Background:  Lipoatrophy can complicate ART and may be due in part to nucleoside reverse transcriptase inhibitor (NRTI) -induced mitochondrial dysfunction. Iron modulates both mitochondrial function and oxidative injury. In previous studies, NRTI-induced peripheral neuropathy was associated with European mitochondrial haplogroup T, and chromosomal HFE polymorphisms (C282Y and to a lesser extent H63D) were protective. Our objective was to evaluate the relationships between these genetic variants and body fat changes observed in HIV-infected individuals after the initiation of ART.

Methods:  AIDS Clinical Trials Group (ACTG) 384 randomized ART-naive subjects to receive didanosine/stavudine or zidovudine/lamivudine in combination with efavirenz and/or nelfinavir. The metabolic substudy A5005s evaluated longitudinal changes in fat distribution by DEXA in a subset of patients at baseline and weeks 16, 32, 48, and 64. Subjects who also consented to participate in the ACTG Human DNA Repository (A5128) had HFE C282Y and H63D genotypes and mitochondrial haplogroups determined. Percentage change in total body, trunk, and limb fat at week 48 or 64 was compared by the Wilcoxon rank-sum test. We used logistic regression to determine whether these variants were associated with lipoatrophy (defined as a ≥10% limb fat loss at week 48 or 64).

Results:  Genetic data and either 48- or 64-week DEXA were available from 96 individuals (58% non-Hispanic white, 10% female). Overall median 48- or 64-week change in limb fat was –8.8% (IQR –28.7, +15.6). Among non-Hispanic white participants, 5 haplogroup J individuals had a 26.1% increase in limb fat at week 48 or 64 vs a 9.7% decrease in non-J individuals (n = 50, p = 0.07). Haplogroup T was present in 4 individuals and was not associated with fat changes. Among all subjects, HFE H63D heterozygotes (nucleotide 187 C>G; n = 23) had significantly less limb fat loss compared to homozygous wild type individuals (+6.1% vs –12.5%, p = 0.02) and were less likely to develop lipoatrophy (OR 0.31 [95%CI 0.10 to 0.95], p = 0.04) after adjustment for age, sex, race, and randomization arm.

Conclusions:  The common HFE H63D polymorphism was associated with protection from significant limb fat loss. There was also a trend toward protection in individuals belonging to mitochondrial haplogroup J. These results suggest that variation in iron metabolism genes and in mitochondrial genes may influence susceptibility to ART-associated lipoatrophy. These findings must be validated in larger studies.