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

• Published in: The Journal of infectious diseases Vol. 207; no. 4; pp. 604 - 611
• Main Authors: McComsey, Grace A., Daar, Eric S., O'Riordan, MaryAnn, Collier, Ann C., Kosmiski, Lisa, Santana, Jorge L., Fichtenbaum, Carl J., Fink, Heidi, Sax, Paul E., Libutti, Daniel E., Gerschenson, Mariana
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.02.2013
• Subjects: 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; Purine nucleoside; Antiretroviral agent; Benzoxazine derivatives; RNA-directed DNA polymerase; Acetylenic compound; Ritonavir; Non nucleoside compound; Mitochondrial DNA; Nucleotide analog; Efavirenz; Tenofovir; Reverse transcriptase inhibitor; Nucleoside analog; Antiviral; Clinical trial; Pyrimidine nucleoside; Emtricitabine; Immunopathology; Purine nucleotide; Acyclic nucleotide; Atazanavir; Enzyme; Transferases; Enzyme inhibitor; Lamivudine; AIDS; Organic phosphonate; Immune deficiency; Infection; Allosteric inhibitor; Peptidases; Nucleotidyltransferases; Dideoxynucleoside; Viral disease; Abacavir; Hydrolases; Protease inhibitor
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jis720

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.