Expanding the roles of community health workers to sustain programmes during malaria elimination: a meeting report on operational research in Southeast Asia.

In Southeast Asia malaria elimination is targeted by 2030. Cambodia aims to achieve this by 2025, driven in large part by the urgent need to control the spread of artemisinin-resistant falciparum malaria infections. Rapid elimination depends on sustaining early access to diagnosis and effective treatment. In much of Cambodia, rapid elimination will rely on a village malaria worker (VMW) network. Yet as malaria declines and is no longer a common cause of febrile illness, VMWs may become less popular with febrile patients, as VMWs do not diagnose or treat other conditions at present. There is a risk that VMWs become inactive and malaria rebounds before the complete interruption of transmission is achieved.During 2021-23 a large-scale operational research study was conducted in western Cambodia to explore how a VMW network could be sustained by including health activities that cover non-malarial illnesses to encourage febrile patients to continue to attend. 105 VMWs received new rapid diagnostic tests (including dengue antigen-antibody and combined malaria/C-reactive protein tests), were trained in electronic data collection, and attended health education packages on hygiene and sanitation, disease surveillance and first aid, management of mild illness, and vaccination and antenatal care.In August 2023 the National Malaria Control Programme of Cambodia convened a stakeholder meeting in Battambang, Cambodia. Findings from the study were reviewed in the context of current malaria elimination strategies. The discussions informed policy options to sustain the relevance of the VMW network in Cambodia, and the potential for its integration with other health worker networks. This expansion could ensure VMWs remain active and relevant until malaria elimination is accomplished.

Two-step spatiotemporal anomaly detection corrected for lag reporting time with application to real-time dengue surveillance in Thailand.

BACKGROUND: Dengue infection ranges from asymptomatic to severe and life-threatening, with no specific treatment available. Vector control is crucial for interrupting its transmission cycle. Accurate estimation of outbreak timing and location is essential for efficient resource allocation. Timely and reliable notification systems are necessary to monitor dengue incidence, including spatial and temporal distributions, to detect outbreaks promptly and implement effective control measures. METHODS: We proposed an integrated two-step methodology for real-time spatiotemporal cluster detection, accounting for reporting delays. In the first step, we employed space-time nowcasting modeling to compensate for lags in the reporting system. Subsequently, anomaly detection methods were applied to assess adverse risks. To illustrate the effectiveness of these detection methods, we conducted a case study using weekly dengue surveillance data from Thailand. RESULTS: The developed methodology demonstrated robust surveillance effectiveness. By combining space-time nowcasting modeling and anomaly detection, we achieved enhanced detection capabilities, accounting for reporting delays and identifying clusters of elevated risk in real-time. The case study in Thailand showcased the practical application of our methodology, enabling timely initiation of disease control activities. CONCLUSION: Our integrated two-step methodology provides a valuable approach for real-time spatiotemporal cluster detection in dengue surveillance. By addressing reporting delays and incorporating anomaly detection, it complements existing surveillance systems and forecasting efforts. Implementing this methodology can facilitate the timely initiation of disease control activities, contributing to more effective prevention and control strategies for dengue in Thailand and potentially other regions facing similar challenges.

Evaluation and comparison of spatial cluster detection methods for improved decision making of disease surveillance: a case study of national dengue surveillance in Thailand.

BACKGROUND: Dengue is a mosquito-borne disease that causes over 300 million infections worldwide each year with no specific treatment available. Effective surveillance systems are needed for outbreak detection and resource allocation. Spatial cluster detection methods are commonly used, but no general guidance exists on the most appropriate method for dengue surveillance. Therefore, a comprehensive study is needed to assess different methods and provide guidance for dengue surveillance programs. METHODS: To evaluate the effectiveness of different cluster detection methods for dengue surveillance, we selected and assessed commonly used methods: Getis Ord [Formula: see text], Local Moran, SaTScan, and Bayesian modeling. We conducted a simulation study to compare their performance in detecting clusters, and applied all methods to a case study of dengue surveillance in Thailand in 2019 to further evaluate their practical utility. RESULTS: In the simulation study, Getis Ord [Formula: see text] and Local Moran had similar performance, with most misdetections occurring at cluster boundaries and isolated hotspots. SaTScan showed better precision but was less effective at detecting inner outliers, although it performed well on large outbreaks. Bayesian convolution modeling had the highest overall precision in the simulation study. In the dengue case study in Thailand, Getis Ord [Formula: see text] and Local Moran missed most disease clusters, while SaTScan was mostly able to detect a large cluster. Bayesian disease mapping seemed to be the most effective, with adaptive detection of irregularly shaped disease anomalies. CONCLUSIONS: Bayesian modeling showed to be the most effective method, demonstrating the best accuracy in adaptively identifying irregularly shaped disease anomalies. In contrast, SaTScan excelled in detecting large outbreaks and regular forms. This study provides empirical evidence for the selection of appropriate tools for dengue surveillance in Thailand, with potential applicability to other disease control programs in similar settings.

Gaps in research and capacity development for malaria surveillance and response in the Asia-Pacific: meeting report.

