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Abstract Background The radical cure of Plasmodium vivax requires treatment with an 8-aminoquinoline drug, such as primaquine and tafenoquine, to eradicate liver hypnozoite stages, which can reactivate to cause relapsing infections. Safe treatment regimens require prior screening of patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency to avoid potential life-threatening drug induced haemolysis. Testing is rarely available in malaria endemic countries, but will be needed to support routine use of radical cure. This study investigates end-user perspectives in Bangladesh on the introduction of a quantitative G6PD test (SD Biosensor STANDARD™ G6PD analyser) to support malaria elimination. Methods The perspectives of users on the SD Biosensor test were analysed using semi-structured interviews and focus group discussions with health care providers and malaria programme officers in Bangladesh. Key emerging themes regarding the feasibility of introducing this test into routine practice, including perceived barriers, were analysed. Results In total 63 participants were interviewed. Participants emphasized the life-saving potential of the biosensor, but raised concerns including the impact of limited staff time, high workload and some technical aspects of the device. Participants highlighted that there are both too few and too many P. vivax patients to implement G6PD testing owing to challenges of funding, workload and complex testing infrastructure. Implementing the biosensor would require flexibility and improvisation to deal with remote sites, overcoming a low index of suspicion and mutual interplay of declining patient numbers and reluctance to test. This approach would generate new forms of evidence to justify introduction in policy and carefully consider questions of deployment given declining patient numbers. Conclusions The results of the study show that, in an elimination context, the importance of malaria needs to be maintained for both policy makers and the affected communities, in this case by ensuring P. vivax, PQ treatment, and G6PD deficiency remain visible. Availability of new technologies, such as the biosensor, will fuel ongoing debates about priorities for allocating resources that must be adapted to a constantly evolving target. Technical and logistical concerns regarding the biosensor should be addressed by future product designs, adequate training, strengthened supply chains, and careful planning of communication, advocacy and staff interactions at all health system levels.

Abstract Background Many malaria-endemic areas experience seasonal fluctuations in case incidence as Anopheles mosquito and Plasmodium parasite life cycles respond to changing environmental conditions. Identifying location-specific seasonality characteristics is useful for planning interventions. While most existing maps of malaria seasonality use fixed thresholds of rainfall, temperature, and/or vegetation indices to identify suitable transmission months, we construct a statistical modelling framework for characterising the seasonal patterns derived directly from monthly health facility data. Methods With data from 2669 of the 3247 health facilities in Madagascar, a spatiotemporal regression model was used to estimate seasonal patterns across the island. In the absence of catchment population estimates or the ability to aggregate to the district level, this focused on the monthly proportions of total annual cases by health facility level. The model was informed by dynamic environmental covariates known to directly influence seasonal malaria trends. To identify operationally relevant characteristics such as the transmission start months and associated uncertainty measures, an algorithm was developed and applied to model realisations. A seasonality index was used to incorporate burden information from household prevalence surveys and summarise ‘how seasonal’ locations are relative to their surroundings. Results Positive associations were detected between monthly case proportions and temporally lagged covariates of rainfall and temperature suitability. Consistent with the existing literature, model estimates indicate that while most parts of Madagascar experience peaks in malaria transmission near March–April, the eastern coast experiences an earlier peak around February. Transmission was estimated to start in southeast districts before southwest districts, suggesting that indoor residual spraying should be completed in the same order. In regions where the data suggested conflicting seasonal signals or two transmission seasons, estimates of seasonal features had larger deviations and therefore less certainty. Conclusions Monthly health facility data can be used to establish seasonal patterns in malaria burden and augment the information provided by household prevalence surveys. The proposed modelling framework allows for evidence-based and cohesive inferences on location-specific seasonal characteristics. As health surveillance systems continue to improve, it is hoped that more of such data will be available to improve our understanding and planning of intervention strategies.

Abstract The Demographic and Health Surveys (DHS) Program has supported three household Malaria Indicator Surveys (MIS) in Madagascar. The results of 13 key malaria indicators from these surveys have been mapped as continuous surfaces using model-based geostatistical methods. The opportunities and limitations of these mapped outputs were discussed during a workshop in Antananarivo, Madagascar in July 2018, attended by 15 representatives from various implementation, policy and research stakeholder institutions in Madagascar. Participants evaluated the findings from the maps, using these to develop figures and narratives to support their work in the control of malaria in Madagascar.

