Effect of First-Line Antituberculosis Therapy on Nevirapine Pharmacokinetics in Children Younger than Three Years Old

Abstract

Nevirapine-based antiretroviral therapy (ART) is one of the limited options in HIV-infected children younger than 3 years old (young children) with tuberculosis (TB) coinfection. To date, there are insufficient data to recommend nevirapine-based therapy during first-line antituberculosis (anti-TB) therapy in young children. We compared nevirapine pharmacokinetics (PK) in HIV-infected young children with and without TB coinfection. In the coinfected group, nevirapine PK was evaluated while on anti-TB therapy and after completing an anti-TB therapy regimen. Of 53 participants, 23 (43%) had TB-HIV coinfection. While the mean difference in nevirapine PK parameters between the two groups was not significant (P > 0.05), 14/23 (61%) of the children with TB-HIV coinfection and 9/30 (30%) with HIV infection had a nevirapine minimum concentration (Cmin) below the proposed target of 3.0 mg/liter (P = 0.03). In multivariate analysis, anti-TB therapy and the CYP2B6 516G>T genotype were joint predictors of nevirapine PK parameters. Differences in nevirapine PK parameters between the two groups were significant in children with CYP2B6 516GG but not the GT or TT genotype. Among 14 TB-HIV-coinfected participants with paired data, the geometric mean Cmin and area under the drug concentration-time curve from time zero to 12 h (AUC0-12) were about 34% lower when patients were taking anti-TB therapy, while the nevirapine apparent oral clearance (CL/F) was about 45% higher. While the induction effect of anti-TB therapy on nevirapine PK in our study was modest, the CYP2B6 genotype-dependent variability in the TB drug regimen effect would complicate any dose adjustment strategy in young children with TB-HIV coinfection. Alternate ART regimens that are more compatible with TB treatment in this age group are needed. (This study has been registered at ClinicalTrials.gov under identifier NCT01699633.).

Keywords: CYP2B6 genotype; children; coinfection; human immunodeficiency virus; nevirapine; pharmacokinetics; tuberculosis.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Mean nevirapine plasma concentration plotted by sampling time after dosing. (A) Plots for all participants in each treatment group; (B) plots for TB-HIV-coinfected children who had paired samples on and off antituberculosis therapy. Error bars represent standard errors of the means.

FIG 2

Nevirapine pharmacokinetic parameters in HIV-infected children by CYP2B6 516G>T genotype. Differences in median nevirapine Cmax, AUC0–12, and CL/F between HIV and TB-HIV groups were significant only for the GG genotype but not the GT or TT genotype. *, P < 0.05; **, P = 0.07.

FIG 3

Nevirapine Cmin and Cmax (A), AUC0–12 (B), and CL/F (C) on and off antituberculosis therapy in 14 TB-HIV-coinfected children with paired samples. The signed-rank test P value for the median change in PK parameters between the two periods (dotted line) is reported.