Abstract
Nevirapine, a component of antiretroviral therapy (ART) in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 (‘lead-in period’), and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high performance liquid chromatography (HPLC) at days 7, 14 (lead-in period) and 28 (full dose period) after ART initiation amongst HIV-1 infected children initiating nevirapine-based ART in southern India. Among the 20 children (50% male, median age 9 years) included in the study, sub-therapeutic trough plasma nevirapine concentration (<4μg/ml) was seen in 65% (13/20) of children during the lead-in period within two weeks of ART initiation and among 10% of children at 4 weeks during full-dose nevirapine. Adherence was documented as ≥95% in all children by both caregiver self-report and pill count. Median nevirapine concentrations achieved at week 1 was 4.8 μg/ml, significantly lower than 8 μg/ml, the concentration achieved at week 4 (p = 0.034). Virological failure at one year of ART was observed in six children, and was not associated with median nevirapine concentration achieved during week 1, 2 or 4. We conclude that the dose escalation strategy currently practiced among young children living with HIV-1 resulted in significant subtherapeutic nevirapine concentration (≤4μg/ml) during the lead-in period. We call for a closer look at pediatric-focused dosing strategies for nevirapine initiation in young children. Further studies to establish age-appropriate threshold nevirapine concentration are warranted in young children to corroborate the role of therapeutic drug monitoring in predicting virological outcome.
Highlights
Nevirapine was the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA for pediatric use since 1998
To overcome the problem of higher concentration of nevirapine in blood and a subsequent greater probability of drug toxicities, a dose escalation strategy was used, where nevirapine was initiated at a half-therapeutic single daily dose during the first two weeks when metabolism is slower than usual, and after 14 days of therapy, the dose was escalated to the age-appropriate full therapeutic dose administered twice daily [3]
While this strategy appeared to solve the theoretical problem of high plasma drug concentration in the first two weeks of nevirapine initiation, the possibility of sub-therapeutic concentration due to higher nevirapine metabolism in young children was not taken into account [4]
Summary
Nevirapine was the first non-nucleoside reverse transcriptase inhibitor (NNRTI) approved by the FDA for pediatric use since 1998. Auto-induction of nevirapine metabolism generally sets in only by the second to fourth week of treatment initiation, resulting in a 1.5 to 2-fold increase in oral clearance This delayed auto induction can give rise to potentially higher than expected plasma concentrations of nevirapine within the first two weeks [2]. To overcome the problem of higher concentration of nevirapine in blood and a subsequent greater probability of drug toxicities, a dose escalation strategy was used, where nevirapine was initiated at a half-therapeutic single daily dose during the first two weeks when metabolism is slower than usual, (the ‘lead-in period’), and after 14 days of therapy, the dose was escalated to the age-appropriate full therapeutic dose administered twice daily [3]. Studies indicate that nevirapine metabolism in young children aged 8 years was more rapid than that observed in children >8 years, and that younger children required higher doses of nevirapine to achieve therapeutic concentration [5,6,7]
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