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The Case for Earlier Treatment of HIV Infection
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Clinical Infectious Diseases Dec 1 2004;39:1699-1704
Scott D. Holmberg,1 Frank J. Palella, Jr.,2 Kenneth A. Lichtenstein,3 and Diane V. Havlir4
1Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; 2Division of Infectious Diseases, Northwestern University Medical School Chicago, Illinois; 3Rose Medical Center, Denver, Colorado; and 4San Francisco General Hospital, University of California, San Francisco
(See the editorial commentary below by Cohen and Boyle)
ABSTRACT
Current US guidelines advise that antiretroviral therapy for asymptomatic HIV patients should definitely be started for those who have CD4+ cell counts of >200 cells/μL, but antiretroviral therapy is often not started at CD4+ cell counts much above that level. Guidelines advocating later therapy for HIV infection have been based mainly on sparse and limited cross-sectional data and have been predicated on avoiding drug-related toxicity and viral drug resistance. However, emerging data about factors that contribute to survival and the availability of newer, less toxic drugs are eroding this position. Earlier initiation of antiretroviral therapy—namely, for patients with CD4+ cell counts of >350 cells/μL—may, in fact, be associated with lower mortality, better immune improvement, and less drug-related toxicity. These findings coincide with the introduction of antiretroviral drugs that have become more effective and less difficult to take. Earlier initiation of therapy may also reduce HIV transmission, an important public health consideration, and may be beneficial in terms of overall therapeutic cost-effectiveness. Given these accumulating data, we believe reconsideration of the "when-to-start" question is timely and justified.
TEXT OF ARTICLE
Opinions concerning the optimal timing for initiation of highly active antiretroviral therapy for HIV infection have gone through major adjustments since the introduction of protease inhibitor drugs in 1996. At first, after dramatic declines in mortality and morbidity, there was enthusiasm for providing potent new combination therapy to HIV-infected persons as early in the course of infection as possible. However, it quickly became clear that HIV could not be eradicated because of a long-lived pool of latently infected cells. Later initiation of therapy did not appear to preclude immunologic restitution to a CD4+ cell count of >200 cells/μL, sufficient for discontinuing antimicrobial prophylaxis for opportunistic infections. There was concern that widespread use of therapy would create an epidemic of infection with multiply drug-resistant strains of HIV, and, as efficacy diminished, the duration of sequential regimens became increasingly shorter, as did the options for salvage therapy.
Perhaps the most influential factor in the paradigm shift regarding therapy initiation has been drug toxicity. Although the life-saving qualities of antiretroviral therapy were impressive, clinicians recognized new toxicities, especially subtle and dramatic body habitus changes (i.e., lipodystrophy), insulin resistance, and hyperlipidemia. These metabolic toxicities were of special concern because pathophysiologic mechanisms were unknown, and potential long-term clinical consequences, such as myocardial infarction and stroke, further diminished enthusiasm for early treatment of HIV disease. In addition, pessimism arose and still exists about the effective or complete treatment of some of these complications of antiretroviral therapy, such as lipodystrophy.
Given these concerns and the growing confidence that antiretroviral therapy is effective even in patients with more advanced disease, clinicians who treat HIV disease are much more cautious about initiating antiretroviral therapy than they were several years ago. The more cautious, "start later" approach has gained greater acceptance, a shift that has been mirrored in a series of recent recommendations for the care of HIV-infected patients in the United States. Although there is widespread agreement not to delay therapy until it is "too late" if there is acknowledged risk of clinical disease, and although the guidelines permit starting therapy at any CD4+ cell count >200 cells/μL, the result has been a tendency to start near that threshold. At recent conferences, presenters have advocated starting therapy at CD4+ cell counts of <275 cells/μL, and at interactive sessions, 25%--30% of participants indicated that they would not start therapy until a patient with modest viral load (plasma HIV RNA load of 30,000 copies/mL) had CD4+ cell counts of <250 cells/μL (Donna Jacobsen, unpublished data). Median CD4+ cell counts at the time of therapy initiation for HIV Outpatient Study participants who start therapy while not hospitalized have fallen from 317 to 272 cells/μL between 1997 and 2003 (authors' unpublished data; χ2 value for trend, 4.34; P = .037), even though several HIV Outpatient Study clinicians are "early treaters." The situation is mirrored in European and British guidelines that indicate "deferral of therapy is actually a reasonable option for a significant proportion of patients" [24, p. S1]. Some researchers have even concluded that "the current emphasis of therapeutic guidelines on initiating therapy at CD4 cell counts above 200 × 106 cells/L should be re-examined" [26, p. 711], sentiments echoed by experts in London and Copenhagen.
