Intermittent preventive treatment with dihydroartemisinin-piperaquine: a new malaria strategy to prevent adverse birth outcomes in Papua, Indonesia

Reducing the adverse outcomes of malaria in pregnancy in Indonesia

The control of malaria in pregnancy in Indonesia, where approximately 10% of pregnant women get infected with malaria, could receive a potential boost through a new study in Papua, Indonesia. A partnership between the Liverpool School of Tropical Medicine (UK) and the Timika Research Facility in Papua Indonesia will conduct a holistic evaluation of a promising new drug-based regimen for preventing malaria and its harmful effects in pregnancy.

When pregnant women contract malaria, the infection can have devastating consequences for pregnancy, resulting in fever which may trigger the preterm onset of labour or even pregnancy loss. It is also possible for women to be infected without showing any outward signs or symptoms, yet if these infections are undetected and left untreated, they can cause severe anaemia in the mother and can interfere with the growth of the fetus leading to low birth weight, which makes babies more vulnerable to infections, growth retardation and dying during the first year of life.

The new study will support the Indonesian Ministry of Health to identify the best way to deliver a new preventive regimen for the control of malaria in pregnancy called intermittent preventive treatment or IPT for short. IPT is used in most countries in Africa but not yet in Asia. With this IPT strategy, pregnant women without symptoms of malaria attending routine antenatal care in selected health facilities in Papua, Indonesia, will receive monthly treatment with a long-acting antimalarial drug called dihydroartemisinin-piperaquine (DP) that provides four weeks of prophylaxis after each dose. Currently women are screened for malaria at their first antenatal care visit and women are treated with DP only if tested positive. In the new strategy, women will receive the drug as monthly prophylaxis without prior blood testing for malaria parasites.

A recent trial in Indonesia has shown that this intervention, when taken as directed, is very effective in preventing malaria in expectant mothers. However, the concept of using drugs for prevention by women who do not have malaria symptoms is new to this region. Indeed, this would be the first time that the IPT strategy would be used in South East Asia. The study is designed to find the best ways for the Ministry of Health to introduce and deliver this new intervention and use stepwise quality improvement approaches to understand what worked, for whom, and why during each step in the implementation phase to help improve delivery of the new intervention and quality of service provision on an ongoing basis. Opportunities to bring the intervention close to the community through health posts where most women receive antenatal care will be strengthened. The study will also determine the costs and cost-effectiveness of the new strategy, compared with the current strategy, to inform policy decision making for malaria prevention among pregnant women in Indonesia. This will also be of relevance to other parts of South East Asia. It is anticipated that the study, by increasing the effectiveness of malaria prevention, has the potential to increase the provision and uptake of additional ANC services that prevent other causes of adverse birth outcomes in pregnancy. The final study results will be shared with the local offices of the Ministry of Health and the National malaria, and reproductive health departments in Indonesia to inform policy decision making for rolling out the strategy. The study will thereby contribute to improved outcomes for mothers and their infants in Indonesia, whose quality of life, health and creative output will be enhanced.

This will be a 32-month study, six months for study preparation, 22 months field work, data collection and data processing, and four months to conclude analysis and reporting.

