4 count is one of the best surrogate markers in medicine, it is not everything. The patient also has to be considered.

Asymptomatic patients with more than 200 CD4 cells/µl

200-350 CD4 cells/µl: Today, the guidelines all recommend an initiation of therapy in this patient group. Even if randomized studies are not available and the risk of infection is rather low, in the long run the risk of developing AIDS can not be excluded (Emery 2008). There is no reason to think the patient 100% safe. We have seen patients with these CD4 cell counts develop Kaposi’s sarcoma, PML or  lymphoma. A look at the calculation presented above (May 2007), gives a rough idea about the individual risk. After ART initiation, a 45 year-old asymptomatic patient with 200-350 CD4 T cells/µl, a viral load below 100,000 copies/ml and not a drug user has an AIDS mortality risk of 3.1% after one year, and 8.7% after five years. With above 350 CD4 T cells/µl at the time of ART initiation, the risk is reduced to 2.0% and 7.3% for the same patient. If the patient was 50 years old and the viral load over 100,000 copies/ml, the five year risk would reduce from 13.1% to 11.0%. Such a reduction of just 1 or 2% may seem insignificant at first. However, in times of well-tolerated antiretroviral therapies, the risk of developing AIDS or even dying from the infection is relevant. Is it worth exposing patients without urgent symptoms to the dangers of AIDS for the sake of a little more quality of life? How much long term toxicity is really saved by one, two or maybe even three years without therapy over a period of twenty or thirty years? The lesser the danger of toxicity, the earlier ART will be initiated in future.

A randomized study from Haiti published in the NEJM, showed that an immediate start also makes sense in developing countries: In 812 patients with 200-350 CD4 cell/µl, only 6 cases of mortality occurred in the group receiving ART immediately compared to 23 cases in the group who had just started an ART. The number of incident cases of tuberculosis was significantly reduced from 36 to 18 (Severe 2010).

Above 350 CD4 cells/µl: For this patient group according to the German-Austrian guidelines, therapy initiation is “acceptable” and, in the presence of additional criteria, “generally recommended” (i.e. hepatitis coinfection, older patients above 50). In the USA, therapy initiation is recommended unrestrictedly up to 500 CD4 cells/µl.

However, even beyond this level, there seems to be an associated risk with CD4 T cell counts and AIDS or mortality. In a large-scale British cohort (>30,000 patient years) with therapy-naïve patients the risk was 24.9 per 1,000 PY at 350-499 CD4 T cell/µl, compared to 15.4 at 500-649 CD4 T cells/µl and 9.6 with more than 650 CD4 T cells/µl. The US HOPS cohort also suggested a survival benefit of patients who initiated ART above 350 CD4 T cells/µl (Palella 2003). This study also evaluated patients who had started with a mono- or dual-therapy. Possibly a difference would not have been visible with contemporary therapies. In addition, the mortality risk was low. According to more recent information from this cohort (Lichtenstein 2006), the risk was 15.9/1000 PY at 200-349 CD4 T cells/µl (350-500 CD4 T cells/µl: 11.5/1000; over 500: 7.5/1000).

In a new study from the US, 17,517 asymptomatic patients were evaluated who started ART between 1996 and 2005 (Kitahata 2009). In this very complex (incomprehensible for the layman) and expensive analysis an advantage was observed already above 500 CD4 T cells/µl. Other studies have not confirmed these results (Sterling 2003). This also applies to the ART cohort collaboration, in which 20,000 patients from 15 mostly European-based cohorts were evaluated, who started antiretroviral therapy after 1997. There was no benefit of starting above 450 CD4 T cells/µl (Sterne 2009).

To raise a heretical question, does early therapy initiation have benefits only in the US, not in Europe? Or are methodological problems of cohort analysis and statistical distortion the reason for this discrepancy? This debate will be interesting to follow. A worldwide randomized study to evaluate optimal therapy initiation with asymptomatic patients with good CD4 T cells is urgently required. Since 2009, worldwide 3,000 patients with more than 500 CD4 T cells/µl are to be enrolled in the START study. One half will start with ART immediately, while the other half will wait until CD4 T cells are below 350 CD4 cells/µl or until symptoms appear. First results are expected in two to three years.

It is important that all asymptomatic patients with allegedly good values are still regularly checked. One should not only watch out for absolute CD4 T cell count, but other factors should also be observed, see following box

Important factors to be considered even with good CD4 T cells

  • Is a tendency of an absolute CD4 drop visible: how fast is it? Always look at relative values (percentage), observe CD4/CD8-ratio, absolute values often vary widely.
  • Because variations exist, a CD4 T cell count should always be controlled before starting therapy. One measurement is not enough.
  • How high is the viral load, does the overall picture make sense? CD4 T cell count drops are rare at lower viral loads <10,000 copies/ml.
  • What levels did the patient previously have? Someone, whose CD4 T cells have always been at 1000 and suddenly falls to 350 probably has a higher immune defect than someone who goes from 450 CD4 T cells to 350.
  • Is the patient ready for therapy? How well informed is he? How compliant will he be? If the patient is reluctant and anxious, more time must is needed for preparation prior to therapy initiation.
  • How old is the patient? The immunologic regeneration capacity decreases with age. The older the patient, the earlier one should start.
  • Are there symptoms which the patient has not noticed or considers not worth mentioning? Examine physically on a regular basis! OHL, thrush, mycoses etc.
  • A drop of 50-100 CD4 cells/µl per year is too much. Do not wait too long with these patients.

Late Presenter: AIDS and/or below 200 CD4 T cells/µl

Although treatment possibilities have dramatically improved, many patients still present at a very late stage of the infection. Questions about beginning an optimal therapy are superfluous as these patients are more or less classified as urgent. There is no consensus regarding the definition of “late presenter”. In most cases, a CD4-cell count below 200/μl and/or a manifest AIDS disease at the time of HIV-diagnosis serves as criterion. “At the time of HIV diagnosis”, however, is broadly defined and ranges from three months to three years. Moreover, some authors also classify the groups “late testers”, “very late presenters” and even “long-term non-presenters”.

At the second “HIV in Europe” conference in November 2009, it was agreed that those patients with a CD4 cell count below 350/µl at initial presentation are to be referred to as late presenters (Antinori 2011). In the US and probably in other countries, they still constitute more than half of all patients (Althoff 2011). Even if this definition makes sense in terms of health policy (patients come “late”, because they have fallen below the recommended threshold value for therapy initiation), it is yet to be seen if this definition prevails. For clinical research, it already raises problems, as very heterogenic patient groups are being put together. Below, late presenters are restricted to patient groups showing symptoms or with less than 200 CD4 T cells/µ.

Incidence and risk factors of a late HIV diagnosis

How frequent are late presenters? Lacking an overall valid definition, rates between 10-44% are currently being reported in different European countries and the US with a recently slightly downward trend (table 5.4).

Table 5.4. frequency of late diagnosis in Europe.
Country Period (n) Definition of late diagnosis % (ADE) Trend over time
Italy(Borghi 2008)



CD4 <200 cells/μl or AIDS <3 months

39 (24)

Decline from 43 to 35%

France(Delpierre 2008)



CD4 <200 cells/μl or AIDS <1 year

38 (17)

Decline from 43 to 32%

Spain(Carnicer 2009)



AIDS <3 months


Not stated

Great Britain(HPA 2009)



CD4 <200 cells/μl


Not stated

USA(CDC 2009)



CD4 <200 cells/μl or AIDS <1 year


Decline from 43 to 36%

Great Britain(UK Chic 2010)



CD4 <200 cells/μl

27 (10)

Not stated

Switzerland(Wolbers 2009)



CD4  <200 cells/μl


No clear trend

Explanation: ADE = AIDS-defining disease.

In the last few years several studies have looked at the risk factors of a late diagnosis (Table 5.5). The characteristics of late presenter, observed in several countries (advanced age, migrant origin, heterosexual transmission, see above) indicate more complex reasons for a late diagnosis. They probably involve patients (less access to health system, lack of information, fear of stigmatization), as well as doctors and members of the health system (among others lack of HIV awareness with certain patient groups). Several studies enforce the notion that, even with high risk patients, many chances of diagnosing HIV at an earlier stage are missed (Duffus 2009, Jenness 2009). As much as 76% out of 263 African patients living in London had visited a general doctor a year before HIV was diagnosed. Of note, 38% were in outpatient care and 15% had received inpatient treatment in the year before HIV diagnosis (Burns 2008).

Table 5.5. Risk factors for late diagnosis in Europe.
Italy (Borghi 2008) Advanced age, male, foreign origin
France (Delpierre 2008) Age over 30 years, non-MSM, hepatitis coinfection, HIV diagnosis before 2003
Spain (Carnicer 2009) Male, age under 30 or over 40 years, MSM or heterosexual transmission. Protective: IVDU.
USA (CDC 2009) Advanced age, male, ethnic origin non-white
Great Britain (UK Chic 2010) Heterosexual transmission
Switzerland (Wolbers 2009) Advanced age, ethnic origin non-white. Protective: MSM, IVDU, living alone

Morbidity, mortality – consequences of a late HIV diagnosis

Up to 90% of AIDS-defining diseases today, appear with viremic – mainly untreated – patients. This applies greatly to classical opportunistic infections such as PCP or CMV retinitis, but also, when not as strict, to tuberculosis or Non-Hodgkin lymphoma (ART-CC 2009). In the German Lymphoma Cohort, two-thirds of patients with newly diagnosed NHL had not previously received ART. 40% of patients with AIDS, a group associated with the highest mortality rate even today, are diagnosed with NHL and HIV infection simultaneously (Hoffmann 2009). In a British analysis counting 387 deaths of HIV-infected patients in the years 2004/2005, as much as 24% of all deaths and 35% of HIV/AIDS-related deaths were ascribed to a late HIV diagnosis (Lucas 2008). An account analysis showed that, treating expenditures increased by 200% with less than 200 CD4 T cells at the time of HIV diagnosis (Krentz 2004). This may be attributed to the immune reconstitution syndrome (IRIS) frequently observed in late presenters (see chapter on “AIDS”).

