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5.5: When to start HAART

by Christian Hoffmann and Fiona Mulcahy

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

But, how high is the individual risk really? The following table lists the (selected) risks of developing AIDS within six months, as identified in 3,326 patients from the pre-HAART era (Phillips 2004). The range of individual risk of progression varies widely - from 0 to almost 50 %. For a 55-year-old patient with a CD4 cell count of 50/µl and a viral load of 300,000 copies/ml, the risk of progressing to AIDS within the next 6 months was 44.8 %; for a 25-year-old patient with 500 CD4 cells/µl and a viral load of 3,000 copies/ml, the risk was only 0.3 %. This demonstrates the importance of these parameters for estimating the individual risk and indication for treatment (see Table 5.1). Surprisingly, the age of the patients, which according to these data significantly increases the risk of progression, has so far not been included in any of the guidelines.

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Table 5.1: Predicted six-month percentage risk of developing AIDS, according to age, viral load and CD4 cell count (data from the pre-HAART era) 100 CD4/µl 200 CD4/µl 350 CD4/µl 35 years Viral load 10,000 5.3 2.0 1.1 Viral load 100,000 10.6 4.1 2.3 55 years Viral load 10,000 10.7 4.6 1.8 Viral load 100,000 20.5 9.2 3.6 From: Phillips A, CASCADE Collaboration. AIDS 2004, 18:51-8. Link: http://amedeo.com/lit.php?id=15090829 The best time for initiation of therapy remains the subject of controversial debate. The risk of AIDS must be weighed against the risks of viral resistance and long-term toxicity. These risks and the realization that eradication cannot be achieved at present have led to the relaxation of treatmentb guidelines in recent years. In a large cohort of over 20,000 patients, the median CD4-cell count at the start of therapy has hovered at around 200/µl for the last few years, after being at 270/µl in 1998 (May 2006). The initial "hit hard and early" dogma of 1996, which recommended therapy from the earliest stages of infection, has been discarded. Instead, it has been replaced by the motto "hit hard but only when necessary". It is now no longer common practice to treat every patient with a viral load above 10,000 copies/ml, independent of the CD4 cell count, as was still recommended in the 1997 US guidelines (Carpenter 1997). Lately, however, there has been a trend in the opposite direction: the pendulum is swinging back. In view of the constantly improving therapy, there is increasing pressure to start it earlier (Holmberg 2004, Schechter 2004). In addition, although the risk of AIDS is low with good CD4-cell counts, it is not nil. The "low" individual risk of AIDS of 1 to 2 % per year just a few years ago, has become relevant in these times when patients are treated for decades. International treatment guidelines agree that all symptomatic patients and patients with less than 200 CD4 cells/µl have to be treated. The situation is less clear for asymptomatic patients with more than 200 CD4 cells/µl. Because of the lack of randomized trials, all the recommendations are based on cohort studies, meta-analyses, and the evaluation of large databanks. However, these data present problems, because they often exclude essential aspects such as compliance or possibly treatment experience, and consist of very heterogeneous patient populations. Consequently, they can be interpreted in different ways. Table 5.2 shows the latest recommendations from the USA, Great Britain and Germany on the start of treatment. Table 5.2: Recommendations from various guidelines on when to initiate therapy Clinical CD4 cells/µl Initiation of HAART is... CDC B+C All values "recommended" (DHHS, GA, GB) CDC A < 200 "recommended" (DHHS, GA, GB) CDC A 200-350 "should be offered" (DHSS) "generally advisable, independent of VL" (GA) "recommended for most patients, but should depend on individual factors"* (GB) CDC A > 350 "most experts recommend deferring with a VL > 100,000, some clinicians will treat; defer with a VL < 100,000" (DHHS) up to 500 CD4 cells "recommended by some experts with a VL 50,000 -100,000; most were hesitant to treat with a VL of 50,000", over 500 CD4 cells "generally avoid" (GA) "to be deferred" (GB) *Individual factors: symptoms, patient wishes, expected adherence, potential toxicity, decline in CD4 cells, level of viral load and age. VL = viral load DHHS: United States Centers for Disease Control and Prevention. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents, October 10, 2006. Link: http://aidsinfo.nih.gov/Guidelines GA: German-Austrian Guidelines on Antiretroviral Therapy of HIV Infection (June 2005). http://www.daignet.de/edia/PDF_D_A_antiretroviral_06_05.pdf GB: British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy, 2005. http://www.bhiva.org/guidelines/2005/BHIVA-guidelines/index.html Guidelines merely provide points of reference and are not set in stone. Therapy may be started earlier; but in individual cases, can (or even should) be deferred. The following chapter discusses the relevant studies on initiation of therapy in chronic HIV infection. The special case of acute HIV infection is referred to in the corresponding chapter. Experiences from practice Even if the indication for HAART seems obvious, it should be clarified whether the patient is indeed ready to start treatment. The problem is not the initiation of HAART, but the continuity. The decision to initiate treatment is often made prematurely. It is usually unwise to prescribe antiretroviral medication to a patient in the first consultation. One should first attain an overall picture of the patient, and try to get to know something about his lifestyle and motives - why he has come to see a doctor, and what he expects. In some cases, patients put themselves under pressure unnecessarily, or let others do so. A single lower CD4 count, a prolonged case of flu seeming to indicate a weakened immune system ("I never had anything like that before"), springtime lethargy, new study results, a promising new drug in the newspaper ("I've heard a lot about T-20"), a partner who has started therapy - none of these are therapeutic indications. It is often particularly difficult to inform people from other cultures that not every person with an HIV infection needs immediate therapy. On the other hand, a patient's desire for one particular therapy also has to be respected. HAART should not be withheld from a patient that wishes to start antiretroviral therapy after extensive discussions, although the levels would still justify waiting. For many patients, treatment can be a psychological support. Not everyone can sleep peacefully in the knowledge that every day a few hundred million viruses are being produced and a huge number of helper cells destroyed within their body. As a rule, as much time as is needed should be taken to make the decision to start therapy. This is usually possible. A well-informed patient complies better with treatment! We recommend that patients come for several consultations to prepare them emotionally for treatment. There are two exceptions: acute HIV infection, and severe immunodeficiency. However, even in the presence of most AIDS-defining conditions, the acute disease should often be treated first before initiating ART, as the potential for complications with PCP, toxoplasmosis or CMV therapies unnecessarily jeopardize treatment options. Not a single study to date has convincingly shown a benefit of commencing HAART simultaneously with OI therapy (however, there is also no study to show that starting HAART early causes harm). If a vacation is planned, it is better to delay therapy so that treatment response and side effects can be adequately monitored. On the other hand, patients may sometimes find one reason after another (stress at work, exams, change of job, etc.) to delay initiation of treatment. Many patients are afraid of AIDS, but often just as afraid of HAART ("the pills are the beginning of the end!"). They may have irrational expectations of HAART and its consequences - starting therapy does not mean that one will be subjected to daily infusions and no longer able to work! Therapy should be explained to every patient from the outset, even when treatment is still not necessary. It is also useful early on to define with patients the individual threshold values for the commencement of therapy, so that therapy is started only when these levels are reached. In our experience, patients are more motivated by this approach. We also tend to start HAART earlier in older patients (above 50 years). Although the regenerative capacity of the immune system in older patients is significantly reduced (Ledermann 2002, Grabar 2004), this has not been acknowledged in any guidelines to date. More importantly, the OI risk also depends on age (Phillips 2004). One example from the CASCADE Study (Table 5.1) exemplifies this: a 25 year-old patient with 100 CD4 