Pregnancy increases the risk of progressing from latent tuberculosis infection (LTBI) to active TB. A 3-month TB-prevention regimen of weekly isoniazid and rifapentine (3HP) shows excellent safety and adherence in non-pregnant people, including those with HIV. We hypothesized that the pharmacokinetics (PK) of rifapentine (RPT) in pregnant women taking 3HP would be comparable to non-pregnant adults and well-tolerated.
IMPAACT 2001 is a Phase I/II study evaluating the PK and safety of 3HP among pregnant women with or without HIV, who had LTBI or a household contact with active pulmonary TB (NCT02651259). Sites were in Haiti, Kenya, Malawi, Thailand, and Zimbabwe. Cohort 1 had dosing and PK sampling in the 2nd and 3rd trimesters; Cohort 2 in the 3rd trimester and postpartum. Isoniazid and RPT were provided at standard doses of 900mg weekly. PK samples were collected with the 1st (predose, 0.5h, 1h, 2h, 4h, 5h, 8h, 12h, 24h, 48h, 72h post-dose) and 12th doses (predose, 1h, 4h, 24h, 48h post-dose). Primary objectives were to estimate the population PK of RPT during pregnancy and post-partum using non-linear mixed effects modeling, and to describe maternal-infant safety outcomes.
We enrolled 50 pregnant women, 25 per cohort. Twenty women had HIV; all were taking efavirenz (EFV)-based antiretroviral therapy (median CD4:510 cells/mm3). All women completed the 3HP regimen. There were no drug-related SAE and no cases of active TB in women or their infants. There was one maternal and fetal death by abruptio placentae from trauma. Among women without HIV, oral clearance (CL/F) of RPT was 36% lower during pregnancy (1.24 L/h) than post-partum (1.68 L/h), with an area under the concentration-time curve (AUC) of 736 and 618 mg*hr/L, similar to historical non-pregnant controls. In women with HIV, CL/F was the same during pregnancy and postpartum (1.60 vs.1.61 L/hr), which was 34% higher (p<0.001) compared to pregnant women without HIV, resulting in a lower AUC of 512 mg*h/L.
Pregnancy does not appear to increase RPT clearance; thus, there is no need for dose adjustment of 3HP in pregnancy. Among women with HIV taking EFV, however, clearance of RPT was higher than expected during pregnancy. Exposures remained in the expected therapeutic range. Initial tolerability and safety results from this small trial are encouraging, given limited options for TB prophylaxis in pregnancy, but larger studies will be needed to characterize its safety in pregnancy definitively.