Implications of Efavirenz Pharmacogenetics When Switching From Efavirenz- to Dolutegravir-containing Antiretroviral Regimens.
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ABSTRACT:
SUBMITTER: Haas DW
PROVIDER: S-EPMC8130017 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Implications of Efavirenz Pharmacogenetics When Switching From Efavirenz- to Dolutegravir-containing Antiretroviral Regimens.
Haas David W DW Acosta Edward P EP
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20210501 10
Many patients switch from efavirenz- to dolutegravir-based regimens. In a phase 1 dolutegravir-efavirenz interaction study, mean dolutegravir minimum concentration decreased by 60% and 85% among CYP2B6 normal and slow/intermediate metabolizers, respectively. Mean efavirenz half-life was 2.7 times greater in slow vs normal metabolizers. Slow metabolizers will experience more prolonged subtherapeutic dolutegravir concentrations. ...[more]
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Project description:BackgroundUnwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood.MethodsWe utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs.ResultsIn the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex.ConclusionsAmong patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.
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Project description:ObjectivesTo determine if double-dose levonorgestrel emergency contraception (EC) in combination with efavirenz or rifampicin, 2 drugs known to decrease levonorgestrel exposure, resulted in similar pharmacokinetics compared to standard-dose levonorgestrel EC without drug-drug interactions.Study designWe conducted a phase 2, open-label, multicenter, partially randomized, 4 parallel group trial in pre-menopausal females ≥16 years old without an indication for EC and not on hormonal contraception. Participants on dolutegravir-based antiretroviral therapy (ART) received levonorgestrel 1.5 mg (control group); those on rifampicin-containing tuberculosis therapy received levonorgestrel 3 mg; those on efavirenz-based ART were randomized 1:2 to levonorgestrel 1.5 mg or 3 mg. Plasma was collected through 48 hours post-dose to assess levonorgestrel pharmacokinetics. Area under the concentration-time curve (AUC) over 8 hours was the primary outcome. Levonorgestrel pharmacokinetic parameters were compared between groups using geometric mean ratios (GMR) with 90% confidence intervals.ResultsThe median (Q1, Q3) age for all participants (n = 118) was 34 (27, 41) years and BMI was 23.2 (20, 26.3) kg/m2. Participants receiving levonorgestrel 1.5mg plus efavirenz (n = 17) had 50% lower AUC0-8h compared to the control group (n = 32) [0.50 (0.40, 0.62)]. Participants receiving levonorgestrel 3 mg had a similar AUC0-8h when receiving either efavirenz (n = 35) [0.99 (0.81, 1.20)] or rifampicin (n = 34) [1.16 (0.99, 1.36)] compared to control. Levonorgestrel 3 mg resulted in similar or higher maximum concentration with either efavirenz [1.17 (0.96, 1.41)] or rifampicin [1.27 (1.09, 1.49)] compared to the control group.ConclusionsDoubling the dose of levonorgestrel EC successfully increased levonorgestrel exposure over the first 8 hours in participants receiving either efavirenz-based ART or rifampicin-containing tuberculosis therapy.ImplicationsAdjusting levonorgestrel emergency contraception from 1.5 mg to 3 mg improves levonorgestrel pharmacokinetic exposure in participants receiving either efavirenz-based antiretroviral regimens or rifampicin-containing tuberculosis therapy. These data support guideline recommendations to double the dose of levonorgestrel emergency contraception in persons on medications that decrease levonorgestrel exposure by inducing levonorgestrel metabolism.
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