There is no doubt that a late HIV diagnosis is associated with higher mortality and morbidity risk. The risk increases with lower CD4 T cells at therapy initiation (Egger 2002, Sterne 2009). An analysis of therapy-naive patients in three major European cohort trials observed 8.3 new AIDS cases per 100 patient years with patients showing less than 200 CD4 cells/μl at the beginning of  therapy – and only 1.8/100 patient years with at least 350 CD4 T cells/μl. The mortality rate was slightly higher with 2.9 versus 0.7/100 (Phillips 2001). Several other cohort trials also found a clear association between CD4 T cells at therapy initiation and AIDS and mortality rates (Cozzi-Lepri 2001, Kaplan 2003, Palella 2003, Braitstein 2006). The lesser the CD4 T cell count, the higher the risk for the following time period, for many years (Lanoy 2007). Increased mortality remains with very low rates (less than 25 CD4 cells/μl) even six years after starting ART (and maybe longer) (ART-CC 2007).

A complete reconstitution of the immune system is rarely the case if the patient’s initial situation is poor – the worse the immune system, the more unlikely a complete recovery (Garcia 2004, Kaufmann 2005, Gras 2007). Viral suppression over several years cannot change that. In a study with patients on ART showing a constant low viral load below 1000 copies/ml for at least 4 years, 44% of patients with less than 100 CD4 cells/μl at initiation of ART failed to reach to 500 CD4 T cells/μl even after 7.5 years. Patients with 100-200 CD4 T cells/μl still showed a risk of 25% (Kelley 2009). Another risk factor, besides low CD4 T cells, is advanced age, which has been observed frequently with late presenters. The ability to regenerate the immune system decreases with age and is probably caused by the degeneration of the thymus (Lederman 2000, Viard 2001, Grabar 2004). A consequence of a late start of ART can also mean that the antigen-specific immune reconstitution against HIV, as well as opportunistic viruses, remain poor. Many studies suggest that the qualitative immune reconstitution can not keep up with the quantitative (Gorochov 1998, Lange 2002). It seems obvious. Where there was once a desert, it takes time to grow a flowerbed. First you will grow weeds. Only, why does the risk of AIDS drop so dramatically with rising CD4 T cell count? How can patients with severe immunosuppression safely discontinue a prophylaxis, as soon as their CD4 T cell count are above 200/ µl? Clinical observations seem to show differently, at least for the time being.

However, the relevance of a limited immune constitution in the long run, is not yet clear. Recent data from the ClinSurv Cohort suggests that a discordant response (low CD4 T cells in spite of good viral suppression) is only associated with higher AIDS risk in the first few months. With virally well-suppressed patients, the CD4 T cells are no longer a good surrogate marker for risk of AIDS (Zoufaly 2009).

In contrast to the immunologic response, the virologic response in combination with poor starting conditions is generally not worse than with other patients. Nevertheless, 89% out of 760 patients with AIDS disease at HIV diagnosis showed a viral load below 500 copies/ml after initiating ART (Mussini 2008).

When to start ART?

Patients with a poor immunological state should begin ART quickly. This recommendation applies for CDC stage C (AIDS-defining diseases) and for all stage B diseases. However, it has not yet been agreed on how quickly one should start ART within the context of an acute opportunistic infection (OI). Up to now, many therapists preferred to tend to the acute disease first and to wait a few weeks before beginning ART. They hoped to avoid the unnecessary high complication potential of OI therapies. The first randomized trial addressing this idea has made this strategy questionable (Zolopa 2009). In ACTG A5164, 282 patients with acute OI (63% PCP, cases of tuberculosis were omitted) were randomized to start ART either immediately or at earliest after completing OI therapy. On average, the “immediate” group started ART 12 days after initiation of OI therapy, whereas the “later” treated group after 45 days. Although the intervals were not so wide apart, already distinct differences were observed after 48 weeks: the group treated immediately showed significantly less fatalities and less new AIDS cases. The risk to have to adjust ART was slightly higher, but not the number of severe undesired incidents, hospitalization or cases of IRIS. The authors concluded that patients with an acute OI (at least of PCP) should immediately start ART. In Germany, the IDEAL study with PCP-and toxoplasmosis patients will check these results in 2011 (contact:

Two randomized trials, SAPIT and STRIDE  involving patients with culturally verified TBC and CD4 T cells <500/µ1 also showed a significant advantage of immediate ART (Abdool 2010, Havlir 2011). In contrast, two other randomized studies showed undesired effects with cryptococcus meningitis and tuberculosis meningitis when initiating ART early (Makadzange 2009, Torok 2009) – it is likely that differentiated recommendations depending on the OI must be given (Lawn 2011). There is also some controversial debate, as to whether patients with malignant lymphomas and newly diagnosed HIV infections should receive ART immediately or after chemotherapy (see chapter on “Lymphoma”).

ART for late presenters – What to start with?

An active OI is an obligatory exclusion criteria in almost every clinical trial. Thus, this patient group is always underrepresented in evaluation of clinical efficacy data. The question, if late presenters should be treated with a special antiretroviral therapy is therefore not clear and depends more than with other patients on individual decision-making (Manzardo 2007) (see chapter on “What to Start With?”). Regarding immunologic success, no relevant difference was measured between NNRTI- and PI-based regimens with late presenters (Landay 2003, Samri 2007). New ARV classes are also considered for late presenters. In favor of raltegravir, are its low interaction potential, its overall tolerance and effectiveness in reducing viral load compared to efavirenz, especially in the first weeks (Murray 2007). As for the CCR5 antagonist maraviroc (not yet permitted in Europe for primary therapy), a meta-analysis showed that CD4 cell increase was overall better than with other agents (Wilkin 2008). Results for its application as an immune modulator have been disappointing (Stepanyuk 2009, Wilkin 2010). This applies also for raltegravir (Hatano 2010) and T-20 (Joly 2010), both showing no effects regarding immune reconstitution.

It should also be noted that increased dual tropic viruses can be expected in late presenters, which does not allow the use of CCR5 antagonists. A more recent study, however, showed relatively high rates of R5-tropic virus strains in late presenters, making this patient group a possible candidate for treatment with coreceptor antagonists (Simon 2010).

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Filed under 6. ART 2011, 6.5. When to Start ART, Part 2 - Antiretroviral Therapy

6.6. What to Start With?

– Christian Hoffmann –

Once the decision has been made to start, the next question is, what to start with? More than two dozen drugs are now available, and the number of theoretically possible combinations seems to be almost infinite. In most guidelines, more than ten different combinations are recommended as “preferred”, while numerous more are listed as “alternatives”.

It would be brilliant if every treatment-naïve patient participated in a clinical study. That would be the best way to continue improving the quality of antiretroviral therapy. However, in practice it is not always possible to sign everyone up for a clinical trial. For information regarding the treatment of naive patients, the following summarizes the available data.

Recommended Initial Regimens

Combinations that we currently recommend for first-line therapy (as of March 2011) are shown in Table 6.1. In the list, there is no order of preference. Moreover, many other combinations are possible. These other combinations may be acceptable in individual cases or in investigational studies, but general recommendations for their use cannot be given. Problematic drugs or combinations that are not advisable for use are listed at the end of this chapter.

Table 6.1. ART combinations suitable for initial therapy (in no order of preference).


  3rd agent


Atazanavir/r (PI)

*ABC + 3TC

plus either

Darunavir/r (PI)
Fosamprenavir/r (PI)
Lopinavir/r (PI)


Saquinavir/r (PI)


Efavirenz** (NNRTI)


Nevirapine*** (NNRTI)Raltegravir**** (INI)
*      Only when HLA typing is possible, caution when risk for cardiovascular events is high.
**     Caution in women of childbearing age (teratogenicity).
***    Beware of hepatotoxicity when CD4 T cells are high (women >250, men >400/µl).
****  Convincing data, but lack of long term experience.

Practical approach to the first regimen – important rules

All current initial regimens consist of two nucleoside analogs combined with either a boosted PI or an NNRTI. No single combination has clearly been shown to be superior to any other. There is no one gold standard. When choosing primary therapy, many factors are involved besides the antiviral potency and tolerability. Individual factors, such as compliance, concurrent illnesses and concomitant medications, as well as the needs of the individual should be included in the decision. One should be aware that primary (first-line) therapy is of great significance and needs to be well prepared for. It is at this time that the chance of viral suppression followed by long-term maintenance of suppression is greatest.

Practical tips for first-line therapy:

  • The first regimen offers the best chance of suppression followed by maintenance. The viral load should decrease to below detection levels within 3-6 months.
  • Do not rush – the patient must be ready for ART. If in doubt, wait and continue to monitor levels.
  • If possible, do not prescribe medication in the first consult with a new patient who brings their results. Do you know the patient well enough? Are they really motivated? Will they come back?
  • For every patient, prescribe the ART they are able to take. Do not insist on theoretically superior combinations.
  • The pros and cons (side effects) of different combinations should be discussed – have enough time for this.
  • The initial regimen should be taken no more then twice daily. Once-daily treatment should be considered if it is important for the patient.
  • The toxicity profiles should not overlap whenever possible – never use several allergenic drugs simultaneously.
  • Ask about other medication (and drug use) – are relevant interactions to be expected?
  • Concomitant illnesses should also be checked – what about the liver (hepatitis), kidneys?
  • All drugs are started on the same day – no “lead-in” mono- or dual therapy.
  • Be sure to check whether the patient would be eligible for a clinical study. All patients, especially if treatment-naïve, should be encouraged to participate in clinical trials, which may help the patient reach a better understanding of the importance of treatment and good adherence. Take your time.

What should be clarified first

Dosing issues & adherence

Can the patient really take drugs several times a day? Do they understand that treatment will probably be lifelong? Is this realistic with regard to the individual, professional and/or social situation? If in doubt, a simpler regimen is preferable to one that is presumed more effective. For example, it is often not realistic to expect patients with adherence problems to take tablets twice a day according to a strict protocol. However, they also need treatment. There have been successful attempts at once-daily regimens for drug users (Staszewski 2000), who might also be suitable for DOT (Directly Observed Therapy) or DAART (Directly Administered ART) together with the substitution program. However, randomized studies have not shown better virological response in the case of DOT (Nachega 2010, Berg 2011). With DAART, response to therapy may probably be improved (Maru 2009). However, the virologic benefit of this strategy wanes following transition to self-administered therapy (Gross 2009, Smith-Rohrberg 2009).

In patients with obvious adherence problems, it should be considered that NNRTI-based regimens that are easy-to-take have a low resistance barrier. Studies such as FIRST have demonstrated that especially in patients with low adherence, the risk for resistance is increased in NNRTI regimens compared to PI regimens (Gardner 2008). Thus, in some cases, a boosted once-daily PI regimen may be preferable. When treatment is not taken 100% on time, the resistance risk may be relatively lower than with PIs than with NNRTIs.

For many patients the numbers of pills or requirements for food intake are important. The range of licensed and recommended initial regimens varies from 2 to 7 pills per day (caution: in many countries, the combination pill Atripla® with one pill QD has not been licensed as first-line).

Some patients find it unacceptable to have to take pills at certain times during the day with fatty foods. Patients today are more demanding than before – justifiably so. There are now alternatives. Even the size or consistency of tablets can be a problem. Such issues must be discussed before initiating therapy as ART needs to become one more part of normal daily life.

Concurrent illnesses

Before starting treatment, possible concurrent illnesses should be identified (anamnesis, examination). This is fundamental in helping make the right choice (Table 6.2).

Table 6.2. Concurrent illnesses requiring caution with specific drugs (not only in first-line therapy). There are no absolute contraindications.
Illness Caution with
Active hepatitis B Nevirapine, boosted PIs (beneficial: Tenofovir+ FTC)
Active hepatitis C Nevirapine, boosted PIs
Active agent use, substitution NNRTIs, ritonavir (possibly beneficial: raltegravir)
Anemia AZT, possibly also 3TC
Arterial hypertension Indinavir
Chronic diarrhea, intestinal diseases Nelfinavir, lopinavir, fosamprenavir, other PIs
Diabetes mellitus PIs
Kidney disease Indinavir, tenofovir, possibly atazanavir
Myocardial infarction Abacavir, ddI, PIs (potentially beneficial: nevirapine)
Pancreatitis ddI
Polyneuropathy d4T, ddI
Psychoses, other CNS illnesses Efavirenz

For example, a patient with diarrhea should not be given fosamprenavir or lopinavir. Use tenofovir or indinavir with caution in patients with renal disease. Atazanavir may also be associated with renal diseases (Mocroft 2010). ddI and d4T are contraindicated in patients with a history of pancreatitis or polyneuropathy and are no longer recommended in first-line therapy. Non-insulin-dependent diabetes can become insulin-dependent with PI treatment. There are some cohort studies that report an association between recent use of abacavir and an increased risk of myocardial infarction (Sabin 2008, Lundgren 2009). Although these observations have not been without debate (Brothers 2009), some experts recommend alternatives when cardiovascular risk is increased (Behrens 2010). However, according to a more recent meta-analysis by the FDA, it has become questionable whether there really is a correlation between abacavir and MI-risk (Ding 2011).

Liver disease and chronic hepatitis must also be taken into account, because the risk of developing severe hepatotoxicity on nevirapine or ritonavir is highest (Sulkowski 2000). Caution is also required with boosted PIs. However, one study conducted in over 1000 patients found no difference between lopinavir/r and an unboosted PI such as nelfinavir in patients coinfected with hepatitis C (Sulkowski 2004). In coinfections with HBV, 3TC or better tenofovir+FTC should be utilized (Avihingsanon 2010). Long term monitoring of HBV over a span of five years or longer is possible with tenofovir (de Vries-Sluijs 2010). However, in HBV-coinfected patients starting ART, two HBV drugs should be integrated in order to reduce the risk of HBV resistance. Avoid Combivir® or Kivexa® in cases of hepatitis B coinfection when no other HBV agent is on board – 3TC alone for HBV is not enough.

Interactions with medications and drugs

Interactions are important in when choosing regimens. Whereas interactions between antiretroviral drugs are well known, those with other medications are often less well characterized (see section on interactions). The urgent need for more research was demonstrated in a study investigating the interactions between ART and lipid lowering agents. In healthy volunteers, the measurement of plasma levels showed that levels of simvastatin were elevated by 3059% after concurrent dosing with ritonavir or saquinavir (Fichtenbaum 2002). Several cases of fatal rhabdomyolysis on simvastatin, atorvastatin and PIs, such as atazanavir, lopinavir and nelfinavir have been described (Hare 2002, Mah 2004, Schmidt 2007). There is even a case report on pravastatin, a currently favored statin (Mikhail 2009), so boosted PIs should be utilized with caution.

Many other drugs should be avoided in combination with particular antiretroviral drugs, as incalculable interactions may occur. These include certain contraceptives. Even drugs that seem unproblematic at first glance can have unfavorable effects. For example, the plasma levels of saquinavir can be reduced by half with administration of garlic capsules (Piscitelli 2002). Even a seemingly harmless agent, such as vitamin C can influence plasma levels. A small study in healthy volunteers showed that vitamin C can significantly lower (14%) unboosted indinavir levels (Slain 2005). Coumarin derivative anticoagulants, such as warfarin can also be a problem; ritonavir can significantly lower plasma levels (Llibre 2002). Further typical problem drugs include migraine remedies, prokinetic drugs and sedatives/hypnotics. One fatal case was described with ergotamine and ritonavir (Pardo 2003). The simultaneous administration of ART and PDE-5 inhibitors (sildenafil, vardenafil, tadalafil) can also be problematic (see section on Sexual Dysfunction).

Drugs or alcohol can interact with ART (Neuman 2006, Mass 2006). For those in substitution programs, the methadone requirement may be significantly increased by certain antiretroviral drugs, such as nevirapine and efavirenz (Clarke 2001). To a lesser extent, this is also true for ritonavir and nelfinavir. There is inconsistent data on lopinavir but it may also require dose adjustments. Raltegravir, again, seems to have no effects (Anderson 2010).

Other interactions have even more dangerous consequences. Several deaths have been reported after simultaneous dosing with ritonavir and amphetamines or MDMA/ecstasy, the popular narcotic gamma hydroxybutyric acid (GHB) or “liquid ecstasy” (Henry 1998, Harrington 1999, Hales 2000). Ritonavir in particular inhibits the metabolism of amphetamines (speed or MDMA/ecstasy), ketamines or LSD (Antoniou 2002). Clinicians and patients are well advised to have an open conversation about drug use before starting therapy. Marijuana and THC appear to have a low potential for interactions (Kosel 2002). Amphetamines seem to be particularly dangerous and neurotoxic in HIV patients (Chana 2006).

Not every agent can be discussed here. Many are described in the respective drug chapters. It is always recommended to check the package insert. Initiation of ART provides a good opportunity to re-evaluate existing prescribed medications.

Additive toxicities

Several potential additive toxicities should be considered in the choice of therapy. If other myelotoxic drugs (i.e., valgancyclovir, cotrimoxazole) are necessary, caution is required with AZT. When treating hepatitis C with interferon and ribavirin, ddI must be avoided. Ribavirin should not be combined with AZT or d4T. d4T should generally be avoided due to its potentially high toxicity. Tenofovir, indinavir, possibly also atazanavir should also be avoided with potentially nephrotoxic drugs. Lastly, it is not advisable during primary therapy to start with potential allergy-inducing agents if anti-infectious prophylaxis with cotrimoxazole or other sulphonamides is necessary. Included here are nevirapine, efavirenz and abacavir, but also fosamprenavir and darunavir. In order not to upset the prophylaxis, it is better to avoid these ARVs. Otherwise, it can be difficult to clearly identify the causative agent for a drug-induced exanthema.

What drug classes should be used?

All combinations currently used as initial regimens consist of two NRTIs plus either a PI, an NNRTI or the integrase inhibitor raltegravir.  A third NRTI (triple nuke) is only used in exceptional cases and is only briefly mentioned here. All other combinations are currently (April 2011) not justified for use outside the framework of clinical studies. Advantages and problems of these three strategies are outlined in Table 6.3.

Table 6.3. Combining drug classes: Advantages (é) and disadvantages (ê).
2 Nukes + PI 2 Nukes + NNRTI 2 NRTIs + INI
é a lot of data, including cli-nical endpoints and severely immunocompromised pts. é equivalent, perhaps even better suppression of viral load than with PIs é very good efficacy, excellent tolerability
é long-term data available é low pill burden, once-daily may be possible é few interactions
é high genetic resistance barrier é leaves PI options é maintains options
ê high pill burden (for the older PIs), some once-daily regimens not licensed ê clinical effect not proven (only surrogate marker studies) ê no long-term data
ê frequent drug interactions ê less data in severely im-munocompromised patients ê once-daily with raltegravir not possible, high costs
ê some PIs with cross-resistance, leaving limited options ê rapidly occurring complete cross-resistance, low resistance barrier ê No clinical endpoints, no long-term data
ê long-term toxicity, lipody-strophy, dyslipidemia with most PIs ê strict monitoring required initially (esp. nevirapine), allergies frequent ê relatively low resistance barrier

Studies comparing these strategies are listed in Table 6.4. The validity of previous milestone trials such as Atlantic (van Leeuwen 2003) is considered limited today due to outdated combinations and are not mentioned here.

Table 6.4. Randomized studies on agents of different classes as initial regimen for therapy-naïve patients.
Study 3rd agent Major results
Large well-powered studies
ACTG 5142(Riddler 2008)

EFV versus LPV/r


Less VF on EFV, severe AEs same (but more lipoatrophy on EFV)
ACTG 5202(Daar 2010)

EFV versus ATV/r


VF same, more severe AEs on EFV (in combination with ABC+3TC), but better lipid profile
ARTEN 5202(Soriano 2011)

NVP versus ATV/r


VF same, slightly more severe AEs and resistances with NVP
STARTMRK(Lennox 2010)

EFV versus RAL


VF same, more AEs
Smaller trials or trials in resource poor countries or in subgroups
ALTAIR(Puls 2010)

EFV versus ATV/r


VF same, AEs same (slightly less increase of peripheral fats with EFV)
KISS(Maggiolo 2009)

EFV versus ATV/r


VF same, AEs same
PHIDISA(Ratsela 2010)

EFV versus LPV/r


VF same, clinical endpoints same (South Africa <200 CD4 T cells/AIDS)
(Sierra-Madero 2010)

EFV versus LPV/r


Less VF under EFV than on LPVr, better lipid profile on EFV (Mexico, <200 CD4 T cells)
NEWART (De Jesus 2010)

NVP versus ATV/r


VF same, but lipids better with NVP
OCTANE II(McIntyre 2010)

NVP versus LPV/r


VF same, but more severe AEs with NVP (African women <200 CD4 T cells)
004(Marcowitz 2009)

EFV versus RAL


VF same, more AEs with EFV
Note: Different (partly randomized) NRTI backbones were utilized, in some cases there were other trial arms. VF= Virologic Failure, AE= Adverse Events. Note: The MERIT study with maraviroc is not mentioned here, as maraviroc is not licensed for first-line therapy.

In most of the trials, the antiviral potency of the regimens was comparable, measured by the number of patients with viral load below the limit of detection. In ACTG 5142, an advantage of efavirenz over lopinavir/r was observed after 96 weeks (12% more patients got to below 50 copies/ml). However, if ART failed, resistance was less frequent in the LPV/r arm and CD4 T cells increased more. The ACTG 5142 trial showed that NNRTIs were possibly more effective than boosted PIs, because they were better tolerated. Resistance, however, occurs faster on NNRTIs than on PIs, which is probably due to the low resistance barrier. This phenomenon was observed in trials such as FIRST, ARTEN and ACTG 5202 (Gardner 2008, Daar 2010, Soriano 2011).

These observations were confirmed in a systematic evaluation of 20 studies that included 7949 patients (see Table 6.5). All of the patients had been treated with either an NNRTI or a boosted PI, and had additionally received 3TC or FTC. Virologic failure was as frequent on NNRTIs as on PIs (4.9% versus 5.3% of patients, p=0.50). However, major differences were observed in patients with virologic failure whose genotypic resistance testing was successful. Mutations were significantly higher with NNRTIs. This applied for NRTI key mutations like the M184 and K65R, and also for other resistance mutations.

Table 6.5. Rates of resistance mutations at therapy failure on first regimens containing NNRTIs or PIs, in percentages (Gupta 2008).





35.3  (29.3-41.6)

21.0 (14.4-28.8)



5.3  (2.4-9.9)

0 (0-3.6)


Resistance to third agent (NNRTI or PI)

53.0  (46-60)

0.9 (0-6.2)


Data on resistance development of the integrase inhibitor raltegravir in initial regimens is limited and long-term data lacking. However, studies testing raltegravir versus efavirenz, showed at least comparable efficacy with overall better tolerability over a period of approximately three years (Markowitz 2009, Lennox 2010).

Thus, the pros and cons for the different strategies continue, and controversy over the best first-line therapy persists. One should be warned against cross-trial comparisons, which are often used as marketing strategy to influence health providers of the effectiveness of a specific treatment (“we achieved over 90% tolerance rates in our study”). In a systematic evaluation of 10 large-scale randomized trials with 2341 therapy-naïve patients receiving AZT+3TC+efavirenz, the success rates (viral load in the ITT analysis <50/copies/ml at 48 weeks) ranged between 37% and 77%. This broad range was seen with use of the same combination in ART-naïve patients. Heterogeneous patient populations and study designs (definition of therapy failure), but also clinician experience and adherence may lead to variations (Hoffmann 2007).

Below, various strategies or primary therapies are discussed. These include:

  1. Two NRTIs plus an NNRTI
  2. Two NRTIs plus a PI
  3. Two NRTIs plus an integrase inhibitor
  4. Three or four NRTIs (triple-nuke, quadruple-nuke)
  5. Once-daily combinations
  6. Experimental combinations (nuke-sparing, intensive approaches)
  7. Problematic primary therapies to be avoided

1. Two NRTIs plus an NNRTI

NNRTIs have an equal, if not superior effect on surrogate markers compared to PI combinations. NNRTIs have performed well in numerous randomized studies: efavirenz-based regimens were superior to unboosted PIs such as indinavir or nelfinavir (Staszewski 1999, Robbins 2003) and at least equivalent to lopinavir/r (Riddler 2003), atazanavir (Daar 2010) or raltegravir (Lennox 2010). Nevirapine-containing regimens were mostly equivalent to atazanavir/r or lopinavir/r (McIntyre 2010, Soriano 2011).

Advantages of NNRTI regimens include the low pill burden and good long-term tolerability. In contrast to PIs, however, data with clinical endpoints is not available. Neither is there any long-term data or studies on severely immunocompromised patients. A disadvantage of NNRTI combinations is the rapid development of cross-resistance. This could result in failure, especially for highly viremic patients, although this has not been confirmed. Resistance upon virologic failure is generally more frequent on NNRTIs than on PIs (Gupta 2008, see above). Allergies are frequent on all NNRTIs. Hepatic adverse events requiring careful monitoring (nevirapine) but also central nervous system side effects and potential teratogenicity (efavirenz) should be considered. The 2NN trial showed no significant difference in efficacy between efavirenz and nevirapine in combination with d4T+3TC (van Leth 2004).

TDF+FTC plus efavirenz is one of the most frequently used combination at present and available as a single pill Atripla®. In the Gilead 934 Study and in a large Switch trial, TDF+FTC plus efavirenz was more effective than AZT+3TC plus efavirenz (Arribas 2008, Fischer 2010). It should be noted that in Europe, approval for Atripla® is stricter than in the US. Although the bioequivalence with each individual substance has been shown, the EMA restricts the use  of Atripla®. It is only approved for patients with virologic suppression under 50 copies/ml for at least three months on their current antiretroviral regimen. Furthermore, patients must not have experienced virologic failure with an earlier treatment combination or be known to have resistance to any of the three components in Atripla®. These slightly strange restrictions should be observed in Europe, as TDF+FTC (Truvada®) and efavirenz (Sustiva®) only require one more pill a day.

TDF+FTC plus nevirapine is also a frequently prescribed regimen. However, there is less data available than for efavirenz. Smaller trials observed an increased risk for therapy failure and for development of resistance, especially when viral load was high (Towner 2004, Lapadula 2008, Rey 2009). The large ARTEN trial also showed a slightly higher risk for resistances under TDF+FTC plus nevirapine, but an altogether comparable efficacy to TDF-FTC plus atazanavir/r (Soriano 2011). In favor of nevirapine are its good lipid profile and the excellent long-term tolerability, despite some risk for severe allergies and hepatotoxicity in the first few weeks.

TDF+3TC plus efavirenz was virologically equivalent to d4T+3TC plus efavirenz in the double blind, randomized Gilead 903 Study, although tolerability was significantly better (Gallant 2004). There are convincing long-term data out to more than 6 years (Cassetti 2007). However, the combination of TDF+3TC is seldom used today in Europe and the US, as there is no FDC available. Moreover, there is no reason to use 3TC instead of FTC.

ABC+3TC plus efavirenz (or nevirapine) is an alternative first-line therapy, if HLA testing to predict hypersensitivity to abacavir is available. The combination ABC+3TC plus efavirenz has been evaluated with success in numerous large trials such as CNA30024 (DeJesus 2004), ZODIAC (Moyle 2004) and ABCDE (Podzamczer 2006). More recent studies such as ACTG 5202 and ASSERT showed slightly less efficacy than on comparable regimens (Daar 2010, Post 2010). In ASSERT, less renal and bone side effects and were observed than with TDF+FTC (Post 2010, Stellbrink 2010). Data on ABC+3TC plus nevirapine are so far limited. An alternative to abacavir should be considered in patients with an increased risk for cardiovascular disease (Behrens 2010), although this has been questioned by a more recent FDA analysis (Ding 2011).

AZT+3TC plus efavirenz or nevirapine were among those regimens most frequently used and have been evaluated in numerous milestone trials (006, Combine, ACTG 384, 5095, 934). Side effects may occur during the first weeks. In the 934 Study, anemia and gastrointestinal problems occurred frequently in some cases, which significantly compromised the efficacy of AZT+3TC in contrast to TDF+FTC (Arribas 2008). Side effects such as increased lipids and lipoatrophy are significantly reduced by changing to TDF+FTC (Fischer 2010). Another disadvantage is the fact that with these combinations (including AZT), QD dosing is not possible. This regimen can only be recommended if there are good reasons not to use tenofovir or abacavir.

2. Two NRTIs plus a PI

The combination of two NRTIs plus one protease inhibitor is the only three-drug combination ART that is supported by efficacy data from randomized studies with clinical endpoints (Hammer 1997, Cameron 1998, Stellbrink 2000). Given the high resistance barrier and the robustness of these regimens, many experts still prefer to use these combinations today, particularly in advanced patients or those with high viral load. Resistance on boosted PIs is significantly less than from NNRTIs; PI/r resistance hardly exists (Gupta 2008). The slightly higher pill burden and frequent gastrointestinal side effects, which complicate compliance, are disadvantages of a PI-containing therapy. Often small factors are important when choosing the right PI, see Table 6.6.

Table 6.6. Frequently used PIs. Issues which may have an impact on treatment decision.







Pill number/day






Once daily dosing?





 no (US: yes)

Intake with food?






Important side  effects

Diarrhea (mild)


Hyperbilirubin., icterus

Diarrhea (mild)


Main study






The following briefly describes the most common combinations:

TDF+FTC plus darunavir/r has been licenced for initial therapy since February 2009 and is one of the preferred first-line regimens in most guidelines. The combination proved at least as effective as TDF+FTC plus lopinavir/r in the ARTEMIS trial. With regard to tolerance it was even better (less diarrhea, less lipid changes) (Ortiz 2008). The effects remain stable out to 96 weeks (Mills 2009). Another advantage of this combination is the once-daily dosing. A disadvantage however for all boosted PIs is that ritonavir must be kept in the refrigerator. This changed in April 2010 with the introduction of ritonavir tablets.

TDF+FTC plus atazanavir/r was approved for first-line in 2008. In the CASTLE trial, atazanavir/r proved virologically equal to lopinavir/r, but with better lipids and similar tolerance (Molina 2010). Although a randomized study showed no difference between unboosted and boosted atazanavir (Malan 2008, Squires 2009), boosting with ritonavir is recommended. The main arguments in favour of this combination are the low number of pills and the good lipid profile. The major disadvantage is hyperbilirubinemia, which often manifests as harmless but disturbing icterus.

TDF+FTC or ABC+3TC plus lopinavir/r have been categorized in many guidelines as a preferred combination. However, after the results of CASTLE, ARTEMIS and ACTG 5142 (see above), lopinavir/r was recently down-graded in the US (by the DHSS) to an alternative regimen. More data is available for TDF+FTC as a backbone for lopinavir/r, although the HEAT study did not find significant differences compared to ABC+3TC (Smith 2008). Since 2009 lopinavir/r has also been licensed for once-daily use, after several studies had shown similar efficacy and tolerability (Molina 2007, Gathe 2009). However, there is some evidence that the potency of once-daily dosing is slightly less than BID (Ortiz 2008, Flexner 2010). Lopinavir/r lost its main advantage of not requiring cool storage compared to other boosted PIs, with the introduction of the Norvir® tablets in 2010.

