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Social and Genetic Challenges to Effective Malaria Treatment in Southeast Asia

Sunday 22 March 2015, 0900 – 1100, Lecture Theatre 5

Philip Kreager
University of Oxford

Philip Kreager
University of Oxford

Programmes to treat and limit the spread of malaria are at a cross-roads. Existing pharmaceutical treatments show worrying signs of declining efficacy, and there is a real danger that incomplete and incorrect usage, together with social and economic obstacles to proper treatment, are creating conditions in which the disease may mutate into forms that are no longer treatable. New malarial medicines, currently in advanced clinical trial, may suffer the same fate as existing treatments if programmes to ensure correct usage are not put in place.  This panel reports state-of-the-art research on malaria and the social contexts that lead to incorrect or non-treatment, including findings of ongoing and early stage projects. It also reviews new methodologies being used to improve our understanding of the issue.   Four areas of concern will be highlighted:  the threat posed by migration as a major vector facilitating infection, and the role of effective mapping of incidence in disease control; that current misuse of certain treatments is dangerous and even fatal for certain phenotypes, and what steps may be taken to avoid this; how better knowledge of social, cultural and economic factors can identify vulnerable groups and help to design projects to overcome obstacles to proper treatment; and the need for historical knowledge of malarial control strategies applied in the era before advanced pharmaceutical treatment, since the significant reduction of the disease achieved by these programmes in the absence of advanced treatments is likely to contain lessens for dealing with the social, health, and economic dimensions of the problem today.


Paper 1: Population Movements and Their Impact on Malaria in Indonesia

Iqbal RF Elyazar
Eijkman-Oxford Clinical Research Unit

Controlling and eliminating malaria in Indonesia is a challenging endeavor. Evidence-based strategic plans should be critically formulated to overcome a complex mosaic of infection risk across the 5000-km long archipelago of thousands of islands and distinctive habitats. About 60% of Indonesians live on the islands of Java and Bali where malaria-free and low risk of infection zones occur. However, sustaining this achievement and preventing the re-introduction of malaria will be very difficult. Population movements incur substantial risk of importing and re-establishing malaria transmission on islands that have eliminated malaria.

This project is designed to comprehensively inform the national evidence-based malaria control strategy of reaching the pre-elimination stage by 2020, and freeing the country of malaria by 2030. Quantifying population movements, along with understanding their geographic and demographic dimensions, will be key to combating threats to sustained elimination. Knowing the importation risks, high risk visit periods, and the most important paths of malaria importation, will allow malaria control authorities to design interventions that can reduce transmission in all regions that are primary sources of infected travelers. Techniques to estimate specific patterns and numbers of human movements using mobile phone usage data among the islands is explored in order to identify specific and high priority threats to elimination.

The leading telecommunication providers in Indonesia are being approached to gather mobile phone data usage from over 170 million subscribers. Data assembled over a 12 month period is necessary to allow for capturing the dynamic period of risk.


Paper 2: G6PD Deficiency and Primaquine Therapy in the Era of Global Malaria Elimination

Ari W. Satyagraha
Eijkman Institute for Molecular Biology

Primaquine, as the only drug that prevents relapse of P. vivax and P. ovale infections and as a very potent gametocytocide for P. falciparum, plays a central role in Indonesia’s malaria elimination program. WHO has recommended several primaquine dosages to be used as hypnocytocidal (0.5 mg/kg for 14 days) or as gametocytocidal (0.75 mg/kg in combination with ACT) treatment, which has been implemented to some degree by different countries in which malaria is endemic. However, despite its potency, primaquine is considered “unsafe” for glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, since it can cause mild to severe hemolysis, acute renal failure and death if not properly treated. G6PD plays an important role in protecting red cells against oxidative damage as the first and limiting enzyme in the pentose phosphate pathway, the only pathway that provides anti-oxidative protection in these cells. Degree of severity in G6PDd individuals depends on the dose, type of G6PD variants, and exposure to other oxidative agents. Thus, characterizing the type of G6PD variants, as well as determining the prevalence of G6PD deficiency, is important in designing primaquine therapy strategies to avoid unnecessary hemolysing of malaria patients living in endemic areas. In our on-going study, we observed direct correlation between malaria endemicity with G6PDd prevalence (0.63% to 40.5%), in which most of the variants discovered fall into the severe type in which G6PD activity is <10% of normal. Genotyping G6PD variants from different ethnic groups across Indonesia showed different patterns from west to east: Vanua Lava (17303T>C) is the dominant phenotype in the east, compared to the more heterogeneous western part of Indonesia, which is comprised of mild to severe phenotypes (Murcia 16578 A>G, Mediterranean 18154 C>T, Chatham 16513 G>A, Viangchan 19451 G>A and Vanua Lava). This result may help the Indonesian health department to plan a strategic malaria treatment that is region specific.


