Category Archives: 6.2. Overview of Antiretroviral Agents

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

Abbrev.

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

FTC

Emtricitabine Gilead Sciences
Epivir®

3TC

Lamivudine ViiV Healthcare
Retrovir®

AZT

Zidovudine ViiV Healthcare
Videx®

DDI

Didanosine Bristol Myers-Squibb
Viread®

TDF

Tenofovir Gilead Sciences
Zerit®

D4T

Stavudine Bristol Myers-Squibb
Ziagen®

ABC

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

EFV

Efavirenz BMS/MSD
Viramune®

NVP

Nevirapine Boehringer
Edurant®*

RPV

Rilpivirine Janssen-Cilag
Intelence®

ETV

Etravirine Janssen-Cilag
Rescriptor®*

DLV

Delavirdine ViiV Healthcare
Protease-Inhibitors (PIs)
Aptivus®

TPV

Tipranavir Boehringer
Crixivan®

IDV

Indinavir MSD
Invirase®

SQV

Saquinavir Roche
Kaletra®

LPV

Lopinavir/Ritonavir Abbott
Norvir®

RTV

Ritonavir Abbott
Prezista®

DRV

Darunavir Janssen-Cilag
Reyataz®

ATV

Atazanavir Bristol Myers-Squibb
Telzir®, Lexiva®

FPV

Fosamprenavir ViiV Healthcare
Viracept®

NFV

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

MVC

Maraviroc ViiV Healthcare
Fuzeon®

T-20

Enfuvirtide Roche
Integrase Inhibitors
Isentress®

RAL

Raltegravir MSD
Combination Drugs
Atripla®

ATP

TDF+FTC+EFV Gilead+BMS+MSD
Combivir®

CBV

AZT+3TC ViiV Healthcare
Complera®*

CPL

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

KVX

3TC+ABC ViiV Healthcare
Trizivir®

TZV

AZT+3TC+ABC ViiV Healthcare
Truvada®

TVD

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.

3TC

ABC

ddI

d4T

FTC

TDF

AZT

3TC

+++

++

+

++

++

ABC

+++

0

0

0

0

+

ddI

+

0

0

0

d4T

+

0

0

0

FTC

0

0

0

+++

0

TDF

++

0

0

+++

0

AZT

++

+

0

0

0

+++ 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).

TDF+FTC

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.

ABC+3TC

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.

AZT+3TC

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).

References

Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J AIDS 2008, 47:74-8.

Behrens GM, Reiss P. Abacavir and cardiovascular risk. Curr Opin Infect Dis 2010, 23:9-14.

Benson CA, van der Horst C, Lamarca A, et al. A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV. AIDS 2004, 18:2269-76.

Berenguer J, González J, Ribera E, et al. Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903. Clin Infect Dis 2008, 47:1083-92.

Bonjoch A, Paredes R, Galvez J, et al. Antiretroviral treatment simplification with 3 NRTIs or 2 NRTIs plus nevirapine in HIV-1-infected patients treated with successful first-line HAART. J AIDS 2005, 39:313-6.

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 ART-related lipodystrophy. Lancet 1999, 354:1112-5.

Brothers CH, Hernandez JE, Cutrell AG, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J AIDS 2009;51:20-28.

Campbell T, Smeaton L, Kumarasamy N, et al. Efficacy and Safety of EFV with either Co-formulated 3TC/ZDV or FTC/TDF for Initial Treatment of HIV-1-infected Men and Women in Diverse Multinational Settings: ACTG PEARLS Study. Abstract 149LB, 18th CROI 2011, Boston.

Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002, 288:207-15.

Clumeck N, Goebel F, Rozenbaum W, et al. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS 2001, 15:1517-26.

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

Cooper D, Bloch M, Humphries, et al. Simplification with fixed-dosed tenofovir/emtricitabine or abacavir/lamivudine in adults with suppressed HIV replication: the STEAL study, a randomized, open-label, 96-week, non-inferiority trial. Abstract 576, 16th CROI 2009 Montréal.

Crane H, Harrington R, Van Rompaey S, Kitahata M. Didanosine and lower baseline body weight are associated with declining renal function among patients receiving tenofovir. Abstr. 780, 13th CROI 2006, Denver.

Crespo M, Ribera E, Suárez-Lozano I, et al. Effectiveness and safety of didanosine, lamivudine and efavirenz versus zidovudine, lamivudine and efavirenz for the initial treatment of HIV-infected patients from the Spanish VACH cohort. J Antimicrob Chemother 2009, 63:189-96.

De la Rosa R, Harris M, Uyeda L, et al. Life-threatening reaction after first ever dose of abacavir in an HIV-1-infected patient. AIDS 2004, 18:578-9.

DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004, 39:1038-46.

DeJesus E, McCarty D, Farthing CF, et al. Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection. CID 2004, 39:411-8.

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.

El-Sahly HM. Development of abacavir hypersensitivity reaction after rechallenge in a previously asymptomatic patient. AIDS 2004,18:359-60.

Eron JJ JR, Murphy RL, Peterson D, et al. A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II). AIDS 2000, 14: 1601-10.

Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. New Eng J Med 1995, 333:1662.

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.

Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, Plazebo-controlled trial. N Engl J Med 1987; 317:185-91.

Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic HIV infection. A double-blind, Plazebo-controlled trial. Ann Intern Med 1990; 112:727-37.

Frampton JE, Perry CM. Emtricitabine: a review of its use in the management of HIV infection. Drugs 2005, 65:1427-48.

Fux C, Simcock M, Wolbers M, et al. Tenofovir treatment is associated with a decrease in calculated glomerular filtration rates in a large observational cohort. Abstract 834, 14th CROI 2007, Los Angeles.

Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006, 354:251-60.

Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005, 40:1194-8.

Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004, 292: 191-201.

Gallant JE, Winston JA, DeJesus E, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS 2008, 22:2155-63.

Galli M, Ridolfo AL, Adorni F, et al. Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. JAIDS 2002, 29: 21-31.

Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004, 350:1850-1861.

Harrigan PR Stone C, Griffin P, et al. Resistance profile of the HIV type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. JID 2000, 181:912-920.