ABC+3TC (or TDF+FTC) plus fosamprenavir/r: In the KLEAN study, this combination proved almost equal to ABC+3TC plus lopinavir/r in regard to both efficacy and tolerability. Better rates of diarrhea or cholesterol levels were, however, not achieved (Eron 2006). In the ALERT study, fosamprenavir/r was as effective as atazanavir/r, both combined with a TDF+FTC backbone (Smith 2006). In Europe, once daily use of fosamprenavir/r has not been licensed, although using a low booster of 100 mg ritonavir should be possible (Hicks 2009, Cohen 2010).

TDF+FTC plus saquinavir/r: Saquinavir was the first PI which showed a survival benefit (Stellbrink 2000). More data with saquinavir is available with AZT backbones than with TDF-containing backbones. In the relatively small GEMINI study saquinavir/r with a TDF+FTC backbone proved to be non-inferior to lopinavir/r (Walmsley 2009). The even smaller BASIC study showed that a once-daily dosing (1000/100) was comparable to atazanavir/r with regard to lipid profiles (Vrouenraetes 2009). The main disadvantage of saquinavir-based regimens is the approved twice-daily dosing and the high pill burden, which is why the combination is rarely used today.

3.Two NRTIs plus one integrase inhibitor

Raltegravir was licensed as the first integrase inhibitor for first-line treatment in 2009. Tolerance and efficacy are both excellent, although once-daily dosing is not possible or slightly weaker (Vispo 2010, Eron 2011) as for now, long-term data covering a period of over 3 years, especially regarding tolerability, are lacking. Indications appear when NNRTIs or PIs are less favorable for primary therapy, especially when interactions are expected.

TDF+FTC (TDF+3TC) plus raltegravir: The promising data of the Phase II study (Markowitz 2009) was confirmed in the large STARTMRK trial, in which raltegravir proved at least as effective as efavirenz (Lennox 2010). Viral load decreased more rapidly in the raltegravir arm and CD4 T cell counts increased. In addition, tolerance was better and effects lasted over 196 weeks (Gotuzzo 2010). It should be noted that data is available for raltegravir with TDF-based backbones while data for ABC+3TC or other backbones is still very limited. A pilot study with ABC+3TC plus raltegravir, however, showed no negative effects (Young 2010).

4. Three or four NRTIs – triple nuke or quadruple nuke

Triple or quadruple nuke therapies have several advantages: fewer interactions, no side effects typical of PIs or NNRTIs, and the fact that all other drug classes can be spared for later. The major disadvantage of triple nuke therapies is that they are virologically less potent than other combinations. While this may not be the case with quadruple nukes, the increasing knowledge of the mitochondrial toxicity of NRTIs makes pure nuke therapies less attractive.

AZT+3TC+ABC in a single tablet Trizivir® (BID) is the classic triple nuke therapy. Since ACTG 5095, Trizivir® is no longer equivalent (Gulick 2004) and clearly less effective than AZT+3TC plus efavirenz. This also applies for developing countries, where Trizivir® is still occasionally propagated (Munderi 2011).

AZT+3TC+TDF: We have had fairly good experience with this approach (Mauss 2005). Given the different resistance pathways of AZT and TDF, the thymidine analog seems to be protective against tenofovir-associated mutations (Rey 2006, see chapter on resistances). However, larger studies have not been conducted. The use of this combination has also met with some criticism (Maggiolo 2009).

AZT+3TC+ABC+TDF: Some studies have reported good responses and low rates of virologic failure on this quadruple nuke therapy (Moyle 2006, Elion 2006, Gulick 2007, Ferrer 2008). However, these studies were not powered to demonstrate equivalence to other combination regimens. In two randomized studies, discontinuation rates were high, due to adverse events (Mallolas 2008, Puls 2010). In the ALTAIR study, it proved less effective than the standard ART regimen (Puls 2010).The long-term toxicity and efficacy of these combinations is still unknown.

TDF+3TC+ABC/ddI should be avoided (Jemsek 2004, Gallant 2005, Khanlou 2005). In up to 49% of patients, early virologic treatment failure has been seen, probably due to a low genetic resistance barrier (Landman 2005). This is also true for treatment-experienced patients who want to simplify their therapy (Hoogewerf 2003, Perez-Elias 2005).

Conclusion: Pure NRTI combinations are not recommendable for first-line therapy. Triple nuke is poorer in comparison to regimens of at least two classes and the results of some of the single-class combinations are truly not good. Data on quadruple nukes is too limited. However, triple and quadruple nuke therapy remains under consideration for maintenance therapy (see Chapter 7).

5. Once-daily combinations

Many drugs have been licensed for QD administration (once-daily, Table 6.7). Some experts still fear that once-daily dosing is unfavorable with respect to the theoretical development of resistance. If one dose is forgotten, 24 hours without treatment goes by. These regimens may therefore be less forgiving, particularly if there are problems with compliance.

It has still not been confirmed that once-daily regimens really improve compliance. A recent meta-analysis, however, suggests  an improvement  (Parienti 2009).

Table 6.7. Antiretroviral drugs and their usage in first-line once-daily regimens.
Trade name Abbrev.


Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Emtriva® FTC


Epivir® 3TC


Retrovir® AZT


QD definitively not possible
Videx® ddI


Must be taken on an empty stomach
Viread® TDF


Zerit® d4T


D4T-XP is no longer coming
Ziagen® ABC


Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Intelence® ETV


QD not possible, no approval for first-line
Rescriptor® DLV


QD not possible, no approval for first-line
Sustiva®, Stocrin® EFV


Viramune® NVP


approval for QD NVP “ext’d release”
Protease inhibitors (PIs)
Aptivus® TPV/r


QD not possible, no approval for first-line
Crixivan® IDV/r


Limited data
Darunavir® DRV/r


Invirase® SQV/r


Studies ongoing
Kaletra® LPV/r


Only for treatment experienced patients
Reyataz® ATV/r


US: Unboosted ATV also approved
Telzir/Lexiva® FPV/r


QD licenced in US but not in Europe
Viracept® NFV


Limited data
Entry inhibitors, integrase inhibitors
Celsentri®, Selzentry® MVC


No approval for first-line
Fuzeon® T-20


QD not possible, no approval for first-line
Isentress® RAL


Probably not possible
Fixed combinations
Atripla® TDF+FTC+EFV


Restricted first-line approval in Europe
Combivir® AZT+3TC


QD not possible due to AZT
Kivexa®, Epzicom® 3TC+ABC


Trizivir® AZT+3TC+ABC


QD not possible due to AZT
Truvada® TDF+FTC


Tolerability of some agents could become worse due to higher peak levels. In the 418-study, QD lopinavir showed more incidence of diarrhea than the twice daily dosage (Molina 2007). Once daily does not only influence the peak levels – but trough levels decrease, especially with boosted PIs, due to the longer intervals between the individual doses. This can be of relevance when viral load is high (Flexner 2009) and with treatment-experienced patients (la Porte 2005). This was true also with raltegravir, which is why raltegravir should not be administered once-daily (Vespo 2010, Eron 2011).

6. Experimental combinations

Antiretroviral therapies need to be more effective and tolerable. Although integrase and entry inhibitors offer new options, investigation on classic ART is still ongoing. Two approaches have attracted great interest: combinations without any NRTIs (nuke-sparing or monotherapies), and so-called induction therapies. Both approaches will be discussed below.


All classical ART regimens have to date included a backbone consisting of two nucleoside or nucleotide analogs. This is mainly historical: nucleoside analogs were the first drugs on the market, and by the time NNRTIs and PIs were under development, treatment with two nucleoside analogs was standard. With growing knowledge of the mitochondrial toxicity of nucleoside analogs, nuke sparing, i.e., omission of NRTIs, is increasingly being investigated, even for first-line therapy. Nuke-sparing with pretreated patients will be discussed later on in the book (see When to Switch).

Data for nuke-sparing as first-line is limited. As shown in Table 6.8, mostly smaller studies have been conducted so far.

NNRTI plus PI: ACTG 5142 was the first large study providing convincing evidence for the nuke-sparing strategy (Riddler 2008, see above). This study showed that a combination of lopinavir/r and efavirenz was not inferior to two NRTIs with either lopinavir/r or efavirenz. A randomized African trial showed that different nuke-sparing regimens (different NNRTIs plus PIs) were inferior to standard ART regimens (Duvivier 2008). In contrast, two other small, randomized studies found no significant difference between nuke-sparing and standard regimens (Harris 2005, Cameron 2005). It is still unclear whether side effects really improve with nuke-sparing regimens. A sub-study of HIVNAT 009 reported that lipoatrophy resolved, and that visceral fat and subcutaneous limb fat increased (Boyd 2005). In CTN 177 nuke-sparing regimens had a favorable effect on lactate levels (Harris 2005). In ACTG 5142 rates of lipoatrophy were lower in the nuke sparing arm (Haubrich 2009). However, adverse events in total were not reduced and dyslipidemia was observed even more frequently (Riddler 2008).

Pilot trials have also shown poor response rates for a double PI, which is why this nuke-sparing approach will probably not be further investigated for now (Ulbricht 2008, van der Lugt 2008, Landman 2009).

INI/CCR5A plus PI: Many studies are ongoing, especially with raltegravir and maraviroc, boosted with one PI, respectively: raltegravir is not only tested with lopinavir/r or atazanavir/r (PROGRESS study, CCTG 589), but also with darunavir/r in treatment naïve patients (RALDAR, NEAT 001). Maraviroc is also combined with darunavir/r. Is this the future? What does the data say?

The PROGRESS study showed a more rapid and impressive reduction of viral load already after 8 weeks, than with the classic combination of TDF+FTC plus lopinavir/r. After 48 weeks, antiviral effect was comparable (Reynes 2010). However, there have been some setbacks. In ACTG 5262, a one-arm study with darunavir/r plus raltegravir, many patients had not achieved a viral load under detection level at week 48 and 5 out of 112 patients developed resistance to raltegravir (Taiwo 2011). Strikingly, these patients already showed several resistance mutations at baseline and there was some doubt whether all patients really were treatment-naïve. However, the SPARTAN study confirmed these results, where 4/63 (6.3%) patients developed raltegravir resistances on a combination of raltegravir and unboosted atazanavir (300 mg BD). On account of these results, the study was discontinued prematurely. Unfortunately, PK data of patients showing virological failure was not available, which could have explained the therapy failure. Raltegravir, however, probably reduces the level of atazanavir (Zhu 2010). A striking observation in SPARTAN was the high rate of severe hyperbilirubinemia (grade 4), with 21% under atazanavir plus raltegravir, compared to no cases in the TDF+FTC plus atazanavir/r (Kozal 2010). This combination can therefore not be recommended in this form. In view of the rather low resistance barrier, a boosted PI as a partner substance seems necessary.


