Table 4.

Major adverse neurological effects associated with ARVs.

Family/Drug	Mechanism of Injury	Neurological Adverse Effects
Nucleoside Analogs (“D Drugs”) ddI, d4T, ddC [102 103 109 287]	Neurotoxicity results in mitochondrial DNA (mtDNA) depletion Inflammatory damage to sensory axons and dorsal root ganglia	Neuromuscular syndrome of acute progressive ascending weakness Neuropathies
Nucleoside Reverse Transcriptase Inhibitor (NRTI) Zidovudine Abacav [104]	Mitochondrial myopathy seen primarily with older NRTI (AZT) and much less common with newer agents	Mitochondrial myopathy Neuropathies
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Efavirenz Nevirapine Rilpivirine [44 106 114]	mtDNA depletion and disruption of BBB integrity Altered calcium hemostasis Decrease in brain creatinine kinase Increase in brain pro-inflammatory cytokines and involvement of the cannabinoid system	Efavirenz Significant side effects reported in ~50% Neuropsychiatric symptoms Increased stroke severity (in mice) Increased vasoreactivity (compared with use of Lopinavir or Ritonavir) Seizures Nevirapine-few neurologic side effects Rilpivirine-side effects similar to Efavirenz but lower incidence of these
Protease Inhibitors Ritonavir Saquinavir Darunavir Lopina [107 110]	Oxidative stress Lipid metabolism alterations Induction of endoplasmic reticulum stress response in macrophages	Circumoral and peripheral paresthesias Taste alterations Increased risk of cerebrovascular disease, given the atherogenic side-effect profile Darunavir does not show neuronal toxicity in cell culture
Integrase Inhibitors Raltegravir Dolutegravir Elutegravir	Activates integrated stress response Elutegravir demonstrates toxicity in cell culture	Insomnia, sleep disturbance, mood change but lower incidence than EFV