Prediction of Neuropsychiatric Adverse Events Associated with Long-Term Efavirenz Therapy, Using Plasma Drug Level Monitoring

• Published in: Clinical infectious diseases Vol. 41; no. 11; pp. 1648 - 1653
• Main Authors: Gutiérrez, Félix, Navarro, Andrés, Padilla, Sergio, Antón, Rosa, Masiá, Mar, Borrás, Joaquín, Martín-Hidalgo, Alberto
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.12.2005; University of Chicago Press; Oxford University Press
• Subjects: Adult; Adverse effects; AIDS; Anti-HIV Agents - adverse effects; Anti-HIV Agents - blood; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiretrovirals; Antiviral agents; Benzoxazines; Biological and medical sciences; Blood plasma; Central nervous system; Central Nervous System Diseases - chemically induced; Confidence intervals; Dosage; Drug addictions; Drug Administration Schedule; Drug Monitoring; Drug therapy; Female; HIV; HIV infections; HIV Infections - drug therapy; HIV/AIDS; Human immunodeficiency virus; Humans; Infectious diseases; Long term; Longitudinal Studies; Male; Medical sciences; Middle Aged; Neurological disorders; Oxazines - adverse effects; Oxazines - blood; Oxazines - pharmacokinetics; Oxazines - therapeutic use; Pharmacology. Drug treatments; Plasma; Psychological aspects; Risk Factors; Toxicity; Toxicology; Virology; Human; Drug addiction; Antiretroviral agent; Benzoxazine derivatives; RNA-directed DNA polymerase; Acetylenic compound; Enzyme; Toxicity; Non nucleoside compound; Transferases; Enzyme inhibitor; Efavirenz; Long term; Blood plasma; Infection; Nucleotidyltransferases; Treatment; Surveillance; Reverse transcriptase inhibitor; Secondary effect; Antiviral; Predictive factor
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1086/497835

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 µg/mL vs. 2.79 ± 1.31 µg/mL; P = .024). A plasma level of 2.74 µg/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 µg/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.