BACKGROUND: This report is based on the 2021 annual meeting of the Asia-Pacific Malaria Elimination Network Surveillance and Response Working Group held online on November 1-3, 2021. In light of the 2030 regional malaria elimination goal, there is an urgency for Asia-Pacific countries to accelerate progress towards national elimination and prevent re-establishment. The Asia Pacific Malaria Elimination Network (APMEN) Surveillance Response Working Group (SRWG) supports elimination goals of national malaria control programmes (NMCPs) by expanding the knowledge base, guiding the region-specific operational research agenda and addressing evidence gaps to improve surveillance and response activities. METHODS: An online annual meeting was hosted from 1 to 3 November 2021, to reflect on research needed to support malaria elimination in the region, challenges with malaria data quality and integration, current surveillance-related technical tools, and training needs of NMCPs to support surveillance and response activities. Facilitator-led breakout groups were held during meeting sessions to encourage discussion and share experience. A list of identified research priorities was voted on by attendees and non-attending NMCP APMEN contacts. FINDINGS: 127 participants from 13 country partners and 44 partner institutions attended the meeting, identifying strategies to address malaria transmission amongst mobile and migrant populations as the top research priority, followed by cost effective surveillance strategies in low resource settings, and integration of malaria surveillance into broader health systems. Key challenges, solutions and best practices for improving data quality and integrating epidemiology and entomology data were identified, including technical solutions to improve surveillance activities, guiding priority themes for hosting informative webinars, training workshops and technical support initiatives. Inter-regional partnerships and SRWG-led training plans were developed in consultation with members to be launched from 2022 onwards. CONCLUSION: The 2021 SRWG annual meeting provided an opportunity for regional stakeholders, both NMCPs and APMEN partner institutions, to highlight remaining challenges and barriers and identify research priorities pertaining to surveillance and response in the region, and advocate for strengthening capacity through training and supportive partnerships.

Patient-level performance evaluation of a smartphone-based malaria diagnostic application.

BACKGROUND: Microscopic examination is commonly used for malaria diagnosis in the field. However, the lack of well-trained microscopists in malaria-endemic areas impacted the most by the disease is a severe problem. Besides, the examination process is time-consuming and prone to human error. Automated diagnostic systems based on machine learning offer great potential to overcome these problems. This study aims to evaluate Malaria Screener, a smartphone-based application for malaria diagnosis. METHODS: A total of 190 patients were recruited at two sites in rural areas near Khartoum, Sudan. The Malaria Screener mobile application was deployed to screen Giemsa-stained blood smears. Both expert microscopy and nested PCR were performed to use as reference standards. First, Malaria Screener was evaluated using the two reference standards. Then, during post-study experiments, the evaluation was repeated for a newly developed algorithm, PlasmodiumVF-Net. RESULTS: Malaria Screener reached 74.1% (95% CI 63.5-83.0) accuracy in detecting Plasmodium falciparum malaria using expert microscopy as the reference after a threshold calibration. It reached 71.8% (95% CI 61.0-81.0) accuracy when compared with PCR. The achieved accuracies meet the WHO Level 3 requirement for parasite detection. The processing time for each smear varies from 5 to 15 min, depending on the concentration of white blood cells (WBCs). In the post-study experiment, Malaria Screener reached 91.8% (95% CI 83.8-96.6) accuracy when patient-level results were calculated with a different method. This accuracy meets the WHO Level 1 requirement for parasite detection. In addition, PlasmodiumVF-Net, a newly developed algorithm, reached 83.1% (95% CI 77.0-88.1) accuracy when compared with expert microscopy and 81.0% (95% CI 74.6-86.3) accuracy when compared with PCR, reaching the WHO Level 2 requirement for detecting both Plasmodium falciparum and Plasmodium vivax malaria, without using the testing sites data for training or calibration. Results reported for both Malaria Screener and PlasmodiumVF-Net used thick smears for diagnosis. In this paper, both systems were not assessed in species identification and parasite counting, which are still under development. CONCLUSION: Malaria Screener showed the potential to be deployed in resource-limited areas to facilitate routine malaria screening. It is the first smartphone-based system for malaria diagnosis evaluated on the patient-level in a natural field environment. Thus, the results in the field reported here can serve as a reference for future studies.

Community engagement among forest goers in a malaria prophylaxis trial: implementation challenges and implications.

