Background:  Peripheral neuropathy (PN) associated with HIV infection or ART may result from mitochondrial injury. We previously reported that European mitochondrial haplo-group T predicted symptomatic PN among non-Hispanic white AIDS Clinical Trials Group (ACTG) 384 participants. In this analysis, we explored associations between African mitochondrial sub-haplo-groups (within major L haplo-groups) and PN on ART among non-Hispanic black ACTG 384 participants. 

Methods:  ACTG 384 was an ART strategy trial that randomized 898 ART-naïve participants in the United States to zidovudine (ZDV) + lamivudine (3TC) vs didanosine (ddI) + stavudine (d4T) combined with efavirenz (EFV), nelfinavir (NFV), or both. PN was ascertained by signs and symptoms during study follow-up. Self-identified non-Hispanic black participants with ACTG Human DNA Repository specimens were included in the analyses. The GeneChip® Human Mitochondrial Resequencing Array 2.0 (Affymetrix) was used to sequence the coding region (approximately 16,000 bases) of each participant’s mitochondrial DNA. Mitochondrial sub-haplo-groups were assigned based on sequence and published algorithms. Associations between PN and 9 African sub-haplo-groups were determined using Fisher’s exact test and logistic regression; analyses were not corrected for multiple comparisons. Persons with PN at baseline were excluded from analyses.

Results:  Of the 384 participants, 526 (59%) had available DNA. Analyses were restricted to 156 (30%) non-Hispanic blacks without baseline PN; 29% female, median age 37 years, baseline CD4 and HIV RNA level 248 cells/mm³ and 4.8 log₁₀ copies/mL, respectively. Of these, 85 (54%) were randomized to receive ddI+d4T and 51 (33%) developed symptomatic PN on study. Individuals with African sub-haplo-group L1c (9 of 16 or 56%) were more likely to develop PN than other sub-haplo-groups (42 of 140 or 30%; p = 0.048). Multivariate analysis found increasing age (OR 1.07, 95%CI 1.03 to 1.12; p = 0.001), randomization to ddI+d4T (6.00, 2.53 to 14.21; p <0.001), and sub-haplo-group L1c (3.68, 1.13 to 11.95; p = 0.03) to be independent predictors of PN after adjustment for sex, baseline CD4 count, and HIV RNA, and randomization to NFV.

Conclusions:  Among non-Hispanic black individuals in ACTG 384, those with mitochondrial sub-haplo-group L1c appeared to be at increased risk for developing PN during ART. This is the first reported association between a mitochondrial genomic variant and ART toxicity in a non-Caucasian population. Replication of this preliminary finding in other non-Hispanic black and African study populations is warranted.