Other Languages

2007
German
Vietnamese

2006
Portuguese

2005
Russian
Spanisch

2003
Persian (Farsi)

5.4. Therapeutic Goals

by Christian Hoffmann and Fiona Mulcahy

In the daily chaos of CD4 cells, viral load, routine laboratory, genotypic and phenotypic resistance testing, tropism and HLA typing, as well as drug plasma levels, the ultimate goal of antiretroviral therapy should always be borne in mind: To prolong the patient's life, while maintaining the best possible qualityn of health and life.

This means, that it is equally important to not only prevent opportunistic infections and malignancies, but also to minimize the side effects of therapy. Ideally, antiretroviral treatment should have as little influence as possible on daily life. Even if a high CD4 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, often lose focus on what really matters. The response to the doctor's query: "How are you?" is often accompanied by a glance toward the CD4 count result on the chart: "That's what I'd like you to tell me!"

It may therefore be useful for both patient and physician to reflect during the good times upon what one realistically aims to achieve. Treatment aimed only at improving laboratory values with little emphasis on the physical and mental well being of the patient cannot be successful. The patient has to be treated, not the viral load.

More? HIV Medicine 2007, Chapter 5.4: Download

HIV Medicine
15th edition
818 pages
PDF, 3.7 MB

Success and failure of treatment Success and failure of treatment can be evaluated using virological, immunological or clinical criteria. Although they are often associated with each other, they should be judged separately. The earliest indicator is virological success or failure. This mainly means decrease, absence of decrease, or increase in viral load. This is followed, often a little later, by immunological treatment success, measured through the CD4 cells, or immunological treatment failure. Clinical treatment failure, if it occurs, usually only becomes apparent much later - first the lab values deteriorate, then the patient! Although the incidence of opportunistic infections after only three months on HAART is approximately halved, the clinical treatment success is not noticed by asymptomatic patients (Ledergerber 1999). Virological treatment success and failure Virological treatment success is generally a decrease in viral load to below the level of detection of 50 copies/ml. This is based on the experience that, the more rapid and greater the decrease in viral load, the longer the therapeutic effect (Kempf 1998, Powderly 1999). In as early as the INCAS Trial, the relative risk of treatment failure (defined here as an increase to above 5,000 copies/ml) in patients who had reached a viral load below 20 copies/ml was 20 times lower than in those who had never reached a level under 400 copies/ml (Raboud 1998). It is not completely clear whether the data obtained from the early HAART era are still valid. On HAART, viral load declines in two phases. An initial, very rapid decrease in the first few weeks is followed by a slower phase, in which plasma viremia declines only 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 even take longer. However, a viral load above the level of detection after 6 months of treatment is almost always seen as failure. The same is true if a rebound in viral load is confirmed, in which - following fast confirmation - it should be considered what can be improved in the therapy (resorption, resistance, compliance?). Virological treatment failure can be recognized quite early - therefore, initial monitoring even after four weeks is useful not only to the patient for psychological reasons ("less viruses, more helper cells"). If the viral load after 4 weeks is not at least substantially less than 5,000 copies/ml, failure of therapy is likely later (Maggiolo 2000). Of those patients, in whom the viral load is not below 500 copies/ml after 8 weeks or at least one log lower than baseline, only 9 % will reach less than 500 copies/ml at 24 weeks (Demeter 2001). According to a new prospective study, the response at 48 weeks can be predicted as early as 7 days (Haubrich 2007) - a control so early on is not part of the routine management. The cut-off point of 50 copies/ml as the success criterion is arbitrary. It is based on the currently available assays for measurement of viral load. Whether 60 copies/ml are worse than 30 copies/ml indicating successful treatment is as yet not proven. At these low levels, methodological inaccuracies must also be considered. A single viral load rebound ("blip") to low levels is often irrelevant (see below). However, to distinguish them, blips are from lower, but still measurable viral loads (50-400 copies/ml). Resistances are frequently detectable in these patients - in one study this was so in 43 % of cases (Nettles 2004). A viral load "below the level of detection" of 50 copies/ml means just that - no more, no less. Even so, numerous studies indicate that replication and therefore development of resistance can continue with an undetectable virus load. 50 viral copies/ml indicate that 5 liters of blood contain 250,000 viruses; in addition, even more actively replicating viruses are present in the lymphatic organs. 