Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz

Abstract

Background. A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Methods. Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration > 10 ng/mL for > 95% of the chemoprevention period. Results. PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), lt 1% of women achieved defined protective PQ coverage. Weekly (960 mg PQ) or low-dose daily (320 or 160 mg PQ) regimens achieved protective PQ coverage for 34% and > 96% of women, respectively. All regimens were safe, with lt = 2% of women predicted to have >= 30 msec QTc increase. Conclusions. For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing.