British journal of pharmacology · 2020
Early or deferred initiation of efavirenz during rifampicin-based TB therapy has no significant effect on CYP3A induction in TB-HIV infected patients.
СтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Aklillu Eleni, Zumla Alimuddin, Habtewold Abiy, Amogne Wondwossen, Makonnen Eyasu, Yimer Getnet, Burhenne Jürgen, Diczfalusy Ulf
Аннотация
BACKGROUND AND PURPOSE: In TB-HIV co-infection, prompt initiation of TB therapy is recommended but anti-retroviral treatment (ART) is often delayed due to potential drug-drug interactions between rifampicin and efavirenz. In a longitudinal cohort study, we evaluated the effects of efavirenz/rifampicin co-treatment and time of ART initiation on CYP3A induction.
EXPERIMENTAL APPROACH: Treatment-naïve TB-HIV co-infected patients (n = 102) were randomized to efavirenz-based-ART after 4 (n = 69) or 8 weeks (n = 33) of commencing rifampicin-based anti-TB therapy. HIV patients without TB (n = 94) receiving efavirenz-based-ART only were enrolled as control. Plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) ratio, an endogenous biomarker for CYP3A activity, was determined at baseline, at 4 and 16 weeks of ART.
KEY RESULTS: In patients treated with efavirenz only, median 4β-OHC/Chol ratios increased from baseline by 269% and 275% after 4 and 16 weeks of ART, respectively. In TB-HIV patients, rifampicin only therapy for 4 and 8 weeks increased median 4β-OHC/Chol ratios from baseline by 378% and 576% respectively. After efavirenz/rifampicin co-treatment, 4β-OHC/Chol ratios increased by 560% of baseline (4 weeks) and 456% of baseline (16 weeks). Neither time of ART initiation, sex, genotype nor efavirenz plasma concentration were significant predictors of 4β-OHC/Chol ratios after 4 weeks of efavirenz/rifampicin co-treatment.
CONCLUSION AND IMPLICATIONS: Rifampicin induced CYP3A more potently than efavirenz, with maximum induction occurring within the first 4 weeks of rifampicin therapy. We provide pharmacological evidence that early (4 weeks) or deferred (8 weeks) ART initiation during anti-TB therapy has no significant effect on CYP3A induction.
LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
EXPERIMENTAL APPROACH: Treatment-naïve TB-HIV co-infected patients (n = 102) were randomized to efavirenz-based-ART after 4 (n = 69) or 8 weeks (n = 33) of commencing rifampicin-based anti-TB therapy. HIV patients without TB (n = 94) receiving efavirenz-based-ART only were enrolled as control. Plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) ratio, an endogenous biomarker for CYP3A activity, was determined at baseline, at 4 and 16 weeks of ART.
KEY RESULTS: In patients treated with efavirenz only, median 4β-OHC/Chol ratios increased from baseline by 269% and 275% after 4 and 16 weeks of ART, respectively. In TB-HIV patients, rifampicin only therapy for 4 and 8 weeks increased median 4β-OHC/Chol ratios from baseline by 378% and 576% respectively. After efavirenz/rifampicin co-treatment, 4β-OHC/Chol ratios increased by 560% of baseline (4 weeks) and 456% of baseline (16 weeks). Neither time of ART initiation, sex, genotype nor efavirenz plasma concentration were significant predictors of 4β-OHC/Chol ratios after 4 weeks of efavirenz/rifampicin co-treatment.
CONCLUSION AND IMPLICATIONS: Rifampicin induced CYP3A more potently than efavirenz, with maximum induction occurring within the first 4 weeks of rifampicin therapy. We provide pharmacological evidence that early (4 weeks) or deferred (8 weeks) ART initiation during anti-TB therapy has no significant effect on CYP3A induction.
LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.