Introduction: Efavirenz commonly causes early neuropsychiatric side effects, but tolerance develops in most patients. There is emerging evidence that efavirenz use may damage neurons, which could result in impaired neurocognitive performance.
Areas covered: The authors conducted a systematic review using the PubMed database, references cited by other articles and conference web sites to determine if there is evidence that efavirenz may contribute to cognitive impairment by damaging nerve cells.
Expert opinion: There is weak clinical evidence suggesting that efavirenz use may worsen neurocognitive impairment or be associated with less improvement in neurocognitive impairment than other antiretrovirals. Efavirenz, especially its major metabolite 8-hydroxy-efavirenz, is toxic in neuron cultures at concentrations found in the cerebrospinal fluid. Extensive metabolizers of efavirenz may therefore be more likely to develop efavirenz toxicity by forming more 8-hydroxy-efavirenz. Several potential mechanisms exist to explain the observed efavirenz neurotoxicity, including altered calcium hemostasis, decreases in brain creatine kinase, mitochondrial damage, increases in brain proinflammatory cytokines and involvement of the cannabinoid system. There is a need for large randomized controlled trials to determine if the neuronal toxicity induced by efavirenz results in clinically significant neurological impairment.