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

Haubrich, Richard Ha,*; Riddler, Sharon Ab,*; DiRienzo, A Gregoryc; Komarow, Laurenc; Powderly, William Gd; Klingman, Karine; Garren, Kevin Wf; Butcher, David Lg; Rooney, James Fh; Haas, David Wi; Mellors, John Wb; Havlir, Diane Vj; for the AIDS Clinical Trials Group (ACTG) A5142 Study Team

doi: 10.1097/QAD.0b013e32832b4377
Clinical Science

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 ≤ 0.023 for all comparisons). Varying the definition of lipoatrophy (≥10 to ≥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.

aUniversity of California San Diego, San Diego, California, USA

bUniversity of Pittsburgh, Pittsburgh, Pennsylvania, USA

cHarvard School of Public Health, Statistical and Data Analysis Center, Boston, Massachusetts, USA

dUniversity College, Dublin, Dublin, Ireland

eNIAID, Division of AIDS, Bethesda, Maryland, USA

fAbbott Laboratories, Abbott Park, Illinois, USA

gBristol-Myers Squibb, Virology Medical Affairs, Plainsboro, New Jersey, USA

hGilead Sciences, Foster City, California, USA

iVanderbilt University School of Medicine, Nashville, Tennessee, USA

jUniversity of California San Francisco, San Francisco, California, USA.

*R.H.H. and S.A.R. contributed equally to the conduct of the study and the writing of this article.

Received 15 October, 2008

Revised 1 February, 2009

Accepted 2 February, 2009

Correspondence to Richard H. Haubrich, MD, Antiviral Research Center, University of California, San Diego, 150 West Washington Street, Suite 100, San Diego, CA 92103, USA. Tel: +1 619 543 8080; fax: +1 619 298 0177; e-mail: rhaubrich@ucsd.edu

© 2009 Lippincott Williams & Wilkins, Inc.