Background:  Peripheral neuropathy is a common complication of nucleoside reverse transcriptase inhibitor (NRTI) therapy for HIV infection and may involve mitochondrial dysfunction due to inhibition of mitochondrial DNA polymerase-γ. We previously described an association between mitochondrial haplogroup T and peripheral neuropathy among white participants in AIDS Clinical Trial Group (ACTG) 384, a study that randomized ART-naive subjects to initiate therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine in combination with efavirenz or nelfinavir. Since the defining polymorphism for haplogroup T (G13368A) is synonymous (does not change an amino acid), we explored 2 non-synonymous polymorphisms, T4216C and A4917G, that have previously been linked with both haplogroup T and human neurodegenerative diseases.

Methods:  We analyzed mtDNA from ACTG 384 participants who contributed specimens to the ACTG Human DNA Repository under protocol A5128. Non-synonymous polymorphisms at positions T4216C and A4917G were determined by 5′ nuclease allelic discrimination Taqman™ and Eclipse™ assays, respectively. Peripheral neuropathy cases were identified by patient-reported symptoms or physical examination findings. Controls did not develop symptomatic peripheral neuropathy during the study. Participants with peripheral neuropathy at baseline were excluded. Logistic regression was used to calculate odds ratios.

Results:  Of the 250 self-identified, white, non-Hispanic subjects from ACTG 384 who were included in this analysis, T4216C and A4917G were present in 53 (21%) and 24 (10%), respectively. Of the 24 individuals with A4917G, all but 1 also had T4216C. Symptomatic peripheral neuropathy (≥grade 1) developed in 70 (28%) of these subjects during study follow-up, 48 (69%) of whom received ddI+d4T at randomization. Both T4216C (OR = 2.5; 95%CI 1.1 to 5.6; p = 0.03) and A4917G (OR = 5.5; 95%CI 1.6 to 18.7; p = 0.006) were more frequent among those with peripheral neuropathy than among those without. In separate models adjusting for age, randomization arm, and baseline CD4 lymphocyte count and plasma HIV-1 RNA level, T4216C and A4917G remained independent predictors of peripheral neuropathy.

Conclusions:  T4216C and A4917G, 2 non-synonymous mitochondrial DNA polymorphisms, were frequent among white ACTG 384 participants, and were associated with the development of peripheral neuropathy among those individuals randomized to receive ddI+d4T. These polymorphisms are known to alter amino acids in mitochondrial complex I subunits and are associated with other human neurodegenerative diseases. Further studies to validate these associations are warranted.