title: Neuronal toxicity of efavirenz: a systematic review.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Stellenbosch University, Faculty of Medicine and Health Sciences, Division of Clinical Pharmacology, Department of Medicine , PO Box 19063; Francie van Zijl Drive, Tygerberg 7505 , South Africa ericdecloedt@sun.ac.za.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Decloedt
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000480:Alkynes; D000818:Animals; D048588:Benzoxazines / Q000009:adverse effects* / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000503:physiopathology; D003521:Cyclopropanes; D004361:Drug Tolerance; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000503:physiopathology; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz; D002118:Calcium