We are concerned that the therapy-initiation pendulum has swung too far in the direction of later initiation—at a CD4+ cell count near 200 cells/μL—rather than earlier initiation—at a CD4+ cell count of >350/μL. We note a growing body of evidence suggesting that earlier treatment with newer, better, and safer drugs is associated with improved survival, more effective immune-system improvement, less toxicity and drug intolerance, and other clinical and public health benefits.
First, improvement in survival is often considered the "gold standard" of the utility of treatment for HIV infection. To consider this issue, the only practical way of determining whether earlier treatment substantially improves survival is through observation of large cohorts of persons. However, for logistical and ethical reasons, this is not possible: a study of >6500 patients, randomly assigned to receive immediate or deferred therapy, with 10 years of observation, would likely be required. Even the large SMART study, which is currently enrolling participants, will not consistently treat patients who have CD4+ cell counts of >350/μL.
It is not well appreciated that recent guidelines on when to initiate therapy have relied on a few short-term, sometimes unpublished cross-sectional analyses of observational cohort and clinical trial data [30--35]. Typically, these analyses just look at survival data for the period after patients in a study start antiretroviral therapy at a particular CD4+ cell count, which does not adjust for "lead-time," the period when a patient could have taken antiretroviral therapy but did not. Also, these studies almost always measure "soft" end points, such as the development of AIDS. Some studies have tried imputing lead times before observation within a cohort, but this is an indirect measurement of true observation time. Data from all such studies are hard to interpret, because they do not use set starting points of observation—that is, a direct head-to-head comparison of persons who do or do not start therapy at specific CD4+ cell counts—and a definitive end point, such as death or undetectable viral load.
To our knowledge, only 2 analyses to date—neither referenced in the latest US [19] or British [25] guidelines—have published data comparing HIV-infected patients who either initiated or deferred therapy from a set start point within a CD4+ cell count stratum of >350 CD4+ cells/μL, and then measured definitive ("hard") outcomes—that is, mortality rates and rates of attainment of undetectable viral loads. In one of these studies [37], HIV-infected patients who started therapy within the CD4+ cell count stratum of 350--500 cells/μL (mean, 404 cells/μL) had a mortality rate 〜60% of the rate for those who delayed taking similar therapy at some point after they had a CD4+ cell count of <350 cells/μL (mean, 258 cells/μL), and they were statistically significantly more likely to achieve an undetectable viral load. This same type of analysis can be applied to the data in the other recent, shorter-term analysis [38], which concluded that, because the difference between those who started therapy at a CD4+ cell count of >350 cells/μL and those who delayed or did not start therapy at a lower CD4+ cell count was not statistically significant (P = .10, log-rank test), "HAART [should] not be initiated for patients with CD4+ cell counts >350 cells/mm2" [38, p. 812]. However, the relative risk of death—defined as the number of deaths per 1000 patient-years of observation—was only 0.45 for the patients who started therapy at a CD4+ cell count of >350 cells/μL, compared with those who were observed from that point but started therapy at lower CD4+ cell counts or not at all. Further, analysis of the data from these 2 studies by usual meta-analytic techniques (i.e., the fixed-effect model) [39, 40] shows the relative risk of death was 0.46 (P = .027, Mantel-Haenszel χ2 test; 95% CI, 0.24--0.88) for those who started therapy at a CD4+ count of >350 cells/μL, compared with those who started at a lower count.
A more recent analysis, an extension of the earlier work summarized above, also indicated that the risk of development of a new opportunistic infection or death was significantly lower for patients who started therapy at CD4+ cell counts of 351--500 cells/μL, compared with those who started at counts of 201--350 cells/μL. (However, because the analysis was limited to only those patients who achieved undetectable viral loads, the numbers being compared and the statistical power were both reduced, and this difference was no longer statistically significant.)
