Category Archives: 6.4. Goals and Principles of Therapy

6.4. Goals and Principles of Therapy

– Christian Hoffmann –

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

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

Success and failure of treatment

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

Virological treatment success and failure

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

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

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

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

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

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

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

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

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

How long does virological treatment success last?

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

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

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

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

Blips – do they mean virological failure?

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

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

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

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

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

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

Immunological treatment failure and success

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

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

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

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

Discordant response

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

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

Grabar 2000
n = 2,236

Moore 2005
n = 1,527

Tan 2007

n = 404

Virological and immunological

48%

56%

71%

Discordant: only immunological

19%

12%

16%

Discordant: only virological

17%

15%

9%

No treatment response

16%

17%

5%

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

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

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

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

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

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

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

Practical considerations in dealing with viral load and CD4 count

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

Clinical treatment success and failure

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

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

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

Grabar 2000

Piketty 2001

Moore 2005

Baseline CD4 T cells (median)

150

73

180-250

Response to ART
Virologic and immunologic

1

1

1

Immunologic response only

1.6 (1.0-2.5)

6.5 (1.2-35.8)

1.9 (1.1-3.0)

Virologic response only

2.0 (1.3-3.1)

9.7 (1.6-58.4)

2.5 (1.5-4.0)

No treatment response

3.4 (2.3-5.0)

51.0 (11.3-229.8)

3.5 (2.3-5.3)

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

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

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

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

2000  (n=964)

2005  (n=1042)

AIDS-defining events

47%

36%

Non-AIDS-defining cancers

11%

17%

Liver diseases

13%

15%

Cardiovascular diseases

7%

8%

Suicide

4%

5%

What can be achieved today?

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

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

CD4 T cells

Viral load

Feb 95 AZT+ddC

23 (4%)

NA

Nov 96 AIDS: Toxoplasmosis, MAC, Candida esophagitis

12 (1%)

815,000

Feb 97 d4T+3TC+SQV

35 (8%)

500

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

17 (4%)

141,000

Mar 98

147 (22%)

<50

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

558 (24%)

100

Mar 00

942 (31%)

<50

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

744 (30%)

130

Jan11

861 (24%)

<50

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

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

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

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

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

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

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

Mortality

(/100 PY)

Morbidity

(/100 PY)

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

29.4 ® 8.8

21.9 ® 3.7*

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

NA

15.1 ® 7.7

Mocroft2000 Europe (7331) All (1994-1998)

NA

30.7 ® 2.5

Mocroft2002 Europe (8556) All (1994-2001)

15.6 ® 2.7

NA

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

NA

12.9 ® 1.3

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

1.7®1.0

NA

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

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

Treatment goal – eradication

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

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

What is the cure?

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

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

CD4 cells/µl

HIV RNA copies/ml

04/03 Acute HIV infection (seroconversion)

203 (8%)

>1 million

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

412 (12%)

>1 million

01/04 ART stopped after 8 months

838 (52%)

<50

06/04

467 (46%)

<25

05/05

1288 (51%)

44

03/11 Seven years without ART

822 (39%)

<25

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

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

The problem with latent reservoirs

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

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

Intensification trials

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

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

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

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

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

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