IPTp with dihydroartemisinin-piperaquine and azithromycin for malaria, sexually transmitted and reproductive tract infections in HIV-infected pregnant women in Kenya and Malawi: a multi-centre 3-arm placebo-controlled trial

In malaria-endemic Africa, HIV and malaria conspire to increase the risks of adverse pregnancy outcomes. For HIV-infected pregnant women, WHO recommends daily cotrimoxazole (CTX) for malaria chemoprevention and prophylaxis against opportunistic infections. However, cross-resistance with sulfadoxine-pyrimethamine (SP) and high levels of antifolate resistance threaten the antimalarial effect of CTX. Recent trials in HIV-infected pregnant women who received daily CTX plus intermittent preventive treatment in pregnancy (IPTp) with mefloquine showed that chemoprevention with an effective antimalarial markedly reduces the risk of malaria compared to CTX alone, though mefloquine was poorly tolerated.

The long-acting combination of dihydroartemisinin–piperaquine (DP) is well tolerated and has shown promise as IPTp in HIV-negative women in East Africa. Monthly DP chemoprevention has also been explored in HIV-infected women on daily CTX in Uganda, but the study was inconclusive due to very low malaria transmission. Additionally, a clinically relevant drug-drug interaction between DP and efavirenz (EFV) was found to reduce DP drug levels. In line with WHO recommendations, many African countries are transitioning from EFV-based to dolutegravir (DTG)-based combination antiretroviral therapies (cARTs). DTG-based cARTs are now recommended by WHO as the preferred first-line regimen in the second and third trimesters of pregnancy, and no drug-drug interaction is expected between DTG and DP. This context provides an opportunity to re-evaluate DP-based malaria chemoprevention in HIV-infected pregnant women receiving daily CTX and DTG-based cARTs.

Study progress

Main Trial and Nested Studies: Data collection for the main trial in Kenya was completed on July 27, 2021 and in Malawi on August 31, 2021. A total of 904 participants were enrolled, with 873 completing follow up. All samples collected in Kenya and Malawi for the primary endpoints (Malaria PCR) are being processed centrally in Kenya between January to March 2022. Data analysis and reporting is planned for August 2022.
Acceptability Studies: Qualitative data collection in Kenya was completed on July 23, 2021 and in Malawi on October 25, 2021. In total, 54 in-depth interviews (25 health workers, 29 pregnant women) and 10 focus group discussions (pregnant women in each arm of the trial) were done. Transcription was completed in January 2022. Data analysis and reporting is planned by December 2022.
Cost Effectiveness Analysis: The collection of the patient-level cost data was completed in conjunction with the IMPROVE feasibility study in Kenya (TRIA-2015-1076-IMPROVE), as originally planned and the facility costing component has been completed. Data cleaning and analysis will be completed by June 2022
Pharmacokinetic studies: Plasma samples collected from pregnant women in Kenya and Malawi are undergoing quantification of antimalarials, antibiotics and ARTs is in process as well as quantification of the effect of drug-drug interactions between IPTp-DP/DP+AZ and ARTs using population PK/PD modelling. Results from the analysis are expected in March 2022.

Dissemination

Since 2017, we have worked with national level stakeholders and collaborators to discuss and share research progress. We have held two annual general meetings attend by IMPROVE 1 and IMPROVE-2 collaborators to ensure synergies between the two studies being undertaken in Kenya and Malawi. Since early 2020, dissemination activities have been paused due to the SARS/Covid19 Pandemic, however with restrictions now easing dissemination of preliminary research results are now being planned. We will first present results to the study population, and then to the local and national health authorities in Kenya and Malawi. The results will subsequently be presented to the WHO via its Guideline Development Group on malaria in pregnancy, and at international scientific conferences and symposia. The study will generate rich datasets which will be exploited systematically by publishing a series of research articles between June and December 2022.

Impact

All impact components described in the Improve EDCTP grant Agreement for the IMPROVE study in HIV-positive women are still equally relevant and applicable. However, the potential importance of this study is likely to have increased further following the recent changes from efavirenz to dolutegravir-based ARTs in many counties in Africa.

Clinical Trials - Project details

Drug Resistance
Drug-based Strategies
Vulnerable Populations

Jul 2017 — Dec 2022

$3.63M

Kenya
Malawi
United Kingdom