Harris M, Back D, Kewn S, et al. Intracellular carbovir triphosphate levels in patients taking abacavir once a day. AIDS 2002, 16:1196-7.

Havlir DV, Gilbert PB, Bennett K, et al. Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression. AIDS 2001, 15: 1379-88.

Havlir DV, Tierney C, Friedland GH, et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis 2000, 182: 321-5.

Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002, 359:1121-2.

Hoy JF, Gahan ME, Carr A, et al. Changes in mitochondrial DNA in peripheral blood mononuclear cells from HIV-infected patients with lipoatrophy randomized to receive abacavir. J Infect Dis 2004, 190:688-92.

Jablonowski H, Arasteh K, Staszewski S, et al. A dose comparison study of didanosine in patients with very advanced HIV infection who are intolerant to or clinically deteriorate on zidovudine. AIDS 1995, 9:463-469.

John M, McKinnon EJ, James IR, et al. Randomized, controlled, 48 week study of switching stavudine and/or protease inhibitors to Combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. JAIDS 2003, 33: 29-33.

Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in HIV-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003; 36:1070-1073

Katlama C, Fenske S, Gazzard B, et al. TRIZAL study: switching from successful HAART to Trizivir (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Medicine 2003, 4: 79-86.

Kirk O, Mocroft A, Reiss P, et al. Chronic kidney disease and exposure to ART in a large cohort with long-term follow-up: The EuroSIDA Study. Abstract 107LB, 17th CROI 2010, San Francisco.

Kuritzkes DR, Marschner I, Johnson VA, et al. Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. AIDS 1999, 13:685-94.

Llibre JM, Domingo P, Palacios R, et al. Sustained improvement of dyslipidaemia in HAART-treated patients replacing stavudine with tenofovir. AIDS 2006, 20:1407-14.

Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002, 359:727-32.

Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008, 358:568-79.

Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 2000, 14:1309-1316.

Martin A, Bloch M, Amin J, et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clin Infect Dis 2009, 49:1591-601.

Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz or abacavir for protease inhibitors in patients with HIV infection. N Eng J Med 2003, 349:1036-46.

Martinez E, Arranz JA, Podzamczer D, et al. Efficacy and safety of NRTIs switch to tenofovir plus emtricitabine (vs. abacavir plus lamivudine (Kivexa) in patients with virologic suppression receiving a lamivudine containing HAART: the BICOMBO study. Abstract WESS102, 4th IAS 2007, Sydney.

Martinez E, Milinkovic A, de Lazzari E, et al. Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults. Lancet 2004, 364:65-7.

Martinez-Picado J, Negredo E, Ruiz L, et al.  Alternation of antiretroviral drug regimens for HIV infection. Ann Intern Med 2003; 139: 81-9.

Mathias AA, Hinkle J, Menning M, Hui J, Kaul S, Kearney BP. Bioequivalence of efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen. J Acquir Immune Defic Syndr 2007;46:167-73.

Mauss S, Berger F, Schmutz G. Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS 2005, 19:93-5.

Mauss S, Corzillius M, Wolf E, et al. Risk factors for the HIV-associated lipodystrophy syndrome in a closed cohort of patients after 3 years of antiretroviral treatment. HIV Med 2002, 3:49-55.

Miller V, Stark T, Loeliger AE, Lange JM. The impact of the M184V substitution in HIV-1 reverse transcriptase on treatment response. HIV Med 2002, 3:135-45.

Mokrzycki MH, Harris C, May H, et a. Lactic acidosis associated with stavudine administration: a report of 5 cases. CID 2000, 30:198-200.

Molina JM, Chene G, Ferchal F, et al. The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with HIV. J Infect Dis 1999, 180: 351-8.

Molina JM, Journot V, Morand-Joubert L, et al. Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. J Infect Dis 2005, 191:830-9.

Molina JM, Marcelin AG, Pavie J, et al. Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial. J Infect Dis 2005, 191:840-7.

Moyle G, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48 week, randomized, open label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J AIDS 2003, 33: 22-28.

Moyle G, Boffito M. Unexpected drug interactions and adverse events with antiretroviral drugs. Lancet 2004, 364:8-10.

Moyle GJ, Dejesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the ziagen once daily in antiretroviral combination study. J AIDS 2005;38:417-425.

Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in HIV infection. J Inf Dis 2002, 185:1251-1260.

Peyriere H, Reynes J, Rouanet I, et al. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J AIDS 2004, 35:269-73.

Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med 2001, 344:984-96.

Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J AIDS 2010, 55:49-57.

Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes–a 96-week analysis. J AIDS 2006; 43: 535-40.

Robbins BL, Srinivas RV, Kim C, et al. Anti-HIV activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-PMPA), Bis PMPA. Antimicrob Agents Chemother 1998, 42:612-7.

Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2293-303.

Rousseau FS, Wakeford C, Mommeja-Marin H, et al. Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in HIV-infected patients. J Infect Dis 2003;188:1652-8.

Saag MS, Cahn P, Raffi F, et al. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 2004, 292:180-9.

Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008, 371:1417-1426.

Saravolatz LD Winslow DL, Collins G, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the AIDS or fewer than 200 CD4 cells per cubic millimeter. New Eng J Med 1996, 335:1099-1106.

Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure (VF) with abacavir/lamivudine than tenofovir/emtricitabine as part of combination therapy in treatment-naïve subjects with screening HIV RNA ³100,000 c/mL. Abstract THAB0303, XVII IAC 2008, Mexico.

Schaaf B, Aries SP, Kramme E, et al. Acute renal failure associated with tenofovir treatment in a patient with AIDS. CID 2003, 37:e41-3.

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

Suo Z, Johnson KA. Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-Phosphonylmethoxypropyl)adenine. J Biol Chem 1998, 273:27250-8.

Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004, 48:2091-6.

Tebas P, Zhang J, Hafner R, et al. Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110. J Antimicrob Chemother 2009 Mar 19.

Valdez JR, Cassetti I, Suleiman JM, et al. The safety and efficacy of switching stavudine to tenofovir df in combination with lamivudine and efavirenz in hiv-1-infected patients: three-year follow-up after switching therapy. HIV Clin Trials 2007;8:381-90.

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.

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).
 