cells/µl and a viral load of 100,000 copies/ml has a risk of approximately 10 % for developing AIDS within six months - at 55 years, this level of risk is reached at 150 CD4 cells/µl and 30,000 copies/ml! It is also important that beside the absolute CD4 count, the percentage is also considered. In particular, when the absolute CD4 count is high, the CD4 percentage is the most important predictor of the AIDS risk. In one study, the risk of progression for patients with more than 350 CD4 cells/µl was increased approximately four fold, if the percentage was below 17 % (Hulgan 2005). Finally, it should also not be forgotten that CD4 cells are actually surrogate markers. As a "surrogate", they are conceived as a replacement for clinical endpoints. Therefore, they are only a rough expression of the clinical reality. Although they usually do this supremely, and even though the CD4-cell count is one of the best surrogate markers in HIV medicine, the patient must also be examined! Symptomatic patients There is consensus that every patient with HIV-associated symptoms should receive antiretroviral therapy. This is mainly true for patients in CDC Stage C (with AIDS), but also for Stage B. Although this should be correct in most cases, it may be advisable to consider the situation more closely in individual cases. To avoid misunderstanding: all OIs, which only occur in severe immunodeficiency, such as CMV, MAC or PCP, and also AIDS malignancies (including the non-AIDS-defining Hodgkin's Disease), should therefore prompt rapid initiation of therapy, especially, as in the case of PML, if there is no specific treatment available. In these cases, rapid initiation of HAART is the only treatment option available. However: Herpes zoster (Stage B) may occur even with a slight immune defect and does not necessarily indicate immunological deterioration. Thrombocytopenia or constitutional symptoms may also have other causes. A further example: tuberculosis (TB), which is an AIDS-defining illness and therefore an "urgent" indication for therapy, can occur as a facultative opportunistic infection, without or with only moderate immunodeficiency. Waiting with HAART can be justified in a TB patient with good CD4 cells (see example in Table 5.3). Table 5.3: Case study, in which HIV treatment, if it had been given in accordance to the guidelines, could have led to almost eleven years of over-treatment. NA = not available CD4 (%) Viral load May 95 Pulmonary tuberculosis (= AIDS) 330 (27) NA Feb 96 End of tuberculosis treatment Patient refuses (urgently recommended) HAART 437 (29) NA Oct 97 Patient refuses (urgently recommended) HAART 402 (33) 29,500 Oct 00 Patient refuses (recommended) HAART 520 (30) 12,500 Jun 02 Doctor does not want to start HAART 521 (29) 7,440 Oct 04 HAART is rarely discussed… 391 (26) 15,300 Nov 06 Nothing new. Will it change again? 336 (26) 11,200 In the British guidelines, pulmonary tuberculosis is considered to be a possible exception. On the other hand, typical marker-illnesses, such as oral candida or oral hairy leukoplakia, can be an indication that the immune system is impaired. They may often precede far more serious illnesses. In such cases, it is advisable to offer the patient therapy, even if the CD4 cell count is relatively stable. The same applies to constitutional or cognitive disturbances. A patient who newly develops concentration deficits, could - if other causes have been ruled out - have developed the first cognitive deficiency associated with HIV. Neuropsychological changes are sometimes seen observed in otherwise asymptomatic patients (Review: McArthur 2005). Asymptomatic patients - below 200 CD4 cells/µl There is a clear indication for initiation of therapy in these patients. 200 CD4 cells/µl is the cut-off, and values should not drop below this level - the risk of severe complications increases significantly after this (Mellors 1997, Egger 2002). For patients with CD4 cells of 200/µl and a high viral load, the six-month risk for AIDS is sometimes greater than 10 % (Phillips 2004). It is therefore advisable not to let this happen: the first manifestation of AIDS may not be an easily treatable infection. If PML, CMV, or toxoplasmosis occurs, the result is often permanently damaging. However, such considerations are redundant for many of the patients that present for the first time. At least one third have a CD4-cell count below 200/µl. Nevertheless, even here the point is not to start therapy within a matter of days, but rather whether HAART is to