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 don't know yet. The most important risk factors for virological treatment failure are antiretroviral treatment (pre-existing resistances) and poor compliance (review: Deeks 2000). It has still not been proven whether the CD4-cell count at the start of therapy plays an important role. In several cohorts, no association has been found (Cozzi Lepri 2001, Phillips 2001, Le Moing 2002). See also the discussion in the chapter "When to start HAART". Many other factors that influence the success of therapy probably remain unknown. Pharmacogenetics is a new field, which, although still in the early phases, is starting to gain importance. It investigates individual genetic factors which influence the success of therapy. Until now, most factors that have been uncovered have predicted intolerance or allergies to, for example, abacavir or nevirapine (see relevant section). But one day, tests will be available that will help antiretroviral therapy to be individualized and the success of therapy to be improved. These will range from individual dosing to tests, which predict results - eg. the CCR5 antagonists (Review: Haas 2006). For the time being, the good news is: morbidity and mortality may be lowered significantly even if the virological success is not complete, i.e., the viral load is not decreased below the level of detection (Mezzaroma 1999, Deeks 2000, Grabar 2000). This is important in patients who have a limited number of treatment options. In such cases, it can sometimes be more sensible to temporarily abandon viral load as a measure of success (see also chapter on "Salvage Therapy"); and to make the stabilization of the CD4 cells the top priority. Patients often remain immunologically stable for relatively long periods of time, even with insufficient viral suppression. A cohort study has shown that CD4 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, in comparison to a few years previously, more has become possible through new drugs and classes of drugs. In the age of T-20, tipranavir, darunavir, etravirine, maraviroc and raltegravir a repeat attempt should be made to reduce the viral load to below the level of detection, even in intensively pre-treated patients. How long does virological treatment success last? Little is known about how long treatments remain effective. The rumor that treatment success is limited to only a few years is still widespread. It originates from the early years of HAART. However, 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 ten years of HAART, a surprisingly 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-na?ve 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 HAART. 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. In the Phase II M97-720 Study, in which 100 patients were originally treated with d4T+3TC+lopinavir/r, 62 % still had less than 50 copies/ml after six years in the ITT analysis, compared to 98 % in the On-Treatment-Analysis (Gulick 2004). Real virological failure was very rare. In the Merck 035 subanalysis, patients on AZT+3TC+indinavir were also followed for six years. In the last ITT analysis, 58 % were still below the level of detection, despite the fact that these patients had been pre-treated with nucleoside analogs (Gulick 2003). These studies clearly show that, providing treatment is not interrupted, viral load may remain below the level of detection for many years, perhaps even decades. Resistances are by no means unavoidable. This has been confirmed by cohort studies, in which virological treatment failure has become significantly less in the last few years (Lohase 2005, Lampe 2006). HAART is getting better and better. In 1996, only 58 % of patients had a viral load of less than 500 copies/ml; in 2003, it was 83 % (May 2006). "Blips" - Do they mean virological failure? Blips are thought to be transient and, almost always, small increases in viral load, so long as the viral load before and after the blip was below the borderline value of 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 HIV patients on HAART and are observed in 20-40 % of patients on HAART (Sungkanuparph 2005). Blips often worry both patients and clinicians: do they signal treatment failure? Although studies indicate that this is not the case in the medium term (Havlir 2001, Moore 2002, Sklar 2002, Mira 2003, Sungkanuparph 2005), the causes of blips have, to a large extent, not been investigated. There has been no association found with compliance. (Di Mascio 2003, Miller 2004). 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 cell count at the start of therapy, 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 (Sungkanuparph 2005), the frequency of blips on NNRTIs was 34 versus 33 % on PIs, and even the size 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 was that the blips did not increase the risk of treatment failure, even with NNRTIs (Martinez 2005). At the beginning of 2005, the study team led by Bob Siciliano set out to determine the meaning of "blips". In a labor-intensive study, 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 (Nettles 2005). The obvious result: the more you look, the more you will 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 could not be associated with either specific clinical data, low plasma levels, or resistances. This observation led the authors to believe, that blips (with low, measurable values) mainly represent biological or statistical exceptions, and are not associatedwith 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. It should be noted that other factors may also be responsible for intermittent viremia. In one large, retrospective analysis, 26 % were caused by intercurrent infections (Easterbrook 2002). For example, syphilis can cause a significant increase in viral load and reduction of CD4 cells (Buchacz 2004). Viral load can also increase temporarily after immunizations (Kolber 2002). Summary: Based on available data, HAART should not be changed, even after repetitive blips. However, caution should be executed for higher blips (> 200-500 copies/ml). Blips are distinguishable from low, repetitive, measurable plasma viremias, in that the risk of resistance is actually increased (Gunthard 1998, Nettlers 2004). Although there does not seem to be a relationship to compliance or drug levels, blips should raise the opportunity to talk to the patient about the subject of adherence. Compliance cannot 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? Everything should be considered before changing a therapy. Each new therapy can cause new problems. Therefore, every suspected increase in the viral load should be controlled within a short interval, before treatment is prematurely changed. Immunological treatment failure and success Immunological treatment success is an increase in the CD4 cells - it is not defined more precisely. Depending on the study, increases by 50, 100 or 200 CD4 cells/µl or increases to above 200 or 500 CD4 cells/µl are defined as success. Failure is usually described as the absence of an increase or as a decrease in the CD4 count in patients receiving HAART. It is difficult to individually predict the immunological success of therapy for patients on HAART, as it varies significantly from one person to another. As with the decrease in viral load, the increase in CD4 count also occurs in 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 1,000 patients, the CD4-cell count increased during the first three months by a median of 21.2 CD4 cells/µl per month; in the following months the increase was only 5.5 CD4 cells/µl (Le Moing 2002). It is still under debate whether the immune system is restored continuously after a long period of viral suppression or whether a plateau is reached after three to four years (Smith 2004, Viard 2004). In our experience, both occurs: patients with CD4 cells that still increase only slowly after 5 or 6 years, and patients whose CD4 cells remain at relatively low level after just a relatively short period of time. The immunological success is not predictable in individual cases. However, the lower the CD4 cell count at baseline, the less likely they are to normalize completely (Valdez 2002, Kaufmann 2003+2005). The immune system often does not recover completely. In the Swiss Cohort, only 39 % of 2,235 patients who had begun HAART in 1996-97 reached a CD4-cell count above 500/µl (Kaufmann 2003, see also below). The introduction of treatment within the first 3-6 months possibly provides certain clues as to how well the immune system will be restored (Kaufmann 2005). Immunological treatment success is not necessarily linked to maximal viral suppression; even partial suppression can result in improved CD4-cell count (Kaufmann 1998, Mezzaroma 1999, Ledergerber 2004). The initial level of viral load is also not significant; what seems to be decisive is that the viral load remains lower than before treatment (Deeks 2002, Ledergerber 2004). In view of the many factors that occur, which are able to influence the success of therapy as well as the individual regeneration capacity (independent of HAART), it no longer makes sense to depend on the CD4-cell count as the deciding criterion for the success of HAART. Virological success is more appropriate for judging the efficacy of specific regimens. Discordant response A discordant response occurs when the therapeutic goals - clinical, immunological and virological - cannot all be achieved (see Table 4.1 for frequencies). So, the treatment may be virologically successful, with no visible immunological response; with the CD4 cells remaining on the low side despite undetectable viral load (Piketty 1998, Renaud 1999, Gabrar 2000, Piketty 2001). In contrast, a HAART regimen can bring about a considerable increase in CD4 cells, even when the viral load is detectable. This is sometimes seen in children (see Pediatric chapter). Table 4.1: Treatment success in prospective cohort studies Response to HAART Piketty 2001 n = 150 Grabar 2000 n = 2,236 Moore 2005 n = 1,527 Virological and immunological 60 % 48 % 56 % Discordant: only immunological 19 % 19 % 12 % Discordant: only virological 9 % 17 % 15 % No treatment response 12 % 16 % 17 % Definition of immunological success: increase in CD4 cells > 100/µl after 30 months (Piketty 2001) or > 50/µl after 6 months (Grabar 2000) or at least once > 50/µl (Moore 2005) Definition of virological success: continually > 1 log less than baseline or < 500 copies/ ml (Piketty 2001) or < 1,000 (Grabar 2000) or < 500 copies/ml (Moore 2005) The reasons for the poor immunological treatment success despite good viral suppression are heterogeneous (Review: Aiuti 2006). Low CD4 cells at baseline as well as low viral load before the start of therapy are just two of many factors (Florence 2003, Kaufmann 2005, Moore 2005, Wolbers 2007). Age also plays an important role: in older patients, immunological response is often only moderate in comparison to virological response. Several studies demonstrated that the probability of not achieving a rise in the CD4-cell count increases with patient age and with progressive decrease in thymus size as detected by computed tomography (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 cells (Dragstedt 2004). In the Swiss cohort, the CD4 cells increased more in women than in men (Wolbers 2007). Other causes for a lack of immunological response may be immuno- or myelosuppressive concomitant therapies. We have seen patients, who have had a suppressed viral load below 50 CD4 cells/µl for years, who only experience significant immunological reconstitution when gancyclovir, cotrimoxazole or azathioprine are withdrawn. Concurrent illnesses such as various autoimmune diseases (Crohn's disease, Lupus erythmatosis) or liver cirrhosis can also have negative effects on the immune response. There is also evidence that certain antiretroviral drugs have negative effects on immune reconstitution. On a combination of TDF+ddI (plus nevirapine) significant decreases in CD4 cells occur (Negredo 2004). The reason may lie in an unfavorable interaction between ddI and tenofovir. In two other studies, the CD4 cells increased significantly more on ABC+3TC, as well as on TDF+FTC, than on AZT+3TC, despite comparable