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PLoS One. 2019 Nov 14;14(11):e0225199. doi: 10.1371/journal.pone.0225199. eCollection 2019.

Changes over time in creatinine clearance and comparison of emergent adverse events for HIV-positive adults receiving standard doses (300 mg/day) of lamivudine-containing antiretroviral therapy with baseline creatinine clearance of 30-49 vs ≥50 mL/min.

Author information

1
Medical Affairs, ViiV Healthcare, Research Triangle Park, NC, United States of America.
2
Medical Research Council Clinical Trials Unit, University College, London, United Kingdom.
3
Statistics, PAREXEL International, Durham, NC, United States of America.
4
Physicians Group, ViiV Healthcare, Research Triangle Park, NC, United States of America.
5
Safety and Medical Governance, GlaxoSmithKline, Stockley Park, United Kingdom.
6
School of Population Health, University of Queensland, Brisbane, Australia.
7
Physicians Group, ViiV Healthcare, Tres Cantos, Spain.
8
HIV Care Research Programme, MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
9
Department of Medicine, University of Zimbabwe, Harare, Zimbabwe.
10
HIV Clinical Trials Unit, Joint Clinical Research Centre, Kampala, Uganda.
11
Healthcare Statistics, ViiV Healthcare, Research Triangle Park, NC, United States of America.
12
Safety and Pharmacovigilance, ViiV Healthcare, London, United Kingdom.

Abstract

A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30-49 mL/min (n = 168) versus ≥50 mL/min (n = 3,132) and treatment regimen. The Grade 3-4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30-49 versus CLcr≥50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30-49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ≥50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30-49 mL/min and those with baseline CLcr ≥50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30-49 mL/min would have similar AE risks in comparison to patients with CLcr ≥50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30-49 mL/min.

Conflict of interest statement

We have the following interests: LLR, ART, CCM, AC, TP, and MSS are employees of ViiV Healthcare and own stock in GlaxoSmithKline. ASW discloses receiving grant funding for the DART trial from the UK Medical Research Council, the UK Department for International Development, and the Rockefeller Foundation; receiving nonfinancial support from ViiV Healthcare, GlaxoSmithKline, Gilead Sciences, and Boehringer Ingelheim, all of which donated drugs for the DART trial; receiving funding from Gilead Sciences for teaching courses on Critical Appraisal; and receiving funding from Janssen for sitting on a Data Safety Monitoring Board. YL was an employee of PAREXEL International and owns stock in GlaxoSmithKline. DMG discloses nonfinancial support from GlaxoSmithKline, Gilead, and Boehringer Ingelheim, all of which provided drugs for the DART trial, and nonfinancial support from Gilead, ViiV Healthcare, CIPLA, and Mylan, all of which donated drugs for HIV trials outside of the submitted work. JD is an employee of and owns stock in GlaxoSmithKline. CG, PM, GM, and CMK have nothing to disclose. HG discloses receiving funds in the form of a grant from MRC/UVRI Uganda Research Unit on AIDS, during which time HG was the Unit Director and drew a salary from MRC (UK) during the conduct of the study. JH and PNM have nothing to disclose. This retrospective analysis of data through 96 weeks from the DART trial was supported by ViiV Healthcare using data provided by the DART trial sponsors, the Medical Research Council of the United Kingdom. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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