Clinical phenotype and risk factors for severe efavirenz-associated neurotoxicity amongst inpatients in Cape Town, South Africa

Abstract

Background: Efavirenz, widely used as first line antiretroviral therapy (ART), is frequently associated with mild transient neuropsychiatric symptoms, usually occurring early in therapy. More severe neurotoxicity has been reported, but the clinical phenotype and risk factors are poorly defined. Methods and materials: We identified adult patients with an efavirenz concentration >4 mg/L (target 1–4 mg/L) at four hospitals in Cape Town, South Africa. Data were extracted from medical records, including clinical symptoms and signs and laboratory abnormalities at the time of efavirenz quantification; severe neurotoxicity was defined as Division of AIDS score > 3. We performed logistic regression to identify associations with neuropsychiatric symptoms and severe neurotoxicity. Results: Data were included from 82 patients: 62 had neuropsychiatric symptoms, 19 had hepatitis, and 1 had no apparent indication for efavirenz quantification. Median age was 38 years (interquartile range (IQR) 29–45), median weight 53 kg (IQR 44–63), 29 (34%) were male, and 49 (63%) patients had concomitant isoniazid exposure. Median efavirenz concentration was 12.1 mg/L (IQR 6.6–20.0). Neuropsychiatric manifestations included ataxia (n = 20) and other cerebellar signs (n = 13), psychomotor slowing (n = 24), psychosis (n = 17), mood disturbance (n = 11), and insomnia/sleep disturbance (n = 4). Compared with hepatitis, neurotoxicity was associated with male sex (adjusted odds ratio (aOR) 20.0, 95% CI 2.0–199.9), higher efavirenz concentrations (aOR 1.2 per 1 mg/L increase, 95% CI 1.0–1.4) and isoniazid exposure (aOR 5.1, 95% CI 1.1–23.5). Severe neuropsychiatric symptoms occurred in 47 (75%) patients with neurotoxicity, after a median of 25 weeks (IQR 9–175) on efavirenz-based ART. Median efavirenz concentration was 20.0 mg/L (the upper limit of assay detection, IQR 13.0–20.0) in those with severe versus 7.0 mg/L (4.5–11.8) in those with mild neurotoxicity (p < 0.01). Amongst patients with severe neurotoxicity, there was complete resolution of symptoms within 1 month in 29/31 (94%) who discontinued efavirenz and in 2/5 (40%) who underwent dose-reduction. 3-month mortality was 11% (n = 45) for patients with severe neurotoxicity. Conclusion: Cerebellar signs were the most frequent clinical manifestation of efavirenz-associated neurotoxicity. There was a concentration-effect relationship for severe neurotoxicity, which occurred late and resolved in most patients after efavirenz discontinuation.