Brief Report: Late Efavirenz-Induced Ataxia and Encephalopathy: A Case Series

Abstract

Background WHO treatment guidelines recommend efavirenz in first line antiretroviral therapy (ART). Efavirenz commonly causes early transient neuro-psychiatric adverse events. We present 20 cases with severe encephalopathy accompanied by ataxia due to efavirenz toxicity Methods Consecutive HIV-infected adults taking efavirenz-containing ART admitted to Tshepong hospital, Klerksdorp, South Africa with ataxia and encephalopathy were included in this case series. Results We identified 20 women admitted to hospital with severe ataxia. All received efavirenz-based ART for a median of 2 years. All had severe ataxia and none had nystagmus. Eleven had features of encephalopathy. Median weight was 34kg (IQR:29.7–35.3); median CD4 count 299 cells/mm3 (IQR:258-300) and most (18 of 19) were virally suppressed. Eight patients had a record of prior weights and 7 of 8 showed signicant weight loss with a median weight loss of 10.8 kg (IQR:8–11.6). All cases had plasma efavirenz assays, 19 were supra-therapeutic (more than twice upper level of therapeutic range) and 15 had concentrations above the upper limit of assay detection. Ataxia resolved after withdrawal of efavirenz at a median time of 2 months (IQR:1.25–4), and recurred in two of three patients when rechallenged. Admissions prior to diagnosis were frequent with 10 cases admitted previously. Three women died. Conclusion Efavirenz toxicity may present with severe reversible ataxia often with encephalopathy years after its initiation; likely in genetic slow metabolizers. We recommend that patients whose weight is <40kg receive lower doses of efavirenz and that therapeutic drug monitoring (TDM) be considered, and efavienz stopped in patients presenting with ataxia.

A proposed management algorithm for late-onset efavirenz neurotoxicity

“…Patients described previously in a similar case series were also all women. [6] It is unclear whether the proposed mechanism of EFV toxicity (resulting from slow metabolism of EFV due to polymorphisms of cytochrome CYP2B6) [2,7,14] may have a sex predilection, as previous studies assessing this have yielded conflicting results. [2,7,14] Some researchers suggest that non-Caucasian females are at high-risk for toxicity even after correcting for age and body weight.…”

“…Unlike a similar case series of EFV toxicity, [6] our patients had an average body weight of 55 kg, with none weighing less than 40 kg. They all received the recommended dose of EFV (600 mg/d).…”

“…[4] A paediatric case series has described late-onset neurotoxicity associated with toxic EFV levels in the form of subacute ataxia in children treated with EFV-containing antiretroviral regimens for more than a year. [5] A more recent case series from Klerksdorp, SA, [6] described late-onset ataxia and encephalopathy in adult patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. These patients were all female with low body weight.…”

“…Our observations do, however, corroborate those described in a similar group of patients. [6] We would also like to highlight the likely role of INH in precipitating this syndrome, and in our experience low body weight is not a necessary factor. The findings from this report support consideration of the removal of EFV as first-line treatment for HIV in SA.…”

Southern African HIV Clinicians Society guidelines for antiretroviral therapy in adults: 2020 update

“…Recently, a late-onset encephalopathy syndrome has been linked to EFV. 23 This is characterised by a subacute encephalopathy and cerebellar dysfunction, frequently presenting months to years after commencing EFV, and is associated with supratherapeutic EFV levels. Patients who are genetically slow metabolisers of EFV may be predisposed to this syndrome.…”