Background:  Peripheral neuropathy can complicate ART with nucleoside reverse transcriptase inhibitors (NRTI), and mitochondrial dysfunction has been implicated in the pathogenesis of peripheral neuropathy. Iron is essential for mitochondrial function. In addition, iron deficiency has been associated with peripheral neuropathy. The C282Y (major) polymorphism in the hemochromatosis (HFE) gene is known to increase total body iron stores and alter cellular transport of iron. The present analysis explored relationships between HFE polymorphisms and nucleoside reverse transcriptase inhibitor (NRTI)-associated peripheral neuropathy.

Methods:  We studied subjects who participated in AIDS Clinical Trials Group (ACTG) Protocol 384, and contributed specimens to the ACTG Human DNA Repository under Protocol A5128. ACTG 384 randomized these previously ART-naïve participants to receive 3- or 4-drug ART with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz (EFV), nelfinavir (NFV), or both, with up to 3 years of follow-up. Peripheral neuropathy cases were identified based on patient-reported symptoms or physical examination findings during the study period. Genotypes at the HFE C282Y and H63D (minor) loci were determined by TaqMan^TM assay. Genotype-phenotype associations were assessed by logistic regression.

Results:  Of 509 participants in ACTG 384 included in this analysis, 147 (29%) developed peripheral neuropathy, 73% of whom had been randomized to receive ddI/d4T. HFE C282Y was present in 16% of whites and 3% of blacks. Among ddI/d4T recipients, HFE C282Y heterozygotes were significantly less likely to develop peripheral neuropathy than those lacking the C282Y allele, adjusting for age, sex, baseline CD4 lymphocyte count and viral load, and EFV or NFV use (5% vs 21%, respectively, in whites; adjusted odds ratio, 0.18; 95% confidence interval 0.04 to 0.8; p = 0.02). Regardless of race/ethnicity, peripheral neuropathy was less common in C282Y heterozygotes than in C282Y non-carriers during ddI/d4T treatment (race-adjusted OR, 0.30; 95%CI 0.1 to 0.8; p = 0.03). Among whites, peripheral neuropathy during ddI/d4T treatment was also less common in H63D heterozygotes than in H63D non-carriers (adjusted OR 0.47; 95%CI 0.21 to 1.03, p = 0.06).

Conclusions:  Iron-loading HFE polymorphisms may be associated with a decreased risk of NRTI-associated peripheral neuropathy. This finding has potential implications for the prevention and management of NRTI-associated peripheral neuropathy, particularly among populations at risk for iron deficiency. Further study of functional mechanisms and confirmation of this association in other cohorts are warranted.