Journal Article

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

Santana, Jorge L., Libutti, Daniel E., Sax, Paul E., Gerschenson, Mariana, Kosmiski, Lisa, O'Riordan, MaryAnn, Fichtenbaum, Carl J., Fink, Heidi, Collier, Ann C., McComsey, Grace A., Daar, Eric S.

2013

Overview

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.

• Publisher: Oxford University Press
• Subject: Adenine - administration & dosage / Adenine - analogs & derivatives / Adenine - therapeutic use / Adipose Tissue - drug effects / Adipose Tissue - metabolism / Adipose tissues / Adult / AIDS / Alkynes / Anti-HIV Agents - administration & dosage / Anti-HIV Agents - therapeutic use / Atazanavir Sulfate / Benzoxazines - administration & dosage / Benzoxazines - therapeutic use / Biological and medical sciences / Biopsies / Body mass index / Cyclopropanes / Deoxycytidine - administration & dosage / Deoxycytidine - analogs & derivatives / Deoxycytidine - therapeutic use / Dideoxynucleosides - administration & dosage / Dideoxynucleosides - therapeutic use / DNA, Mitochondrial - drug effects / DNA, Mitochondrial - genetics / DNA, Mitochondrial - metabolism / Drug Combinations / Drug Therapy, Combination / Emtricitabine / Fats / Female / Fundamental and applied biological sciences. Psychology / HIV 1 / HIV Infections - drug therapy / HIV-Associated Lipodystrophy Syndrome - physiopathology / Human viral diseases / Humans / Infectious diseases / Lamivudine - administration & dosage / Lamivudine - therapeutic use / Major and Brief Reports / MAJOR ARTICLES AND BRIEF REPORTS / Male / Medical sciences / Microbiology / Mitochondria - drug effects / Mitochondrial DNA / Oligopeptides - administration & dosage / Oligopeptides - therapeutic use / Organophosphonates - administration & dosage / Organophosphonates - therapeutic use / Oxidative phosphorylation / Pyridines - administration & dosage / Pyridines - therapeutic use / Registered nurses / Reverse Transcriptase Inhibitors - administration & dosage / Reverse Transcriptase Inhibitors - therapeutic use / Ritonavir - administration & dosage / Ritonavir - therapeutic use / RNA / Tenofovir / Treatment Outcome / Viral diseases / Viral diseases of the lymphoid tissue and the blood. Aids