virological success. However, it remains to be shown whether this is really a problem of myelotoxicity of AZT or a pure coincidence (DeJesus 2004, Pozniak 2006). Practical considerations in dealing with viral load and CD4 cells § Viral load 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 HAART. § Viral load should be below 50 copies/ml after 3-4 months (with high initial viral load, after 6 months at the latest) - if it is not, look for a cause! § The greater the decrease in viral load, the more durable the response to treatment. § Transient, low-level increases in viral load (blips) are usually insignificant - but VL should be monitored at short intervals (e.g. 2-4 weeks after such blips). § The older the patient, the greater the risk of a discordant response (well-suppressed viral load with no significant increase in CD4 count). § In contrast to viral load, increase in CD4 cells, i.e. immunological success, is difficult to influence. § CD4 cells are probably better predictors of the individual risk of AIDS. § Once CD4 count is good, it requires less frequent monitoring. Remember that 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 success is almost always evaluated on the reduction of clinical endpoints (AIDS-defining illnesses, death), although the improvement on HAART in a patient with considerable constitutional symptoms should also be seen as clinical success. Clinical treatment success is not always easy to measure and is dependent on both virological and immunological treatment success. Table 4.2: Morbidity and Mortality, based on virological or immunological treatment success. Definition see Table 4.1. 95 % confidence intervals are shown in parentheses Grabar 2000 Piketty 2001 Moore 2005 CD4 cells at baseline* 150 73 180-250 Treatment success: Complete = Reference 1 1 1 Only immunological, RR 1.6 (1.0-2.5) 6.5 (1.2-35.8) 1.9 (1.1-3.0) Only virological, RR 2.0 (1.3-3.1) 9.7 (1.6-58.4) 2.5 (1.5-4.0) None, RR 3.4 (2.3-5.0) 51.0 (11.3-229.8) 3.5 (2.3-5.3) RR = relative risk *median. Clinical endpoint: progression/death (Grabar 2000, Piketty 2001), death (Moore 2005). In the Swiss cohort, out of those with a constantly undetectable viral load, the proportion of patients developing AIDS or dying was 6.6 % after 30 months. In contrast, this proportion was 9.0 % in patients with viral rebound and even 20.1 % if the viral load was never suppressed to undetectable levels (Ledergerber 1999). The importance of sustained virological treatment success for clinical success has also been reported by other cohorts (Salzberger 1999, Thiebaud 2000). Clinical failure is usually defined as the development of an AIDS-associated condition or even death. Clinical failure, arising from a failing HAART regimen, has to be distinguished from clinical failure that can ascribed to simply starting HAART too late. This is particularly true, for example in immune reconstitution inflammatory syndrome (IRIS), where pre-existing, subclinical infections manifest themselves during the first weeks following initiation of antiretroviral therapy (see "AIDS" chapter). An OI in the presence of increasing CD4 cells does not necessarily indicate failure of HAART, but rather, simply put, that the immune system starts working again. On the other hand, if a patient develops serious side effects or even dies, this should clearly be regarded as treatment failure. Luckily, this is rare. It should be noted that there might also be other causes. Many severe, life-threatening events that affect HIV infected patients on HAART today are associated neither with HAART nor AIDS (Reisler 2003). What can be achieved? Every HIV clinician sees the remarkable strides made possible by HAART 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 (Mocroft 2000). Some illnesses that occur only with severe immunodeficiencies are rarely seen today. CMV retinitis or MAC disease have become unusual. Table 4.3: Patient case (female, 41 years) illustrating the success of HAART* 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 June 97 Treatment interruption 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 Jan 07 712 (38 %) < 50 * Excellent immune reconstitution despite initial severe immunodeficiency and several AIDS-defining illnesses. All prophylaxis (MAC, Toxoplasmosis, PCP) has now been discontinued. Today, AIDS cases 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 AIDS cases. 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). In an investigation on 3,990 HIV patients in Denmark, compared with 380,000 individuals from the non-infected population, the average increase in life expectancy increased in a 25-year old HIV patient from 19.9 years between 1995-1999 to 32.5 years between 2000-2005; this increased to 38.9 years when patients with HCV were excluded, which was fairly close to the 51.1 years of the normal population (Lohse 2007). Data from prospective, controlled studies on this dramatic change is still limited, however. So far, there have been few randomized trials with clinical endpoints (Hammer 1997, Cameron 1998, Stellbrink 2000). The success of these studies was comparatively unassuming from a design point of view. In the ABT-247 trial, in which 1,090 clinically advanced patients received ritonavir liquid formulation or placebo in addition to their ongoing treatment, the probability of AIDS and death in the ritonavir arm after 29 weeks was 21.9 % and 37.5 % in the placebo arm (Cameron 1998). Because studies of mono- or dual therapy are no longer ethically justifiable and the number of clinical endpoints that occur is now extremely low, controlled prospective trials, in which the clinical superiority of the treatment should be proven, simply last too long these days. Unrealistically large study populations would also now be required given the extremely low probability of progression, and