Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus–Infected Women Receiving Efavirenz. (19th December 2017)

• Record Type: Journal Article
• Authors: Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna; Huang, Liusheng; Natureeba, Paul; Kakuru, Abel; Muhindo, Mary; Nakalembe, Mirium; Havlir, Diane; Kamya, Moses; Aweeka, Francesca; Dorsey, Grant; Rosenthal, Philip J; Savic, Radojka M
• Is Part Of: Journal of infectious diseases. Volume 217:Number 6(2018)
• Page Start: 964
• Page End: 972
• Publication Date: 2017-12-19
• Subjects: intermittent preventive treatment during pregnancy -- dihydroartemisinin-piperaquine -- HIV infection -- drug–drug interaction; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jix660
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract : Dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy; however, HIV-infected women receiving efavirenz-based antiretroviral therapy have low piperaquine concentrations compared with HIV-negative women. Daily low dose DHA-PQ is predicted to maximize protective efficacy and safety of DHA-PQ chemoprevention in this population. 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), <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 ≤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. Clinical Trials Registration: NCT02282293.