be started at all. Is the patient going to return? We have now made it our practice to start PCP prophylaxis in such patients, and use the first two weeks for diagnostic procedures (fundoscopy! thoracic x-ray, ultrasound) to provide informative counseling - as well as exploring whether the patient is eligible to enter a study - and to identify patients with psychosocial issues. Requirements with respect to pill burden and dosing schedules need to be raised. HAART is started only when these issues have been addressed. The risk of AIDS remains elevated in these patients even after initiation of HAART. This is logical - severe immunodeficiency requires time to reconstitute, and patients therefore remain at risk during the initial months. However, this risk is relatively low: in an analysis of treatment-naïve patients with less than 200 CD4 cells/µl at the beginning of therapy, 8.3 new AIDS-defining illnesses per 100 patient years were observed - in patients with at least 350 CD4 cells/µl this value was 1.8/100 patient years. Similarly, mortality was slightly elevated at 2.9 versus 0.7/100 patient years (Phillips 2001). Asymptomatic patients - 200-350 CD4 cells/µl Even in these patients, most guidelines recommend starting treatment, although the risk of developing AIDS is rather low. In the MACS Cohort, frozen blood samples obtained in the years 1985-1988 were analyzed and correlated with the clinical course of disease in these patients (Phair 2002). Not a single patient with more than 200 CD4 cells/µl and a viral load below 20,000 copies/ml became ill with AIDS within the following year. On the other hand, a long-term risk of AIDS, especially with a high viral load, cannot be completely excluded. One should not feel too secure. We have seen a few patients, who have developed Kaposi's sarcoma, PML or a lymphoma with 200-350 CD4 cells/µl. In EuroSIDA, the risk of developing PCP or esophageal thrush at more than 200 CD4 cells was 1.6 % (Podlekareva 2006). In times of well-tolerated HAART combinations, an annual AIDS risk of 1 or 2 % becomes relevant. What is really gained in quality of life if one waits and exposes patients to such a risk? What is actually saved in long-term toxicity in these 1, 2 or 3 therapy-free years, which can perhaps be "taken out"? It is clear that: the less worries one has about long-term side effects, the earlier HAART will be used in the future. Asymptomatic patients - above 350 CD4 cells/µl In many current guidelines, the border of 350 CD4 cells/µl is the threshold above which it is recommended to defer therapy. In the MACS Cohort, not a single patient with more than 350 CD4 cells/µl and a viral load below 60,000 copies/ml became ill with AIDS within one year (Phair 2002). Most studies (see Table 5.5) found no advantage for patients, who began HAART whilst still at these CD4 cell levels. However, there were a few exceptions: a matched-pair analysis indicated a small, though statistically significant clinical benefit if HAART was started with CD4 cells above this level (Opravil 2002). 283 patients, who were started on HAART with a count above 350 CD4 cells/µl, were matched by age, sex, CD4 cell count, viral load and risk group for HIV infection with control patients who had been untreated for at least 12 months. At follow up after three years, the AIDS risk was more than twice as high in the untreated group. The 52 illnesses (10 AIDS cases, and otherwise oral candidiasis, OHL, and herpes zoster), which occurred additionally in the untreated group, have to be compared to the side effects of HAART. 35 % of the control patients had to discontinue HAART, 51 patients because of gastrointestinal complaints, 25 because of CNS, renal problems, or lipodystrophy - a high price in contrast to the clinical benefit. However, it should be noted that due to newer, more tolerable therapies, these data may no longer be valid. Another study demonstrated a survival benefit if HAART is started with more than 350 CD4 cells/µl (Palella 2003). In this analysis from the American HOPS Cohort, patients were assigned to groups based on the first (baseline) CD4 cell count. Patients of the same group, who had either started ART immediately or waited until they had "dropped" into a lower group, were compared. This design eliminated a problem encountered in cohort studies, in that a patient's risk is usually only determined at the time when therapy is started ("lead time bias") - the clock was theoretically started at the same time point for all patients. However, the