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.

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 < 0.001; lopinavir versus lopinavir-efavirenz, p = 0.013. Figure 1d: Median percent change in extremity fat from baseline by selected nucleoside reverse transcriptase inhibitor (NRTI). Vertical bars represent interquartile range. P values at 96 weeks: stavudine versus zidovudine, p = 0.043; stavudine versus tenofovir, p < 0.001; zidovudine versus tenofovir, p < 0.001.