The need for lifelong antiretroviral therapy of HIV-1 disease argues for the use of first line regimens with the most favorable efficacy and safety profiles. The current study (ACTG 5142) identified important differences in the metabolic effects of two first-line regimens - efavirenz or lopinavir/r with 2 NRTI - recommended by the US DHHS guidelines for treatment of HIV-1 infection in adolescents and adults [16
]. Each component of these regimens - NRTI, efavirenz and lopinavir/r, contributed to the important differences in metabolic outcomes. Specifically, lipoatrophy was more frequent with efavirenz + 2 NRTI than lopinavir/r + 2 NRTI. This unexpected difference was observed with zidovudine or stavudine plus lamivudine as the NRTI, but not with tenofovir plus lamivudine. These finding are relevant to the selection of initial treatment regimens, particularly in resource-limited settings, where stavudine or zidovudine plus lamivudine are often the only NRTI available. The study also determined that the NRTI-sparing regimen of lopinavir/r-efavirenz had the lowest risk of lipoatrophy, but the greatest likelihood of serum lipid elevations and resulted in more frequent use of lipid lowering agents. This profile should restrict the use of lopinavir/r-efavirenz for initial therapy to circumstances in which NRTI cannot be used.
The study used an a priori
defined, objective measure of lipoatrophy (≥ 20% decline from baseline to week 96 in extremity fat). The findings were not due to differential discontinuations of either randomized regimen or NRTI component, were consistent across different definitions of lipoatrophy (10% - 40%) in sensitivity analyses, and were not altered by inclusion of baseline covariates. As-treated analyses that censored information after regimen/NRTI change yielded concordant results to ITT. Statistical testing confirmed that the effect of randomized regimen component (efavirenz versus lopinavir) was independent of NRTI. Most of the lipoatrophy differences between efavirenz and lopinavir were seen in the strata that received zidovudine and stavudine, though a small sample size in the stavudine stratum may have limited statistical power. A previous small prospective study suggested that efavirenz caused less lipoatrophy than a PI-based regimen (nelfinavir); this study does not support that finding [17
In other studies, patients initiating stavudine or zidovudine regimens lost subcutaneous fat at a rate of 12-15% per year [8
]. Several years of fat loss would be required before lipoatrophy was visibly evident in most patients. Consistent with previous studies, in ACTG A5142, lipoatrophy was most frequent and cumulative in incidence over time in stavudine-containing regimens [8
]. The pathogenesis of lipoatrophy is incompletely defined, but the prevailing hypothesis is that NRTI-mediated mitochondrial dysfunction in adipocytes leads to fat cell apoptosis and depletion [22
]. Results from the present study support this model as there was a clear gradation in incidence of lipoatrophy (defined both by categorical and continuous DEXA metrics) that parallels the impact of NRTI on mitochondrial DNA and RNA in vitro: stavudine > zidovudine > tenofovir. Previous studies of tenofovir-containing regimens also found significantly less lipoatrophy than was seen in stavudine-containing regimens [25
] and the infrequent occurrence of lipoatrophy in subjects on the NRTI-sparing regimen of ACTG 5142 is also consistent with this model.
However, this study revealed complex interactions between the NRTI component of the regimen and efavirenz or lopinavir/r. The frequency of lipoatrophy was greater with efavirenz than lopinavir/r when stavudine or zidovudine were used. The mechanism of greater lipoatrophy with stavudine or zidovudine plus efavirenz compared to lopinavir/r is not clear. A recent randomized comparison of atazanavir with or without ritonavir, given with stavudine and lamivudine, suggested that ritonavir may mitigate the limb fat loss of the regimen. After 96 weeks, the group with ritonavir had 20% less lipoatrophy (defined by DEXA scan as in A5142), a reduction from 49% to 29% (p < 0.05) [28
]. Potential mechanisms that could explain these results include a protective effect from the mitochondrial toxicity of NRTI by ritonavir (or lopinavir and ritonavir) or efavirenz-related enhancement of the effect.