methods of this study are not without criticism. For example, patients that had started mono or dual therapy were also included, and the first patients to enter the analysis were from 1994. With the treatment available today, a difference may not have been observed. The mortality risk was, however, low. New data from the HOPS cohort (Lichtenstein 2006) calculated that at 200-349 CD4 cells/µl it was 15.9/1,000 person years (350-500 CD4 cells/µl: 11.5; over 500: 7.5). Why has no randomized study been performed so far to address this question? An editorial on the cohort described above provided calculations (Lane 2003): in order to design a randomized study with 80 % power on starting treatment above or below 250 CD4 cells/µl, 650 events would be required to detect a 20 % difference in mortality. With a probability for progression of 1 % per patient year, around 6,500 would have to be followed for 10 years. Despite these logistical problems, a large, global randomized trial on the optimal treatment start is, according to many experts, urgently needed. It is currently being planned. Following the success of the SMART trial, in which 6,000 patients on treatment interruptions were investigated (see "Treatment interruptions"), this has now become realistic. Practical tips for starting therapy in asymptomatic patients § Below 200 CD4 cells/µl treatment should be started as soon as possible. § "As soon as possible" does not mean "immediately": one should still take the time to get acquainted with the patient, give proper counseling, start prophylaxis - it's not usually a question of having to start within a few days! § Above 200 CD4 cells/µl, there is even more time - the individual course of the CD4-cell count is important. Beware the percentage values! § A decrease of more than 50-100 CD4 cells/µl per year is too much! Don't delay too long in such patients! § Because of considerable variability, a single CD4 cell count should be repeated before starting therapy. § Above 350 CD4 cells/µl: wait, but continue to monitor levels every three months. § The higher the viral load, the more frequent checks of CD4 cell counts are necessary: > 100,000 copies/ml, at least every two months. § Initiation of treatment may be justified at levels above 350 CD4 cells/µl - if viral load is very high, CD4 cell count is decreasing rapidly or the patient requests it (after careful counseling). § Consider whether a patient is suitable for enrolment in a clinical trial! Consequences for the further course of disease In the discussion about the start of treatment, it is often argued that beginning later can have an unfavorable effect on the success of therapy. However, does the time point actually influence virological or immunological treatment success? Do the so-called late presenters really have a worse prognosis? The following is a summary of the data. Virological treatment success with unfavorable starting points At first glance, many cohort studies have clearly demonstrated that virological response was poorer if the CD4-cell count at initiation of treatment was low and the viral load high (Casado 1998, Mocroft 1998 + 2000, Miller 1999, Wit 1999, Deeks 1999, Chaisson 2000, Grabar 2000, Yamashita 2001, Palella 2003, Wood 2005). In a meta-analysis of 30 prospective studies, baseline CD4-cell count was important for viral load decline on treatment (Skowron 2001). It might appear straightforward: the higher the viral load and the lower the CD4-cell count, the less the virological success of HAART. Defenders of an early initiation of HAART, who often cite this data, forget three important points: First, this is not true for a few cohorts in which only treatment-naïve patients were studied, or in which therapy-naïve and treatment-experienced patients are differentiated (Cozzi-Lepri 2001, Phillips 2001, Le Moing 2002). Previous NRTI therapy has been a risk factor for virological treatment failure in many cohorts (Casado 1998, Deeks 1999, Chaisson 2000, Grabar 2000, Le Moing 2002). In the HOPS Cohort, lack of prior therapy was predictive of long-term treatment success (Holmberg 2003). Pre-treatment with NRTI is a rarity today, and besides modern HAART regimens are so effective that even in patients with a high viremia, high success rates can be achieved. Secondly, the relative risk of virological failure was often only increased in patients with substantial immunosuppression (below 50 CD4 cells/µl) or very high viral load (above 100,000 copies/ml). At levels above 200 CD4 cells/µl or a viral load of less than 100,000 copies/ml, differences could generally not be detected (see below). Thirdly, only a few of these studies considered adherence. It is difficult to measure, but crucial for virological response (Le Moing 2002, Wood 2004). A patient who starts HAART under emergency conditions at 30 CD4 cells/µl (and who went to the physician only shortly before or even after clinical manifestation of AIDS) may have a different view on sickness and health, and may be less adherent than someone who seeks medical advice with a good CD4 cell count and begins HAART after thorough reflection. It seems clear that the benefit of HAART differs for such patients. Summary: in these times of modern HAART regimens, it is questionable whether the viral load of a therapy-naïve, compliant patient with low CD4 cells and high viral load is actually more difficult to decrease than when a more favorable starting point is taken. Immunological treatment success with unfavorable initial values Multiple factors can influence the increase in CD4 cells: age, thymus size or extent of thymus degeneration (see chapter "Goals of Therapy"). But, do baseline CD4 cell levels at the initiation of therapy play a role? Several cohorts found no association (Cozzi-Lepri 2001, Pezzotto 2001, Yamashita 2001). In the Swiss Cohort, having a low CD4-cell count was a clear risk factor for not attaining 500 CD4 cells/µl after four years (Kaufmann 2005). Furthermore, in our experience immune reconstitution is rarely complete if values were low initially; the more damaged the immune system, the less likely a complete recovery in the long run (Garcia 2004). Another consequence of starting therapy later can be that antigen-specific immune reconstitution remains impaired, both against HIV and other opportunistic infections. Diverse studies suggest that qualitative immune reconstitution does not initially occur at the same pace as quantitative reconstitution (Gochorov 1998, Lange 2002). One can make the analogy with a patch of desert where weeds will grow before flowers. So, what are the clinical consequences of these lab data? Why does the risk of AIDS decrease so impressively and rapidly with a rising CD4 cell count? The weed does not appear to be so bad after all. Why can even severely immunodeficient patients discontinue their prophylaxis quite safely, once their CD4 cell count has risen to above 200/µl? The clinical observations - at least in the short term - are contradictory. Clinical therapeutic success with unfavorable initial values Most studies have found a clear correlation between CD4 cells at the start of treatment and rates of both AIDS and death (Hogg 2000, Grabar 2000, Cozzi-Lepri 2001, Kaplan 2001 + 2003, Phillips 2001, Egger 2002, Palella 2003, Sterling 2003). Above all, when starting therapy with less than 50 CD4 cells, the risk for developing AIDS remains permanently high (Hogg 2003). In other cohorts, the risk remained elevated even below 200 CD4 cells/µl (Phillips 2001, Sterling 2001, Kaplan 2003). Data from the largest study to date (Egger 2002), in which almost 13,000 patients on HAART were analyzed, confirmed that the CD4-cell count at the start of treatment correlated highly with the probability later of AIDS or death. In comparison to the patients who started HAART with less than 50 CD4 cells/µl, the risks with higher levels of helper cells were significantly less (see Table 5.4). One should note the moderate difference between the groups above 200 CD4 cells/µl. Viral load at baseline was only relevant if it was at a very high level, i.e. above 100,000 copies/ml. Table 5.4: Risk of progression in the ART Cohort Collaboration (Egger 2002) Baseline CD4 cells/µl Relative risk 50-99 versus < 50 0.74 (0.62-0.89) 100-199 versus < 50 0.52 (0.44-0.63) 200-349 versus < 50 0.24 (0.20-0.30) > 350 versus < 50 0.18 (0.14-0.22) Are there any differences between 200-350 and >350 CD4 cells/µl? In the above-mentioned meta-analysis, the difference was minimal (Egger 2002). The AIDS rate was 2.3 versus 1.8; the mortality rate 1.0 versus 0.7 per 100 patient years. This means one case of AIDS in 200 patient years! Very large, randomized studies would probably be necessary to detect a difference between the two patient groups. Other cohort studies have also posed the question of whether there is a difference if patients first start at a CD4-cell count of 200-350 cells or earlier. So far, most have not been able to detect an advantage for starting treatment early (Table 5.5). However, the observation periods were usually relatively short. It is possible that differences may emerge in the longer term.will be found in the long term. A problem of many cohort studies is that they do not consider the success of HAART on an individual level. In a complex analysis of almost 10,000 patients, which considered the baseline values as well as the values after six months (Chene 2003), the response to HAART was predictive of decreased mortality and AIDS related morbidity irrespective of baseline CD4 counts. Table 5.5: The influence of CD4-cell count on treatment success. Comparison between 200-350 CD4 cells/µl and > 350 CD4 cells/µl at initiation of HAART. Study Less AIDS, fewer deaths? More pronounced increase in CD4 cells? Improved virological response? Canadian Cohort (Chaisson 2000, n=553) ** ** No (trend) ICONA Cohort, Italian (Cozzi-Lepri 2001, n=1,421) No No No CDC database, USA (Kaplan 2001, n=10,885) No ** ** John Hopkins Cohort (Sterling 2003, n=333) No ** No Swiss, Frankfurt, EuroSIDA Cohorts (Phillips 2001, n=3,226) No ** No Swiss Cohort (matched pair) (Opravil 2002, n=2x283) Yes ** ** MACS Cohort (Ahdieh-Grant 2003, n=349) No ** ** HOPS Cohort (Palella 2003, n=1,464) Yes ** Yes Barcelona Cohort, single-center (Garcia 2004, n = 861) No No (trend) ** ** not specified Finding the optimal time to start treatment is one of the most difficult decisions of HIV therapy. To conclude, here are a few typical arguments about the pros and cons of starting therapy. Arguments for and against an EARLY start Statement Counter "The lower the CD4 count, the longer the patient will remain at risk later." "This statement applies mainly to patients with substantial immune defects, in whom therapy has to be started. The earlier one starts, the more long-term toxicities will occur!" "A lower CD4 count often implies that only moderate immunological-virological treatment success is possible - at some stage, the destruction is irreversible." "This is mainly true for patients with substantial immunosuppression. However, the virological response does not seem to be reduced in treatment-naïve patients." "The longer one waits, the fitter the virus becomes via immune escape variants, and the more difficult it is to treat." "Interesting laboratory hypothesis. But, where's the relevant clinical data?" "The worse the condition of the patient, the worse the tolerability of HAART." "Ancient medical wisdom. But, does it apply here? We are referring to asymptomatic patients…" "HIV should be treated as early as possible, as should any other infectious disease." "HIV is not akin to any other infectious disease. HIV cannot be cured like many bacterial infections. Herpes viruses, for which there is no cure, are also treated only as needed." "It has been proven that patients are less infectious on treatment." "And may be more prone to risk behavior. In addition, the risk of transmission of primary resistance mutations increases." Arguments for and against a LATE start Statement Counter "The earlier one starts, the sooner and more certain the side effects." "The question is: does one more year without therapy, but with an increasing risk of AIDS, really make a difference?" "The earlier one starts, the higher the risk for resistances." "In compliant patients, the risk is very low with today's treatments." "Even a bad immune system can regenerate; after all, prophylaxis can be safely stopped after a rise in CD4 count." "This may be true for some patients, but not for all. There are indications that the qualitative response remains impaired." "It is never too late to start therapy at 200 CD4 cells." "Some AIDS diseases may occur even in this scenario; there is no certainty that PML or lymphoma might not develop." References on starting therapy 1. Ahdieh-Grant L, Yamashita TE, Phair JP, et al. When to initiate highly active antiretroviral therapy: a cohort approach. Am J Epidemiol 2003, 157:738-46. http://amedeo.com/lit.php?id=12697578 2. Carpenter CC, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. JAMA. 1997;277:1962-9. http://amedeo.com/lit.php?id=9200638 3. Casado JL, Perez-Elias MJ, Antela A, et al. Predictors of long-term respones to protease inhibitor therapy in a cohort of HIV-infected patients. AIDS 1998; 12:F131-F135. http://amedeo.com/lit.php?id=9708403 4. Chaisson RE, Keruly JC, Moore RD. Association of initial CD4 cell count and viral load with response to HAART. JAMA 2000; 284:3128-29. 5. Chene G, Sterne JA, May M, et al. 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