therefore, such investigations will only rarely be undertaken in the future (Raffi 2001). One of the few to have underpinned the value of HAART on the basis of clinical endpoints is the SMART study (see chapter on treatment interruptions). Due to the lack of randomized studies, data from the large cohorts, such as Euro-SIDA, the Swiss cohort, and the American HOPS cohort, have to be relied upon to document the decline in AIDS mortality (see Table 4.4). Table 4.4: Decline in morbidity and mortality in large cohorts Where? (n) Patients (Period) Mortality (/100 PY) Morbidity (/100 PY) Palella 1998 USA (1255) < 100 CD4+ T-cells/µl (1/94-6/97) 29.4 ® 8.8 21.9 ® 3.7* Ledergerber 1999 Switzerland (2410) 6 months before versus 3 months after HAART (9/95-12/97) NA 15.1 ® 7.7 Mocroft 2000 Europe (7331) All (94-98) NA 30.7 ® 2.5 Mocroft 2002 Europe (8556) All (94-01) 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 * MAC, PCP, CMV. Mortality/Morbidity each per 100 py = patient years In the Swiss cohort, the effect of HAART increases over time - after more than two years on HAART, the risk of progression was only 4 % of the risk without HAART (Sterne 2005). However, a completely new analysis of several large cohorts (with over 20,000 patients) showed that in the recent years, the rates of AIDS and mortality have not decreased further - in 1997 as well as in 2003, the risk of AIDS was around 6 %. HAART is possibly being started too late in many cases. In the last few years, every second patient had just 200 CD4 cells at the start of treatment (May 2006). The effect of HAART on the incidence of individual AIDS diseases is probably different: the most obvious is the decline of viral OIs, although this is not so pronounced for fungal OIs (D'Arminio 2005). The effect of HAART is equally as apparent on the clinical course as it is on the 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. These effects are discussed in more detail in the corresponding chapters. Treatment aim: Cure In a chapter on the aims of therapy, the possibility of a cure also has to be discussed. Whoever speaks of cure will eventually achieve it. Following the success of antiretroviral therapies in the last 20 years, which help most patients to control infection for decades, many now believe that the next 20 years should concentrate on cure as the main aim of therapy. What is cure? One important question is whether complete eradication is necessary for a cure. Does the last virus actually have to be removed from the body? Cure could also mean that the body is able to control the infection without the help of medication - analogous to other infections, such as herpes simplex or varicella zoster, in which only small amounts of the virus persist. A very few HIV patients, the so-called "elite controllers" have already succeeded in this. These patients, a few of which are found in every large centre, have normal CD4 cells for many years, and even more impressively, a viral load that remains below the level of detection of normal assays without antiretroviral therapy (Table 4.5). Only when the lymph nodes are examined with ultrasensitive methods, can the virus be detected in comparatively minute amounts. What makes the HIV-specific immune response of these patients so effective; what makes the virus in these people so "unfit"; which genetic changes are responsible? These questions are currently occupying many leading working groups worldwide. Table 4.5: Example of an "elite controller" from our clinic Date (HA)ART CD4 cells Viral load 04/03 Acute HIV infection (Western blot: 5 bands) 203 (8 %) > 1 Mill 04/03 Start with ART (AZT+3TC+IDV/r) 412 (12 %) > 1 Mill 06/03 702 (51 %) 2,000 01/04 ART stopped after 8 months 838 (52 %) < 50 06/04 467 (46 %) < 25 05/05 1,288 (51 %) 44 01/07 Three years without antiviral therapy 841 (44 %) < 25 Comment: It is unclear whether HAART had an effect during the acute infection. Such courses are also seen without treatment. In some cases, different VL tests were used. Notable are the initial very low and later very high percentages of CD4 cells. The problem with latent reservoirs At this point in time, eradication of HIV in the sense of a cure is still unrealistic. The main problem lies in the pool of latently HIV-infected cells, which probably comprise a lifelong reservoir (review: Saksena 2003). Even after years of sufficient viral suppression to below 20-50 copies/ml, cellular viral transcription still takes place in these cells (Finzi 1999, Furtado 1999, Zhang 1999, Sharkey 2000). This is particularly true for blood cells, but also applies to lymph nodes and sperm (Lafeuillade 2001, Nunnari 2002). Replication probably also takes place in the cells of the gastrointestinal tract long after there is no trace left in the blood. How long does it take for the last latently infected cells to be removed? In a study on 62 patients, whose viral load had been successfully suppressed on HAART for seven years, a half-life of 44.2 months was calculated for the latently infected reservoir (Siciliano 2003). The calculated time to eradication of these reservoirs was 73.4 years. Even in a highly selected group of patients, without even a single viral blip measured during a minimum of three years of stable HAART, and with an overall trend for a slightly more rapid decrease in infected cells, the time to eradication was 51.2 years. Latently infected reservoirs consist of very heterogeneous cell populations, the stability of which is probably even independent of residual viral replication. Therefore, even complete inhibition of viral replication would probably be insufficient to eradicate HIV (Strain 2004). Different methods have been used in the last few years to attempt to flush out these latent reservoirs (IL-2, hydroxyurea or OKT), but all have failed (Kulkosky 2002, Pomerantz 2002). In summer 