Guidelines for the treatment of HIV-infected adults in low- to middle-income countries recommend the nonnucleoside reverse transcriptase inhibitor efavirenz (efavirenz) as backbone therapy, combined with tenofovir disoproxil fumarate and either lamivudine or emtricitabine.1 In most settings, 3 antiretrovirals are administered as a single tablet in a fixed-dose combination (FDC), reducing pill burden, costs and improving adherence2 but also ensuring that dose adjustments are limited.
Efavirenz commonly causes transient neuropsychiatric side effects, usually shortly after treatment initiation, which are usually mild to moderate in severity.3,4 More recently, it has been recognized that efavirenz, especially its 8-OH metabolite, can cause neuronal toxicity.5 We describe a case series of 20 patients with severe ataxia with encephalopathy and from a single center over a 20-month period, all of whom had high efavirenz concentrations. This case series suggests that severe ataxia and encephalopathy due to toxic efavirenz concentrations has been underrecognized and presents with a clear clinical phenotype.
We conducted a chart review of patients with suspected efavirenz-induced ataxia and encephalopathy admitted to the 220-bed Department of Internal Medicine at a secondary level hospital (Tshepong) in Klerksdorp, South Africa, where over 24,000 individuals are receiving antiretroviral therapy (ART) in the public sector (Annual Performance Plan, subdistrict Malosana, North West Province of South Africa, Dec 2016). The case definition used was onset of ataxia while on efavirenz-based ART, no other cause of ataxia identified, and reversal of symptoms with withdrawal of efavirenz. Other causes of ataxia were excluded (hypothyroidism, vitamin B12 deficiency, alcohol abuse, neurosyphilis, intracranial mass lesions, and malignancy with paraneoplastic manifestations). Ataxia was defined as being truncal if unable to balance when sitting, standing, or walking, or limb ataxia as having intention tremor, dysmetria, and dysdiadokinesia. All patients had efavirenz discontinued and had plasma efavirenz concentrations taken within 1–3 days after their last efavirenz dose. Efavirenz concentrations were measured on these specimens batched a few weeks after the blood draw, using liquid chromatography with tandem mass spectrometry as previously described in the University of Cape Town Division of Clinical Pharmacology's accredited laboratory in South Africa.6 The upper limit of the assay was 20 mg/L and therapeutic efavirenz concentrations were defined as 1–4 mg/L.7
Between January 2015 and August 2016, we identified 20 adult women admitted to the hospital with severe ataxia who were receiving efavirenz-based ART. Eleven women had truncal ataxia of which 8 were unable to sit unaided, 5 had limb ataxia, and 4 had both truncal and limb ataxia. Eleven women had features of encephalopathy with impaired consciousness, psychosis, and delirium during some part of their stay. Their median age and weight was 30.5 years (24.0–36) and 37.9 kg (34.1–42.6), respectively. In 8/20 women, a prior weight was able to be abstracted from clinical records 6–12 months before admission; 7 had weight loss gain, and their median weight loss gain was 10.8 kg (interquartile range: 8–11). Their median duration of efavirenz treatment was 2.00 years (1.00–5.5), and 17 of 20 women were virally suppressed, although 2 of them did not have a recent viral load result.
We were unable to find an alternative cause of cerebellar signs in virtually all women. The cerebrospinal fluid of 19 women had no abnormal findings, and 1 was clotted. Brain imaging was available from the admission of 19 women: 9 women showed no abnormality, 7 had generalized atrophy, 1 had cerebellar atrophy, 1 had a pineal cyst, and the scan of 1 suggested encephalitis (normal cerebrospinal fluid).
All 20 women had an efavirenz plasma concentration result. The median duration from the last reported efavirenz dose to the blood draw for efavirenz concentration was 19.0 hours (interquartile range: 17.0–40). Fifteen women's serum efavirenz concentration (including 2 women taking rifampin-containing TB treatment) was greater than 20 mg/L, the limit of detection of the assay, and no efavirenz concentration result was in the therapeutic range. In the single patient with ataxia in the presence of nystagmus who initially was diagnosed with phenytoin toxicity, co-existent efavirenz toxicity was suspected only when ataxia persisted despite resolution of nystagmus. In this patient, repeat phenytoin concentrations were below therapeutic range. Her efavirenz concentration, however, was supratherapeutic, and her symptoms resolved after withdrawal of efavirenz, suggesting efavirenz toxicity as an additional cause of these patients' ataxia.
