Severe efavirenz associated neurotoxicity: A retrospective cohort study

Priyadarshini Arnab; Roland Croxford; Janet Scott; Sameshan Perumal; Zahraa Mohammed; Lubbe Wiesner; Karen Cohen; Sean Wasserman

doi:10.4102/sajid.v38i1.522

Severe efavirenz associated neurotoxicity: A retrospective cohort study

S Afr J Infect Dis. 2023 Jul 24;38(1):522. doi: 10.4102/sajid.v38i1.522. eCollection 2023.

Authors

Priyadarshini Arnab¹, Roland Croxford², Janet Scott², Sameshan Perumal³, Zahraa Mohammed¹, Lubbe Wiesner⁴, Karen Cohen⁵, Sean Wasserman¹

Affiliations

¹ Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
² Department of Health, DP Marais Hospital, Western Cape Government, Cape Town, South Africa.
³ Department of Statistics, Faculty of Sciences, University of Cape Town, Cape Town, South Africa.
⁴ Division of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
⁵ Division of Clinical Pharmacology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.

Abstract

Background: Efavirenz (EFV) is associated with neuropsychiatric symptoms. Severe neurotoxicity has been reported but the clinical phenotype and risk factors are poorly defined.

Objectives: To characterise clinical presentations, risk factors and outcomes to help clinicians recognise severe neurotoxicity earlier.

Method: The authors retrospectively identified adults with supratherapeutic EFV concentrations (> 4 mg/L) obtained during routine clinical care in Cape Town, South Africa. Clinical and laboratory data at the time of EFV quantification were extracted from medical records. Logistic regression was performed to identify associations with neuropsychiatric symptoms, and with severe neurotoxicity.

Results: Eighty one patients were included; 62 with neuropsychiatric manifestations (most frequently ataxia [n = 20] and psychomotor slowing [n = 24]); and 19 with hepatotoxicity. Overall, 28 (34.6%) were male, 49 (60.5%) had concomitant isoniazid exposure, and median EFV concentration was 12.1 mg/L (interquartile range [IQR]: 6.6-20.0). Neuropsychiatric symptoms were associated with longer duration of EFV therapy, adjusted odds ratio (aOR) 1.3/180-day increment (95% confidence interval [CI]: 1.0-1.7); higher EFV concentrations, aOR 1.2/1 mg/L increase (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 EFV initiation. Severe symptoms odds were 1.2-fold higher (95% CI: 1.1-1.4) per 1 mg/L increase in EFV concentration. Symptoms resolved completely within 1 month in 25 (76%) patients with severe neurotoxicity who discontinued EFV.

Conclusion: A concentration-effect relationship for severe neurotoxicity exists, which occurred late and resolved in most patients after EFV discontinuation.

Contribution: The authors highlighted clinical heterogeneity and morbidity of EFV-associated neurotoxicity.

Keywords: Cape Town; cerebellar; efavirenz; isoniazid; neurotoxicity; risk factors.