Background:  Peripheral neuropathy is a common complication of nucleoside reverse transcriptase inhibitor (NRTI) therapy. In Adult AIDS Clinical Trials Group (ACTG) Study 384, ART-naive subjects were randomized to receive either didanosine (ddI)/stavudine (d4T) or zidovudine (ZDV)/lamivudine (3TC), each in combination with efavirenz and/or nelfinavir. Peripheral neuropathy was much more common in ddI/d4T arms. NRTI toxicity is due in part to interactions with mitochondrial DNA polymerase-γ, but reasons for variable susceptibility to NRTI-associated peripheral neuropathy are not known. It is plausible that susceptibility to mitochondrial damage is influenced by genetic variation in mitochondrial DNA. Mitochondrial haplogroups are defined by patterns of linked polymorphisms that may have functional effects. We defined mitochondrial haplogroups in ACTG 384 participants to determine whether mitochondrial DNA polymorphisms were associated with development of symptomatic peripheral neuropathy.

Methods:  DNA from ACTG 384 participants who contributed specimens to the ACTG Human DNA Repository under protocol A5128 was analyzed. Ten polymorphisms that define European mitochondrial haplogroups were genotyped by 5′ nuclease allelic discrimination Taqman assay. Peripheral neuropathy was ascertained based on a new co-morbid diagnosis of peripheral neuropathy or by subjective patient symptom grading. Univariate analyses were performed using Fisher’s exact test and simple logistic regression.

Results:  A total of 526 ACTG 384 study subjects (53% of total enrolled) had DNA available for analysis. Symptomatic peripheral neuropathy (≥ grade 1) developed in 149 (28%) during study follow-up, of whom 114 (77%) were on ddI/d4T at the time of peripheral neuropathy and 35 (23%) were on ZDV/3TC. The proportion with any symptomatic peripheral neuropathy did not differ by race or sex. Mitochondrial haplogroup T was present in 9% of Caucasians and < 2% of African Americans. This haplogroup was associated with peripheral neuropathy in Caucasian subjects (OR= 2.9 [95% CI 1.3 to 6.9]; p = 0.013), particularly in those who received ddI/d4T (OR = 5.2 [95% CI 1.7 to 16.2]; p = 0.004).

Conclusions:  Mitochondrial haplogroup T was more frequent in Caucasians who developed subjective peripheral neuropathy while on ddI/d4T during Study 384. The polymorphism that defines this haplogroup is located in the ND5 region of the mitochondrial gene encoding Complex I respiratory transport chain subunits and may point to variations in this gene that predispose individuals to mitochondrial toxicity. Further study of functional mechanisms and confirmation of this association in other cohorts are warranted.

Keywords: antiretroviral therapy; peripheral nervous system diseases; mitochondrial DNA