Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy.
Peripheral neuropathy is an important complication of antiretroviral therapy. Nucleoside reverse-transcriptase inhibitor (NRTI)-associated mitochondrial dysfunction, inflammation and nutritional factors are implicated in its pathogenesis. Pharmacogenetic and genomic studies investigating NRTI neurotoxicity have only recently become possible via the linkage of HIV clinical studies to large DNA repositories. Preliminary case-control studies using these resources suggest that host mitochondrial DNA haplogroup polymorphisms in the hemochromatosis gene and proinflammatory cytokine genes may influence the risk of peripheral neuropathy during antiretroviral therapy. These putative risk factors await confirmation in other HIV-infected populations but they have strong biological plausibility. Work to identify underlying mechanisms for these associations is ongoing. Large-scale studies incorporating clearly defined and validated methods of neuropathy assessment and the use of novel laboratory models of NRTI-associated neuropathy to clarify its pathophysiology are now needed. Such investigations may facilitate the development of more effective strategies to predict, prevent and ameliorate this debilitating treatment toxicity in diverse clinical settings.
Department of Medicine, Vanderbilt University, 2525 West End Avenue, Suite 600, Nashville, TN 37203-31738, USA. asha.kallianpur@vanderbilt.edu
Asha R
AR
Kallianpur
Todd
T
Hulgan
D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006432:Hemochromatosis / Q000209:etiology / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012307:Risk Factors
D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors