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

Abstract

(1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3–16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.

CYP3A and CYP2B6 Genotype Predicts Glucose Metabolism Disorder among HIV Patients on Long-Term Efavirenz-Based ART: A Case-Control Study

“…We also showed that cases had significantly elevated HOMA-IR, FSG, FSI, and TG levels than controls, indicating the presence of GMDs. The overall observed genotype and allele frequency proportions were similar to the findings of previous studies from Ethiopia [ 29 , 30 ].…”

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

“…In contrast to the CYP2B6 polymorphisms, the selected ABCB1 SNP (rs3842, c.4036A > G), had no significant influence on [EFV] or [8‐OH‐EFV]. Previous studies in African and European HIV cohorts reported both higher 8,9,11–13 and lower [EFV] 10 in carriers of the minor rs3842 G allele.…”

“…OH-EFV]. Previous studies in African and European HIV cohorts reported both higher8,9,[11][12][13] and lower [EFV] 10 in carriers of the minor rs3842 G allele.Regression analysis for predictors of [EFV] and [8-OH-EFV]/[EFV] interindividual variation excluded the ABCB1 rs3842 SNP, demographic parameters and comedications as explanatory variables, retaining only CYP2B6 rs3745274 and rs28399499 genotypes or inferred CYP2B6 metabolic phenotypes in the final models. Since inference of CYP2B6 phenotypes was based on the combined CYP2B6 genotypes, regression models including either CYP2B6 genotypes or phenotypes, had similar predictive power, accounting for 48 and 35% of the interindividual variability of [EFV] and [8-OH-EFV]/[EFV], respectively.…”

“…By contrast, discordant and opposite effects have been reported on the influence of the selected ABCB1 SNP (rs3842; c.4036G > A) on EFV plasma concentrations. [8][9][10][11][12][13] The peculiar structure of the present-day Brazilian population, especially its extensive admixture of 3 major ancestral roots, namely Native American, European and sub-Saharan African 14 renders inappropriate the extrapolation of pharmacogenetic data derived from other ethnic groups. Recognition of this fact prompted the creation of the Brazilian Pharmacogenetics Network 15 and translated into pharmacogenetic trials in Brazilian cohorts.…”

“…The CYP2B6 SNPs selected for this study, namely rs3745274 (c.516G > T) and rs28399499 (c.983 T > C), encode CYP2B6 isoforms with reduced or null activity, respectively; there is consistent evidence from diverse populations of increased [EFV] and reduced [8‐OH‐EFV]/[EFV] in carriers of variant alleles of these SNPs (reviewed in 7 ). By contrast, discordant and opposite effects have been reported on the influence of the selected ABCB1 SNP (rs3842; c.4036G > A) on EFV plasma concentrations 8–13 …”