Project: Impact of dolutegravir-based antiretroviral regimen on the pharmacokinetic profile and placental penetration of piperaquine administered for preventive treatment of Malaria among pregnant women in Malawi

Acronym	PENETRATE (Reference Number: TMA2017CDF-1897)
Duration	01/09/2018 - 31/08/2021
Project Topic	Background: Dihydroartemisinin-piperaquine (DP) has been identified as an effective alternative to sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) in areas where SP resistance is high. In malaria endemic settings in Africa, human immunodeficiency virus (HIV) infection is also highly prevalent and HIV-infected pregnant women are on antiretroviral therapy (ART) and trimethoprim-sulphamethoxazole, to which resistance is increasingly reported. Recent evidence has shown that the current efavirenz based ART reduces exposure below purported efficacious concentrations of piperaquine, the longer acting partner drug of DP, during IPTp, and different dosing regimens for DP have been suggested. Due to safety and drug-interaction concerns of efavirenz based ART, a number of countries in malaria endemic settings are planning to adopt dolutegravir-based ART regimen for first-line treatment. However, there are recent potential concerns of possible dolutegravir associated neural tube defects among children born to women who were on dolutegravir-based ART at the time of conception or were exposed to it during first trimester of pregnancy. This has prompted national HIV programmes to delay rolling out of dolutegravir in women of child bearing potential and for first line ART initiation during pregnancy, with the view of revising this position when more safety data is available. This implies that HIV infected pregnant women would in the near future be on either efavirenz- or dolutegravir-based ART regimens. As countries aim to optimize the new proposed DP regimens for when coadministered with standard ART regimens (whether efavirenz or dolutegravir-based ART), there is a genuine need to understand their impact on the pharmacokinetic profile and placental penetration of the promising IPTp candidate, dihydroartemisinin-piperaquine. Aim:The PENETRATE study will determine the impact of standard ART on the pharmacokinetic profile and placental penetration of piperaquine administered as DP for intermittent preventive treatment of malaria in pregnant women in Malawi. Methods: A pharmacokinetic cohort study, nested within two large on-going EDCTP-MRC funded clinical trials (IMPROVE I & II), will be conducted in two steps among HIV uninfected and matched HIV-infected pregnant women commenced on dolutegravir-based ART in Malawi. In step I, intensive plasma blood samples will be collected over a period of 28 days following intake of DP to compare pharmacokinetic (PK) parameters of piperaquine between the HIV-infected and HIV-uninfected groups. In step II, two similar separate cohorts of women from the IMPROVE trials will have a paired maternal plasma and umbilical cord vein sample collected at delivery to compare the ratio of maternal/umbilical cord piperaquine concentrations between HIV-uninfected and HIV infected pregnant women on standard ART. EDCTP scope: The PENETRATE study will promote the career development of the lead investigator by allowing him to strengthen his basic and clinical pharmacology skills while acquiring skills in applied and clinical pharmacometrics, and establishing himself as an independent scientist in Malawi. Expected impact: Findings of the PENETRATE study will inform accurate dosing of DP when co-administered with standard ART, thereby informing the dosing regimen of dihydroartemisinin-piperaquine in the IMPROVE II clinical trial and contributing to the pool of evidence needed by WHO to recommend use of DP for IPTp among HIV-uninfected and -infected pregnant women on standard ART in Sub-Saharan Africa.
Network	EDCTP2
Call	Career Development Fellowships 2017

Project partner

Number	Name	Role	Country
1	University of Malawi, College of Medicine	Coordinator	Malawi