Nevirapine

Efavirenz

CNS side effects

Rare

58-66%

Severe CNS side effects

Very rare

5-7%

Hepatotoxicity

17%

8%

Dyslipidemia

No

Frequent

Gynecomastia

No

Occasional

Rash

15%

5%

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.

References

Andries K, Azijn H, Thielemans T, et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48:4680-6.

Calmy A, Nguyen A, Lange J, et al. Nevirapine administered once daily is as efficient as a twice-daily dosing. a collaborative cohort study. Abstract 786, 15th CROI 2008, Boston.

Chu KM, Boulle AM, Ford N, et al. Nevirapine-associated early hepatotoxicity: incidence, risk factors, and associated mortality in a primary care ART programme in South Africa. PLoS One 2010, 5:e9183.

Cohen CJ, Berger DS, Blick G, et al. Efficacy and safety of etravirine (TMC125) in treatment-experienced HIV-1-infected patients: 48-week results of a phase IIb trial. AIDS 2009, 23:423-6.

Conway B. Initial therapy with protease inhibitor-sparing regimens: evaluation of nevirapine and delavirdine. Clin Infect Dis. 2000, Suppl 2:S130-4.

Cozzi-Lepri A, Phillips AN, d’Arminio Monforte A, et al. Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the I.Co.N.A.) study. J Infect Dis 2002, 185: 1062-9.

Cunningham CK, Chaix ML, Rekacewicz C, et al. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal HIV type 1 transmission: a substudy of pediatric ACTG 316. JID 2002, 186:181-8.

Daar E, Tierney C, Fischl M, et al. ACTG 5202: Final results of ABC/3TC or TDF/FTC with either EFV or ATV/r in treatment-naive HIV-infected patients.  Abstract 59, 17th CROI 2010, San Francisco.

D’Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med 1996, 124:1019-30.

Das K, Clark AD Jr, Lewi PJ, et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related NNRTIs that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 2004;47:2550-60.

De Lazzari E, León A, Arnaiz JA, et al. Hepatotoxicity of nevirapine in virologically suppressed patients according to gender and CD4 cell counts. HIV Med 2008, 9:221-6.

Fumaz CR, Tuldra A, Ferrer MJ, et al. Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus PI-containing regimens. J AIDS 2002, 29:244-53.

Gallego L, Barreiro P, del Rio R, et al. Analyzing sleep abnormalities in HIV-infected patients treated with Efavirenz. Clin Infect Dis 2004, 38:430-2.

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.

Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC 125 – new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003;17:F49-54.

GESIDA 26/02 Study Group. Failure of Cetirizine to prevent nevirapine-associated rash: a double-blind placebo-controlled trial for the GESIDA 26/01 Study. J Acquir Immune Defic Syndr 2004, 37:1276-1281.

Gruzdev B, Rakhmanova A, Doubovskaya E, et al. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS 2003;17: 2487-94.

Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004, 350:1850-1861.

Gutiérrez-Valencia A, Viciana P, Palacios R, et al. Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events: a randomized trial. Ann Intern Med. 2009, 151:149-56.

Haas DW, Bartlett JA, Andersen JW, et al. Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult ACTG collaboration. Clin Infect Dis 2006, 43:783-6.

Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18:2391-2400.

Haïm-Boukobza S, Morand-Joubert L, Flandre P, et al. Higher efficacy of nevirapine than efavirenz to achieve HIV-1 plasma viral load below 1 copy/ml. 70. AIDS 2011, 25:341-4.

Harris M, Alexander C, O’Shaughnessy M, Montaner JS. Delavirdine increases drug exposure of ritonavir-boosted protease inhibitors. AIDS 2002; 16: 798-9.

Hirschel B, Perneger T. No patient left behind–better treatments for resistant HIV infection. Lancet 2007; 370:3-5.

Johnson JA, Li JF, Morris L, et al. Emergence of drug-resistant hiv-1 after intrapartum administration of single-dose nevirapine is substantially underestimated. J Infect Dis 2005, 192:16-23.

Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004, 351:229-40.

Kakuda TN, Schöller-Gyüre M, Workman C, et al. Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients. Antivir Ther 2008, 13:655-61.

Kakuda TN, Wade JR, Snoeck E, et al. Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther 2010, 88:695-703.

Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005, 10:489-98.

Katlama C, Clotet B, Mills A, et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther 2010, 15:1045-52.

Launay O, Roudiere L, Boukli N, et al. Assessment of cetirizine, an antihistamine, to prevent cutaneous reactions to nevirapine therapy: results of the viramune-zyrtec double-blind, placebo-controlled trial. Clin Infect Dis 2004, 38:e66-72.

Lazzarin A, Campbell T, Clotet B, et al. DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:39-48.

Lochet P, Peyriere H, Lotthe A, et al. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 2003, 4:62-6.

Lockman S, Hughes MD, McIntyre J, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. NEJM 2010, 363:1499-509.

MacArthur RD, Novak RM, Peng G, et al. A comparison of three HAART strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial. Lancet 2006, 368:2125-35.

Madruga JV, Cahn P, Grinsztejn B, et al. DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:29-38.

Manfredi R, Calza L. Nevirapine versus efavirenz in 742 patients: no link of liver toxicity with female sex, and a baseline CD4 cell count greater than 250 cells/microl. AIDS 2006, 20:2233-6.

Martin AM, Nolan D, James I, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS 2005, 19:97-9.

Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz or abacavir for protease inhibitors in patients with HIV infection. N Eng J Med 2003; 349:1036-46.

Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001, 15: 71-5.

Mbuagbaw LC, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals. Cochrane Database Syst Rev 2010, 12:CD004246.

McIntyre J, M Hughes M, J Mellors J, et al. Efficacy of ART with NVP+TDF/FTC vs LPV/r+TDF/FTC among antiretroviral-naïve women in Africa: OCTANE Trial 2/ACTG A5208. Abstract 153LB, 17th CROI 2010, San Francisco.

Miller V, Staszewski S, Boucher CAB, Phair JP. Clinical experience with NNRTIs. AIDS 1997, 11 (suppl A): S157-164.

Mocroft A, Staszewski S, Weber R, et al. Risk of discontinuation of nevirapine due to toxicities in antiretroviral-naive and -experienced HIV-infected patients with high and low CD4+ T-cell counts. Antivir Ther 2007;12:325-33.