Supporting such findings are studies showing that HIV suppression and increases in CD4+ T lymphocyte number and function are much more easily accomplished when treatment is started at a CD4+ count above, rather than below, 350 cells/μL and even at counts of >500 cells/μL. Immunologic and virologic responses are better when treatment is started early, and initiation of HAART at early stages of chronic HIV infection seems to allow almost complete normalization of T cell subsets and preservation of T cell functions. Conversely, when treatment is stopped—for example, in "strategic" treatment interruptions—CD4+ cell counts and viral loads usually return to their pretreatment levels. Thus, the decision of when to start therapy could be critical to the long-term preservation of immune function.
Given this accumulating evidence, some proponents later therapy initiation are beginning to concede that immediate initiation of therapy for a person with a CD4+ cell count of 350 cells/μL will likely result in a lower risk of AIDS or death than that for deferred initiation of therapy. Nonetheless, they speculate that issues of toxicity and virologic failure may diminish long-term effectiveness.
Thus, second, we think that the issue of toxicity, a frequent reason that clinicians delay therapy, needs reconsideration. The current generation of antiretroviral drugs appears to have better short-term toxicity profiles than do earlier drugs. Further, and perhaps more important, there is a growing appreciation that a low CD4+ cell count is itself a major risk factor for drug-related toxicity [50]. For example, in the HIV Outpatient Study, the factor most strongly associated with the presence of body habitus abnormalities (i.e., lipodystrophy) was the nadir CD4+ cell count: 30.8% of patients with nadir count of <200 cells/μL but only 3.3% of patients with a nadir count of >350 cells/μL developed lipoatrophy. Host factors other than receipt of antiretroviral drugs (advanced age, sex, and race) were also prominently associated with an increased risk of lipodystrophy. Peripheral neuropathy is a frequently diagnosed toxicity associated with the use of some nucleoside reverse-transcriptase inhibitors, but several analyses suggest that this, too, is much more likely to occur among persons with low nadir CD4+ cell counts and that advanced disease predisposes to a higher risk of neuropathy. In persons taking newer drugs, such as tenofovir, both lipodystrophy and peripheral neuropathy are also less frequent among those who start therapy at higher CD4+ cell counts than among those who start at lower counts. In patients coinfected with HIV and hepatitis C virus, liver fibrosis is more frequent among those who start treatment at low CD4+ cell counts. Loss of bone density also appears more closely related to host risk factors and advanced HIV infection than to the use of antiretroviral agents. Because of these data, we think that delaying therapy until a later stage of HIV disease progression may actually predispose patients to drug-associated toxicities.
Third, although we appreciate concerns about the potential exhaustion of therapeutic options for patients who start therapy earlier, there are now 20 FDA-approved drugs—19 that belong to the 3 usual classes of antiretroviral drugs and 1 approved fusion inhibitor drug—for the treatment of HIV infection. New drugs in the 4 established classes; new classes of agents, such as entry inhibitors and integrase inhibitors; and immune modulators, such as interferons, are being developed and approved for use. Thus, the dramatic mortality reductions that were first observed in 1996 have been durable, without evidence of recrudescent death rates, and the list of novel drugs available for inclusion in "salvage" antiretroviral therapy regimens continues to grow.
The "pill burden" and dosing for most newer antiretroviral therapy regimens, with respect to both the number and type of agents, have dropped markedly in the past few years; less frequent dosing may be especially important for patient adherence. For example, patients seen in the HIV Outpatient Study in 1997 took an average of 13 pills each day for antiretroviral therapy and opportunistic infection prophylaxis, but by 2003, a random sample of 165 HIV Outpatient Study patients showed they were taking a mean of 5.6 pills per day, and few patients were taking more than 12 pills per day. There are now options for once- or twice-daily regimens with a daily pill burden of 2 or 3 pills—sometimes coformulated preparations—and many of these antiretroviral medications have greater efficacy and tolerability but less toxicity and likelihood of development of resistance than those available earlier.
Fourth, the cost of initial antiretroviral therapy, including hospitalization, is putatively twice as high for patients with late-stage AIDS than for patients with early-stage HIV infection (i.e., patients with >500 CD4+ cells/μL) ($30,261 vs. $15,404). Also, there is an apparent cost benefit with respect to quality-adjusted life years for patients who start antiretroviral therapy early (at CD4+ cell counts of 350 cells/μL) rather than at some point later in the course of infection.
