Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: Protease inhibitor–mediated neurotoxicity

Abstract

Protease inhibitor exposure is an unrecognized risk factor for the development of HIV-SN, which may potentiate neuronal damage in HIV-infected DRGs, possibly through the loss of macrophage-derived trophic factors.

Cytokine Genotype Suggests a Role for Inflammation in Nucleoside Analog-Associated Sensory Neuropathy (NRTI-SN) and Predicts an Individual's NRTI-SN Risk

“…Clinical details including age, 2,3 plasma lactate 24 exposure to protease inhibitors, 25,26 and perhaps hepatitis C status 27 have previously been associated with NRTI-SN risk. Demographic details of study patients (n ϭ 55, Table 4A) identify patient height as the only feature associated with NRTI-SN status (p ϭ 0.0001).…”

Impact of current antiretroviral therapies on neuroAIDS

“…In vitro experiments using rat dorsal root ganglion have demonstrated neuronal injury (neurite retraction) following exposure to early NRTIs, for instance, didanosine, zalcitabine and stavudine, or PIs, such as indinavir, probably due to mitochondrial injury [33,34]. The ARV-induced toxicity was increased in the presence of the HIV-1 protein, gp120 [34]. Of note, zidovudine exposure did not result in dorsal root ganglion injury, recapitulating clinical observations [33].…”

“…The incidence of ARV-induced toxic neuropathy was initially high owing to the use of dideoxynucleosides [32]. In vitro experiments using rat dorsal root ganglion have demonstrated neuronal injury (neurite retraction) following exposure to early NRTIs, for instance, didanosine, zalcitabine and stavudine, or PIs, such as indinavir, probably due to mitochondrial injury [33,34]. The ARV-induced toxicity was increased in the presence of the HIV-1 protein, gp120 [34].…”

Targeting Neuroprotection as an Alternative Approach to Preventing and Treating Neuropathic Pain

“…Neurotoxicity of indinavir was demonstrated in vitro on dorsal root ganglia (DRG) cultures, and an increased risk for ATN was reported with exposure to indinavir in two independent studies. 10,16 Nonetheless, evaluation of protease inhibitors as an independent risk factor for ATN in a larger cohort (1159 HIV-infected individuals) did not confirm their toxicity, except for amprenavir and lopinavir, which may slightly increase the risk for ATN. 17 Finally.…”

“…the increase in survival of HIV-infected patients with prolonged medication exposure is associated with an increased risk of neuropathy. 13,16 The pathogenesis of ATN remains poorly understood, although mitochondrial toxicity of NRTIs has been known for many years, based on their inhibition of the mitochondrial DNA polymerase-␥. 18 Indeed, increased numbers of abnormal mitochondria in nerves and significantly reduced cellular mtDNA content were evidenced in patients treated with ddC (zalcitabine).…”