Mitochondrial DNA Variation, Antiretroviral Therapy, and Incidence of Diabetes Among Men With and Without HIV.

Background: Mitochondrial dysfunction is implicated in the development of diabetes mellitus (DM), which is more common in people with HIV (PWH) than in people without HIV (PWoH). Variation in mitochondrial DNA (mtDNA) and mitochondrial-toxic antiretroviral therapy (ART) may influence the susceptibility to DM but is underexplored in men with HIV. Methods: Men from the Multicenter AIDS Cohort Study (MACS) without DM and with fasting glucose data were included. Type 2 DM was defined by fasting glucose ≥ 126 mg/dL, DM medication use, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. Exposure to mitochondrial-toxic ART (D-drugs or zidovudine) was categorized as a binary variable based on ever or never exposed. Mitochondrial DNA haplogroups were determined using HaploGrep from genotyping data. Associations between incident DM, mtDNA haplogroups of European and African origin, and interactions between mtDNA haplogroups and mitochondrial-toxic ART were analyzed. Results: Among 2598 men (667 self-reported as non-Hispanic Black and 1616 self-reported as non-Hispanic White), 1349 were men with HIV. In PWH, African haplogroup L3 was associated with a higher risk of incident DM (hazard ratio [HR], 1.92; 95% CI, 1.19-3.10) compared to other African-ancestry haplogroups, after adjusting for principal components of nuclear genetic ancestry, age, body mass index, hepatitis B and C status, smoking, and HIV-specific factors. D-drugs were independently associated with an increased risk of developing DM (HR, 2.8; 95% CI, 1.5-5.3). Conclusions: The African mtDNA haplogroup L3 increased the risk of incident DM in men with HIV. In PWH, D-drugs independently increased the risk of DM.