Background: Efavirenz (EFV) is the backbone of first-line antiretroviral therapy (ART) for HIV-1 infection in most low- and middle-income countries (LMIC). Isoniazid (INH) is recommended as TB preventive therapy for all individuals (including pregnant women) living with HIV in TB-endemic LMIC. A secondary metabolic pathway for efavirenz, CYP2A6, is inhibited by INH, creating a potential drug-drug interaction. We report the interaction of EFV and INH during pregnancy and postpartum.
Methods: Pregnant women 14-34 weeks gestation, infected with HIV, on/starting ART, were recruited from eight LMIC into a phase-IV randomized double-blind placebo-controlled trial (IMPAACT P1078). The study had two arms: early (at enrollment) and deferred initiation (at 12 weeks post-partum) of INH 300mg daily for 28 weeks. Women underwent intensive PK sampling (before INH/Placebo dosing and 1, 2, 4, 6, 8, 12 h after), or sparse PK sampling (~2 h post dose) at ≥ 2 weeks after recruitment and again at 12-21 weeks after delivery. CYP2B6 genotypes that predict EFV exposure were determined. EFV PK was described by a two-compartment disposition model and elimination with a liver model.
Results: EFV concentrations from 21 intensively PK-sampled and 767 sparsely PK-sampled women were included. Median weight, age, and gestational age at enrollment were 67kg (range 38-166), 29years (18-45), and 28 weeks (14-34), respectively. CYP2B6 slow, intermediate and normal metabolizers had oral clearances of 2.74, 9.90 and 14.1 L/h, respectively. After adjusting for CYP2B6 genotype and weight, pregnancy increased EFV clearance by 17% (p< 0.001). INH decreased EFV clearance by 8% in normal metabolizers and 14% in slow and intermediate metabolizers (p< 0.001) regardless of pregnancy status.
Conclusions: Pregnancy increased plasma EFV clearance while INH decreased plasma EFV exposure, especially in intermediate and slow metabolizers. The clinical implications of these interactions warrant further investigation.