Finally, but not least important, a potential public health benefit of earlier antiretroviral treatment is that it apparently reduces sexual transmission of HIV by reducing HIV viremia and shedding and, possibly, by reducing the transmission fitness of HIV as well. Over time, the population health benefit of earlier treatment, coupled with risk-reduction programs, may be substantial. Although this benefit might arguably be offset by transmission of drug-resistant strains, the occurrence of drug-resistance mutations in the HIV strains infecting antiretroviral therapy--naive patients in the United States has been low, and it is thought that "transmission of resistant strains is, and will remain, a relatively minor public health problem" [68, p. 1016].
In summary, we think that the information currently available and accumulating supports initiation of therapy for asymptomatic HIV-infected patients at CD4+ cell counts of >350 cells/μL—certainly >275 cells/μL—and that we should be receptive to the possibility, as we observe patients treated with newer drugs, that perhaps even earlier initiation of treatment is warranted. Clinicians might consider when they would initiate treatment for themselves if they were HIV infected. Certainly, there are many imponderable considerations that affect when a physician and a patient decide the time is right to start antiretroviral therapy, particularly patient reluctance to start potentially life-long, multidrug therapy. Also, physicians are not always good at assessing the adherence of their patients to prescribed antiretroviral regimens. However, for asymptomatic patients who request it or are likely to be adherent, the decision of when to start antiretroviral therapy must be informed by the best available, if unavoidably imperfect, data.
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EDITORIAL COMMENTARY
Antiretroviral Therapy: The "When to Start" Debates
Calvin J. Cohen1 and Brian A. Boyle2
1Community Research Initiative New England, Harvard Vanguard Medical Associates, and Harvard Medical School, Boston, Massachusetts; and 2Weill Medical College, Cornell University, New York
With the recent approval of several new antiretrovirals and with new research regarding the efficacy and safety of HAART comes a necessary revisiting of the timing of initiation of treatment for HIV infection. This is an important part of the dialogue regarding HIV medicine, and it ensures clinicians are providing, and patients are receiving, the best possible care based on available data.
Although a "hit hard, hit early" approach to treatment was advocated when HAART first became available, clinicians and guidelines have, since that time, moved away from that approach. Among the factors driving the postponment of treatment have been the recognition of the cumulative and potentially irreversible toxicities of some HAART regimens, the limitations of current HAART, the inability to eradicate HIV with current approaches, and the long-term impact of HIV antiretroviral resistance on the need for life-long treatment options. Support for the deferment of therapy has come from cohort studies comparing individuals who started HAART with CD4 cell counts of 200--350 cells/mm3 and those who started with higher CD4 cell counts. Generally speaking, these studies have demonstrated that both cohorts had similar HAART response rates and adequate immune recovery, noting that patients in the two cohorts were at similar risk of HIV-related complications or mortality. Taken as a whole, these data have led some, if not many, clinicians and patients to postpone HAART until it is clearly needed. Although clinicians continue to "hit hard" when they initiate HAART, they do not need to "hit early."
It is well recognized by most, however, that our knowledge regarding the ideal time to start HAART is limited and that some studies indicate that delay of therapy may be associated with loss of immune function, risk of morbidity and mortality, and ongoing risk of HIV transmission. Therefore, as newer medications address some, if not all, of the limitations of earlier regimens and as new research is published regarding antiretroviral toxicities and resistance, it is reasonable to consider whether the balance has changed sufficiently to warrant an earlier commencement of HAART. For example, whereas several of the first-approved protease inhibitors were frequently associated with toxicities—including abnormal lipid values, insulin resistance, and frequent gastrointestinal intolerance—newer protease inhibitors have been associated with far fewer of such important adverse effects. Similarly, although the first nucleoside reverse-transcriptase inhibitors were associated with multiple adverse effects—including lipoatrophy, anemia, and neuropathy—comparative studies have documented that newer agents are equally, if not more, effective and allow for a significant reduction in the incidence of these toxicities in the first 3 years of observation. Newer regimens also have the advantage of being simpler than prior regimens in common use; they require as few as 2 pills taken just once daily (e.g., an efavirenz tablet with a coformulated tablet of either tenofovir/emtricitabine or lamivudine/abacavir) and minimal regard to concomitant ingestion of food and fluid. Therefore, as treatment is made both safer and easier, it is reasonable for the field to revisit whether the immunologic decline and other potential risks accompanying untreated HIV infection are worth preventing by starting treatment, if the patient is willing, before the CD4 cell count has declined to 200--350 CD4 cells/mm3 or an HIV-infection--related complication has occurred.