2005, a pilot study on valproic acid, an antiepileptic treatment used worldwide, caused a stir as they discovered that valproic acid, an inhibitor of histon deacetylase-1 (HDAC1), caused a release of HIV from dormant T cells (Lehrman 2005). In three out of four HIV patients, the number of infected dormant T cells decreased significantly, and the half-life sank to 2-3 months -much less in comparison to other studies, which have reported 44.2 months under classical HAART (Siciliano 2003). Summary: based on the currently available medication, eradication is still not possible. Washing out the reservoirs, or simply eliminating all infected memory cells is either unsuccessful, too toxic or much too dangerous. It remains to be seen whether valproic acid or other immune therapies given in addition to HAART, will provide a perspective. Due to the complexity of the immune system, which is only gradually beginning to be understood, a solution seems to be a long way off. References on aims of therapy 1. Aiuti F, Mezzaroma I. Failure to reconstitute CD4+ T-cells despite suppression of HIV replication under HAART. AIDS Rev 2006; 8: 88-97. Abstract: http://amedeo.com/lit.php?id=16848276 2. Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004, 18:2075-2079. http://amedeo.com/lit.php?id=15577629 3. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998, 351:543-9. http://amedeo.com/lit.php?id=9492772 4. Cozzi Lepri A, Phillips AN, d'Arminio Monforte A, et al. When to start HAART in chronically HIV-infected patients: evidence from the ICONA study. AIDS 2001, 15:983-90. http://amedeo.com/lit.php?id=11399980 5. d'Arminio Monforte A, Sabin CA, Phillips A, et al. The changing incidence of AIDS events in patients receiving highly active antiretroviral therapy. Arch Intern Med 2005, 165:416-23. http://amedeo.com/lit.php?id=15738371 6. Deeks SG, Barbour JD, Grant RM, Martin JN. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 2002, 16: 201-7. http://amedeo.com/lit.php?id=11807304 7. Deeks SG. Determinants of virological response to antiretroviral therapy: implications for long-term strategies. Clin Infect Dis 2000, 30 Suppl 2: S177-84. http://amedeo.com/lit.php?id=10860903 8. Demeter LM, Hughes MD, Coombs RW, et al. Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. Ann Intern Med 2001; 135: 954-64. Abstract: http://amedeo.com/lit.php?id=11730396 9. Di Mascio M, Markowitz M, Louie M, et al. Dynamics of intermittent viremia during highly active antiretroviral therapy in patients who initiate therapy during chronic versus acute and early HIV type 1 infection. J Virol 2004, 78:10566-73. http://amedeo.com/lit.php?id=15367623 10. Di Mascio M, Markowitz M, Louie M, et al. Viral blip dynamics during highly active antiretroviral therapy. J Virol 2003; 77:12165-72. http://amedeo.com/lit.php?id=14581553 11. Dragsted UB, Mocroft A, Vella S, et al. predictors of immunological failure after initial response to highly active antiretroviral therapy in HIV-1-infected adults: A EuroSIDA study. J Infect Dis 2004, 190:148-55. http://amedeo.com/lit.php?id=15195254 12. Easterbrook PJ, Ives N, Waters A, et al. The natural history and clinical significance of intermittent viraemia in patients with initial viral suppression to < 400 copies/ml. AIDS 2002; 16:1521-7. http://amedeo.com/lit.php?id=12131190 13. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999, 5: 512-7. http://amedeo.com/lit.php?id=10229227 14. Florence E, Lundgren J, Dreezen C, et al. Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study. HIV Med 2003;4:255-62. http://amedeo.com/lit.php?id=12859325 15. Furtado MR, Callaway DS, Phair JP, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999, 340:1614-22. http://amedeo.com/lit.php?id=10341273 16. Goetz MB, Boscardin WJ, Wiley D, Alkasspooles S. Decreased recovery of CD4 lymphocytes in older HIV-infected patients beginning HAART. AIDS 2001, 15:1576-9. http://amedeo.com/lit.php?id=11504992 17. Grabar S, Kousignian I, Sobel A, et al. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004, 18:2029-2038. http://amedeo.com/lit.php?id=15577624 18. Grabar S, Le Moing V, Goujard C, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of HAART. Ann Intern Med 2000, 133: 401-10. http://amedeo.com/lit.php?id=10975957 19. Gulick RM, da Silva B, McMillan F, et al. Lopinavir/ritonavir (LPV/r)-based therapy in antiretroviral (ARV)-naïve, HIV-infected patients: 6-year follow-up of study 720. Abstract P28, 7th Int Congress Drug Ther HIV Inf 2004, Glasgow. 20. Gulick RM, Meibohm A, Havlir D, et al. Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine. AIDS 2003; 17:2345-2349. http://amedeo.com/lit.php?id=14571186 21. Gunthard HF, Wong JK, Ignacio CC, et al. Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent antiretroviral therapy. J Virol 1998, 72:2422-8. http://amedeo.com/lit.php?id=9499103 22. Haas D. Human genetic variability and HIV treatment response. Current HIV/AIDS Reports 2006, 3:53-58. http://amedeo.com/lit.php?id=14583845 23. 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 Study Team. N Engl J Med 1997, 337:725-33. http://amedeo.com/lit.php?id=9287227 24. Haubrich R, Riddler S, Ribaudo H, et al. Initial viral decay to assess the relative antiretroviral potency of PI-, NNRTI-, and NRTI-sparing regimens for first line therapy of HIV-1 infection: ACTG 5160s. Abstract 137, 14th CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/28232.htm 25. Havlir DV, Bassett R, Levitan D, et al. Prevalence and predictive value of intermittent viremia with combination HIV therapy. JAMA 2001, 286:171-9. http://amedeo.com/lit.php?id=11448280 26. Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4-cell count in HIV-1-infected individuals remaining viraemic with HAART. Swiss HIV Cohort Study. Lancet 1998, 351:723-4. 