Treatment with efavirenz in children associated with a mild increase in neuro-psychiatric symptoms

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A study by researchers at the department of internal medicine, Radboud University Medical Centre, Netherlands reveals children from Tanzania living with HIV on the antiretroviral drug, efavirenz, experience mild increases in neuro-psychological side-effects, including lower competence and school performance scores. Given the widespread use of paediatric efavirenz, more research is needed to better understand this connection, in addition to neuro-psychological symptom screening for children on the drug.

The research fills a critical research gap, presenting the first comprehensive evaluation, using validated psychiatric tools, of children on efavirenz in sub-Saharan Africa.

Between June and December 2017, 141 children were included in this analysis which sought to compare competence (social involvement, activities, and school performance); ‘internalising’ problems such as depression and anxiety; ‘externalising’ problems such as rule-breaking, or aggression; cognitive performance (intelligence and working memory); and adherence among children living with HIV.

Data from one other trial used a brief behavioural screener, called a Strengths and Difficulties Questionnaire (SDQ), and found no difference in prevalence of mental disorders between efavirenz and ritonavir-boosted lopinavir. But other observational studies, case reports and clinical observations have, conversely, reported high rates of neuro-psychiatric symptoms – up to 39% – with some describing severe symptoms of psychosis, ataxia and seizures. But small sample sizes and a lack of validated tools for psychiatric assessment in children limit the generalisation of these results.

We know that side-effects relating to the brain are well-known in adults on efavirenz. Up to 30% will experience neuro-psychiatric symptoms such as impaired concentration, sleep disturbances, depression, anxiety, and hallucinations. These symptoms are often temporary, but recent studies have indicated that, for some, they may persist for years. These side-effects have led the World Health Organisation (WHO) to recently update their recommendation for efavirenz as the preferred first-line therapy for all treatment-naïve people starting antiretroviral treatment (ART), instead now recommending dolutegravir, which is highly effective and far better tolerated.

In this multicentre, cross-sectional, observational study, children aged 6 to 12 were recruited from three clinics in Tanzania – 72 children (51%) were on efavirenz and 69 (49%) were on non-efavirenz regimens.

Data for the study was extracted via several means. The child’s caretaker provided demographic and socio-economic data, HIV disclosure and general health status of the child via a survey. Past clinical data was also acquired, including viral load results. The researchers conducted their own nutrition assessment of the child based on age, height and weight parameters.

The caretaker also filled out a Child Behaviour Checklist for ages 6-18 years (CBCL/6-18), which is a standardised 120-item questionnaire that looks at a child’s competence – such as questions around hobbies, friendships, school grades – and behavioural and emotional problems.

Other tests conducted with the child measured general non-verbal cognitive ability, and short-term and working memory. The caretaker was also asked to assess adherence and asked if the child had experienced any CNS symptoms known to affect adults on efavirenz in the last week.

After controlling for any influencing socio-demographic factors, the data reveals lower competence scores for children on efavirenz – 30% scored below the ‘normal’ range compared to 22% in the non-efavirenz group. Further analysis shows that these scores are driven by lower school performance for those children on efavirenz. Interestingly, intelligence, as measured by cognitive ability, was similar between the two groups, so this cannot explain the difference in school performance.

“Neurocognitive problems or mood problems might have played a part,” note the authors in their discussion. “For example, 19 (26%) of 72 children on efavirenz reported problems paying attention at school compared with eight (12%) of 69 children in the non-efavirenz group.”

They continue, “follow-up research into these attentional control networks (inhibiting irrelevant distractions, sustaining attention, dividing attention, and shifting attention) might be fruitful.”

The data also revealed increases in total and internalising behavioural problems, notably anxious and affective symptoms, compared to the non-efavirenz group – but these were statistically insignificant. Around 39% of the efavirenz group had been prescribed a lower dose than WHO recommendation – in a further subgroup analysis of children prescribed at or higher than the WHO dose, they found these symptoms to be more pronounced.

Efavirenz still remains a highly effective and clinically relevant treatment for children and adults living with HIV. But considering these findings, and the substantial evidence we already have for adults, the authors call for increased clinical awareness and adequate follow-up of neuro-psychiatric symptoms for efavirenz in children.

Summary
Background: Efavirenz is commonly prescribed for children with HIV infection, yet little is known about risks of neuropsychiatric side-effects. We aimed to compare competence (social involvement, activities, and school performance) and psychopathology (internalising and externalising problems), cognitive performance (intelligence and working memory), and adherence in Tanzanian children on an efavirenz-based versus a non-efavirenz-based regimen.
Methods: In this multicentre, cross-sectional, observational study, we included consecutive children (aged 6–12 years) with HIV infection, on combination antiretroviral therapy (cART) for at least 6 months, and with viral loads of less than 1000 copies per mL from HIV care clinics of three primary health facilities and three referral hospitals in Moshi, Kilimanjaro, Tanzania. Children with acute illnesses, medication switch in the 6 months before the study visit, and any history of brain injury or developmental delay before cART initiation were excluded. All interviews and assessments were done by trained local research nurses under the supervision of a medical doctor. The primary outcomes, competence and psychopathology, were measured with the Child Behavior Checklist. We used ANCOVA to assess differences between groups. This study is registered with ClinicalTrials.gov, number NCT03227653.
Findings: Between June 19, 2017, and Dec 14, 2017, 141 children were analysed, of whom 72 (51%) used efavirenz-based cART and 69 (49%) used non-efavirenz-based cART. After controlling for age, sex, and clinical and demographic confounders, we observed lower competence (adjusted mean difference −2·43 [95% CI −4·19 to −0·67], p=0·0071), largely driven by lower school performance scores (adjusted mean difference −0·91 [–1·42 to −0·40], p=0·00055), in the efavirenz group than in the non-efavirenz group. More total (adjusted mean difference 5·96 [95% CI −1·12 to 13·04], p=0·098) and internalising (adjusted mean difference 2·00 [–0·29 to 4·29], p=0·086) behavioural problems were seen in the efavirenz group than in the non-efavirenz group, although these findings were non-significant. No differences were found in externalising problems (adjusted mean difference 0·78 [95% CI −1·55 to 3·11], p=0·51).
Interpretation: Our results suggest that treatment with efavirenz in children is associated with a mild increase in neuropsychiatric symptoms, especially in children who receive doses higher than or equal to the WHO recommended doses for efavirenz. Clinical awareness and adequate follow-up of neuropsychiatric symptoms in efavirenz in children remain warranted.

Authors
Lisa Van de Wijer, Deborah N Mchaile, Quirijn de Mast, Blandina T Mmbaga, Nanda NJ Rommelse, Ashanti Duinmaijer, André JAM van der Ven, Arnt FA Schellekens, Grace D Kinabo

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