Malaria in pregnancy is a major cause of maternal and neonatal death in Papua, Indonesia. In our recent trial in Papua we showed that monthly intermittent preventive treatment (IPTp) with the long-acting artemisinin-based combination dihydroartemisinin-piperaquine (DP) among pregnant women in the second and third trimester protected with long-lasting insecticide-treated nets was safe, tolerable and efficacious compared to the current policy of single screening at ANC booking and treatment of RDT-positive cases. The Ministry of Health (MOH) Indonesia now plans to pilot the strategy in the routine health system in Papua, Indonesia. This study will assess the programme effectiveness of IPTp-DP delivery through antenatal care services and women's adherence to the monthly 3-day DP treatment regimen in a 'real life' setting. The study will be undertaken in nine community health centres in the lowlands and their associated health posts in Timika city. In the first 18 months, we will support MOH to implement the intervention using quality improvement (QI) approaches to continuously strengthen service delivery, uptake and adherence through plan-do-study-act cycles. We will also support the MoH to collect safety data for pharmacovigilance. A mixed-methods evaluation will be conducted towards the end of the pilot using exit interviews to assess delivery effectiveness, home visits to assess adherence, and qualitative research to explore provider perceptions of the drivers of successful integration, scalability and user acceptability. The primary outcome is adherence and delivery effectiveness, defined as the proportion of pregnant women who receive the first dose of IPTp-DP by DOT at ANC and have the correct number of DP tablets for subsequent doses on exit, and when visited at home have verified they completed the course. We will also determine cost-effectiveness compared to current policy and the cost of implementing IPTp-DP from the provider (MOH) perspective.

Community: The ultimate beneficiaries will be mothers and their infants (see Pathways to Impact).

National policymakers and stakeholders: The National Malaria Control Programme in Indonesia sets policy for malaria control with input from Maternal and Child Health, WHO, UNICEF and other experts. MOH Indonesia has invited our research team to support the pilot implementation of the new malaria chemoprevention strategy to prevent adverse pregnancy outcomes in Papua, Indonesia. This study will provide essential evidence for the most promising delivery strategies to roll-out this new strategy. The addition of quality improvement (QI) approaches will identify what works, for whom, and why during the first year of the pilot providing actionable evidence to optimise roll out and strengthen the quality of service delivery. Costing analyses will provide essential information related to financing requirements and economic implications (i.e. change in resource use). Results will be discussed at a stakeholders' meeting involving National, Provincial and District Health Offices, partners and local communities. Based on emerging consensus, policy guidelines will be prepared and disseminated. It is anticipated that policy impact will occur within 6-12 months after study completion and will result in increased effectiveness of malaria prevention, and potentially also increased uptake of other ANC services, leading to improved outcomes for mothers and their infants in Indonesia, whose quality of life, health and creative output will be enhanced.

Regional Level: The Asia Pacific Malaria Elimination Network (APMEN) and regional offices of WHO are key beneficiaries. The results from the IPTp-DP trial in Indonesia were discussed with 110 MOH representatives from 18 countries in Asia/Pacific at a regional APMEN meeting held in collaboration with WHO-WPRO and -SEARO in 2017. Given the interest in the original trial, the findings of this study would be important for the development of similar strategies for other Asian countries with moderate-to-high transmission, such as Papua New Guinea, and in sub-Saharan Africa.
WHO and International policy makers: WHO and other international policy makers are important beneficiaries as the bodies who set global policy and prioritise future investments in health. The PI and the site PI provide regular advice to the WHO evidence review group meetings and ad hoc WHO Technical Consultations on malaria in pregnancy, and the co-PI is on ad hoc consultations on malaria chemotherapy. LSTM investigators are also active members of the global Roll Back Malaria Working Group on malaria in pregnancy.

CORE Group: Our research will inform the work of CORE group, a network of 50+ NGOs that generates collaborative actions and learning to improve community-focused public health practices with particular emphasis to women of reproductive age and children under 5.

UK Government: The UK Government has made tackling malaria in the developing world a priority. This research will contribute directly to UK policy, and the UK's achievements will contribute directly to reaching international targets set out in the WHO Global technical strategy for malaria 2016-2030 call for a drop in malaria case incidence and death rates of at least 40 per cent by 2020 and the UN Sustainable Development Goals 3, 5 and 10.
Researcher and health worker capacity: Research capacity in the Indonesian research partner institutes will be enhanced by providing training and mentorship on implementation and health systems research methods for research staff and students. Health worker capacity will also be strengthened through training on the administration of IPTp.

Commercial private sector: The manufacturers of DP will also benefit from the results of the study by generating evidence for use of DP as IPTp in pregnancy in SE Asia.