Table 6.8. Prospective studies on nuke-sparing regimens in treatment-naive patients and patients with little prior treatment experience (intent-to-treat analyses).

n (naive)

Combination          (Study) Percentage <50 copies/ml
Staszewski 1999

148 (126)*

EFV+IDV           (006-Study) 47% at 48 weeks
Boyd 2003

61 (0)*

EFV+IDV/r     (HIVNAT 009) 69% at 96 weeks
Allavena 2005

86 (65)*

EFV+LPV/r                 (BIKS) 73% at 48 weeks (<400)
Riddler 2008

253 (253)

EFV+LPV/r      (ACTG 5142) 83% at 96 weeks
Harris 2009

14 (14)

NVP+LPV/r          (CTN 177) 78% at 48 weeks
Ward 2006

63 (63)

EFV+ATV/r          (BMS 121) 63% at 48 weeks
Kozal 2010

63 (63)

RAL+ATV              (Spartan) 81% at 24 weeks
Mills 2010

60 (60)

MVC+ATV/r       (A4001078) 89% at 24 weeks
Nozza 2010

7 (7)

MVC+LPV/r 100% at 24 weeks
Reynes 2010

103 (103)

RAL+LPV/r     (PROGRESS) 83% at 48 weeks
Taiwo 2011

112 (112)

RAL+DRV/r      (ACTG 5262) 26% VF at 48 weeks
*Patients all PI-naïve. VF=Virologic Failure

Promising first results were shown with the combination atazanavir/r and low dosed maraviroc (Mills 2010). Resistances were not observed in this study; however, larger studies with maraviroc and darunavir/r are in planning. The combination of maraviroc and a boosted PI could also be important, as the tropism test does not always show valid results. There is also a risk for patients starting an insufficient monotherapy if non-R5-viruses are not recognized.

With regard to the data available, it is still premature to be able to recommend nuke-sparing as an equal alternative in its own right.

Monotherapy, alternating therapy

Can it get any easier? Several studies introduced a very avant-garde concept in the summer of 2003: monotherapy with boosted PIs. With respect to the high resistance barrier of boosted PIs, success was considerable (Gathe 2009). Lipoatrophy can be avoided (Kolta 2011).However, in many studies, low-level viremia was found to be more frequent on monotherapies. In the MONARK study, only 64% (compared to 75% on AZT+3TC+lopinavir/r) of the patients on lopinavir/r achieved a viral load of less than 50 copies/ml at 48 weeks (Delfraissy 2008). At 96 weeks it was only 47% (Ghosn 2009). Darunavir/r also started to show weaker effects in a small pilot study (Patterson 2009). According to one overview, the overall efficacy of monotherapy is slightly less effective to standard ART (Bierman 2009). This strategy is not recommended for treatment-naïve patients. In view of the constantly growing choice of well-tolerated combinations, it is difficult to find good arguments for monotherapy other than cost aspects.

Another approach is alternating therapy, which involves changing treatment every few weeks. In the SWATCH Study (Martinez-Picado 2003) a total of 161 patients were randomized to a regimen of d4T+ddI+efavirenz or AZT+3TC+nelfinavir. A third arm changed between the two regimens every three months when the viral load was below the level of detection. After 48 weeks, virologic failure in the alternating arm was significantly reduced. There was no difference for any other parameters (CD4 T cells, side effects, adherence, and quality of life). Considering the fact that several therapies are well-tolerated, alternating strategies, which can be very confusing for the patient, have never gained much attraction.

Induction with 4 or 5 drugs

Some experts speculate on whether more intensive approaches than conventional triple combinations are necessary for patients with high viral load. Because of fear of rapid development of resistance, some physicians give initial treatment with an induction of four or even five drugs, and then simplify to a triple combination once the viral load has dropped below the level of detection.

This theoretical concept has not yet been validated, and is based on hypotheses or smaller proof-of-concept studies (Ramratnam 2004) in which it has been shown that the viral load falls faster under intensive combinations than under standard therapies with three active drugs. Approaches in which multiple individual drugs (usually nucleoside analogs) are given have to be distinguished from approaches in which three instead of two classes of drugs are used.

Multiple individual drugs: Current data indicates that there is no benefit to using this strategy. Giving two PIs or two NNRTIs instead of one sometimes produces even negative results (Katzenstein 2000, van Leth 2004). There is also no evidence in favor of giving three instead of two NRTIs (Staszewski 2003, Orkin 2004, Mallolas 2008, Hammer 2010). In ACTG 5095 with 765 patients, there was clearly no difference between Combivir® plus efavirenz and Trizivir® plus efavirenz, not even when the starting viral load was higher, or with regard to resistance (Gulick 2005).

More drug classes: The data on whether to use three or two drug classes is less clear. However large studies on this subject, such as ACTG 388 (Fischl 2003), ACTG 384 (Robbins 2003, Schafer 2003), INITIO (Yeni 2006) or FIRST (May Arthur 2006) were conducted with old combinations with nelfinavir as the main PI and ddI+d4T as the backbone. Therefore, validity of these studies is limited. A more recent randomized study with additional doses of T-20 in late presenters showed some effect on the viral load after 24 weeks, but these results were not sustained through week 48 (Joly 2010).

In summary, it is questionable whether intensification of therapy leads to any improvement at all and produces anything more than toxicity and cost. The studies above indicate that supposed improved efficacy (not shown in many trials) is counterbalanced by more side effects. Indeed, there is the risk of scaring patients away with the higher number of pills and side effects. It is unclear whether and in which patients such intensification of therapy is useful, and which drugs would be optimal.

7. Suboptimal first-line therapies

Combinations generally considered to be suboptimal include all forms of mono- and dual therapy, especially two nucleoside analogs. Even one nucleoside analog plus one NNRTI is not good as shown by the INCAS Trial (Montaner 1998). When using NRTIs, it is important to make sure that they are not competing for the same pocket. The thymidine analogs AZT and d4T are even antagonistic (Pollard 2002). According to a warning letter by the company BMS in March 2011, d4T should generally be avoided (not only in first-line).

Full dose ritonavir can be rejected as an active agent, as the tolerability is very poor. There is no longer a reason to use ddI, indinavir or nelfinavir in a first-line regimen. Some drugs, such as T-20, etravirine, and tipranavir are not licensed for use in primary therapy. Drugs such as ddC (HIVID®), saquinavir-SGC (Fortovase®) and amprenavir (Agenerase®) have been taken off the market.

NNRTI combinations act non-competitively at the same site, and furthermore all can cause a rash, making differential diagnosis difficult. Efavirenz levels seem to be lowered considerably in combination with nevirapine (Veldkamp 2001). In the wake of the 2NN Study, it seems clear that the combination of efavirenz and nevirapine should be avoided. The study arm with this combination fared worse than the other arms, mainly due to toxicity (Van Leth 2004). NNRTIs should also not be combined with raltegravir alone – the resistance barrier is probably too low.

TDF in a triple nuke combination should not be administered. Many studies have reported poor response rates, particularly in combination with ABC+3TC (Hoogewerf 2003, Jemsek 2004, Khanlou 2005, Gallant 2005) (see Triple Nukes).

TDF+ddI: at least five trials looking at TDF+ddI plus an NNRTI resulted in a high failure rate, and some were stopped prematurely (Leon 2005, Podzamczer 2005, Maitland 2005, van Lunzen 2005, Torti 2005). BMS even issued a warning letter concerning TDF+ddI. The combination of TDF+ddI no longer has a place in antiretroviral therapy.

Starting gradually: All drugs should be started simultaneously. Highly significant differences were shown between patients who had received three drugs immediately compared to those patients who were started on only two drugs (Gulick 1998, Ait-Khaled 2002). This is significant in the long-term. A large cohort study showed that the risk of virologic failure was doubled even years later if dual therapy had been the starting regimen, even for as little as a few weeks (Phillips 2002). Initiating triple therapy gradually, as is sometimes practiced due to concerns of side effects, is wrong and dangerous.

Avoidable mistakes in first-line therapy

  • Mono- or dual therapy (except in controlled trials) as well as a gradual introduction of therapy – always start with a complete ART regimen
  • Starting at a lowered dose (except for nevirapine)
  • T-20, delavirdine, tipranavir, etravirine, maraviroc (not licensed for primary therapy in Europe)
  • ddC (HIVID®), SQV-SGC (Fortovase®), amprenavir (Agenerase®) – distribution has been stopped
  • Ritonavir (not tolerated – only for use as low-dose booster)
  • AZT+d4T and 3TC+FTC (antagonistic effects)
  • D4T in general without a good reason, if there is any
  • TDF+ddI (diverse reasons), d4T+ddI (toxicities)
  • TDF in triple-nuke therapy (especially without thymidine analogs)
  • Simultaneous introduction of ABC and NNRTIs without prior HLA testing (allergy potential)
  • Efavirenz+nevirapine (too toxic)
  • Efavirenz or nevirapine+raltegravir (low resistance barrier)


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Filed under 6. ART 2011, 6.6. What to Start With?, Part 2 - Antiretroviral Therapy

6.7. When to Switch

– Christian Hoffmann –

Antiretroviral therapy has to be modified frequently, even though the rates of modification and interruptions have declined during recent years. In EuroSIDA, among almost 1200 patients who began ART after 1999, at one year after initiation, only 70% of patients remained on their original regimen. 24% had changed, and 6% were off all treatment (Mocroft 2005). In an evaluation of the Swiss cohort, 42% of 1318 patients beginning with ART between 2005 and 2008 had modified therapy after one year, 22% of them due to side effects (Elzi 2010). In general, ART is changed for three main reasons (interruptions will be discussed separately):

  1. Acute side effects
  2. Long-term toxicity (or concerns regarding them)
  3. Virologic treatment failure

Switching due to acute side effects

Not every acute side effect requires immediate modification. Mild nausea or diarrhea at the beginning can and should be tolerated. Gastrointestinal side effects that occur during the first weeks are not dangerous and often improve spontaneously or can be treated symptomatically. The same is true for some allergic reactions and for relatively mild CNS disorders. Talking with the patient, suggestions on how to tolerate or palliate certain problems with the idea that these will not continue indefinitely will help. However, certain adverse drug events almost always require discontinuation or changing of ART (see box).

Side effects that almost always require discontinuation/change of ART

  • Severe diarrhea, which persists despite loperamide even after several weeks (usually with nelfinavir, lopinavir/r, fosamprenavir/r, saquinavir/r)
  • Severe nausea, which persists despite metoclopramide, which requires continuous treatment or leads to significant weight loss (usually AZT, ddI)
  • Persistent sleeping disorder (efavirenz)
  • Polyneuropathy (d4T, ddI, possibly also 3TC) often resolves very slowly
  • Severe anaemia (AZT)
  • Severe, progressive muscular weakness (d4T, ddI)
  • Pancreatitis (ddI, ddI+TDF, d4T+ddI, in rare cases lopinavir/r)
  • Lactic acidosis (most often d4T+ddI, but also all other NRTIs)
  • Severe allergies with involvement of mucous membranes, fever (typically aba-cavir, all NNRTIs, more rarely fosamprenavir or darunavir)
  • Renal failure (tenofovir, indinavir), nephrolithiasis (indinavir)
  • Hepatotoxicity with transaminases >5 x normal values (nevirapine, tipranavir)
  • Jaundice (nevirapine, atazanavir, indinavir, tipranavir)
  • Rhabdomyolysis (raltegravir)
  • Severe repetitive onychitis (indinavir, possibly also 3TC)
  • Depression, psychosis (efavirenz, possibly also AZT)

Switching due to concerns over long-term toxicity

In the last few years, many clinicians have started to change virologically successful combinations out of concern for cumulative long-term toxicities, especially in cases of lipodystrophy and dyslipidemia. The switch strategy is based on the assumption that not all antiretroviral agents have similar toxicities. The most important switch studies are discussed below.

PI replacement with other agentsPIs may cause side effects in the long-term. Among these are lipodystrophy with abdominal and fat accumulation at the back of the neck, but also gastrointestinal side effects and dyslipidemia. The data on replacement of a successful PI with other classes, such as NNRTI, NRTI or more recently integrase inhibitors shows the following picture: replacement is virologically safe in most cases, provided viral load is constantly suppressed and no evidence of resistance exists (see Table 7.1).

Table 7.1. Randomized studies on switching from PIs to other drugs.



VL Effect

Effect of switch on lipids (L) or lipodystrophy (LD)
PI to  NVP
Barreiro 2000




L unchanged, LD better
Ruiz 2001




L possibly better, LD unchanged
Arranz-Caso 2005




L better, LD better
Becker 2001




L unchanged
Molina 2005




L/LD n.a., side effects similar
Clumeck 2001




L better, LD subjectively better
Opravil 2002




L better, LD unchanged
Katlama 2003




L better, LD better
Keiser 2002




L better
Negredo 2002




L only better on NVP, LD unchanged
Calza 2005




L actually worse if the PI arm contained lipid reducer
Martinez 2003



Trend against ABC

L only better on ABC, LD probably unchanged
Eron 2010Martinez 2010







L betterL better
In all studies (except Martinez 2003), randomization was against continuing PIs. All had an open-label design and all patients had been on PIs for several months at the time of the switch, with undetectable viral load. VL=viral load in the switch arm versus the continuing arm. Wk=weeks, LD=lipodystrophy, L=lipids, n.a.=not available, n.s.=not significant. *Here only 62% of patients were taking a PI, the rest were on NNRTIs or a triple nuke regimen.

Taken together, these studies show that lipid levels are most likely to improve after switching to other agents, in particular abacavir and raltegravir, and to a lesser extent, efavirenz. In cases of lipodystrophy the effects are clearly poorer. Quality of life and treatment satisfaction improved significantly in the switch arms of most studies, probably due to the reduced pill burden. A large study focused on investigating quality of life showed a clear improvement after switching from PIs to efavirenz (Campo 2010).

Switching from a PI to other drugs poses an increased risk of virologic failure, particularly with prior NRTI treatment and the associated resistance mutations. One example of what could happen when the drug is changed for strategic reasons is shown in Table 7.3. This case demonstrates how careful one must be when switching drugs, if there is a past history of inadequate treatment (i.e., dual therapy).

There is a risk of a higher virological failure when switching from PI based regimens to triple nuke, especially in patients with prior NRTI pretreatment. The SWITCHMARK trials showed similar results for the integrase inhibitor raltegravir (Eron 2010). In these two large-scale phase II studies, a total of 702 patients on a stable and functioning lopinavir-containing regimen were randomized to change to raltegravir or to continue with lopinavir. Lipids improved with the switch, however after 24 weeks a non-inferiority of raltegravir compared to lopinavir/r in efficacy was seen. In the ITT analysis, only 82% of patients on raltegravir compared to 88% on the continued PI maintained viral load below the limit of detection after 24 weeks. The viral load breakthrough applied especially for pre-treated patients with previous therapy failure (66%). A smaller, open-label randomized study in Spain, did not make the same observations, however. Patients were below detection for a longer period (Martinez 2010).

Potential side effects also need to be considered with every switch. Although less frequently than with treatment naïve patients, a rash or hepatotoxicity can be expected with nevirapine, and efavirenz may be associated with adverse CNS events. There is the risk of a hypersensitivity reaction with abacavir. There is still no data on a change or a PI substitution with maraviroc yet, but it is being investigated.

Switching to atazanavir

Possibly the PI does not always have to be replaced with another drug class. In cases of dyslipidemia switching to atazanavir could make sense as it is associated with a comparably good lipid profile (Gatell 2007, Soriano 2008, Mallolas 2009). Lipodystrophy and glucose metabolism may also be improved (Stanley 2009), although not endothelial function (Flammer 2010, Murphy 2010). There may be additional favorable effects on the lipids when atazanavir is unboosted and ritonavir is omitted, which seems to work well with pretreated patients with a viral load below detection (Sension 2009, Elion 2010, Ghosn 2010). Patients must be informed about the risk of jaundice, which is typical for atazanavir.

Replacement of thymidine analogs with other NRTIs

The thymidine analog d4T, which plays a leading role in mitochondrial toxicity, is frequently replaced with other nucleoside analogs. Despite their heterogeneity, most studies show that lipoatrophy improves if d4T, and probably also AZT, is replaced (recent review: Curran 2011). In particular, the subcutaneous fat of the limbs increases, although at first the improvement is often unrecognizable clinically and can only be detected in DEXA scans (Martin 2004). Histological investigations have shown that the elevated rate of apoptosis in adipocytes normalizes when d4T has been replaced (Cherry 2005, McComsey 2005).

Based on the available data, it seems advisable to replace d4T with another nucleoside analog. According to a warning letter by the company BMS of March 2011, d4T should only be used, if other antiretroviral substances can not be applied and duration of treatment should be as short as possible and patients should change to a more suitable therapy alternative whenever possible. unfortunately, it may still need to play a role in resource-poor regions for the time being. A dose reduction may be able to reduce adverse events (McComsey 2008). With regard to AZT, a replacement should be considered when lipoatrophy becomes manifest.

To avoid a hypersensitivity reaction the patient’s HLA status should be known before switching to abacavir (Carr 2002).

Table 7.2. Controlled clinical studies on switching from d4T or AZT to other drugs (all randomized, except McComsey 2004).




Effect of switch
Carr 2002
Martin 2004


ABC instead of d4T or AZT


LA better, lipids unchanged
John 2003


AZT instead of d4T and ABC instead of PI


LA of limbs slightly better, lipids and abdominal fat unchanged
Moyle 2003


ABC instead of d4T or PI/NNRTI, or AZT+ABC instead of d4T+PI


LA better (when replacing d4T)Lipids better (when replacing PI)
McComsey 2004


AZT or ABC instead of d4T


LA better, lactate better
Moyle 2005


TDF or ABC instead of d4T or AZT


LA better, lipids better on TDF
Valantin 2010


TDF+FTC instead of 2 NRTIs


Lipids better
Fischer 2009


TDF+FTC instead of AZT+3TC


LA better, lipids better
Ribera 2008


TDF instead of D4T


Lipids better, lactate better, LA slowly better
Tebas 2009


ABC or nuke sparing instead of d4T or AZT


LA better
Milinkovic 2007


TDF or d4T reduction (30 mg) instead of d4T


LA, lipids better (TDF effects better than d4T reduction)
No study showed any difference with respect to virologic failure. Wk=weeks, LA=lipoatrophy. In McComsey 2004 and Moyle 2005, only patients with LA were investigated.

Switching to tenofovir

Studies on therapy-naïve patients have shown that the short-term toxicity of tenofovir is lower than of d4T or AZT (Gallant 2004+2006). In the 903 Study, lipids improved in patients that were switched from d4T to tenofovir. There was also an increase of the mean limb fat after three years (Madruga 2007). Several studies, some of them randomized trials, point in the same direction. Lipids, lipoatrophy and mitochondrial toxicity and patient’s satisfaction improve on tenofovir (Milinkovic 2007, DeJesus 2008, Ribera 2008, Fischer 2010).

Recently, a double-blind, placebo-controlled, randomized study showed unexpected results. In ACTG A5206, the addition of tenofovir alone to existing virologically-suppressed ART regimens improved lipid parameters compared to placebo (Tungsiripat 2010). However, the mechanism of the lipid-lowering effect warrants further study. In a retrospective study, replacing d4T with tenofovir improved both lipids and liver enzymes (Schewe 2006).

It must be noted that negative effects may arise when switching too quickly to tenofovir. Randomized studies have observed a stronger reduction of bone density on tenofovir, compared to other NRTIs (Martin 2009, Stellbrink 2010). The potential nephrotoxicity of tenofovir is another point. Switching to tenofovir-containing triple nuke combinations must be avoided, as several studies have shown a high risk for an increase in viral load when switching to this combination (Hoogewerf 2003, Perez-Elias 2005), even after many years on successful ART. The resistance barrier is too low, as the following example shows.

