Neuropsychiatric and Neurocognitive Manifestations in HIV-Infected Children Treated With Efavirenz in South Africa—A Retrospective Case Series

Abstract

Background: Efavirenz is associated with transient neuropsychiatric manifestations but the impact on neurocognition in children is unknown. Genetically slow metabolizers of efavirenz may be at risk of toxicity. This study describes neuropsychiatric and neurocognitive manifestations of South African children with suspected efavirenz neurotoxicity. Method: This retrospective study describes clinical features of 12 children with features consistent with efavirenz neurotoxicity between 2008 and 2014. Results: Twelve children (4 males, 8 females) aged 3–12 years (median 8.4 years) were referred to a dedicated pediatric neuroHIV service. Eight were of indigenous African (black) ancestry and 4 were of mixed ancestry. The total duration on efavirenz-containing ART at the time of referral was 6–72 (mean 31) months. Two children (both of black ancestry) were phenotypically slow metabolizers and presented with acute manifestations and high plasma efavirenz concentrations above normal range resulting in discontinuation of efavirenz. Ten other children had clinical presentations compatible with efavirenz neurotoxicity but had normal or sub-therapeutic plasma efavirenz concentrations and continued treatment with efavirenz. The acute neuropsychiatric manifestations reported included drowsiness, seizures, sleep disturbances, personality changes, ataxia, and slurred speech. These were noticed 2–8 weeks (mean 5 weeks) after commencing efavirenz and resolved over a few weeks. Nine children had neurocognitive deficits and showed poor performance in all neurocognitive domains that were tested. Interpretation: Efavirenz causes transient neuropsychiatric adverse effects and may contribute to poor long-term neurocognitive outcomes in HIV-infected children. Prospective studies comparing efavirenz-treated and efavirenz-naïve children are needed to further elucidate the manifestations of efavirenz toxicity.

Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study

“…With the current recommended weight-band pediatric efavirenz dose, our findings indicate that on average one-fourth of Ethiopian HIV-infected children experience higher plasma drug exposure ≥4 µg/mL. This is a concern since such higher plasma efavirenz exposure is associated with treatment-induced neuropsychiatric manifestations and liver enzyme abnormalities [16,34], increased psychopathology [44], and poor long-term neurocognitive outcomes in HIV-infected children [45].…”

Advances in mass spectrometry imaging for toxicological analysis and safety evaluation of pharmaceuticals

“…In addition to the targeted analysis of drug accumulation in organs, the comprehensive studies of drug distribution in the body from a temporal (absorption, distribution, metabolism, excretion) and spatial (different organs) perspective are important for drug development and safety evaluation (Russo et al, 2018; Satoh et al, 2018). Four drugs of emtricitabine, tenofovir, efavirenz, and rilpivirine are currently used in antiretroviral therapy, but several organ toxicities associated with these drugs were observed in the clinic (Cez et al, 2018; Hammond et al, 2019). As shown in Figure 3A, MALDI‐MSI strategy has been employed to determine whether these four chemicals in murine liver, brain, kidney, spleen, and heart tissues, to understand the distributions in vivo exposure (Seneviratne et al, 2020).…”

The cognitive remediation of attention in HIV-associated neurocognitive disorders (HAND): A meta-analysis and systematic review

“…For example, Underwood et al (2015) found that prolonged treatment with efavirenz (a non-nucleoside reverse transcriptase inhibitor) (NNRTI) and raltegravir (integrase inhibitor) may play a role in HIV-associated cognitive decline and poorer cognitive function in children living with HIV. A cognate study by Hammond et al (2019) found that children in a South African study showed no cognitive gains after receiving efavirenz. The study hypothesised that efavirenz, due to its pharmacokinetic profile (genetically slow metabolites), may be a risk factor for neurotoxicity, leading to the poor neurocognitive outcomes associated with HAND.…”