Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202.

TitleChanges in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202.
Publication TypeJournal Article
Year of Publication2013
AuthorsMcComsey GA, Daar ES, O'Riordan MA, Collier AC, Kosmiski L, Santana JL, Fichtenbaum CJ, Fink H, Sax PE, Libutti DE, Gerschenson M
JournalJ Infect Dis
Volume207
Issue4
Pagination604-11
Date Published2013 Feb 15
ISSN1537-6613
KeywordsAdenine, Adipose Tissue, Adult, Anti-HIV Agents, Atazanavir Sulfate, Benzoxazines, Deoxycytidine, Dideoxynucleosides, DNA, Mitochondrial, Drug Combinations, Drug Therapy, Combination, Emtricitabine, Female, HIV Infections, HIV-1, HIV-Associated Lipodystrophy Syndrome, Humans, Lamivudine, Male, Mitochondria, Oligopeptides, Organophosphonates, Pyridines, Reverse Transcriptase Inhibitors, Ritonavir, Tenofovir, Treatment Outcome
Abstract

BACKGROUND: The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear.

METHODS: A5202 randomized antiretroviral therapy-naive human immunodeficiency virus-infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF-emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests.

RESULTS: Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m(2), 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, -341 [interquartile range, -848 to 190; P = .03] and -400 [-661 to -221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, -12.45 [interquartile range, -24.70 to 2.90; P = .003] and -8.25 [-13.90 to -1.30; P < .001], optical density × 10(3)/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03).

CONCLUSIONS: ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels.

CLINICAL TRIALS REGISTRATION: NCT00118898.

DOI10.1093/infdis/jis720
Alternate JournalJ. Infect. Dis.
PubMed ID23204164
PubMed Central IDPMC3549598
Grant ListAI065348 / AI / NIAID NIH HHS / United States
AI068634 / AI / NIAID NIH HHS / United States
AI068636 / AI / NIAID NIH HHS / United States
AI069434 / AI / NIAID NIH HHS / United States
AI38855 / AI / NIAID NIH HHS / United States
G12 MD007601 / MD / NIMHD NIH HHS / United States
GM103341 / GM / NIGMS NIH HHS / United States
MD000173 / MD / NIMHD NIH HHS / United States
MD007601 / MD / NIMHD NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
UM1 AI069412 / AI / NIAID NIH HHS / United States