Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: An adult AIDS clinical trials group study

Todd Hulgan, David W. Haas, Jonathan L. Haines, Marylyn D. Ritchie, Gregory K. Robbins, Robert W. Shafer, David B. Clifford, Asha R. Kallianpur, Marshall Summar, Jeffrey A. Canter

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118 Scopus citations

Abstract

Objective: HIV nucleoside reverse transcriptase inhibitors (NRTI) can cause peripheral neuropathy that is a result of mitochondrial injury. Polymorphisms in the mitochondrial genome define haplogroups that may have functional implications. The objective of this study was to determine if NRTI-associated peripheral neuropathy is associated with European mitochondrial haplogroups. Design: Case-control study of Adult AIDS Clinical Trials Group (ACTG) study 384 and ACTG Human DNA Repository participants. Methods: ACTG study 384 was a treatment strategy trial of antiretroviral therapy with didanosine (ddl) plus stavudine (d4T) or zidovudine plus lamivudine given with efavirenz, nelfinavir, or both. Subjects were followed for up to 3 years. Peripheral neuropathy was ascertained based on signs and symptoms. For this analysis, polymorphisms that define European mitochondrial haplogroups were characterized in a majority of ACTG 384 participants, and associations with peripheral neuropathy were assessed using logistic regression. Results: A total of 509 subjects were included in this analysis of whom 250 (49%) were self-identified as white, non-Hispanic. Mitochondrial haplogroup T was more frequent in subjects who developed peripheral neuropathy. Among 137 white subjects randomized to receive ddl plus d4T, 20.8% of those who developed peripheral neuropathy belonged to mitochondrial haplogroup T compared to 4.5% of control subjects (odds ratio, 5.4; 95% confidence interval, 1.4-25.1; P = 0.009). Independent predictors of peripheral neuropathy were randomization to receive ddl plus d4T, older age, and mitochondrial haplogroup T. Conclusions: A common European mitochondrial haplogroup may predict NRTI-associated peripheral neuropathy. Future studies should validate this relationship, and evaluate non-European mitochondrial haplogroups and other NRTI toxicities.

Original languageEnglish
Pages (from-to)1341-1349
Number of pages9
JournalAIDS
Volume19
Issue number13
DOIs
StatePublished - Sep 2 2005

Keywords

  • Drug toxicity
  • HIV
  • Mitochondrial DNA
  • Peripheral neuropathies
  • Pharmacogenetics
  • Reverse transcriptase inhibitors

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    Hulgan, T., Haas, D. W., Haines, J. L., Ritchie, M. D., Robbins, G. K., Shafer, R. W., Clifford, D. B., Kallianpur, A. R., Summar, M., & Canter, J. A. (2005). Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: An adult AIDS clinical trials group study. AIDS, 19(13), 1341-1349. https://doi.org/10.1097/01.aids.0000180786.02930.a1