Severe Neurotoxicity Associated with supra-therapeutic Efavirenz concentrations: a retrospective cohort study

Introduction Efavirenz, still used for first line antiretroviral therapy, is associated with neuropsychiatric symptoms, often occurring early in therapy. Severe neurotoxicity has been reported but the clinical phenotype and risk factors are poorly defined. Methods We retrospectively identified adults with supratherapeutic efavirenz concentrations (> 4 mg/L) obtained as part of routine clinical care at five hospitals in Cape Town, South Africa. Clinical and laboratory data at the time of efavirenz quantification were extracted from medical records. Logistic regression was performed to identify associations with neuropsychiatric symptoms, and with severe neurotoxicity (defined as Division of Allergy and Infectious Diseases altered mental status or ataxia ≥ Grade 3). Results and Discussion 81 patients were included; 28 (34.6%) were male and 49 (60.5%) had concomitant isoniazid exposure. Median efavirenz concentration was 12.1 mg/L (interquartile range (IQR) 6.6-20.0). The most frequent neuropsychiatric manifestations were ataxia in 20 patients and psychomotor slowing in 24. The presence of any neuropsychiatric symptoms were associated with: longer duration, per 180 days, of efavirenz therapy (aOR 1.3; 95% CI, 1.0-1.7); increasing efavirenz concentrations per 1 mg/L increase (aOR 1.2; 95% CI, 1.1-1.4); higher efavirenz concentrations per 1 mg/L increase (aOR 1.2; 95% CI, 1.0- 1.4); and isoniazid exposure (aOR 8.2; 95% CI, 2.5-26.7). Severe neuropsychiatric symptoms occurred in 47 (75%) patients at a median of 5.9 months (IQR 2.1-40.8) after efavirenz initiation. Odds of having severe symptoms compared with mild symptoms were 1.2-fold higher (95% CI, 1.1-1.4) for every 1 mg/L increase in efavirenz concentration. Among patients with severe neurotoxicity, symptoms resolved completely within 1 month in the 29 (94%) who discontinued efavirenz. Conclusion We describe a distinct clinical phenotype and factors. There were duration- and concentration dependent effects, and higher risk with concomitant INH exposure and those with lower CD4 count. Despite most patients with severe neurotoxicity having symptom resolution within 1 month after stopping EFV, the overall 3-month mortality was high in this population.

Grantor

Department of Medicine

Year dc:date.issued

2023

Author dc:creator

• Arnab, Priyadarshini

Advisors dc:contributor.advisor

• Wasserman, Sean
• Cohen Karen

• Medicine

Handle dc:identifier.uri

http://hdl.handle.net/11427/37960

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/37960