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No Risk of Myocardial Infarction Associated With Initial Antiretroviral Treatment Containing Abacavir: Short and Long-Term Results from ACTG A5001/ALLRT
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Clin Infect Dis. (April 2011) 52 (7): 929-940.
"In conclusion, we studied individuals who initiated ART with and without abacavir as part of randomized clinical trials. Over a period of up to 6 years from ART initiation, we observed a very low absolute risk of MI and serious CVD events. We found no evidence of an increased risk of MI or serious CVD associated with the use of abacavir as part of initial treatment over the first year of ART and the longer term that was consistent in as-treated and sensitivity analyses. Classic CVD risk factors were the strongest predictors of MI and serious CVD events and should be the main focus in assessing CVD risk among HIV-1 infected individuals.....Factors associated with an increased hazard of MI in the cohort included increased age (short-term analysis, P = .08; long-term analysis, P < .001), a pretreatment history of 2 or more CVD risk factors (P = .005; P = .008), and current or prior smoking history (P = .16; P = .05)."
Heather J. Ribaudo,1 Constance A. Benson,2 Yu Zheng,1 Susan L. Koletar,3 Ann C. Collier,4 Judith J. Lok,1 Marlene Smurzynski,1 Ronald J. Bosch,1 Barbara Bastow,5 and Jeffrey T. Schouten,4 for the ACTG A5001/ALLRT Protocol Team
1Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; 2Division of Infectious Disease, University of California, San Diego; 3Division of Infectious Diseases, Ohio State University, Columbus; 4School of Medicine, University of Washington, Seattle; and 5Social & Scientific Systems, Silver Spring, Maryland
Abstract
Background. Observational and retrospective clinical trial cohorts have reported conflicting results for the association of abacavir use with risk of myocardial infarction (MI), possibly related to issues that may bias estimation of treatment effects, such as time-varying confounders, informative dropout, and cohort loss due to competing events.
Methods. We analyzed data from 5056 individuals initiating randomized antiretroviral treatment (ART) in AIDS Clinical Trials Group studies; 1704 started abacavir therapy. An intent-to-treat analysis adjusted for pretreatment covariates and weighting for informative censoring was used to estimate the hazard ratio (HR) of MIs after initiation of a regimen with or without abacavir.
Results. Through 6 years after ART initiation, 36 MI events were observed in 17,404 person-years of follow-up. No evidence of an increased hazard of MI in subjects using abacavir versus no abacavir was seen (over a 1-year period: P = .50; HR, 0.7 [95% confidence interval {CI}, 0.2-2.4]); over a 6-year period: P = .24; HR, 0.6 [95% CI, 0.3-1.4]); these results were robust over as-treated and sensitivity analyses. Although the risk of MI decreased over time, there was no evidence to suggest a time-dependent abacavir effect. Classic cardiovascular disease (CVD) risk factors were the strongest predictors of MI.
Conclusion. We find no evidence to suggest that initial ART containing abacavir increases MI risk over short-term and long-term periods in this population with relatively low MI risk. Traditional CVD risk factors should be the main focus in assessing CVD risk in individuals with human immunodeficiency virus infection.
Recommended first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection includes the use of two nucleoside or nucleotide reverse-transcriptase inhibitors (NRTIs) combined with one or more agents from other antiretroviral drug classes (nonnucleoside reverse-transcriptase inhibitors [NNRTIs], protease inhibitors [PIs], or integrase inhibitors) [1, 2]. Lifelong treatment is required to maintain HIV suppression, improve immune function, and minimize morbidity and mortality associated with HIV disease progression. Therefore, understanding long-term risks associated with ART is paramount.
The observational Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort reported that current or recent use of abacavir was associated with increased risk of myocardial infarction (MI) [3]; data from other cohort studies and clinical trials of abacavir have provided conflicting results [4-11]. For example, although analyses of the Strategies for Management of Antiretroviral Therapy (SMART) study found more than a 4-fold increase in risk [4], a GlaxoSmithKline meta-analysis of randomized trials found no increased risk [5] and an association detected in the French Agence Nationale de Recherches sur le SIDA (ANRS) cohort was not apparent after cocaine and intravenous drug users were excluded from the analysis cohort [10]. These differences may be explained by confounding and population differences, as well as differences in analytical approach. Because abacavir was considered an attractive ART for subjects with cardiovascular disease (CVD) risk [6,12-14], confounding is particularly problematic [15-17]. Recent treatment guidelines now caution against the use of abacavir in subjects with high CVD risk [1, 2], which will further confound analyses addressing this issue.
Previous analyses have focused on the increased relative risk of MI associated with abacavir. When an event is rare-as is MI in this context-even very large relative risks may have limited population-level relevance, making estimation of absolute risk difference essential.
We ascertained population level CVD risk associated with initiating ART with abacavir-containing regimens using a cohort of ART-naive persons randomly assigned ART through prospective clinical trials. Our unique cohort provides a means to address confounding and channeling bias issues of traditional observational cohorts. Our analytical approach and estimation of absolute risk places the CVD risk associated with abacavir for the treatment of ART-naive populations into a broader clinical context.