Muro E, Droste JA, Hofstede HT, et al. Nevirapine plasma concentrations are still detectable after more than 2 weeks in the majority of women receiving single-dose nevirapine: implications for intervention studies. J AIDS 2005; 39:419-421.

Nguyen A, Calmy A, Delhumeau C, et al. A randomized crossover study to compare efavirenz and etravirine treatment. AIDS 2011, 25:57-63.

Parienti JJ, Massari V, Rey D, Poubeau P, Verdon R. Efavirenz to nevirapine switch in HIV-1-infected patients with dyslipidemia: a randomized, controlled study. Clin Infect Dis 2007;45:263-6.

Piketty C, Gerard L, Chazallon C, et al. Virological and immunological impact of non-nucleoside reverse transcriptase inhibitor withdrawal in HIV-infected patients with multiple treatment failures. AIDS 2004, 18:1469-71.

Podzamczer D, Olmo M, Sanz J, et al. Safety of switching nevirapine twice daily to nevirapine once daily in virologically suppressed patients. JAIDS 2009, 50:390-6.

Rahim S, Ortiz O, Maslow M, et al. A case-control study of gynecomastia in HIV-1-infected patients receiving HAART. AIDS Read 2004, 14:23-4.

Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008, 358:2095-106.

Ritchie MD, Haas DW, Motsinger AA, et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity. Clin Infect Dis 2006, 43:779-82.

Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349: 2293-303.

Ruxrungtham K, Pedro RJ, Latiff GH, et al. Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naïve, NNRTI-experienced patients: study TMC125-C227. HIV Med 2008, 9:883-96.

Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005;191:825-9.

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.

Sheran M. The NNRTIs efavirenz and nevirapine in the treatment of HIV. HIV Clin Trials 2005, 6:158-68.

Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J AIDS 2004; 36: 1011-1019.

Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. NEJM 1999, 341:1865-73.

Storfer S, Leith J, Piliero P, Hall D. Analysis of hepatic events within the 2NN study: controlling for ethnicity and CD4+ count at initiation of nevirapine therapy. Abstract PE9.6/2. 10th EACS 2005. Dublin.

Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of hepatitis C or B virus infection. JAMA 2000, 283: 74-80.

Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002, 35:182-9.

Tambuyzer L, Vingerhoets J, Azijn H, et al. Characterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies. AIDS Res Hum Retroviruses 2010, 26:1197-205.

TMC125-C223 Writing Group. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS 2007; 21:F1-10.

Torre D, Tambini R, Speranza F. Nevirapine or efavirenz combined with two nucleoside reverse transcriptase inhibitors compared to HAART: a meta-analysis of randomized clinical trials. HIV Clin Trials 2001, 2: 113-21.

Trottier B, Di Perri G, Madruga JV, et al. Impact of the background regimen on virologic response to etravirine: pooled 48-week analysis of DUET-1 and -2. HIV Clin Trials 2010, 11:175-85.

van den Berg-Wolf M, Hullsiek KH, Peng G, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. HIV Clin Trials 2008, 9:324-36.

Van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS 2001, 15: 2407-14.

Van Heeswijk RP, Veldkamp AI, Mulder JW, et al. The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals. AIDS 2000, 14:F77-82.

Van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003, 17:987-99.

Van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004, 363:1253-63.

Vingerhoets J, Azijn H, Fransen E, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 2005;79:12773-82.

Waters L, Fisher M, Winston A, et al. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS 2011, 25:65-71.

Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis 2005, 192:958-66.

Winston A, Pozniak A, Smith N, et al. Dose escalation or immediate full dose when switching from efavirenz to nevirapine-based highly active antiretroviral therapy in HIV-1-infected individuals? AIDS 2004, 18:572-4.

Wit FW, Kesselring AM, Gras L, et al. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA Cohort Study. Clin Infect Dis 2008.

Wolf E, Koegl C, Theobald T, et al. Nevirapine-associated hepatotoxicity: no increased risk for females or high CD4 count in a single-centre HIV cohort. Abstract H1063, 46th ICAAC 2006, San Francisco.

Wyen C, Hendra H, Vogel M, et al. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. J Antimicrob Chemother 2008.

Yazdanpanah Y, Sissoko D, Egger M, et al. Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or NNRTIs: indirect comparison of controlled trials. BMJ 2004, 328:249.

Yuan J, Guo S, Hall D, et al. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS 2011 Apr 18. [Epub ahead of print]

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)

Pills*/day

Comments
Atazanavir/r

1 x 300/100

1 x 2

No limitation
Darunavir/r

2 x 600/100

2 x 2

No limitation
Darunavir/r

1 x 800/100

1 x 3

Only approved in PI-naïve patients
Fosamprenavir/r

2 x 700/100

2 x 2

Should be used instead of amprenavir
Fosamprenavir/r

1 x 1400/200

1 x 4

Approval only in US (PI-naïve patients)
Indinavir/r

2 x 800/100

2 x 3

Higher rate of nephrolithiasis (?)
Lopinavir/r

2 x 400/100

2 x 2

The only fixed booster combination
Lopinavir/r

1 x 800/200

1 x 4

PI-naive patients
Saquinavir/r

2 x 1000/100

2 x 3

Officially approved for boosting
Tipranavir/r

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.

References

Albrecht M, Bosch RJ, Hammer SM, et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. New Eng J Med 2001, 345:398-407.

Ananworanich J, Hirschel B, Sirivichayakul S, et al. Absence of resistance mutations in antiretroviral-naive patients treated with ritonavir-boosted saquinavir. Antivir Ther. 2006;11:631-635.

Anson BD, Weaver JG, Ackerman MJ, et al. Blockade of HERG channels by HIV protease inhibitors. Lancet 2005, 365:682-6.

Baxter J, Schapiro J, Boucher C, Kohlbrenner V, Hall D, Scherer J, Mayers D. Genotypic changes in HIV-1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir. J Virol 2006, 80:10794-10801.

Bittner B, Riek M, Holmes B, Grange S. Saquinavir 500 mg film-coated tablets demonstrate bioequivalence to saquinavir 200 mg hard capsules when boosted with twice-daily ritonavir in healthy volunteers. Antivir Ther 2005, 10:803-10.

