Chemoprevention with monthly IPTp with dihydroartemisinin-piperaquine for malaria in HIV-infected pregnant participants on daily cotrimoxazole in Kenya and Malawi (IMPROVE-2)

Pregnant women represent a vulnerable population for malaria. HIV-infected women are, particularly at risk. In HIV-infected pregnant women, WHO recommends daily cotrimoxazole (CTX), an antifolate drug, for malaria chemoprevention and prophylaxis against opportunistic infection. However, there is cross-resistance with sulphadoxine-pyrimethamine (SP), and high levels of antifolate resistance threaten the antimalarial effect of CTX. Recent trials with intermittent preventive therapy (IPT) with mefloquine in HIV-infected women on daily CTX, suggested that chemoprevention with an effective antimalarial markedly improves the protection against malaria compared to daily CTX alone. However, mefloquine was not well tolerated. 
The long-acting combination of dihydroartemisinin-piperaquine (DP) is well tolerated and has shown great promise as IPTp in HIV-negative women in East-Africa. Chemoprevention with monthly DP has also been explored in HIV-infected pregnant women on daily CTX in Uganda. Unfortunately, the study was inconclusive because malaria transmission was too low and a clinically relevant drug interaction with efavirenz (EFV) was found reducing the exposure to DP. WHO now recommends dolutegravir (DTG) based combination antiretroviral therapy (ARTs) as the preferred firstline regimen including for pregnant women in the 2nd and 3rd trimester of pregnancy for the prevention of mother-to-child transmission of HIV. As a result, many countries in Africa are now transitioning to DTG-based combination antiretroviral therapy (cARTs). No such drug-drug interaction is expected between DTG and DP. We will, therefore, assess the safety and efficacy of malaria chemoprevention with monthly DP in HIV-infected women on daily CTX and DTG-based cARTs. 

This will be a multi-centre, 2-arm, parallel, placebo-controlled, individually randomised, phase-3, superiority trial in 898 (449 per arm) HIV-infected pregnant women receiving daily CTX and cARTs to compare the efficacy of monthly IPTp-DP (‘CTX-DP’) against monthly placebo-DP (‘CTX-alone’) (allocation ratio 1:1). The study will be conducted in about 8 sites in high malaria endemic and high HIV endemic areas in southern Malawi and western Kenya. These are the same sites in Malawi and Kenya where the trial in HIV-negative women (IMPROVE) will be conducted. 

UK Research and Innovation

Drug-based Strategies
Impact of Interventions
Vulnerable Populations

Oct 2018 — Sep 2021

$3.51M

Kenya
Malawi

Intermittent preventive treatment in pregnancy (IPTp)