Abstract Background The Malaria Atlas Project (MAP) has worked to assemble and maintain a global open-access database of spatial malariometric data for over a decade. This data spans various formats and topics, including: geo-located surveys of malaria parasite rate; global administrative boundary shapefiles; and global and regional rasters representing the distribution of malaria and associated illnesses, blood disorders, and intervention coverage. MAP has recently released malariaAtlas, an R package providing a direct interface to MAP’s routinely-updated malariometric databases and research outputs. Methods and results The current paper reviews the functionality available in malariaAtlas and highlights its utility for spatial epidemiological analysis of malaria. malariaAtlas enables users to freely download, visualise and analyse global malariometric data within R. Currently available data types include: malaria parasite rate and vector occurrence point data; subnational administrative boundary shapefiles; and a large suite of rasters covering a diverse range of metrics related to malaria research. malariaAtlas is here used in two mock analyses to illustrate how this data may be incorporated into a standard R workflow for spatial analysis. Conclusions malariaAtlas is the first open-access R-interface to malariometric data, providing a new and reproducible means of accessing such data within a freely available and commonly used statistical software environment. In this way, the malariaAtlas package aims to contribute to the environment of data-sharing within the malaria research community.

Abstract The goal to eliminate malaria from the Asia-Pacific by 2030 will require the safe and widespread delivery of effective radical cure of malaria. In October 2017, the Asia Pacific Malaria Elimination Network Vivax Working Group met to discuss the impediments to primaquine (PQ) radical cure, how these can be overcome and the methodological difficulties in assessing clinical effectiveness of radical cure. The salient discussions of this meeting which involved 110 representatives from 18 partner countries and 21 institutional partner organizations are reported. Context specific strategies to improve adherence are needed to increase understanding and awareness of PQ within affected communities; these must include education and health promotion programs. Lessons learned from other disease programs highlight that a package of approaches has the greatest potential to change patient and prescriber habits, however optimizing the components of this approach and quantifying their effectiveness is challenging. In a trial setting, the reactivity of participants results in patients altering their behaviour and creates inherent bias. Although bias can be reduced by integrating data collection into the routine health care and surveillance systems, this comes at a cost of decreasing the detection of clinical outcomes. Measuring adherence and the factors that relate to it, also requires an in-depth understanding of the context and the underlying sociocultural logic that supports it. Reaching the elimination goal will require innovative approaches to improve radical cure for vivax malaria, as well as the methods to evaluate its effectiveness.

Abstract Background Reliable measures of disease burden over time are necessary to evaluate the impact of interventions and assess sub-national trends in the distribution of infection. Three Malaria Indicator Surveys (MISs) have been conducted in Madagascar since 2011. They provide a valuable resource to assess changes in burden that is complementary to the country’s routine case reporting system. Methods A Bayesian geostatistical spatio-temporal model was developed in an integrated nested Laplace approximation framework to map the prevalence of Plasmodium falciparum malaria infection among children from 6 to 59 months in age across Madagascar for 2011, 2013 and 2016 based on the MIS datasets. The model was informed by a suite of environmental and socio-demographic covariates known to influence infection prevalence. Spatio-temporal trends were quantified across the country. Results Despite a relatively small decrease between 2013 and 2016, the prevalence of malaria infection has increased substantially in all areas of Madagascar since 2011. In 2011, almost half (42.3%) of the country’s population lived in areas of very low malaria risk (20%) increased from only 2.2% in 2011 to 9.2% in 2016. A comparison of the model-based estimates with the raw MIS results indicates there was an underestimation of the situation in 2016, since the raw figures likely associated with survey timings were delayed until after the peak transmission season. Conclusions Malaria remains an important health problem in Madagascar. The monthly and annual prevalence maps developed here provide a way to evaluate the magnitude of change over time, taking into account variability in survey input data. These methods can contribute to monitoring sub-national trends of malaria prevalence in Madagascar as the country aims for geographically progressive elimination.

Abstract The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species. It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission. The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so—at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations. That problem excludes a large number of people from safe and effective treatment of the latent stage of vivax malaria: the G6PD deficient, pregnant or lactating women, and young infants. These groups were estimated to comprise 14.3% of populations resident in the 95 countries with endemic vivax malaria. Another important obstacle regarding primaquine in the business of killing hypnozoites is its apparent metabolism to an active metabolite exclusively via cytochrome P-450 isozyme 2D6 (CYP2D6). Natural polymorphisms of this allele create genotypes expressing impaired enzymes that occur in over 20% of people living in Southeast Asia, where more than half of P. vivax infections occur globally. Taken together, the estimated frequencies of these primaquine ineligibles due to G6PD toxicity or impaired CYP2D6 activity composed over 35% of the populations at risk of vivax malaria. Much more detailed work is needed to refine these estimates, derive probabilities of error for them, and improve their ethnographic granularity in order to inform control and elimination strategy and tactics.

Abstract Background Plasmodium vivax is the most prevalent human malaria parasite and is likely to increase proportionally as malaria control efforts more rapidly impact the prevalence of Plasmodium falciparum. Despite the prominence of P. vivax as a major human pathogen, vivax malaria qualifies as a neglected and under-studied tropical disease. Significant challenges bringing P. vivax into the laboratory, particularly the capacity for long-term propagation of well-characterized strains, have limited the study of this parasite’s red blood cell (RBC) invasion mechanism, blood-stage development, gene expression, and genetic manipulation. Methods and results Patient isolates of P. vivax have been collected and cryopreserved in the rural community of Ampasimpotsy, located in the Tsiroanomandidy Health District of Madagascar. Periodic, monthly overland transport of these cryopreserved isolates to the country’s National Malaria Control Programme laboratory in Antananarivo preceded onward sample transfer to laboratories at Case Western Reserve University, USA. There, the P. vivax isolates have been cultured through propagation in the RBCs of Saimiri boliviensis. For the four patient isolates studied to-date, the median time interval between sample collection and in vitro culture has been 454 days (range 166–961 days). The median time in culture, continually documented by light microscopy, has been 159 days; isolate AMP2014.01 was continuously propagated for 233 days. Further studies show that the P. vivax parasites propagated in Saimiri RBCs retain their ability to invade human RBCs, and can be cryopreserved, thawed and successfully returned to productive in vitro culture. Conclusions/significance Long-term culture of P. vivax is possible in the RBCs of Saimiri boliviensis. These studies provide an alternative to propagation of P. vivax in live animals that are becoming more restricted. In vitro culture of P. vivax in Saimiri RBCs provides an opening to stabilize patient isolates, which would serve as precious resources to apply new strategies for investigating the molecular and cellular biology of this important malaria parasite.

Abstract The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia–Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.

Abstract Background The prevalence and variants of G6PD deficiency in the Plasmodium vivax-endemic zones of Madagascar remain unknown. The admixed African-Austronesian origins of the Malagasy population make it probable that a heterogeneous mix of genetic variants with a spectrum of clinical severity will be circulating. This would have implications for the widespread use of P. vivax radical cure therapy. Two study populations in the P. vivax-endemic western foothills region of Madagascar were selected for G6PD screening. Both the qualitative fluorescent spot test and G6PD genotyping were used to screen all participants. Results A total of 365 unrelated male volunteers from the Tsiroanomandidy, Mandoto, and Miandrivazo districts of Madagascar were screened and 12.9% were found to be phenotypically G6PD deficient. Full gene sequencing of 95 samples identified 16 single nucleotide polymorphisms, which were integrated into a genotyping assay. Genotyping (n = 291) found one individual diagnosed with the severe G6PD Mediterranean C563T mutation, while the remaining G6PD deficient samples had mutations of African origin, G6PD A- and G6PD A. Conclusions Deployment of P. vivax radical cure in Madagascar must be considerate of the risks presented by the observed prevalence of G6PDd prevalence. The potential morbidity associated with cumulative episodes of P. vivax clinical relapses requires a strategy for increasing access to safe radical cure. The observed dominance of African G6PDd haplotypes is surprising given the known mixed African-Austronesian origins of the Malagasy population; more widespread surveying of G6PDd epidemiology across the island would be required to characterize the distribution of G6PD haplotypes across Madagascar.

Abstract Background Malaria remains a major public health problem in Madagascar. Widespread scale-up of intervention coverage has led to substantial reductions in case numbers since 2000. However, political instability since 2009 has disrupted these efforts, and a resurgence of malaria has since followed. This paper re-visits the sub-national stratification of malaria transmission across Madagascar to propose a contemporary update, and evaluates the reported routine case data reported at this sub-national scale. Methods Two independent malariometrics were evaluated to re-examine the status of malaria across Madagascar. First, modelled maps of Plasmodium falciparum infection prevalence (PfPR) from the Malaria Atlas Project were used to update the sub-national stratification into ‘ecozones’ based on transmission intensity. Second, routine reports of case data from health facilities were synthesized from 2010 to 2015 to compare the sub-national epidemiology across the updated ecozones over time. Proxy indicators of data completeness are investigated. Results The epidemiology of malaria is highly diverse across the island’s ecological regions, with eight contiguous ecozones emerging from the transmission intensity PfPR map. East and west coastal areas have highest transmission year-round, contrasting with the central highlands and desert south where trends appear more closely associated with epidemic outbreak events. Ecozones have shown steady increases in reported malaria cases since 2010, with a near doubling of raw reported case numbers from 2014 to 2015. Gauges of data completeness suggest that interpretation of raw reported case numbers will underestimate true caseload as only approximately 60–75 % of health facility data are reported to the central level each month. Discussion A sub-national perspective is essential when monitoring the epidemiology of malaria in Madagascar and assessing local control needs. A robust assessment of the status of malaria at a time when intervention coverage efforts are being scaled up provides a platform from which to guide intervention preparedness and assess change in future periods of transmission.