Cahn P, FourieJ, Grinsztejn  B, et al. Efficacy and safety at 48 weeks of once-daily vs twice-daily DRV/r in treatment-experienced HIV-1+ patients with no DRV resistance-associated mutations: The ODIN Trial. Abstract 57, 17th CROI 2010, San Francisco.

Calza L, Manfredi R, Colangeli V, et al. Efficacy and safety of atazanavir-ritonavir plus abacavir-lamivudine or tenofovir-emtricitabine in patients with hyperlipidaemia switched from a stable protease inhibitor-based regimen including one thymidine analogue. AIDS Patient Care STDS 2009, 23:691-7.

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.

Carey D, Amin J, Boyd M, Petoumenos K, Emery S. Lipid profiles in HIV-infected adults receiving atazanavir and atazanavir/ritonavir: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2010, 69:1878-88.

Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2. Lancet 2007;369:1169-78.

Cohen C, Nieto-Cisneros L, Zala C, et al. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin 2005, 21:1683-92.

Colonno RJ, Thiry A, Limoli K, Parkin N. Activities of atazanavir (BMS-232632) against a large panel of HIV type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother 2003, 47:1324-33.

Condra JH, Petropoulos CJ, Ziermann R, et al.  Drug resistance and predicted virologic responses to HIV type 1 protease inhibitor therapy. J Infect Dis 2000, 182: 758-65.

Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995, 374:569-71.

Conradie F, Sanne I, Venter W, et al. Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient. AIDS 2004, 18:1084-5.

Cooper D, Zajdenverg R, Ruxrungtham K, Chavez L. Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naive patients: results of BI 1182.33. Abstract PL13.4. 8th ICDTHI 2006, Glasgow.

Daar ES, Tierney C, Fischl M, et al. ACTG 5202: Final results of ABC/3TC or TDF/FTC with either EFV or ATV/r in treatment-naive HIV-infected patients.  Abstract 59, 17th CROI 2010, San Francisco.

De Meyer S, Hill A, Picchio G, DeMasi R, De Paepe E, de Béthune MP. Influence of baseline protease inhibitor resistance on the efficacy of darunavir/ritonavir or lopinavir/ritonavir in the TITAN trial. J AIDS 2008, 49:563-4.

De Meyer S, Vangeneugden T, Lefebvre E, et al. Phenotypic and genotypic determinants of TMC114 (darunavir) resistance: POWER 1, 2 and 3 pooled analysis. Abstract P196, 8th ICDTHI 2006; Glasgow, Scotland.

De Meyer SM, Spinosa-Guzman S, Vangeneugden TJ, de Béthune MP, Miralles GD. Efficacy of once-daily darunavir/ritonavir 800/100 mg in HIV-infected, treatment-experienced patients with no baseline resistance-associated mutations to darunavir. J AIDS 2008, 49:179-82.

Demeter LM, Jiang H, Mukherjee AL, et al. A randomized trial of therapeutic drug monitoring of protease inhibitors in antiretroviral-experienced, HIV-1-infected patients. AIDS 2009, 23:357-68.

Dragsted UB, Gerstoft J, Youle M, et al. A randomized trial to evaluate lopinavir/ritonavir versus saquinavir/ritonavir in HIV-1-infected patients: the MaxCmin2 trial. Antivir Ther 2005, 10:735-43.

Dragstedt UB, Gerstoft J, Pedersen C, et al. Randomised trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human HIV type-1 infected patients: the MaxCmin1 trial. J Inf Dis 2003, 188:635-42.

Eholie SP, Lacombe K, Serfaty L, et al. Acute hepatic cytolysis in an HIV-infected patient taking atazanavir. AIDS 2004, 18:1610-1.

Elston RC, Yates P, Tisdale M, et al. GW433908 (908)/ritonavir (r): 48-week results in PI-experienced subjects: A retrospective analysis of virological response based on baseline genotype and phenotype. Abstract MoOrB1055, XV Int AIDS Conf 2004; Bangkok.

Eron J, Yeni P, Gather J, et al. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomized non-inferiority trial. Lancet 2006; 368:476-482.

Flammer AJ, Vo NT, Ledergerber B, et al. Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial. Heart 2009, 95:385-90.

Flexner C, Tierney C, Gross R, et al. Comparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naive patients: results of AIDS clinical trials group (ACTG) A5073, a 48-week randomized controlled trial. Clin Infect Dis 2010, 50:1041-52.

Friend J, Parkin N, Liegler T, et al. Isolated lopinavir resistance after virological rebound of a rit/lopinavir-based regimen. AIDS 2004, 18:1965-6.

Gatell J, Salmon-Ceron D, Lazzarin A, et al. Efficacy and safety of atazanavir-based HAART in pts with virologic suppression switched from a stable, boosted or unboosted PI treatment regimen: the SWAN Study. CID 2007;44:1484-92.

Gathe J, Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is noninferior to twice-daily dosing and results in similar safety and tolerability in antiretroviral-naive subjects through 48 weeks. J AIDS 2009 Feb 16.

Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS 2004, 18:1529-37.

Ghosn J, Carosi G, Moreno S, et al. Unboosted atazanavir-based therapy maintains control of HIV type-1 replication as effectively as a ritonavir-boosted regimen. Antivir Ther 2010;15:993-1002.

González-García J, Cohen D, Johnson M, et al. Short communication: Comparable safety and efficacy with once-daily versus twice-daily dosing of lopinavir/ritonavir tablets with emtricitabine + tenofovir  DF in antiretroviral-naïve, HIV type 1-infected subjects: 96 week final results of the randomized trial M05-730. AIDS Res Hum Retroviruses 2010, 26:841-5.

Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with HIV infection and prior antiretroviral therapy. N Engl J Med 1997, 337: 734-9.

Haas DW, Arathoon E, Thompson MA, et al. Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. AIDS 2000, 14: 1973-8.

Haerter G, Manfras BJ, Mueller M, et al. Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir. AIDS 2004, 18:952-5.

Hammer SM, Saag MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296:827-843.

Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with HIV infection and CD4 cell counts of 200 per cubic millimeter or less. ACTG 320. N Engl J Med 1997, 337:725-33.