27. Kaufmann GR, Perrin L, Pantaleo G, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med 2003; 163:2187-95. http://amedeo.com/lit.php?id=14557216 28. Kaufmann GR, Furrer H, Ledergerber B, et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 2005;41:361-72. http://amedeo.com/lit.php?id=16007534 29. Kempf DJ, Rode RA, Xu Y, et al. The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir. AIDS 1998, 12: F9-14. http://amedeo.com/lit.php?id=9543434 30. Kolber MA, Gabr AH, De La Rosa A, et al. Genotypic analysis of plasma HIV-1 RNA after influenza vaccination of patients with previously undetectable viral loads. AIDS 2002, 16: 537-42. http://amedeo.com/lit.php?id=11872996 31. Kulkosky J, Nunnari G, Otero M, et al. Intensification and stimulation therapy for HIV type 1 reservoirs in infected persons receiving virally suppressive HAART. J Infect Dis 2002, 186:1403-11. http://amedeo.com/lit.php?id=12404155 32. Lafeuillade A, Khiri H, Chadapaud S, Hittinger G, Halfon P. Persistence of HIV-1 resistance in lymph node mononuclear cell RNA despite effective HAART. AIDS 2001, 15:1965-9. http://amedeo.com/lit.php?id=11600824 33. Lampe FC, Gatell JM, Staszewski S, et al. Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002. Arch Intern Med 2006; 166: 521-8. Abstract: http://amedeo.com/lit.php?id=16534038 34. Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA 1999, 282: 2220-6. http://amedeo.com/lit.php?id=1060597 35. Ledergerber B, Egger M, Opravil M. et al. Clinical progression and virological failure on HAART in HIV-1 patients: a prospective cohort study. Lancet 1999, 353: 863-8. http://amedeo.com/lit.php?id=10093977 36. Ledergerber B, Lundgren JD, Walker AS, et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004, 364:51-62. http://amedeo.com/lit.php?id=15234856 37. Lederman MM, McKinnis R, Kelleher D, et al. Cellular restoration in HIV infected persons treated with abacavir and a protease inhibitor: age inversely predicts naive CD4 cell count increase. AIDS 2000, 14: 2635-42. http://amedeo.com/lit.php?id=11125881 38. 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. http://amedeo.com/lit.php?id=16099290 39. Le Moing V, Chene G, Carrieri MP, et al. Predictors of virological rebound in HIV-1-infected patients initiating a protease inhibitor-containing regimen. AIDS 2002, 16:21-9. http://amedeo.com/lit.php?id=11741159 40. Le Moing V, Thiebaut R, Chene G, et al. Predictors of long-term increase in CD4(+) cell counts in HIV-infected patients receiving a protease inhibitor-containing antiretroviral regimen. J Infect Dis 2002, 185: 471-80. http://amedeo.com/lit.php?id=11865399 41. Lohse N, Obel N, Kronborg G, et al. Declining risk of triple-class antiretroviral drug failure in Danish HIV-infected individuals. AIDS 2005, 19:815-22. http://amedeo.com/lit.php?id=15867496 42. Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 2007; 146: 87-95. http://amedeo.com/lit.php?id=17227932 43. Maggiolo F, Migliorino M, Pirali A. Duration of viral suppression in patients on stable therapy for HIV-1 infection is predicted by plasma HIV RNA level after 1 month of treatment. J AIDS 2000, 25:36-43. http://amedeo.com/lit.php?id=11064502 44. Marimoutou C, Chene G, Mercie P, et al. Prognostic factors of combined viral load and CD4+ cell count responses under triple antiretroviral therapy, Aquitaine cohort, 1996-1998. JAIDS 2001, 27:161-7. http://amedeo.com/lit.php?id=11404538 45. Martinez V, Marcelin AG, Morini JP, et al. HIV-1 intermittent viraemia in patients treated by non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS 2005;19:1065-1069. http://amedeo.com/lit.php?id=15958838 46. May MT, Sterne JA, Costagliola D, et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet 2006; 368: 451-8. http://amedeo.com/lit.php?id=16890831 47. Mezzaroma I, Carlesimo M, Pinter E, et al. Clinical and immunologic response without decrease in virus load in patients with AIDS after 24 months of HAART. Clin Infect Dis 1999, 29:1423-30. http://amedeo.com/lit.php?id=10585790 48. Miller LG, Golin CE, Liu H, et al. No evidence of an association between transient HIV viremia ("Blips") and lower adherence to the antiretroviral medication regimen. J Infect Dis 2004, 189:1487-96. http://amedeo.com/lit.php?id=15073687 49. Mira JA, Macias J, Nogales C, et al. Transient rebounds of low-level viraemia among HIV-infected patients under HAART are not associated with virological or immunological failure. Antivir Ther 2002, 7:251-6. http://amedeo.com/lit.php?id=12553479 50. Mocroft A, Brettle R, Kirk O, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study. AIDS 2002, 16:1663-71. http://amedeo.com/lit.php?id= 12172088 51. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000, 356:291-6. http://amedeo.com/lit.php?id=11071184 52. Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003;362:22-9. http://amedeo.com/lit.php?id=12853195 53. Moore AL, Youle M, Lipman M, et al. Raised viral load in patients with viral suppression on HAART: transient increase or treatment failure? AIDS 2002, 16:615-8. http://amedeo.com/lit.php?id=11873005 54. Moore DM, Hogg RS, Yip B, et al. Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syndr 2005; 40: 288-93. http://amedeo.com/lit.php?id=16249702 55. Negredo E, Molto J, Munoz-Moreno JA, et al. Safety and efficacy of once-daily didanosine, tenofovir and nevirapine as a simplification antiretroviral approach. Antivir Ther 2004, 9:335-42. http://amedeo.com/lit.php?id=15259896 56. Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 2005, 293:817-29. http://amedeo.com/lit.php?id=1571377 57. Nettles RE, Kieffer TL, Simmons RP, et al. Genotypic resistance in HIV-1-infected patients with persistently detectable low-level viremia while receiving highly active antiretroviral therapy. Clin Infect Dis 2004, 39:1030-7. http://amedeo.com/lit.php?id=15472857 58. Nunnari G, Otero M, Dornadula G, et al. Residual HIV-1 disease in seminal cells of HIV-1-infected men on suppressive HAART: latency without on-going cellular infections. AIDS 2002, 16:39-45. http://amedeo.com/lit.php?id=11741161 59. Palella FJ JR, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced HIV infection. N Engl J Med 1998, 338:853-60. http://amedeo.com/lit.php?id=9516219 60. Phillips AN, Miller V, Sabin C, et al. Durability of HIV-1 viral suppression over 3.3 years with multi-drug antiretroviral therapy in previously drug-naive individuals. AIDS 2001, 15: 2379-84. http://amedeo.com/lit.php?id=11740188 61. Phillips AN, Staszewski S, Weber R, et al. HIV viral load response to ART according to the baseline CD4 cell count and viral load. JAMA 2001, 286:2560-7. http://amedeo.com/lit.php?id=11722270 62. Phillips AN, Youle M, Lampe F, et al. CD4 cell count changes in individuals with counts above 500 cells/mm and viral loads below 50 copies/ml on antiretroviral therapy. AIDS 2002; 16: 1073-5. 63. Piketty C, Castiel P, Belec L, et al. Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease. AIDS 1998, 12:745-50. http://amedeo.com/lit.php?id=9619806 64. Piketty C, Weiss L, Thomas F, et al. Long-term clinical outcome of HIV-infected patients with discordant immunologic and virologic responses to a protease inhibitor-containing regimen. J Infect Dis 2001, 183:1328-35. http://amedeo.com/lit.php?id=11294663 65. Pomerantz RJ. Reservoirs of HIV type 1: the main obstacles to viral eradication. Clin Infect Dis 2002, 34: 91-7. http://amedeo.com/lit.php?id=11731950 66. Powderly WG, Saag MS, Chapman S, et al. Predictors of optimal virological response to potent ART. AIDS 1999, 13:1873-80. http://amedeo.com/lit.php?id=10513645 67. 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. http://amedeo.com/lit.php?id=17057609 68. Raboud JM, Montaner JS, Conway B, et al. Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy. AIDS 1998, 12: 1619-24. http://amedeo.com/lit.php?id=9764780 69. Raffi F, Chene G, Lassalle R, et al. Progression to AIDS or death as endpoints in HIV clinical trials. HIV Clin Trials 2001, 2:330-5. http://amedeo.com/lit.php?id=11590536 70. Reisler RB, Han C, Burman WJ, Tedaldi EM, Neaton JD. Grade 4 events are as important as AIDS events in the era of HAART. J AIDS 2003; 34: 379-86. http://amedeo.com/lit.php?id=14615655 71. Renaud M, Katlama C, Mallet A, et al. Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen. AIDS 1999, 13:669-76. http://amedeo.com/lit.php?id=10397561 72. Saksena NK, Potter SJ. Reservoirs of HIV-1 in vivo: implications for antiretroviral therapy. AIDS Rev 2003; 5:3-18. http://amedeo.com/lit.php?id=12875103 73. Salzberger B, Rockstroh J, Wieland U, et al. Clinical efficacy of protease inhibitor based antiretroviral combination therapy--a prospective cohort study. Eur J Med Res 1999, 4:449-55. http://amedeo.com/lit.php?id=10585299 74. Sharkey ME, Teo I, Greenough T, et al. Persistence of episomal HIV-1 infection intermediates in patients on HAART. Nat Med 2000, 6: 76-81. http://amedeo.com/lit.php?id=10613828 75. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Med 2003;9:727-728. http://amedeo.com/lit.php?id=12754504 76. Sklar PA, Ward DJ, Baker RK, et al. Prevalence and clinical correlates of HIV viremia ('blips') in patients with previous suppression below the limits of quantification. AIDS 2002, 16:2035-41. http://amedeo.com/lit.php?id=12370502 77. Smith CJ, Sabin CA, Youle MS, et al. Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy. J Infect Dis 2004, 190:1860-8. http://amedeo.com/lit.php?id=15499544 78. Smith K, Aga E, Bosch RJ, Valdez H, et al. Long-term changes in circulating CD4 T lymphocytes in virologically suppressed patients after 6 years of highly active antiretroviral therapy. AIDS 2004, 18:1953-6. http://amedeo.com/lit.php?id=15353982 79. Steel A, Clark S, Teo I, et al. No change to HIV-1 latency with valproate therapy. AIDS 2006; 20: 1681-2. 80. 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. 81. Sterne JA, Hernan MA, Ledergerber B, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005, 366:378-84. http://amedeo.com/lit.php?id=16054937 82. Strain MC, Gunthard HF, Havlir DV, et al. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci U S A 2003, 100:4819-24. http://amedeo.com/lit.php?id=12684537 83. Sungkanuparph S, Overton ET, Seyfried W, et al. Intermittent episodes of detectable HIV viremia in patients receiving nonnucleoside reverse-transcriptase inhibitor-based or protease inhibitor-based highly active antiretroviral therapy regimens are equivalent in incidence and prognosis. Clin Infect Dis, 41:1326-32. http://amedeo.com/lit.php?id=16206110 84. Teixeira L, Valdez H, McCune JM, et al. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. AIDS 2001, 15:1749-56. http://amedeo.com/lit.php?id=11579235 85. Thiebaut R, Morlat P, Jacqmin-Gadda H, et al. Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment. AIDS 2000, 14:971-8. http://amedeo.com/lit.php?id=10853978 86. Valdez H, Connick E, Smith KY, et al. Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease. AIDS 2002, 16:1859-66. http://amedeo.com/lit.php?id=12351945 87. Viard JP, Burgard M, Hubert JB, et al. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 2004, 18:45-9. http://amedeo.com/lit.php?id=15090828 88. Viard JP, Mocroft A, Chiesi A, et al. Influence of age on CD4 cell recovery in HIV-infected patients receiving highly active antiretroviral therapy: evidence from the EuroSIDA study. J Infect Dis 2001, 183: 1290-4. http://amedeo.com/lit.php?id=11262215 89. Wolbers M, Battegay M, Hirschel B, et al. Predictors for CD4 cell count increase for patients with sustained viral load suppression within 1 year after starting cART: The Swiss HIV cohort study. Abstract 518, 14th CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/28568.htm 90. Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999, 340: 1605-13. http://amedeo.com/lit.php?id=10341272