Abstract
Efavirenz-based combination antiretroviral-therapy (cART) is the recommended regimen during tuberculosis (TB) therapy. In a multi-national parallel prospective-cohort study, we investigated the impact of population and pharmacogenetic variations for efavirenz pharmacokinetics, auto-induction, and immunologic outcome during antituberculosis treatment. A total of 921 treatment-naïve HIV patients with (196 Ethiopians and 231 Tanzanians) or without TB co-infection (285 Ethiopians and 209 Tanzanians) were enrolled and treated with efavirenz-based cART. TB-HIV patients started rifampicin-based anti-TB therapy 4 weeks before cART. Efavirenz plasma concentrations were measured on the 4th and 16th weeks of cART. Genotyping for CYP2B6, CYP3A5, ABCB1, UGT2B7, and SLCO1B1 was done. CD4 cells-count was measured at baseline, 12th, 24th, and 48th weeks of cART. Among HIV-only cohort, plasma efavirenz concentration and median CD4 cell count were significantly higher in Tanzanians than Ethiopians, and both CYP2B6 genotype and population-variation were significant predictors of efavirenz plasma concentration. Within-population analyses indicated a pronounced efavirenz autoinduction in Tanzanians as reflected by a significant decrease of plasma efavirenz concentration over time (p = 0.0001), but not in Ethiopians. Among TB-HIV cohort, there were no significant between-population differences in plasma efavirenz concentrations or CD4 cell-recovery, and CYP2B6 genotype but not population-variation was a significant predictor of efavirenz plasma exposure. In Tanzanian patients, short-term anti-TB co-treatment significantly reduced the mean plasma efavirenz concentration in CYP2B6*1/*1 genotype at week-4 (p = 0.005), but not at week-16 of cART. In Ethiopian patients, anti-TB cotreatment increased the mean plasma efavirenz concentration among CYP2B6*6 carriers at week-4 (p = 0.003) and week-16 (p = 0.035) of cART. In general, long-term anti-TB co-treatment increased plasma efavirenz concentration at week 16 of cART in both Ethiopians and Tanzanians being higher in CYP2B6*6/*6 > *1/*6 > *1/*1 genotypes. In TB-HIV patients, baseline body mass index (BMI), viral load, and WHO clinical-stage but not genotype, population-variation, or efavirenz concentration were significant predictors of immunologic outcome at week-48. In summary efavirenz auto-induction, pharmacokinetics, and the immunologic outcome are influenced by population-variation, anti-TB co-medication, and CYP2B6 genotype. CYP2B6 genotype is a significant predictor of efavirenz plasma exposure regardless of population-variation or antituberculosis co-treatment, but population-variation is insignificant during antituberculosis treatment. CYP2B6 genotype, population, and geographic differences need to be considered for efavirenz dosage-optimization.
Highlights
Tuberculosis (TB) continues to be the most common cause of mortality among patients infected with human immunodeficiency virus (HIV)
A total of 921 treatment naïve HIV patients with or without TBHIV coinfection were enrolled in a multi-national parallel prospective cohort study: 427 TB-HIV co-infected patients (196 in Ethiopia and 231 in Tanzania) and 494 HIV patients without TB coinfection (285 in Ethiopia and 209 in Tanzania)
Our result indicates different efavirenz plasma exposure and immunologic outcome profiles between Ethiopians and Tanzanian HIV patients depending on the presence or absence of antituberculosis co-medication
Summary
Tuberculosis (TB) continues to be the most common cause of mortality among patients infected with human immunodeficiency virus (HIV) The burden of this dual global epidemic of HIV and TB is extremely high in sub-Saharan Africa with the World Health Organization (WHO) estimating 86% of the deaths related to HIV associated TB coming from this region (WHO, 2017). Effective treatment for both TB and HIV diseases simultaneously poses numerous challenges because of potential interactions between antituberculosis and antiretroviral, clinical deterioration from immune reconstitution inflammatory syndrome, overlapping adverse events, and high medication burden (Tiberi et al, 2017). Patients homozygous for the defective CYP2B6*6 variant allele, which is more common among African populations as compared to Caucasians, tend to experience higher levels of efavirenz when it is co-administered with rifampicin (Kwara et al, 2011)
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