RESULTS
A total of 5056 eligible ART-naive individuals initiated randomized ART in one of the 6 ALLRT parent studies; of these, 3381 (67%) enrolled into ALLRT (Figure 1). As of 30 June 2009, 4640 (92%) and 1122 (22%) had 1 and 6 years follow-up, respectively; of these, 4290 (92%) and 619 (55%) remained on their randomized ART regimen. Median study follow-up was 3.1 years; median follow-up on initial ART was 2.8 years. Participants were relatively young (77% were <45 years old), predominantly male (82%), and racially and ethnically diverse (Table 2).
Consistent with designs of the parent studies, approximately 44% of subjects initiated an NRTI plus NNRTI regimen, 20% initiated a regimen containing an unboosted PI, and 29% initiated a regimen containing a boosted PI; 34% initiated an abacavir-containing regimen (54% in protocol A5202, 45% in protocol A5095, and 1% in protocol A5014), 9% initiated a didanosine-containing regimen, and 21% initiated a regimen containing tenofovir disoproxil fumarate (85% in A5202 and 15% in A5142). Of 1704 subjects who initiated an abacavir-containing regimen, 74% and 44% of those still in follow-up continued to receive abacavir at 1 and 6 years, respectively; of 3352 subjects who initiated a non-abacavir-containing regimen, 2% had initiated abacavir by 1 year (8% by 6 years) (Table 3).
Over the first year of ART, 12 MIs were observed (3 in the abacavir group and 9 in the non-abacavir group, over 1586 and 3097 person-years (PYs) of follow-up, respectively) (Table 3). Twenty-four additional MIs were observed over a subsequent follow-up to 6 years (5 in the abacavir group and 19 in the non-abacavir group). The estimated cumulative MI incidence over 6 years was 1.0% and 1.2% for the abacavir and non-abacavir groups, respectively.
In unadjusted and adjusted analyses, associations between abacavir use as part of initial ART and the hazard of MI were not detected either in the short term or in the long term (unadjusted short-term analysis, P = .52; unadjusted long-term analysis, P = .21; adjusted short-term analysis, P = .60; adjusted long-term analysis, P = .25; Table 4). Factors associated with an increased hazard of MI in the cohort included increased age (short-term analysis, P = .08; long-term analysis, P < .001), a pretreatment history of 2 or more CVD risk factors (P = .005; P = .008), and current or prior smoking history (P = .16; P = .05). There was no evidence of interactions between abacavir use as part of initial treatment and age (P = .46; P = .98) or the presence of 2 or more CVD risk factors (P = .46; P = .10). No evidence of violation of proportional hazard assumption was found (P = .89). Lower age, male sex, minority race/ethnicity, a history of injection drug use, documented pretreatment diabetes, detectable HIV-1 RNA level, the absence of dyslipidemia, and continuing to receive an initial ART regimen were associated with a higher probability of being censored from our cohort (data not shown). However, IPCW did not substantially change our model estimates or inference. Consistent results were observed across all of our sensitivity analyses (Table 5). The most extreme results came from analyses that included only contemporary regimens. This included 1677 subjects with 8 MIs in the abacavir group and 1819 subjects with 5 MIs in the non-abacavir group (hazard ratio, 1.7; P = .33).
Figure 2 shows model-based estimates of cumulative incidence of MI over time. The results are displayed for the full cohort and most extreme sensitivity analysis. They highlight the very low absolute MI risk in this population and demonstrate that, with the exception of the very high risk group (older smokers with 2 or more CVD risk factors), a small absolute risk difference is associated with abacavir use, even when estimated from our most extreme sensitivity analysis.
To enhance the power of our study to analyze the adverse CVD effect associated with abacavir, the event of interest was expanded to include additional pre-specified serious CVD events (Table 1). A total of 37 events were observed during the first year of ART; 97 events (including the 36 MIs) were observed over a maximum of 6 years of follow-up (17,283 PY). The findings from these analyses gave results that were generally consistent with those for MI events (Table 5).
DISCUSSION
This analysis of 5056 individuals who initiated ART in 6 randomized clinical trials aims to contribute to clinical decision-making with respect to risk for CVD events and choice of initial ART regimens, specifically with respect to abacavir. Overall MI incidence in our cohort was 2.1 events per 1000 PY (95% CI, 1.8-3.7), compared with between 3.1-5.0 events per 1000 PY from prior studies in this area [3, 5-7], demonstrating a low absolute risk of MI in this typical HIV-1 cohort of individuals initiating ART. We did not find evidence of increased short-term or long-term risk of MI or of serious CVD events associated with abacavir use as part of initial ART. This result was robust in as-treated analysis and a range of sensitivity analyses. An increased risk of MI events was detected for persons of older age and with classic CVD risk factors, such as smoking and prior CVD history.
