To evaluate whether the differences in lipoatrophy between the efavirenz and lopinavir arms were sensitive to the definition of lipoatrophy, analyses were repeated with lipoatrophy defined as at least 10, 20, 30, or 40% loss in extremity fat from baseline to week 96. The differences between the efavirenz and lopinavir arms were still significant regardless of the definition of lipoatrophy, with odds ratios ranging from 2.1 to 5.1 (Supplemental Digital Content 1; Supplementary Fig. 1; Table 4; P < 0.003). This was most apparent for zidovudine and stavudine as the selected NRTI. For tenofovir, odds ratio close to 1 and wide CIs indicate little difference in lipoatrophy between efavirenz-containing or lopinavir/r-containing regimens. As-treated analyses yielded similar results (data not shown).
For subjects randomized to receive an NRTI-containing regimen, the median percentage increase in extremity fat was 17.2% (IQR −0.82 to 48.5) at week 96 with tenofovir compared with 2.4% (IQR −21.5 to 22.7) with zidovudine. By contrast, half of the subjects on stavudine lost at least 10.1% extremity fat (IQR −34.0 to 19.1; Fig. 1d). The differences between NRTI were significant for tenofovir vs. stavudine or zidovudine (P < 0.001, for both comparisons) and between zidovudine and stavudine (P = 0.043), and corresponded to median extremity fat changes of 1.2, 0.14, and −0.48 kg, for tenofovir, zidovudine, and stavudine, respectively.
Trunk fat increased from a median of 8.2 kg (IQR 5.0–12.2) at entry to 10.4 kg (IQR 6.8–14.4) at week 96. There were no significant differences at weeks 48 or 96 by randomized treatment or NRTI selection in either percentage change in trunk fat or percentage of subjects with more than 20% gain in trunk fat.
Median cholesterol and triglyceride values increased with time in all treatment arms (P < 0.005 for all comparisons of baseline vs. week 96; Supplemental Digital Content 1; Supplementary Fig. 2a–d). The median increases in total cholesterol, non-HDL cholesterol, and HDL cholesterol were significantly greater for the lopinavir–efavirenz arm compared with the lopinavir arm or the efavirenz arm at all time points. For example, at week 96, the median (IQR) total cholesterol increase for the lopinavir–efavirenz, efavirenz, and lopinavir arms was 57 (25–94), 33 (10–57), and 32 mg/dl (8–60), respectively. In addition, the median increase in triglycerides was larger for the lopinavir–efavirenz arm (62 mg/dl at week 96) compared with the lopinavir (46 mg/dl) and efavirenz (19 mg/dl) arms at all time points (P ≤ 0.030 for all pairwise comparisons). The median increases in total, non-HDL and HDL cholesterol were not significantly different between the lopinavir and efavirenz arms at most time points between weeks 24–96, but triglycerides were significantly higher in the lopinavir arm at all time points between 24 and 96 weeks. As-treated analyses gave similar results.
The total cholesterol-to-HDL cholesterol ratio was similar at baseline between randomized arms (median value 4.3, IQR 3.6–5.3) and increased in the lopinavir–efavirenz arm until week 72 (median increases 0.13–0.39), decreased in the efavirenz arm (median reductions of 0.12–0.39, P < 0.05 compared with the lopinavir–efavirenz arm through week 72) and remained nearly unchanged in the lopinavir arm (median reductions of 0.02–0.10, P < 0.05 compared with the lopinavir–efavirenz arm through week 48). The total cholesterol-to-HDL cholesterol ratio was significantly higher in the lopinavir arm than in the efavirenz at 12 and 24 weeks (P ≤ 0.013), but not after week 24.
At week 96, median total cholesterol had increased by 41 mg/dl (IQR 17–62) for subjects on stavudine, 33 mg/dl (IQR 8.5–54) for subjects on zidovudine, and 22.5 mg/dl (IQR 4–58) for subjects on tenofovir (P = 0.02 for stavudine vs. tenofovir; P > 0.05 for other comparisons). There were similar differences between NRTI for increases in non-HDL cholesterol at week 96. Differences between NRTI for increases in HDL cholesterol and triglycerides were less marked (data not shown).
By week 120, 124 (16%) of study subjects had taken lipid-lowering drugs at some point while on study. In the lopinavir–efavirenz arm, 63 subjects (25%) started lipid-lowering drugs, compared with 28 in the efavirenz arm (11%) and 33 (13%) in the lopinavir arm. Lipid-lowering agents were used in 15% of subjects on stavudine, 12% on zidovudine, and 11% on tenofovir.