Hammer SM, Vaida F, Bennett KK, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 2002;288:169-80.

Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the RESIST studies: an analysis of combined data from two randomised open-label trials. Lancet 2006, 368:466-475.

Hicks CB, Dejesus E, Sloan LM, et al. Comparison of once-daily fosamprenavir boosted with either 100 or 200 mg of ritonavir, in combination with abacavir/lamivudine: 96-week results from COL100758. AIDS Res Hum Retroviruses. 2009 Mar 25.

Jemsek JG, Arathoon E, Arlotti M, et al. Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients. CID 2006, 42:273-80.

Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 2006, 20:711-718.

Johnson M, Soriano V, Brockmeyer N, et al. Early virological and immunological response is comparable for nevirapine and RTV-boosted atazanavir: An ARTEN sub-analysis. Abstract H-924c, 49th ICAAC 2009, San Francisco.

Kagan RM, Shenderovich M, Ramnarayan K, Heseltine PNR. Emergence of a novel lopinavir resistance mutation at codon 47 correlates with ARV utilization. Antivir Ther 2003, 8:S54.

Katlama C, Valantin MA, Algarte-Genin M, et al. Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS 2010, 24:2365-74.

Kempf DJ, Isaacson JD, King MS, et al. Analysis of the virological response with respect to baseline viral phenotype and genotype in PI-expe-rienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antiviral Therapy 2002, 7:165-174.

Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the HIV protease by coadministration with ritonavir. Antimicrob Agents Chemother 1997, 41:654-60.

Koh Y, Nakata H, Maeda K, et al. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor UIC-94017 (TMC114) with potent activity against multi-PI-resistant HIV in vitro. Antimic Ag Chemo 2003; 47: 3123-3129. http://aac.asm.org/cgi/content/abstract/47/10/3123

Lallemand F, Salhi Y, Linard F, Giami A, Rozenbaum W. Sexual dysfunction in 156 ambulatory HIV-infected men receiving HAART combinations with and without protease inhibitors. J AIDS 2002, 30: 187-90.

Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 2000, 14:1943-8.

Le Tiec C, Barrail A, Goujard C, Taburet AM. Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet 2005, 44:1035-50.

MacManus S, Yates PJ, Elston RC, et al. GW433908/ritonavir once daily in antiretroviral therapy-naive HIV-infected patients: absence of protease resistance at 48 weeks. AIDS 2004, 18:651-5.

Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007; 370:49-58.

Malan DR, Krantz E, David N, et al. Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J AIDS 2008, 47:161-7.

Malan DR, Krantz E, David N, Wirtz V, Hammond J, McGrath D. Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J AIDS 2008; 47:161-167.

Mallolas J, Podzamczer D, Milinkovic A, et al. Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study. J AIDS 2009, 51:29-36.

McCallister S, Valdez H, Curry K, et al. A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients. J AIDS 2004, 35:376-82.

McComsey G, Rightmire A, Wirtz V, et al. Changes in body composition with ritonavir-boosted and unboosted atazanavir treatment in combination with lamivudine and stavudine: A 96-week randomized, controlled study. Clin Infect Dis. 2009 Mar 20.

Meraviglia P Angeli E, Del Sorbo F, et al. Risk factors for indinavir-related renal colic in HIV patients: predictive value of indinavir dose/body mass index. AIDS 2002, 16:2089-2093.

Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. 30. AIDS 2009, 23:1679-88.

Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008, 372:646-655.

Molina JM, Andrade-Villanueva J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J AIDS 2010, 53:323-32.

Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses 2007;23:1505-14.

Murphy RL, Berzins B, Zala C, et al. Change to atazanavir/ritonavir treatment improves lipids but not endothelial function in patients on stable antiretroviral therapy. AIDS 2010, 24:885-90.

Nolan D. Metabolic complications associated with HIV protease inhibitor therapy. Drugs 2003, 63:2555-74.

Noor MA, Parker RA, O’mara E, et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS 2004, 18:2137-2144.

Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008, 22:1389-1397.

Parkin N, Stawiski E, Chappey C, Coakley E. Darunavir/amprenavir cross-resistance in clinical samples submitted for phenotype/genotype combination resistance testing. Abstract 607, 15th CROI 2008, Boston.

Podzamczer D, Ferrer E, Consiglio E, et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther 2002, 7:81-90.

Pozniak A, Opravil M, Beatty G, Hill A, de Béthune MP, Lefebvre E. Effect of baseline viral susceptibility on response to darunavir/ritonavir versus control protease inhibitors in treatment-experienced HIV type 1-infected patients: POWER 1 and 2. AIDS Res Hum Retroviruses 2008, 24:1275-80.

Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008, 358:2095-2106.

Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003, 349: 2293-303.

Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in ART-naive HIV-1-infected patients. JAIDS 2004, 35:22-32.

Rotger M, Taffe P, Bleiber G, et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis 2005, 192:1381-6.

Schnell T, Schmidt B, Moschik G, et al. Distinct cross-resistance profiles of the new protease inhibitors amprenavir, lopinavir, and atazanavir in a panel of clinical samples. AIDS 2003, 17:1258-61.

Schrooten W, Colebunders R, Youle M, et al. Sexual dysfunction associated with protease inhibitor containing HAART. AIDS 2001, 15: 1019-23.

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.

Sham HL, Kempf DJ, Molla A, et al. ABT-378, a highly potent inhibitor of the HIV protease. Antimicrob Agents Chemother 1998, 42:3218-24.

Smith K, Weinberg W, DeJesus E, et al. Efficacy and safety of once-daily boosted fosamprenavir or atazanavir with tenofovir/emtricitabine in antiretroviral-naive HIV-1 infected patients: 24-week results from COL103952 (ALERT). Abstract H-1670, 46th ICAAC 2006, San Francisco.

Soriano V, Arastéh K, Migrone H, et al. Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN Trial. Antivir Ther 2011, 16:339-48.

Soriano V, Garcia-Gasco P, Vispo E, et al. Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viraemia: final results of the SLOAT trial. J Antimicrob Chemother 2008; 61:200-5.

Squires KE, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J AIDS 2004, 36: 1011-1019.