This study also found that baseline factors can influence the development of lipoatrophy independent of regimen and NRTI used. Male subjects had 2.85 fold greater odds of lipoatrophy compared to women (P = 0.029). Unexpectedly, subjects with higher baseline CD4 cell counts tended to have more lipoatrophy, a finding that contrasts with previous reports which found either no association [21
] or more lipoatrophy associated with lower CD4 cell count [19
]. Subjects with greater initial limb fat were not protected from lipoatrophy. Race and baseline lipids did not add to the prediction of those at risk for lipoatrophy. In some but not all previous, mostly retrospective, cross-sectional studies of non-randomized ART, increasing age was associated with a greater risk of lipoatrophy.[20
] In this study, a borderline protective effect (odds ration 0.7, P = 0.054) of age was found after accounting for other factors. Differences between our study and others can be explained by different populations and study designs-prospective, randomized in this study versus observational cohorts in previous studies.
Serum lipids increased in all study arms after the initiation of antiretroviral therapy. Unexpectedly, this study found no significant difference in cholesterol fractions between the lopinavir and efavirenz arms of the study. There was also no difference in the use of lipid lowering agents between the lopinavir and efavirenz arms throughout the study. However, triglycerides were uniformly higher among subjects receiving lopinavir/r-containing regimens. Consistent with prior data, stavudine was associated with the greatest lipid elevations among the NRTI. Although the study was too short in duration to detect clinical consequences, the magnitude of total cholesterol changes seen in this study is similar to that seen in cohort studies where an association between lipids and an increased risk of cardiovascular events was found [29
]. In one study, an increased myocardial infarction relative rate of 1.3 was seen per 39 mg/dL increase in total cholesterol [29
There are limitations of this study. NRTI choice was not randomized, but selected prior to randomization, although the distribution of the NRTI chosen was not different across the arms nor was duration of exposure to NRTI agents. The open label design could have affected the use of lipid lowering agents, and the study had inadequate follow-up to discern whether differences in lipid abnormalities would result in increased risk for clinical events such as cardiovascular or cerebrovascular disease. The is no universally agreed upon definition for clinical lipoatrophy and this study did not include a case definition or data collection instrument to capture clinically-apparent fat loss primarily because such definitions contain significant subjective bias. However, our measure (DEXA) of lipoatrophy was objective, and hence the open-label design is unlikely to have significantly influenced these data. Furthermore, clinically defined lipoatrophy would have been subject to ascertainment bias, particularly with prior data suggesting that one treatment, i.e., stavudine, was associated with lipoatrophy. As changes in extremity fat measured by DEXA have been associated with clinically-defined lipoatrophy in previous studies [21
], the magnitude and significance of the lipoatrophy findings suggest they would be clinically relevant.
This study provides important new information for clinicians and patients on the relative risk and benefits of available antiretroviral regimens for initial therapy of HIV-1 infection. The risk of lipoatrophy can be minimized with a NRTI-sparing regimen or one containing tenofovir and lamivudine as the NRTI component. Although lipoatrophy was infrequent on lopinavir/r plus efavirenz, this combination was suboptimal because of greater increases in triglycerides and use of lipid lowering agents, and more frequent selection of efavirenz resistance [11
]. Unexpectedly, lipoatrophy was less common with lopinavir/r than efavirenz regimens containing zidovudine or stavudine, but cholesterol increases were similar and triglyceride increases were greater with lopinavir/r. These findings re-affirm the central role of tenofovir as a component of NRTI-containing regimens for initial therapy and question the use of stavudine or zidovudine in combination with lamivudine and an NNRTI, which are among the most commonly used regimens worldwide [16
]. Indeed, after the study was fully enrolled, stavudine was moved from a preferred to an alternative recommended agent in the US DHHS guidelines (10/29/2004 version)[33
]. This report adds to the analyses of virologic outcome from ACTG 5142, which showed significantly shorter time to virologic failure for lopinavir/r than efavirenz given with 2 NRTI [11
]. Careful selection of regimen components can minimize the risk of lipoatrophy and may improve the risk/benefit ratio of treatment, favoring earlier initiation of antiretroviral therapy.