Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis

Abstract

Objective: In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions.

Methods: Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters.

Results: Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls.

Conclusion: CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Fig. 1

Relationships between human genetic variants and log levonorgestrel clearance among women in A5375. Left panel: relationship of CYP2B6 metabolizer group with plasma levonorgestrel clearance in women with HIV on efavirenz, who received a single 1.5 mg or 3 mg oral dose of levonorgestrel. Middle panel: relationship of NAT2 acetylator group with plasma levonorgestrel clearance in women being treated for tuberculosis with isoniazid and rifampin, and who received a single 3 mg oral dose of levonorgestrel. Right panel: relationship of UGT1A1 genotype with plasma levonorgestrel clearance in women with HIV on dolutegravir, who received a single 1.5 mg oral dose of levonorgestrel. Error bars indicate the median and interquartile range. The markers are unadjusted for BMI or age. The dashed line indicates median log levonorgestrel clearance (1.47) in the dolutegravir control group. P values from multivariable linear regression are shown. DTG, dolutegravir; EFV, efavirenz; INH, isoniazid; Inter, intermediate; LNG, levonorgestrel; RIF, rifampin.

Fig. 2

Relationships between human genetic variants and levonorgestrel AUC_0-8h among women in A5375. Left panel: relationship between levonorgestrel dose and levonorgestrel AUC_0-8h among CYP2B6 normal and intermediate metabolizers in women with HIV on efavirenz, and who received a single 1.5 mg or 3 mg oral dose of levonorgestrel. Panel second from left: relationship between levonorgestrel dose and levonorgestrel AUC_0-8h among CYP2B6 poor metabolizers in women with HIV on efavirenz, and who received a single 1.5 mg or 3 mg oral dose of levonorgestrel. Panel second from right: relationship between NAT2 genotype and levonorgestrel AUC_0-8h among women with tuberculosis on isoniazid and rifampin, and who received a single 3 mg oral dose of levonorgestrel. Right panel: levonorgestrel AUC_0-8h in women with HIV on dolutegravir, and who received a single 1.5 mg oral dose of levonorgestrel. Error bars indicate the median and interquartile range. Clear and gray shaded markers represent 1.5 mg or 3 mg doses of levonorgestrel, respectively. The markers are unadjusted for BMI or age. The horizontal dashed line indicates a median AUC_0-8h in the dolutegravir control group. P values from multivariable linear regression are shown. DTG, dolutegravir, EFV, efavirenz, INH, isoniazid, Inter, intermediate, inter, intermediate, LNG, levonorgestrel, RIF, rifampin.