Table 7.3. Example of what could happen on switching drugs (n.k.=not known).
Date ART

CD4 cells

Viral load

1996-98 AZT+ddC



Since 1998 AZT+3TC+NFV (always under the limit of detection)



Nov. 2002 Findings: significant lipoatrophy. Decision to switch



Feb. 2003 ABC+3TC+NFV



Apr. 2003 ABC+TDF+NVP (= targeted regimen,  notes below)



May 2003 Severe rash, ALT/AST > 500 U/l



Jun. 2003 ABC+TDF+3TC
Aug. 2003 Resistance: M41L+D67N+M184V+L210W+T215Y



Sep. 2003 AZT+3TC+NFV



Oct. 2003



Oct. 2004



Notes: On account of possible allergies to both ABC and NVP, ART was changed in February 2003 in two steps. Rash with hepatic involvement occurred on NVP, so in July 2003 NVP was replaced by 3TC – a triple nuke. The resistance mutations then detected were acquired almost certainly on the earlier treatment with AZT+ddC, but sufficiently suppressed while on PI therapy.

In practice, changes are often made that go further than PI and d4T/AZT, such as replacement of ddI, simply due to concerns over long-term toxicity. Such switching is based on laboratory studies showing a certain hierarchy with respect to mitochondrial toxicity (see chapter on Mitochondrial Toxicity).

A lot of attention is being drawn to simplification of therapy, in which mono- or nuke-sparing strategies are being used (see below). So far, there is no clear clinical evidence to show that this procedure has any benefit for the patient. If the patient has no complaints, a switch to monotherapy or nuke-sparing can not be justified and subjects the patient to unnecessary risks. Below, current data on this topic will be discussed.

Switching to nuke-sparing

Nuke-sparing is the attempt to completely avoid NRTIs in antiretroviral therapy. In treatment-naïve patients nuke-sparing proved virologically effective (see previous chapter) and is presently being investigated in treatment experienced patients with well suppressed viral load (Table 7.4). Data however is still very limited.

In ACTG 5116, the largest study so far with 236 patients on successful ART, the switch to lopinavir/r plus efavirenz compared to efavirenz plus NRTIs led to higher discontinuation rates due to increased virologic failure and other side effects (Fishl 2007). The results of this study are contrary to those of some other studies and to the results of lopinavir/r plus efavirenz with ART-naïve patients (Riddler 2008). At this point in time, it seems too early to recommend nuke-sparing as a transition strategy simply on the basis of theory. This not only concerns the new drug classes of integrase inhibitors and CCR5 antagonists (no data yet), but also monotherapies with boosted PIs (see below). Several studies are ongoing with raltegravir in combination with atazanavir/r (BATAR), darunavir/r (RALDAR, SPARE) and lopinavir/r (KITE). Results are expected in one to two years.

Table 7.4. Studies on switching to nuke-sparing regimens.


Switch to


Main effects of the switch




Lopez-Corles 2003




Virologically effective
Boyd 2005(HIVNAT 009)




Virologically effective, but many side effects due to IDV, LA probably slightly better
Negredo 2009 (MULTINEKA)




Virologically effective, lipids and mitochondrial DNA better
Tebas 2009 (ACTG 5110)




Virologically effective, lipodystrophy better
Tebas 2007 (ACTG 5125)




Many metabolic disturbances and LA better
Fischl 2007 (ACTG 5116)




Trend towards more virologic failure, more side effects
Ruane 2009




Virologically safe, but in 26% blips
Allavena 2009




Virologically safe
Ripamonti 2009 (CARDS)




Virologically safe, good PK data also for ATV (unboosted)
LA = lipoatrophy, * in Switch Arm (these studies were randomized) ** 7 patients received other PIs, among them 4 atazanavir

Switching due to virologic failure

Any change in treatment due to virologic failure requires experience, a certain degree of finesse and decisiveness. There are many possibilities for mistakes here. On the one hand, there is a threat of acquiring more resistance (if they have not already developed), but on the other hand, young physicians often want to quickly change treatment, which is not always necessarily the right solution. In many cases a frequent change of therapy confuses the patient and causes anxiety. If the problem is adherence, switching the regimen without talking about adherence may not be the solution. A switch only brings up more misunderstandings and, consequently, may generate later resistance. It is always important to explain to patients, who often tend to be skeptical (“should I save the other drugs for later?”) when and why treatment changes must be made.

As a rule of thumb, ART should be changed quickly with insufficient viral suppression and/or a rise in plasma viremia, as otherwise future options could be limited. One speaks of insufficient viral suppression or virologic failure if the viral load is repeatedly above the level of detection. A switch is not recommended with temporary viremia (blips – more on this topic in the chapter Principles of Therapy). Even single point mutations can be a problem. Abacavir, 3TC, FTC and ddI lose their efficacy in the presence of the K65R mutation, which is often selected by tenofovir-containing triple nuke therapies. Viral replication with insufficient plasma levels are the best breeding ground for resistance. Therefore, it is recommended to act fast if a clear virologic failure should occur. The longer one waits, the more complicated it becomes. An insufficient viral suppression means, as stated before, a repeated viral load above 50 copies/ml. Some clinicians tolerate levels of up to 500 or even 1000 copies/ml for months. We believe such hesitation is not justified in most cases when patients have good options and good adherence. A patient’s frequent assertions of not having symptoms should not count too much, either. Obviously, such thoughts do not always play a role in clinical reality. In an analysis in Great Britain 34% out of 694 patients remained on a virologically unsuccessful combination for over 6 months. Factors associated with an early switch were low CD4 T cells, a high viral load and older age (Lee 2008).

Arguments for a rapid switch in the case of virologic failure Arguments for a later switch in the case of virologic failure
The virus becomes incapable of generating more resistance New therapies bear the risk of new toxicities/ intolerance, which can lead to a termination of therapy
Options are maintained Most patients are immunologically stable for a long time with low viremia (clinically)
The switch is more successful with less resistance Replication fitness is reduced on failing treatment
The lower the viral load at time of switch, the better the response to the new therapy Resistance testing is often not possible with low viral load, even though they are there, so you may switch “blindly”
The following regimens do not have to be as complex as the present one – some things can be simplified (QD, no more d4T/ddI, etc.) It is sometimes difficult to explain to the patient why change of a well-tolerated and simple regimen is necessary

To date, only a few randomized trials have investigated two randomized strategies in patients in whom several ART combinations have failed: either the patients change immediately or when the viral load reaches a certain level (early versus deferred switch). The preliminary results of some small randomized studies indicate that even in such cases one can wait a short time (Nasta 2006, Tenorio 2009). However, these trials were small. It seems difficult to recruit physicians and patients to participate in such strategy trials.

With failing PI therapies there is more time. In the prospective Johns Hopkins Cohort there was no association between a deferral of ART modification and mortality in the course of treatment in patients on a PI showing virologic failure (Petersen 2008). This is why in the TITAN study, the number of acquired PI mutations had no effect on the success of darunavir/r, although it did play a role for lopinavir/r (De Meyer 2008).

In cases of clinical treatment failure (disease progression) or immunological failure (stagnation or decrease in the level of CD4 T cells) where the viral load remains below 50 copies/ml, the value of a change in therapy is unclear. Some combinations such as TDF+ddI are clearly unfavorable for immunological reconstitution (Negredo 2004). This may also be the case for AZT-containing regimens; such combinations should be changed.

It is important that when virologic failure occurs, the individual situation of the patient is carefully analyzed. In particular, several questions need to be addressed:

What are the reasons for the measurable viral load? A viral load above 50 copies/ml does not necessarily mean that resistance mutations have developed. A frequent cause may be a blip (see section on Goals and Principles of ART). These transient and, almost always, small increases in viral load usually have no relevance. However, a measurable viral load may be due to treatment failure. It may indicate insufficient plasma drug levels (measure these if possible). This may be due to drug malabsorption, drug interactions or simply insufficient dosing (e.g., in larger, heavy patients).

How is the patient’s adherence? Adherence is critical. Any difficulties related to the regimen should be openly addressed. Is it the number of pills? Do restrictions in food intake cause problems? Would once-daily treatment be better? Are there other reasons, such as depression? Any misunderstanding on how to take the drugs? The risks of resistance development as a result of non-compliance should be reiterated. If plasma levels are sufficient and viral load remains detectable (monitor blips at short intervals – within a few weeks), treatment should be changed as soon as possible.

How vulnerable is the present combination? NNRTI regimens are extremely sensitive, and cross-resistance can develop particularly rapidly for the class. A prompt change in therapy is more vital than with the other drug classes. Delaying this by even a few days or weeks may be too long. Rapid development of resistance can also be expected with 3TC/FTC and probably with the integrase inhibitor raltegravir. A PI-containing regimen without an NNRTI may allow a little more time, but the credo still applies. The higher the viral load at the time of modification, the lower the chance of success. One should not wait too long.

What options does the patient have, and what are the consequences of the change in therapy? The more options that remain available the sooner they should be utilized. Therapy can often be intensified quite easily (e.g., adding abacavir plus an NNRTI). In such cases, the decision to change or intensify a regimen is less difficult. On the other hand, it may be advisable in certain circumstances to continue therapy in a patient, even if the plasma viremia is not completely suppressed. Often, the viral load does not rise above the baseline value, and the CD4 T cells remain stable or even increase. Some experts advocate waiting in these cases. Resistance to nucleoside analogs are to be expected, so NNRTIs and PIs can be saved by waiting.

Even when multiple resistance mutations are already present, one is probably able to wait (see above). Especially in patients with adherence problems, it does not make sense to run through new drug classes. Adherence will not automatically be better with newer regimens. One should talk with the patient, find out what needs to be made better, and clarify if they are really ready for intensification or modification of therapy.

Virologic failure: to be considered before changing therapy

  • How resistance-sensitive is the present therapy? NNRTIs, 3TC/FTC, raltegravir: rapid development of resistance, change quickly
  • The lower the viral load, the greater the prospect of success with a change
  • Are you sure it is virologic failure and not a temporary blip?
  • Are there other reasons for a detectable virus load? What about malabsorption/drug uptake?
  • Do you know all the other therapies the patient is taking? Ask. Whether a gastric stimulant prescribed by the family doctor (i.e., PPIs) or herbal agents prescribed by an alternative practioner, it should all be laid out
  • Has the patient been adherent to current ART or have there been misunderstandings? Was the therapy discontinued ad hoc?
  • What do the plasma levels say and what does the patient say?
  • What options are there and what does a change mean for the patient? Is the patient able to start a new therapy?
  • Does a reasonably up-to-date resistance test exist? (if not, do one)
  • If relevant mutations against the current agents have already developed, calmly wait and prepare the patient for a new regimen, possibly with more adherence counseling

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Filed under 6. ART 2011, 6.7. When to Switch?, Part 2 - Antiretroviral Therapy