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Timing of HAART Initiation and Clinical Outcomes in Human Immunodeficiency Virus Type 1 Seroconverters
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Arch Intern Med
September 26, 2011
ABSTRACT
Background To estimate the clinical benefit of highly active antiretroviral therapy (HAART) initiation vs deferral in a given month in patients with CD4 cell counts less than 800/μL.
Methods In this observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), we constructed monthly sequential nested subcohorts between January 1996 and May 2009, including all eligible HAART-naive, AIDS-free individuals with a CD4 cell count less than 800/μL. The primary outcome was time to AIDS or death in those who initiated HAART in the baseline month compared with those who did not, pooled across subcohorts and stratified by CD4 cell count. Using inverse probability-of-treatment weighted survival curves and Cox proportional hazards regression models, we estimated the absolute and relative effects of treatment with robust 95% confidence intervals (CIs).
Results Of 9455 patients with 52 268 person-years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/μL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43-0.81), 0.75 (0.49-1.14), and 1.10 (0.67-1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44-1.15), 0.51 (0.33-0.80), and 1.02 (0.49-2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14-38) and 34 (20-115) in CD4 cell count strata of 200 to 349 and 350 to 499/μL, respectively.
Conclusion Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500/μL (but not 500-799/μL) was associated with slower disease progression.
Comment
This analysis of 9455 HIV-1 seroconverters confirms the clinical benefit of initiating HAART with CD4 cell counts of 200 to 349/μL. We estimated a 25% reduction in the relative hazard of AIDS or death and a 49% reduction in the relative hazard of death from all causes at CD4 cell counts of 350 to 499/μL. The relatively low incidence of AIDS and death in individuals with CD4 cell counts of 350 to 499/μL indicates that patients and health care providers need to weigh the risks and benefits for each individual over an extended period of treatment.
Although many studies have compared disease progression in patients starting HAART at different stages of disease with follow-up beginning at the time of treatment initiation, it is now appreciated that this study design is not ideally suited to inform the "when to start" question due to unobserved lead time and clinical events that occur during the time when patients are deferring therapy.17-18 Kitahata et al,5 Sterne et al,6 and Cain et al7 report findings from observational analyses tailored to estimate the effect of early HAART initiation on clinical outcomes using data primarily from seroprevalent cohorts. Although the comparison groups differ and, thus, the effect estimates from these studies estimate different parameters, one can compare the conclusions of the studies in broad terms. The present findings agree with those of Kitahata, Sterne, and Cain and their colleagues, who found that deferring HAART to a CD4 cell count less than 350/μL is detrimental. Kitahata et al,5 but not Sterne et al,6 further conclude that deferring HAART to a CD4 cell count less than 500/μL is detrimental. (Cain et al7 began observing patients at first CD4 cell count less than 500/μL and, thus, do not report effect estimates for treatment at CD4 cell counts greater than 500/μL.) Unlike Kitahata et al, we did not observe a benefit at the population level for initiation at 500 to 799/μL after adjusting for confounding.
The absolute risk of AIDS-related morbidity and mortality in the population can drive the degree to which HAART initiation is beneficial at a particular stage of disease. In the present study, the weighted survival curves, absolute risks of disease progression, and NNT provide additional insight regarding the benefit that patients in resource-rich settings can expect from HAART at different CD4 strata. At CD4 cell counts of 350 to 499/μL, the benefits of treatment initiation become evident only beyond 2 years, suggesting that patients need to consider the long-term course of treatment, including the risk of adverse effects of HAART during an extended period.19
The decision to initiate therapy is a dynamic process, influenced by changes in the patient's condition and readiness to adhere to the lifelong regimens that are available to treat HIV. We reflected this dynamic process in the analysis by considering each month while a patient was AIDS free and HAART naive as a point in time when therapy could have been initiated rather than representing patients at a single point in time, such as the first measured CD4 cell count in a particular range. We then observed these individuals during an average of 4.7 years as they experienced the clinical consequences of initiating HAART (or not) at that point in time. By allowing individuals to contribute to multiple subcohorts as long as they remained eligible, we effectively estimated a weighted average of the benefit of initiating therapy at any time while an individual had a CD4 cell count in a given CD4 stratum compared with the prognosis that they would have experienced if they had not initiated HAART at that time. The resulting relative and absolute effect estimates can be used to help inform patient decisions about whether the benefit of therapy at this particular stage of disease is sufficient to outweigh the challenge of adhering to treatment, the risk of adverse effects, and the financial cost of medications over a longer period of treatment.
We acknowledge that if the ultimate treatment patterns of the deferrers had been different, the results of the study would have been different. In eTable 2, we describe the type and timing (relative to CD4 cell count) of antiretroviral drug therapy received by patients who composed the deferred group for each CD4 strata. To evaluate the potential effect of individuals who were not treated consistent with the current standard of care, we censored the outcomes of those who waited too long or used suboptimal regimens, but the magnitude of the effect estimates was unaffected (S1 and S2 in Figure 3). We also considered the possibility that the null effect in the 500 to 799/μL stratum was due to individuals who deferred HAART only briefly, but these patients composed only approximately 5% of the deferred group. Although the comparison groups did not follow standardized treatment algorithms, they do represent the real-world experience of thousands of HIV-infected patients in care during the study period. We believe that these findings complement those from other recent studies5-7 that explicitly compared 2 specific, narrowly defined treatment alternatives.
Patient well-being is adversely affected by many serious non-AIDS-defining conditions. For example, immunodeficiency and uncontrolled viremia have been implicated in the development of cardiovascular disease20-21 and non-AIDS-defining malignancies.22-23 Although CASCADE does not pool data on non-AIDS morbidity, this analysis reflects the most serious outcome (death) due to non-AIDS conditions.
We considered several alternative approaches to conducting this analysis in an effort to assess the robustness of these findings. We examined the effect of more restrictive inclusion criteria. To address confounding, we adjusted for a set of 20 covariates that we had a priori reason to suspect were associated with different rates of disease progression. We examined a wide range of possibilities for truncating the weights before deciding on a method that controlled for confounding without introducing instability in the estimates (eTable 5). Despite this, we cannot rule out the possibility that patients who initiated therapy had an inherently better or worse prognosis than did those who deferred therapy related to unmeasured factors. We were reassured that in the 50 to 199/μL CD4 strata, where we can compare with results from a randomized trial conducted in a resource-rich setting, the present estimate is similar to that from the trial.3
In the absence of results from well-conducted, long-term, randomized trials in patients with CD4 cell counts greater than 350/μL, treatment decisions will need to be made based on the available evidence from observational cohorts. We used a novel approach applied to a unique cohort of seroconverters to reduce the potential for lead time bias. We found that treatment initiation at CD4 cell counts of 350 to 499/μL was associated with slower disease progression. We did not observe any benefit to treatment initiated at 500 to 799/μL.
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