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 two NRTIs – recommended by the US DHHS guidelines for treatment of HIV-1 infection in adolescents and adults . 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 plus two NRTIs than with lopinavir/r plus two NRTIs. 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 vs. 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 .
In other studies, patients initiating stavudine or zidovudine regimens lost subcutaneous fat at a rate of 12–15% per year . 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 [8,10,18–21]. 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 [22–24]. 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 [25–27] 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 with 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) . 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 with 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  or more lipoatrophy associated with lower CD4 cell count [19,20]. 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 nonrandomized antiretroviral therapy, increasing age was associated with a greater risk of lipoatrophy . In this study, a borderline protective effect (odds ratio 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 vs. 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 [29,30]. In one study, an increased myocardial infarction relative rate of 1.3 was seen per 39 mg/dl increase in total cholesterol .
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. There 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, that is, stavudine, was associated with lipoatrophy. As changes in extremity fat measured by DEXA have been associated with clinically defined lipoatrophy in previous studies [21,25,31,32], 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 . 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 . 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) . This report adds to the analyses of virologic outcome from ACTG 5142, which showed significantly shorter time to virologic failure for lopinavir/r than for efavirenz given with two NRTIs . Careful selection of regimen components can minimize the risk of lipoatrophy and may improve the risk-to-benefit ratio of treatment, favoring earlier initiation of antiretroviral therapy.
This work was supported by grants AI 068636 (AIDS Clinical Trials Group Central Grant), AI 068634, AI 069471, AI 27661, AI 069439, AI 25859, AI 069477, AI 069513, AI 069452, AI 27673, AI 069470, AI 069474, AI 069411, AI 069423, AI 069494, AI 069484, AI 069472, AI 38858, AI 069501, AI 32783, AI 069450, AI 32782, AI 069465, AI 069424, AI 38858, AI 069447, AI 069495, AI 069502, AI 069556, AI 069432, AI 46370, AI 069532, AI 46381, AI 46376, AI 34853, AI 069434, AI 060354, AI 064086, AI 36214, AI 069419, AI 069418, AI 50410, AI 45008, RR 00075, RR 00032, RR 00044, RR 00046, RR 02635, RR 00051, RR 00052, RR 00096, RR 00047, RR 00039, and DA 12121 from the National Institute of Allergy and Infectious Disease, National Institutes of Health. The collaborating pharmaceutical companies provided Lopinavir–ritonavir (Abbott), efavirenz and stavudine XR (Bristol-Myers Squibb), and tenofovir DF (Gilead).
Author contributions: The initial concept for the study was conceived by S.A.R., R.H.H., A.G.DiR., D.V.H. and J.W.M. The final clinical trial protocol was developed by the study team. All data were collected at the study sites of the AIDS Clinical Trials Group and analyzed by Dr A.G.DiR. and L.K. at the Statistical and Data Management Center for the ACTG. R.H.H. and S.A.R. wrote the first draft of the article with critical review by all authors. All authors, including industry representatives, participated in the development of the study protocol and analysis plan, reviewed the study data reports, and approved the final manuscript.
Conflicts of interest: R.H.H. reports having received speaking honoraria or consultant fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck, Schering and Roche and has received research support from Abbott, GlaxoSmithKline, Pfizer and Tibotec.
S.A.R. reports having received lecture or consultation fees from Bristol-Myers Squibb and grant support from Schering-Plough and Hoffman-LaRoche.
W.G.P. reports having received lecture or consultation fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and Tibotec and grant support from GlaxoSmithKline.
K.W.G. is an employee of Abbott Laboratories.
D.L.B. is an employee of Bristol-Myers Squibb.
J.F.R. is an employee of Gilead Sciences.
D.W.H. reports having received research grants from Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Tibotec, Tanox, Gilead Sciences, and Bavarian Nordic, and has served on an Advisory Board for GlaxoSmithKline.
J.W.M. reports that he is a consultant to Gilead Sciences, Merck, Panacos, and Idenix Pharmaceuticals, has received grant support from Merck, and owns stock options in RFS Pharma.
A.G.DiR., L.K., K.K. and D.V.H. declare that they have no conflicts of interest.
Additional contributions: The study team gratefully acknowledges the participation of the study volunteers. In addition to the authors, other members of the A5142 study team include: Barbara Brizz (SSS), protocol specialist; Pat Cain (Stanford University Medical Center), protocol field representative; Marlene Cooper and Mary Dobson (Frontier Science and Technology Research Foundation), laboratory data coordinators; Michael Dorosh (University of Colorado Health Sciences Center), community representative; Pualani Kondo (University of Hawaii), protocol laboratory technologist; David Rusin (Frontier Science and Technology Research Foundation), data manager; Kathleen Squires (Thomas Jefferson University), Co-Investigator; Paul Tran (Division of AIDS, National Institute of Allergy and Infectious Disease), protocol pharmacist. Additional high enrolling investigators: Mitchell Goldman (Indiana University); Hector Bolivar (University of Miami). Additional pharmaceutical collaborators include Mick Hitchcock and Michael Wulfsohn of Gilead Sciences; and Scott C. Brun and Richard A. Rode of Abbott Laboratories.
Participating Sites and Site Personnel: Karen Coleman, RN (Northwestern University), Beverly Sha, MD (Rush University), and Oluwatoyin Adeyemi, MD (Cook County CORECenter) – Northwestern University; W. Keith Henry, MD and Winston Calvert, MD – University of Minnesota; Michael Morgan, FNP and Brenda Jackson, RN – Vanderbilt University; Mitchell Goldman, MD and Janet Hernandez, RN – Indiana University; Margaret A. Fischl, MD – University of Miami School of Medicine; Carl J. Fichtenbaum, MD and Jenifer Baer, RN – University of Cincinnati; Suzette Byars and Mae Stewart- University of Alabama; Hannah Edmondson-Melancon, RN, MPH and Connie A. Funk, RN, MPH – University of Southern California; Jolene Noel Connor, RN, BSN and Madeline Torres, RN, BSN – Columbia Collaborative HIV/AIDS Clinical Trials Unit; William E. Maher, MD and Laura Laughlin, RN – The Ohio State University; Mary Adams, RN and Christine Hurley, RN – University of Rochester; Clara Zelasky, PA-C and David Wohl, MD – University of North Carolina-Chapel Hill; Deborah McMahon, MD and Barbara Rutecki, MSN, MPH, CRNP – University of Pittsburgh; Princy Kumar, MD and Ioulia Vvedenskaya – Georgetown University; Gary M. Cox, MD and Deitra Wade, RN – Duke University Medical Center; Paul Sax, MD and Jon Gothing, RN – Harvard/BMC ACTU; A. A. Amod, FCPath, Durban International Clinical Trials Unit; Benigno Rodriguez, MD, MSc and Barbara Philpotts, BSN, RN – Case Western Reserve University; Harvey Friedman, MD and Aleshia Thomas, RN – University of Pennsylvania, Philadelphia; Beverly Putnam, MSN and Cathi Basler, MSN – Colorado ACTU; William A. O'Brien, MD, MS and Gerianne Casey, RN – UTMB-Galveston; Ilene Wiggins, RN and Gerianne Casey, RN – Johns Hopkins University; Margrit Carlson, MD and Eric Daar, MD – University of California, Los Angeles; Abby Olusanya, NP and Melissa Schreiber, PA – University of California, Davis Medical Center; Charles Davis, MD and Becky Boyce, RN – University of Maryland, Inst. of Human Virology; Ge-Youl Kim, RN, BSN and Kimberly Gray RN, MSN- Washington University in St. Louis; Joann Volinski, RN – University of California, San Francisco; Jane Norris, PA-C and Sandra Valle PA-C- Stanford University; Julie Hoffman, RN and Susan Cahill, RN – University of California, San Diego; Donald Garmon, NP and Donna Mildvan, MD – Beth Israel Medical Center: Janet Forcht, RN and Charles Gonzalez, MD – New York University/NYC HHC at Bellevue Hospital Center; Karen Tashima, MD and Deborah Perez, RN – The Miriam Hospital; Philip Keiser, MD and Tianna Petersen, MS – UT Southwestern Medical Center at Dallas; Nancy Hanks, RN and Scott Souza, PharmD – University of Hawaii at Manoa and Queen's Medical Center; Ann C. Collier, MD and Sheryl Storey, PA-C – University of Washington, Seattle; Valery Hughes, FNP and Todd Stroberg, RN – Cornell University; Gregory Smith RN and Ighovera Ofotokun MD – Emory University.
ClinicalTrials.gov Identifier: NCT00050895.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; lipoatrophy; metabolic complication; nonnucleoside reverse-transcriptase inhibitor; protease inhibitor; treatment naive