title: Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine, Divisions of General Internal Medicine & Public Health, Nashville, TN, USA. asha.kallianpur@vanderbilt.edu
authors.forename: Asha R
authors.initials: AR
authors.lastname: Kallianpur
authors.forename: Todd
authors.initials: T
authors.lastname: Hulgan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Canter
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Robbins
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
authors.forename: David B
authors.initials: DB
authors.lastname: Clifford
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D006432:Hemochromatosis / Q000150:complications / Q000235:genetics; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000150:complications / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins