title: Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring.
abstract: BACKGROUND
  Data on long-term central nervous system (CNS) toxicity associated with efavirenz therapy are scarce, and risk factors remain largely unknown. We aimed to determine whether monitoring the plasma concentration of efavirenz could predict neuropsychiatric adverse events associated with long-term therapy with efavirenz.
  
  
  METHODS
  We performed a longitudinal study involving 17 consecutive human immunodeficiency virus (HIV)-infected subjects with virological suppression after at least 6 months of antiretroviral therapy with an efavirenz-containing regimen. Efavirenz plasma concentrations were measured at study entry and at different time points through an 18-month study period.
  
  
  RESULTS
  Median duration of efavirenz therapy before study entry was 18 months (range, 6-27 months). Ten (58.8%) of the patients experienced CNS-related adverse effects, ranging from insomnia and abnormal dreams to depression with suicidal ideation. In 4 (23.5%) of the cases, CNS toxicity led to efavirenz discontinuation. Mean (+/- standard deviation) plasma levels were higher for patients experiencing neuropsychiatric symptoms (5.10 +/- 2.15 microg/mL vs. 2.79 +/- 1.31 microg/mL; P = .024). A plasma level of 2.74 microg/mL had a sensitivity of 90.9% and specificity of 72% to predict CNS toxicity (area under the curve, 0.839; 95% confidence interval, 0.73-0.95; P < .0001). Patients having efavirenz plasma concentrations > 2.74 microg/mL at any time point of the study were 5.68 times more likely to experiencing CNS toxicity than were other patients (95% confidence interval, 1.97-16.37).
  
  
  CONCLUSIONS
  In patients with HIV infection receiving long-term therapy with efavirenz-containing antiretroviral regimens, CNS toxicity is related to efavirenz plasma levels. Patients achieving higher plasma levels are at increased risk of experiencing neuropsychiatric adverse events.
authors.affiliation: Internal Medicine Department, Hospital General Universitario de Elche, Alicante, Spain. gutierrez_fel@gva.es
authors.forename: Félix
authors.initials: F
authors.lastname: Gutiérrez
authors.forename: Andrés
authors.initials: A
authors.lastname: Navarro
authors.forename: Sergio
authors.initials: S
authors.lastname: Padilla
authors.forename: Rosa
authors.initials: R
authors.lastname: Antón
authors.forename: Mar
authors.initials: M
authors.lastname: Masiá
authors.forename: Joaquín
authors.initials: J
authors.lastname: Borrás
authors.forename: Alberto
authors.initials: A
authors.lastname: Martín-Hidalgo
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D048588:Benzoxazines; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000009:adverse effects* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012307:Risk Factors
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; C098320:efavirenz