Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.

TitleHemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.
Publication TypeJournal Article
Year of Publication2006
AuthorsKallianpur AR, Hulgan T, Canter JA, Ritchie MD, Haines JL, Robbins GK, Shafer RW, Clifford DB, Haas DW
Date Published2006 Jul 13
KeywordsAdolescent, Adult, Aged, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Case-Control Studies, CD4 Lymphocyte Count, Female, Genetic Predisposition to Disease, Genotype, Hemochromatosis, Heterozygote, Histocompatibility Antigens Class I, HIV Infections, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Peripheral Nervous System Diseases

OBJECTIVE: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN.

DESIGN: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens.

METHODS: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression.

RESULTS: : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042].

CONCLUSIONS: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Alternate JournalAIDS
PubMed ID16847405
Grant List5K12HD43483 / HD / NICHD NIH HHS / United States
AI25903 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI46339 / AI / NIAID NIH HHS / United States
AI54999 / AI / NIAID NIH HHS / United States
AT002508 / AT / NCCIH NIH HHS / United States
NS32228 / NS / NINDS NIH HHS / United States
RR000095 / RR / NCRR NIH HHS / United States