Pharmacogenetics of nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy

Abstract

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.

Figure 1. Concept of environmentally determined genetic expression

Extreme genetic or extreme environmental changes can each lead to a phenotype when present alone, but most exposures lie between these two extremes: the effects of normally silent genetic variants (e.g., mitochondrial DNA or HFE polymorphisms) may be unmasked only in the presence of significant environmental insults (HIV infection and/or treatment with mitochondrial-toxic drugs). Reproduced with permission from [19].

Figure 2. The human mitochondrial DNA genome showing the location of known mitochondrial disease-causing variants and variants associated with increased or decreased risk of peripheral neuropathy on nucleoside reverse-transcriptase inhibitor therapy

Synonymous polymorphisms are designated by light gray bars and nonsynonymous polymorphisms are represented by dark gray bars with amino acid changes indicated. cyt b: Cytochrome b; DEAF: Mitochondrial deafness; LHON: Leber hereditary optic neuropathy; KSS: Kearns–Sayre Syndrome; MELAS: Mitochondrial encephalopathy, lactic acidosis and stroke; MERRF: Myoclonic epilepsy with ragged red fibers; NARP: Neuropathy, ataxia and retinitis pigmentosa. Illustration copied and adapted from [202] under licensing terms outlined at [203].

Figure 3. Estimated effects of mitochondrial DNA and HFE gene variants in different pharmacogenomic studies of peripheral neuropathy based on the ACTG study 384 data, shown as multivariate-adjusted odds ratios

The estimated effects were observed in separate analyses using slightly different statistical approaches, designated by shaded blocks [104,122,123]. (A) ORs adjusted for other listed potential confounders shown and in the case of nongenetic factors, for mitochondrial haplogroup T. This model was also adjusted for randomization to blinded non-NRTI study arms containing nelfinavir and/or efavirenz; these factors were not statistically associated with peripheral neuropathy (data not shown). (B) ORs from separate models adjusted for age, sex, baseline CD4 count and HIV RNA concentration, randomization to (ddI plus d4T) treatment and concomitant antiretroviral drugs. (C) ORs from separate models adjusted for age, baseline CD4 count and HIV RNA concentration, randomization to (ddI plus d4T) treatment, and concomitant antiretroviral drugs. d4T: Stavudine; ddI: Didanosine; HFE: Hemochromatosis; mtDNA: Mitochondrial DNA; NRTI: Nucleoside reverse-transcriptase inhibitors; OR: Odds ratio.