So, where should the starting point for HAART be? As mentioned, cohort studies have been analyzed for the past several years, and it appears clear that delaying treatment until the CD4 cell count is <200 cells/mm3 leads to a higher risk of HAART failure and HIV-infection--related complications, including opportunistic infections. Clearly, as is accepted in all HIV-infection treatment guidelines, HAART should be initiated at a CD4 cell count somewhere above this threshold, but how far above remains open to debate. Unfortunately, for at least the next several years, this question cannot be addressed by results of randomized studies, given that there are none with results expected in the near future that compare earlier versus later treatment. Thus, the decision-making will continue to be based on extrapolation from available data, which leave several uncertainties as to the optimal course.
It has been demonstrated that there is progressive immunologic damage in individuals who are not receiving HAART and that, in some, this damage may not be fully reversed, despite initiation of HAART and a rising CD4 cell count. However, some studies have documented significant immunologic recovery in patients receiving HAART and an impressive ability of the recovered immune system to restore control of a preexisting opportunistic infection, as demonstrated by the CD4 cell count, even after cessation of secondary prophylaxis. It therefore remains uncertain to what degree this immune reconstitution is incomplete in some clinically important manner and to what degree this is the case when treatment is deferred in accord with current standards.
There are also uncertainties about the desirability of starting treatment sooner, even though medications have now improved sufficiently and have minimal demonstrable toxicity over a few years of use. For example, Holmberg et al. cite data that document a decrease in the incidence of lipoatrophy among patients who start treatment at higher CD4 cell counts, compared with patients who start similar regimens at lower CD4 counts. This finding, although important, is almost certainly dependent upon the HAART regimen used. For example, a recent Gilead Sciences 903 study documented a 3% rate of reported lipodystrophy and relatively normal limb fat levels (as demonstrated by whole-body dual-energy absorptiometry) in a population who started treatment with efavirenz, tenofovir, and lamivudine at a mean CD4 cell count of 276 cells/mm3, of whom 39% had CD4 cell counts of <200 cells/mm3. The low rates of lipodystrophy and other toxicities found in this study suggest that it may be possible to lower the rate of such complications by administering improved treatments, even if treatment is initiated at CD4 cell counts closer to the 200 cells/mm3 threshold. It remains a point of conjecture how much more this rate would be reduced if this well-tolerated treatment were started at higher CD4 cell counts or whether long-term therapy will reveal new or increased rates of known or currently unknown toxicities.
There are a few considerations that suggest that delaying treatment has potential advantages. First, as demonstrated by the examples mentioned above, there continue to be improvements in treatment that address some of the limitations of the current options. The current standard of care for initial treatment is significantly better than previous options, and it is at least plausible that improvements may continue in the next few years; those who postpone treatment may be best able to avoid the limitations of current treatments by delaying therapy, as long as it is safe to delay. Second, the Data Collection on Adverse Events of Anti--HIV Drugs (DAD) study has demonstrated that there is a small but definable risk of cardiovascular complications associated with starting currently preferred antiretroviral treatment. Most, though not all, regimens currently in use result in some measurable perturbation of the lipid profile and some changes in levels of cholesterol fractions. However, in the DAD study, the increase in the rate of cardiovascular events was observed even when controlling for lipid-profile changes; therefore, it is not clear to what degree accounting for this aspect of care will address the concerns raised by the study. There is also some controversy on how to interpret the observed changes. Although there have been data to suggest that some of the elevations in lipid values observed during treatment may be a return to a pretreatment "norm," the data from the Bristol-Meyers Squibb 034 study and the Gilead Sciences 903 study show few associated lipid changes, compared with the changes associated with other preferred treatment options. This suggests that the suppression of HIV replication is not necessarily associated with what might have been considered a "pseudonormalization" of lipid levels; elevations in levels of lipid fractions may reflect some adverse complication of treatment rather than HIV suppression. Finally, there remain other measurable adverse events associated with even currently preferred regimens, including statistically significant, though clinically minor, reductions in bone density, increases in insulin resistance, and a small but still present risk of lipodystrophy.
In addition to the continuing potential for toxicity, emergence of antiretroviral resistance is an important consideration. Regimens associated with a low risk of long-term toxicity—for example, nonucleoside reverse-transcriptase inhibitor--based HAART—are associated with the development of 2-class antiretroviral resistance, if treatment fails. It has been demonstrated that, once resistance develops, the presence of the resistant HIV variants has implications for the success of future regimens, even if the mutations are not detected with commercial resistance assays. It is possible that earlier initiation of treatment can result in a higher risk of development of resistance in patients for whom treatment may be desirable but optional, and this resistance is a life-long burden, if it should emerge.
Ultimately, however, the decision to start treatment at a higher rather than a lower CD4 cell count is but one event in a small window of time in the life of a person with HIV infection. Even if the issue is whether to initiate treatment at a CD4 cell count of 500 cells/mm3 or at 250 cells/mm3, the time between these is perhaps 5 years or less. For a person with HIV infection who is facing a lifetime of decision-making about treatment, this decision is important, but it is dwarfed by decisions about how long to receive treatment once it is initiated, since this is more likely to be decades than years. There are studies that demonstrate the interaction of these two issues. Studies of treatment interruption have consistently shown an association between the individual's nadir CD4 cell count and the length of the HAART interruption or "drug holiday". Patients who have the highest nadir count before treatment appear to have the slowest loss of CD4 cells after stopping therapy, compared with patients who have similar CD4 cell counts at the time of the interruption but lower nadir counts before treatment. One could initiate treatment at a higher CD4 cell count to allow a person to maintain an elevated CD4 cell count and to extend the length of the treatment interruption. However, although the CD4 cell count nadir is associated with the degree of loss of CD4 cells during treatment interruption, it has also been noted that a significant number of patients with a nadir CD4 cell count of 200--350 cells/mm3 also have significant durations of interruption—up to 6 months or even longer—before treatment is started again on the basis of standard treatment criteria. Further, although initiation of treatment at higher CD4 cell counts may allow longer interruptions, it is not clear whether, over time, there is more or less total time receiving medication if it is started at a higher count, since if the individual starts therapy later, the period of time before HAART was initiated must be included in the equation. Finally, even if the duration of HAART interruptions can be extended by starting earlier, it remains uncertain whether starting and then maintaining treatment is, over the long term, a better or worse strategy than approaches guided by the CD4 cell count—for example, starting treatment when indicated by current guidelines, then interrupting treatment once the CD4 cell count is again above a certain threshold, and subsequently restarting treatment when indicated by clinical and laboratory parameters.
This last issue has become critical enough to be the focus of one of the largest trials ever attempted in the arena of HIV-infection treatment. The Strategic Management of Antiretroviral Therapy (SMART) trial is comparing truly long-term outcomes for patients with a CD4 cell count >350 cells/mm3 at study entry who either (1) receive best available treatment regimen continuously or (2) defer antiretroviral treatment until they achieve a CD4 cell count of 〜250 cells/mm3, receive it only for the time needed to restore their CD4 cell count to >350 cells/mm3 for a period of a few months, and then stop treatment again. Because multiple metrics are needed to assess the long-term implications of these treatment strategies, the study gathers data on multiple parameters, including body-shape changes and the incidences of anal dysplasia and neurologic complications, among others. It was written into the SMART protocol that once treatment is perfected, there will be fewer reasons to pursue a strategy of intermittent therapy. At present, there are >2200 persons enrolled in this study.
Certainly, the measurable abnormalities and subtle findings that have been observed over these past few decades in persons with untreated HIV infection, as well as the periodic episodes of unexpected illness observed at higher CD4 cell counts, make one yearn for complete suppression in everyone infected, while we await the eradication "bullet." It is gratifying to see that some clinicians appraise recent treatment and research advances regarding antiretroviral toxicity as sufficient to prompt initiation of HAART earlier than currently recommended by treatment guidelines. Nevertheless, despite recent improvements in HAART, there remain potential disadvantages to doing so, including risks of antiretroviral toxicity and emergence of resistance, and, in a field anchored by evidence-based medicine, there is limited evidence of the advantages. It remains uncertain whether the field will ever get to the point of antiretroviral-therapy "nirvana" in which all clinicians and all patients will agree on the "when to start" issue; until then, important research continues to address this most central aspect of care in the life-long battle against HIV infection.
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