Insights into the role of bioactivation mechanisms in the toxic events elicited by non-nucleoside reverse transcriptase inhibitors

The indisputable benefits of combined antiretroviral therapies (cARTs) have lead to a dramatic change in the prognosis of human immunodeficiency virus (HIV) infection; a life-threatening disease a few decades ago is now perceived as a chronic illness in developed countries. However, as the eradication of HIV seems unlikely in the near future, chronic treatment with cART is unavoidable and increased concerns regarding the long-term adverse effects of these therapies are emerging. According to the World Health Organization, the most globally prescribed initial cART includes a non-nucleoside reverse transcriptase inhibitor (NNRTI). The currently approved NNRTIs are a class of chemically distinct compounds that share the possibility of undergoing biotransformation into electrophilic metabolites capable of reacting with biomacromolecules to afford covalent DNA and protein adducts that could be at the genesis of toxicity. Insights into the bioactivation mechanisms of the NNRTIs nevirapine, efavirenz, etravirine, and rilpivirine are presented in this review.