Paper 3: Factors affecting treatment-seeking behaviour in a malaria-endemic area in eastern Indonesia: a cross-sectional study

Dewi Ismajani Puradiredja
Oxford ISSF Wellcome Programme

Lenny L. Ekawati
Eijkman-Oxford Clinical Research Unit

Background: Malaria continues to be a severe public health problem in Indonesia, with approximately 130 million Indonesians living at risk. In the absence of effective prevention, appropriate treatment-seeking behaviour and accessibility of adequate health services are essential for decreasing the risk of severe complications, deaths and transmission of the disease. This cross-sectional study aimed to investigate factors affecting treatment-seeking in 3 malaria-endemic communities in Alor district in eastern Indonesia.

Methods: Mixed (qualitative/quantitative) methods were employed, including: (1) a GPS-aided household census to enumerate the study population (n=3077); (2) ethnographic research, including observations and semi-structured interviews with community members and health care providers (n=44); (3) a structured community-based survey (n=350) and semi-structured interviews with health care providers (n=6), and a check of diagnostic facilities and malaria treatment records at the field sites.

Results: Guided by a socio-ecological framework, thematic content analysis identified different spheres of influence on malaria-treatment seeking behaviour, including local (mis-)understandings about the disease and its transmission, as well as competing socio-economic concerns at the individual and social levels, and the lack of adequate diagnostic and treatment facilities at the structural level. Multiple regression analyses was used to explore associations of personal and socio-economic correlates with appropriate treatment-seeking behaviour.

Conclusions: This study highlights the needs of populations in malaria-endemic areas in eastern Indonesia; to address them we must understand the complexity of multiple interacting factors, avoiding simplified assumptions about obstacles to appropriate treatment-seeking behaviour.


Paper 4: Invisible Crises, Neglected Histories: Southeast Asia in Global Context

Mark Harrison
University of Oxford

This paper introduces a major new project (funded by the Wellcome Trust) which will begin later this year in Oxford and which involves collaboration between researchers from a number of disciplines and with universities in the Southeast Asian region. The project will examine the problem of malaria in Asia as whole, but Southeast Asia is one of the main focal points, partly because it is a dynamic region as far as malaria is concerned and partly because the history of the disease in that region has much to offer the world as a whole.

One premise of the project is that malaria outside Africa has been largely forgotten by the global community. This is partly because Africa has suffered the heaviest burden of malaria mortality and the social economic consequences which follow from that. However, the number of malaria cases in Asia has been greatly underestimated, as has their impact on the health, livelihoods and economies of the countries most affected. Vivax malaria (the dominant form in Asia) is thought to be relatively benign despite an increasing amount of evidence to the contrary.

Rather harder to explain is the fact that there are aspects of malaria – such as its stubborn adherence to and resurgence in urban environments – which remain practically invisible within nations. Asia – and Southeast Asia in particular – is also currently the source of worrying developments which threaten to become more widespread; namely, resistance to arteminsinal drugs and the emergence of new species of parasite (P. knowlesi) among humans.

These problems have complex historical roots and their solution is more likely if historians work together with malariologists, anthropologists and public health workers in order to understand the complex dynamics of the disease. History can also help to retrieve and evaluate interventions which have been largely forgotten, but which may offer useful solutions to present-day problems. Southeast Asia saw several important innovations, for example species sanitation, which worked effectively in some former British and Dutch colonies. Historians, epidemiologists and others will work together to assess these interventions and where appropriate bring them back as viable policy options.