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Changes in Proteinuria and Albuminuria With Initiation of Antiretroviral Therapy: Data From a Randomized Trial Comparing Tenofovir Disoproxil Fumarate/Emtricitabine Versus Abacavir/Lamivudine

Wyatt, Christina M. MD*; Kitch, Douglas MS; Gupta, Samir K. MD; Tierney, Camlin PhD; Daar, Eric S. MD§; Sax, Paul E. MD; Ha, Belinda PhD; Melbourne, Kathleen PharmD#; McComsey, Grace A. MD**for the AIDS Clinical Trials Group Study A5224s Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1st, 2014 - Volume 67 - Issue 1 - p 36–44
doi: 10.1097/QAI.0000000000000245
Clinical Science

Background: Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria.

Methods: We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz.

Results: At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components.

Conclusions: In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.

*Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY;

Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA;

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN;

§Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA;

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;

ViiV Healthcare, Research Triangle Park, NC;

#Gilead Sciences, Foster City, CA; and

**Department of Pediatrics, Case Western Reserve University, Cleveland, OH.

Correspondence to: Christina M. Wyatt, MD, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 (e-mail: christina.wyatt@mssm.edu).

Supported by Award Numbers U01AI068636, AI068634, and AI38855 from the National Institute of Allergy and Infectious Diseases, UL1 RR 025005 from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health supported by National Institute of Mental Health (NIMH), and the National Institute of Dental and Craniofacial Research (NIDCR).

Presented at the 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013, Atlanta, GA.

C.M.W. has received research grants from Gilead Sciences, Inc and honoraria from Bristol-Myers Squibb; S.K.G. has received research grants from Merck & Co., Inc, Janssen Pharmaceutics, Inc, and Gilead Sciences, Inc, travel support from Gilead Sciences, Inc and received advisory/consultancy/lecture fees from Bristol-Myers Squibb and Merck & Co., Inc; C.T. has received payment for participation on a data monitoring committee for Janssen Therapeutics; E.S.D. has received research grants from Bristol-Myers Squibb, Gilead Sciences, Inc, Merck & Co., Inc and ViiV Healthcare and has received consultancy/advisory fees from Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Pharmaceuticals., Inc, Merck & Co., Inc, Abbvie, Inc, Teva, and ViiV Healthcare; P.E.S. has received research grants from Bristol-Myers Squibb, Gilead Sciences, Inc and GlaxoSmithKline and is a consultant or scientific advisory board member for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck & Co., Inc and Janssen Pharmaceutics, Inc; B.H. is an employee and stockholder of ViiV Healthcare; K.M. is an employee and stockholder in Gilead Sciences, Inc; G.A.M. has served as a scientific advisor for Bristol-Myers Squibb, GlaxoSmithKline, Merck, and Gilead Sciences, Inc and has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, Abbott, Merck & Co., Inc and Gilead Sciences and has served as the DSMB Chair for a Pfizer-sponsored study. The remaining author has no conflicts of interest to disclose.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Study medications were provided by Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline.

Registered at ClinicalTrials.gov (NCT00118898).

Received February 05, 2014

Accepted May 01, 2014

© 2014 by Lippincott Williams & Wilkins