Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Induced Neuropathy and Mitochondrial Toxicity: Limitations of the Poly-γ Hypothesis and the Potential Roles of Autophagy and Drug Transport

Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of highly active antiretroviral therapy (HAART)-the current standard of care for treating human immunodeficiency virus (HIV) infection. Despite their efficacy, NRTIs cause numerous treatment-limiting adverse effects, including a distinct peripheral neuropathy, called antiretroviral toxic neuropathy (ATN). ATN primarily affects the extremities with shock-like tingling pain, a pins-and-needles prickling sensation, and numbness. Despite its negative impact on patient quality of life, ATN remains poorly understood, which limits treatment options and potential interventions for people living with HIV (PLWH). Elucidating the underlying pathophysiology of NRTI-induced ATN will facilitate the development of effective treatment strategies and improved patient outcomes. In this article, we will comprehensively review ATN in the setting of NRTI treatment for HIV infection.