Stanley TL, Joy T, Hadigan CM, et al. Effects of switching from lopinavir/ritonavir to atazanavir/ritonavir on muscle glucose uptake and visceral fat in HIV-infected patients. AIDS 2009, 23:1349-57.

Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999, 341:1865-73.

Stellbrink HJ, Hawkins DA, Clumeck N, et al. Randomised, multicentre phase III study of saquinavir plus zidovudine plus zalcitabine in previously untreated or minimally pretreated HIV-infected patients. Clin Drug Invest 2000, 20:295-307.

Van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003, 17:987-99.

Voigt E, Wickesberg A, Wasmuth JC, et al. First-line ritonavir/indinavir 100/800 mg twice daily plus nucleoside reverse transcriptase inhibitors in a German multicentre study: 48-week results. HIV Med 2002, 3:277-282.

Walmsley S, Avihingsanon A, Slim J, et al.  Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J AIDS 2009 Feb 12.

Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002, 346:2039-46.

Walmsley S, Bredeek U, Avihingsanon A, et al. Evaluation of the impact of highly active antiretroviral therapy (HAART) on lipid profiles – data from the 24-week interim analysis of the Gemini Study: saquinavir/r (SQV/r) BID vs lopinavir/r (LPV/r) BID plus emtricitabine/tenofovir (FTC/TDF) QD in ARV-naïve HIV-1-infected patients. Abstract TuPeB069, 4th IAS 2007, Sydney.

Wasmuth JC, Lambertz I, Voigt E, et al. Maintenance of indinavir by dose adjustment in HIV-1-infected patients with indinavir-related toxicity. Eur J Clin Pharmacol 2007;63:901-8.

Youle M. Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. J Antimicrob Chemother 2007;60:1195-205.

Zajdenverg R, Badal-Faesen S, Andrade-Villanueva J, et al. Lopinavir/ritonavir (LPV/r) tablets administered once- (QD) or twice-daily (BID) with NRTIs in antiretroviral-experienced HIV-1 infected subjects: results of a 48-week randomized trial (Study M06-802). Abstract TUAB104, 5th IAS 2009, Cape Town.

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

Preface

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).

References

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.

Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 1996;272:1955-8.

Allers K, Hütter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 2011, 117:2791-9.

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.

Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 2006, 57:619-627.

Brumme ZL, Goodrich J, Mayer HB, et al. Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals. J Infect Dis 2005, 192:466-74.

Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use coreceptor use correlates with disease progression in HIV-1–infected individuals. J Exp Med 1997, 185:621-8.

Dean M, Carrington M, Winkler C, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 1996;273:1856-62.

Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 1996;381:661-6.

Doranz BJ, Rucker J, Yi Y, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996;85:1149-58.

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.

Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996;382:722-5.

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.

Tsamis F, Gavrilov S, Kajumo F, et al. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J Virol 2003;77:5201-8.

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.

Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 2007;81:2359-71.

Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 5256. Abstract 285, 17th CROI 2010, San Francisco.

Wilkin T, Ribaudo H, Gulick R. The relationship of CCR5 inhibitors to CD4 cell count Changes: A meta-analysis of recent clinical trials in treatment-experienced subjects Abstract 800, 15th CROI 2008, Boston.

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

Clotet B, Capetti A, Soto-Ramirez LE, et al. A randomized, controlled study evaluating an induction treatment strategy in which enfuvirtide was added to an oral, highly active antiretroviral therapy regimen in treatment-experienced patients: the INTENSE study. J Antimicrob Chemother 2008, 62:1374-8.

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.

Gandhi RT, Bosch RJ, Aga E, et al. No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy. J Infect Dis 2010, 201:293-6.

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.

Greenberg ML, Melby T, Sista P, et al. Baseline and on-treatment susceptibility to enfuvirtide seen in TORO 1 and 2 to 24 weeks. Abstract 141, 10th CROI 2003, Boston. http://www.retroconference.org/2003/Abstract/Abstract.aspx?AbstractID=1687

Harris M, Joy R, Larsen G, et al. Enfuvirtide plasma levels and injection site reactions using a needle-free gas-powered injection system (Biojector). AIDS 2006, 20:719-23.

Joly V, Fagard C, Descamps D, et al. Intensification of HAART through the addition of enfuvirtide in naive HIV-infected patients with severe immunosup-pression does not improve immunological response: results of a prospective randomised multicenter trial. Abstract 282, 17th CROI 2010, San Francisco.

Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998, 4:1302-1307.

Kilby JM, Lalezari JP, Eron JJ, et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses 2002, 18:685-93.

Lalezari JP, Henry K, O’Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003, 348:2175-85.

Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003, 348:2186-95.

Lehrman G, Hogue IB, Palmer S, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 2005; 366: 549-55.

Lu J, Sista P, Cammack N, Kuritzkes D, et al. Fitness of HIV-1 clinical isolates resistant to T-20 (enfuvirtide). Antiviral therapy 2002, 7:S56

Melby T, Sista P, DeMasi R, et al. Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2. AIDS Res Hum Retroviruses 2006; 22: 375-85.

Menzo S, Castagna A, Monachetti A, et al. Resistance and replicative capacity of HIV-1 strains selected in vivo by long-term enfuvirtide treatment. New Microbiol 2004, 27:51-61.

Mink M, Mosier SM, Janumpalli S, et al. Impact of human immunodeficiency virus type 1 gp41 amino acid substitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency of enfuvirtide in vitro. J Virol 2005, 79:12447-54.

Molto J, Ruiz L, Valle M, et al. Increased antiretroviral potency by the addition of enfuvirtide to a four-drug regimen in antiretroviral-naive, HIV-infected patients. Antivir Ther 2006; 11: 47-51.

Nelson M, Arasteh K, Clotet B, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J AIDS 2005, 40:404-12.

Raffi F, Katlama C, Saag M, et al. Week-12 response to therapy as a predictor of week 24, 48, and 96 outcome in patients receiving the HIV fusion inhibitor enfuvirtide in the T-20 versus Optimized Regimen Only (TORO) trials. Clin Infect Dis 2006, 42:870-7.