Our analysis was unique in including a long-term cohort of HIV-1-infected persons initiating ART in randomized clinical trials, and our intent-to-treat analysis with adjustment only for pretreatment covariates provides a broad population-level perspective of the risk of MI associated with abacavir-containing initial regimens. This analytic framework contrasts with use of time-updated covariates for drug exposure and/or risk factors [4, 6, 7, 10] or censoring follow-up at discontinuation of abacavir [5] that have been used in other studies. Although such studies are attractive for their simplicity, in the presence of related and temporally confounded effects, adjustment for time-updated effects is likely to induce or attenuate the estimated risk associated with the exposure of interest [16, 33]. Although the as-treated censoring approach is also often preferred because it is seen to more clearly isolate the direct effect of the exposure of interest (in this case, abacavir use), not only does this have the potential to introduce an informative censoring bias, it is important to note that such censoring changes the question being addressed to one that is a purely hypothetical scenario: estimating the effect of abacavir use under the condition that, once treatment with abacavir is started, it is never discontinued. Because toxicity issues, individual ART fatigue, and regimen failure dictate that most regimens will at some time be discontinued or modified, the resulting parameter estimates do not relate to real-life situations. For completeness, we performed an as-treated analysis as a sensitivity analysis and found consistent conclusions.
A criticism of the intent-to-treat approach is that, although it is suited for the analysis of randomized trials because of cross-over between strategies, it is not relevant in the context of understanding the effect of specific drugs in cohort data. On the contrary, such inference remains critically important in understanding population-level drug effects that are implicitly adjusted for prescribing biases and drug-taking behavior of the population under study-in our case a relatively young (median age, 37 years) cohort with well-controlled HIV disease over the course of follow-up-overall, 83% of the total follow-up period was spent with HIV-1 RNA levels <400 copies/mL, and 63% was spent with CD4+ cell counts >350 cells/mm3.
IPCW methodology was used in our long-term analysis to investigate the influence of informative censoring bias due to premature study discontinuation and individuals not enrolling into ALLRT. Noninformative censoring is a fundamental assumption of any survival analysis that is often not fully scrutinized. Assuming that subjects with a given covariate history who are no longer in follow-up can be represented by similar subjects who remain in follow-up, IPCWs adjust for potential informative censoring by weighting uncensored data to create a pseudo-population in which censoring does not exist [33, 34]. IPCW methodology did not dramatically impact our results. This could mean that informative censoring is not a concern for this analysis, that informative censoring exists but differential effects cancel each other out, or that our model for informative censoring has failed to adjust for the key variables that drive the informative censoring. This latter scenario reflects the failure of the key assumption of no unmeasured confounding that underpins all IPCW methodology. Of note, almost half of the censoring in our analysis was administrative, which can reasonably be assumed to be noninformative.
One study limitation concerns the power to detect a difference between abacavir-containing and non-abacavir-containing initial regimens, because only 36 MI events were observed during 6 years (17,404 PY) of follow-up. Furthermore, some of the comparator groups contained ART agents that are no longer commonly used and other agents that may have been implicated with adverse lipid profiles or increased CVD risk [1, 35, 36]. However, studies of similar size to our own have demonstrated significant results [4, 11], and our sensitivity analyses that restricted contemporary regimens (those including 2 or 3 NRTIs with NNRTI or boosted-PI) and excluded regimens that have also been implicated with increased CVD risk provided consistent conclusions to our main result.
The strength of our cohort is randomized ART assignment that lessens the potential for confounding and channeling bias that can complicate interpretation of treatment associations from observational data. These are particularly problematic for investigating MI risk with abacavir, because past prescribing practices favored abacavir regimens for individuals at high CVD risk [6, 12-14]. Because only 3 of the studies included in our analysis involved a randomized abacavir strategy, we were not able to estimate the direct effect of the abacavir randomization in a classic meta-analysis sense [37]. Rather, our approach relies on the assumption that the relative effect of interest is consistent across included studies. That is, the effect of abacavir in non-abacavir studies-had they included randomized abacavir-is assumed to be the same as that in the studies with randomized abacavir. Such an assumption is reasonable. All of the studies were conducted at the same clinical sites, had similar entry criteria, and, with the exception of a brief period early in follow-up, used the same mechanism for MI identification. Furthermore, sensitivity analyses restricting the cohort only to studies including randomized abacavir were consistent with findings of the entire cohort.
In conclusion, we studied individuals who initiated ART with and without abacavir as part of randomized clinical trials. Over a period of up to 6 years from ART initiation, we observed a very low absolute risk of MI and serious CVD events. We found no evidence of an increased risk of MI or serious CVD associated with the use of abacavir as part of initial treatment over the first year of ART and the longer term that was consistent in as-treated and sensitivity analyses. Classic CVD risk factors were the strongest predictors of MI and serious CVD events and should be the main focus in assessing CVD risk among HIV-1 infected individuals.
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