Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment

Abstract

Background: The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection.

Methods: Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids.

Results: Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm.

Conclusion: Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Trial registration: ClinicalTrials.gov NCT00050895.

Conflict of interest statement

Conflicts of interest: Dr. Haubrich 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.

Dr. Riddler reports having received lecture or consultation fees from Bristol-Myers Squibb and grant support from Schering-Plough and Hoffman-LaRoche.

Dr. Powderly reports having received lecture or consultation fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and Tibotec and grant support from GlaxoSmithKline.

Dr. Garren is an employee of Abbott Laboratories.

Dr. George was an employee of Bristol-Myers Squibb.

Dr. Rooney is an employee of Gilead Sciences.

Dr. Haas 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.

Dr. Mellors 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.

Dr. DiRienzo, Ms. Komarow, Dr. Klingman and Dr. Havlir declare that they have no conflicts of interest.

Figures

Figure 1

Figure 1a: Percent of subjects with lipoatrophy (greater than 20 percent loss of extremity fat from baseline) by randomized treatment arm. Figure 1b: Percent of subjects with lipoatrophy (greater than 20 percent loss of extremity fat from baseline) by selected NRTI. Figure 1c: Median percent change in extremity fat from baseline by randomized treatment arm. Vertical bars represent interquartile range. P values at 96 weeks: efavirenz versus lopinavir, p = 0.007; efavirenz versus lopinavir-efavirenz, p