Reynes K, Pellegrin I, Peytavin G, et al. Induction treatment with enfuvirtide combined with antiretrovirals optimized background in treatment failure patients: 16 weeks data from INDEED Study. Abstract P7.4/02, 11th EACS 2007, Madrid

Root MJ, Kay MS, Kim PS. Protein design of an HIV-1 entry inhibitor. Science 2001;291:884-8.

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.

Stocker H, Kloft C, Plock N, et al. Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings. Antimicrob Agents Chemother 2006, 50:667-73.

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.

References

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.

Normal
0

false
false
false

EN-US
JA
X-NONE

/* Style Definitions */
table.MsoNormalTable
{mso-style-name:”Normale Tabelle”;
mso-tstyle-rowband-size:0;
mso-tstyle-colband-size:0;
mso-style-noshow:yes;
mso-style-priority:99;
mso-style-parent:””;
mso-padding-alt:0in 5.4pt 0in 5.4pt;
mso-para-margin:0in;
mso-para-margin-bottom:.0001pt;
mso-pagination:widow-orphan;
font-size:10.0pt;
font-family:”Times New Roman”,”serif”;}

Table 2.2. Overview of antiretroviral drugs.

Trade name

Abbrev.

Drug

Manufacturer

Nucleosideand Nucleotide Reverse-Transcriptase-Inhibitors (NRTIs)

Emtriva®

FTC

Emtricitabine

Gilead Sciences

Epivir®

3TC

Lamivudine

ViiV HealthcareGSK

Retrovir®

AZT

Zidovudine

ViiV HealthcareGSK

Videx®

DDI

Didanosine

Bristol Myers-SquibbMS

Viread®

TDF

Tenofovir

Gilead Sciences

Zerit®

D4T

Stavudine

Bristol Myers-SquibbMS

Ziagen®

ABC

Abacavir

GSK ViiV Healthcare

Non-Nucleoside Reverse-Transcriptase-Inhibitors (NNRTIs)

Sustiva®(, Stocrin®)

EFV

Efavirenz

BMS/MSD

Viramune®

NVP

Nevirapine

Boehringer

Edurant®*

RPV

Rilpivirine

Janssen-Cilag

Intelence®

ETV

Etravirine

Janssen-CilagTibotec

Rescriptor®*

DLV

Delavirdine

ViiV HealthcarePfizer

Protease-Inhibitors (PIs)

Aptivus®

TPV

Tipranavir

Boehringer

Crixivan®

IDV

Indinavir 

MSD

Invirase®

SQV

Saquinavir

Roche

Kaletra®

LPV

Lopinavir/Ritonavir

Abbott

Norvir® (als Booster)*

RTV

Ritonavir

Abbott

Prezista®

DRV

Darunavir

TibotecJanssen-Cilag

Reyataz®

ATV

Atazanavir

Bristol Myers-SquibbBMS

Telzir®(, Lexiva®)

FPV

Fosamprenavir

ViiV HealthcareGSK

Viracept®

NFV

Nelfinavir

Roche/ViiV HealthcarePfizer

EntryInhibitors

Celsentri®,  (Selzentry®)

MVC

Maraviroc

PfizerViiV Healthcare

Fuzeon®

T-20

Enfuvirtide

Roche

Integrase Inhibitors

Isentress®

RAL

Raltegravir

MSD

Combination Drugs

Atripla®

ATP

TDF+FTC+EFV

Gilead+BMS+MSD

Combivir®

CBV

AZT+3TC

ViiV HealthcareGSK

Complera®*Kivexa® (Epzicom®)

CPLKVX

TDF+FTC+RPV3TC+ABC

Gilead+Janssen-CilagGSK

Trizivir®

TZV

AZT+3TC+ABC

GSK

Truvada®

TVD

TDF+FTC

Gilead

Kivexa®, Epzicom®

KVX

3TC+ABC

ViiV Healthcare

Trizivir®

TZV

AZT+3TC+ABC

ViiV Healthcare

Truvada®

TVD

TDF+FTC

Gilead Sciences

Trade name

Abbrev.

Drug

Manufacturer

 

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Emtrivaâ

FTC

Emtricitabine

Gilead

 

Epivirâ

3TC

Lamivudine

GSK/ViiV

 

Retrovirâ

AZT

Zidovudine

GSK/ViiV

 

Videxâ

ddI

Didanosine

BMS

 

Vireadâ

TDF

Tenofovir

Gilead

 

Zeritâ

d4T

Stavudine

BMS

 

Ziagenâ

ABC

Abacavir

GSK/ViiV

 

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Sustivaâor Stocrinâ

EFV

Efavirenz

BMS/MSD

 

Viramuneâ

NVP

Nevirapine

Boehringer

 

Intelenceâ

ETV

Etravirine

Tibotec

 

Rescriptorâ

DLV

Delavirdine

Pfizer/ViiV

 

Protease Inhibitors (PIs)

Aptivusâ

TPV

Tipranavir*

Boehringer Ingelheim

 

Crixivanâ

IDV

Indinavir*

MSD

 

Inviraseâ

SQV

Saquinavir*

Roche

 

Kaletraâ

LPV

Lopinavir/Ritonavir

Abbott

 

Norvirâ

RTV

Ritonavir

Abbott

 

Prezistaâ

DRV

Darunavir*

Tibotec

 

Reyatazâ

ATV

Atazanavir*

BMS

 

Telzirâ or Lexivaâ

FPV

Fosamprenavir*

GSK/ViiV

 

Viraceptâ

NFV

Nelfinavir*

Roche/Pfizer/ViiV

 

Entry Inhibitors

Celsentriâor Selzentryâ

MVC

Maraviroc

Pfizer/ViiV

 

Fuzeonâ

T-20

Enfuvirtide

Roche

 

Integrase Inhibitors

Isentressâ

RAL

Raltegravir

MSD

 

Combination drugs

Atriplaâ

ATP

TDF+FTC+EFV

Gilead+BMS+MSD

 

Combivirâ

CBV

AZT+3TC

GSK/ViiV

 

Kivexaâ or Epzicomâ

KVX

3TC+ABC

GSK/ViiV

 

Trizivirâ

TZV

AZT+3TC+ABC

GSK/ViiV

 

Truvadaâ

TVD

TDF+FTC

Gilead

 

* 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

Leave a comment

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