Only 10 cases were suspected as having efavirenz toxicity on their first admission; the others had been clinically reviewed 2–4 times before diagnosis. Most women were switched from efavirenz to a lopinavir/ritonavir-based ART regimen. Two women had recurrence of ataxia when efavirenz was restarted, one when efavirenz 600 mg daily was inadvertently reintroduced at a local clinic, and another when the patient was rechallenged with ART containing a daily dose of efavirenz 400 mg (her repeat efavirenz concentration was >20 mg/L); both recovered when efavirenz was withdrawn. One woman had a successful efavirenz rechallenge at a daily dose of 400 mg. Three patients died. One with neuroleptic malignant syndrome that occurred after the introduction of risperidone, the other was not virologically suppressed, had a CD4 count of 70 cells/mm3, and passed away at home 2 weeks after being discharged. The third patient died 2 months after discharge with a poorly defined cause of death.
We describe a case series of 20 HIV-infected women on ART who presented with efavirenz-induced ataxia and encephalopathy, apparently caused by supratherapeutic efavirenz concentrations. The ataxia and encephalopathy developed after a median of 2 years on efavirenz and was reversed once efavirenz was withdrawn. Ataxia was so severe that several patients were unable to walk and/or sit unaided. High concentrations of efavirenz, resolution of symptoms after its withdrawal, and recurrence of ataxia on rechallenge with efavirenz in 2 patients strongly suggest efavirenz as the most likely cause of symptoms.
Before the diagnosis of efavirenz toxicity, several patients had been admitted previously, suggesting that clinicians were not aware of this diagnosis.
The 20 patients with this syndrome were diagnosed over 20 months in a single center, suggesting that late efavirenz-induced ataxia and encephalopathy is underrecognized. Dizziness and occasional ataxia are common early efavirenz neuropsychiatric side effects, which typically resolve spontaneously within weeks despite continuing efavirenz.8 However, ataxia has rarely been reported as a late manifestation of efavirenz neurotoxicity, as occurred in our case series. There are isolated case reports of late ataxia due to efavirenz in children and 1 case report of an adult with fatal encephalopathy and ataxia, who had vacuolar axonopathy involving the brain at autopsy.9–11
The ataxia and encephalopathy we observed was related to high efavirenz concentrations, and, as 12 of our cases weighed less than 40 kg, they should have been prescribed lower doses of efavirenz.12 However, all received an FDC tablet containing efavirenz 600 mg daily. FDCs are convenient for public health programs and improve adherence, but hamper individualization of therapy. In a study of long-term efavirenz neuropsychiatric toxicity, body weight < 60 kg and higher efavirenz concentrations increased the risk of experiencing CNS toxicity.13 Moreover, it seems that recent weight loss possibly due to efavirenz toxicity may further exacerbate toxicity.12
The cases we described are likely to be genetic slow metabolizers of efavirenz, as their efavirenz concentrations were extremely high. Efavirenz is primarily metabolized by the cytochrome P450 (CYP) isoenzyme 2B6. Several loss-of-function single-nucleotide polymorphisms in CYP2B6 have been identified, leading to high efavirenz concentrations, which increases the risks of toxicity.14–16 Toxicities related to efavirenz concentrations, like the ataxia and encephalopathy we describe here, occur more commonly in populations with a high prevalence of CYP2B6 slow metabolizer genotypes, like sub-Saharan Africa and India.17,18 Individuals on efavirenz who are underweight or slow metabolizers of efavirenz are at a higher risk of developing severe ataxia and encephalopathy with chronic exposure to high concentrations of efavirenz. It may therefore be appropriate for those countries using efavirenz as their antiretroviral regimen backbone to make therapeutic drug monitoring for efavirenz available when suspicion of toxicities exists, or when patients are cotreated with inhibitors or stimulators of P450 enzyme.19
This is a case series, and the conclusions that can be drawn from it are limited. There is no control group, so we are unable to comment on the risk for this condition. All cases were women, so our findings may not apply to men. Patients were diagnosed by internists and were not evaluated in a standardized fashion by a neurologist or psychiatrist, nor were detailed psychiatric or psychometric tests were undertaken. Finally, we did not ascertain the efavirenz metabolizer genotype.
We describe a clinical syndrome of ataxia and encephalopathy due to high concentrations of efavirenz in underweight women on long-term ART. The toxicity was severe, but reversible after withdrawal of efavirenz. Future research should determine the incidence of this condition and explore associations with slow metabolizer genotypes. In the interim, we propose that patients on efavirenz presenting with cerebellar ataxia or encephalopathy should have efavirenz concentrations measured immediately, but in settings where efavirenz concentration assays are unavailable, efavirenz should be withdrawn.
The patients included in this series and the staff of the PHRU for supporting data and specimen collection.
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