BACKGROUND: Malaria transmission in Southeast Asia is increasingly confined to forests, where marginalized groups are exposed primarily through their work. Anti-malarial chemoprophylaxis may help to protect these people. This article examines the effectiveness and practical challenges of engaging forest-goers to participate in a randomized controlled clinical trial of anti-malarial chemoprophylaxis with artemether-lumefantrine (AL) versus a control (multivitamin, MV) for malaria in northeast Cambodia. METHODS: The impact of engagement in terms of uptake was assessed as the proportion of people who participated during each stage of the trial: enrolment, compliance with trial procedures, and drug intake. During the trial, staff recorded the details of engagement meetings, including the views and opinions of participants and community representatives, the decision-making processes, and the challenges addressed during implementation. RESULTS: In total, 1613 participants were assessed for eligibility and 1480 (92%) joined the trial, 1242 (84%) completed the trial and received prophylaxis (AL: 82% vs MV: 86%, p = 0.08); 157 (11%) were lost to follow-up (AL: 11% vs MV: 11%, p = 0.79); and 73 (5%) discontinued the drug (AL-7% vs MV-3%, p = 0.005). The AL arm was associated with discontinuation of the study drug (AL: 48/738, 7% vs 25/742, 3%; p = 0.01). Females (31/345, 9%) were more likely (42/1135, 4%) to discontinue taking drugs at some point in the trial (p = 0.005). Those (45/644, 7%) who had no previous history of malaria infection were more likely to discontinue the study drug than those (28/836, 3%) who had a history of malaria (p = 0.02). Engagement with the trial population was demanding because many types of forest work are illegal; and the involvement of an engagement team consisting of representatives from the local administration, health authorities, community leaders and community health workers played a significant role in building trust. Responsiveness to the needs and concerns of the community promoted acceptability and increased confidence in taking prophylaxis among participants. Recruitment of forest-goer volunteers to peer-supervise drug administration resulted in high compliance with drug intake. The development of locally-appropriate tools and messaging for the different linguistic and low-literacy groups was useful to ensure participants understood and adhered to the trial procedures. It was important to consider forest-goers` habits and social characteristics when planning the various trial activities. CONCLUSIONS: The comprehensive, participatory engagement strategy mobilized a wide range of stakeholders including study participants, helped build trust, and overcame potential ethical and practical challenges. This locally-adapted approach was highly effective as evidenced by high levels of trial enrolment, compliance with trial procedures and drug intake.

Spatiotemporal reproduction number with Bayesian model selection for evaluation of emerging infectious disease transmissibility: an application to COVID-19 national surveillance data.

BACKGROUND: To control emerging diseases, governments often have to make decisions based on limited evidence. The effective or temporal reproductive number is used to estimate the expected number of new cases caused by an infectious person in a partially susceptible population. While the temporal dynamic is captured in the temporal reproduction number, the dominant approach is currently based on modeling that implicitly treats people within a population as geographically well mixed. METHODS: In this study we aimed to develop a generic and robust methodology for estimating spatiotemporal dynamic measures that can be instantaneously computed for each location and time within a Bayesian model selection and averaging framework. A simulation study was conducted to demonstrate robustness of the method. A case study was provided of a real-world application to COVID-19 national surveillance data in Thailand. RESULTS: Overall, the proposed method allowed for estimation of different scenarios of reproduction numbers in the simulation study. The model selection chose the true serial interval when included in our study whereas model averaging yielded the weighted outcome which could be less accurate than model selection. In the case study of COVID-19 in Thailand, the best model based on model selection and averaging criteria had a similar trend to real data and was consistent with previously published findings in the country. CONCLUSIONS: The method yielded robust estimation in several simulated scenarios of force of transmission with computing flexibility and practical benefits. Thus, this development can be suitable and practically useful for surveillance applications especially for newly emerging diseases. As new outbreak waves continue to develop and the risk changes on both local and global scales, our work can facilitate policymaking for timely disease control.

A systematic review of the data, methods and environmental covariates used to map Aedes-borne arbovirus transmission risk.

BACKGROUND: Aedes (Stegomyia)-borne diseases are an expanding global threat, but gaps in surveillance make comprehensive and comparable risk assessments challenging. Geostatistical models combine data from multiple locations and use links with environmental and socioeconomic factors to make predictive risk maps. Here we systematically review past approaches to map risk for different Aedes-borne arboviruses from local to global scales, identifying differences and similarities in the data types, covariates, and modelling approaches used. METHODS: We searched on-line databases for predictive risk mapping studies for dengue, Zika, chikungunya, and yellow fever with no geographical or date restrictions. We included studies that needed to parameterise or fit their model to real-world epidemiological data and make predictions to new spatial locations of some measure of population-level risk of viral transmission (e.g. incidence, occurrence, suitability, etc.). RESULTS: We found a growing number of arbovirus risk mapping studies across all endemic regions and arboviral diseases, with a total of 176 papers published 2002-2022 with the largest increases shortly following major epidemics. Three dominant use cases emerged: (i) global maps to identify limits of transmission, estimate burden and assess impacts of future global change, (ii) regional models used to predict the spread of major epidemics between countries and (iii) national and sub-national models that use local datasets to better understand transmission dynamics to improve outbreak detection and response. Temperature and rainfall were the most popular choice of covariates (included in 50% and 40% of studies respectively) but variables such as human mobility are increasingly being included. Surprisingly, few studies (22%, 31/144) robustly tested combinations of covariates from different domains (e.g. climatic, sociodemographic, ecological, etc.) and only 49% of studies assessed predictive performance via out-of-sample validation procedures. CONCLUSIONS: Here we show that approaches to map risk for different arboviruses have diversified in response to changing use cases, epidemiology and data availability. We identify key differences in mapping approaches between different arboviral diseases, discuss future research needs and outline specific recommendations for future arbovirus mapping.

Forest malaria and prospects for anti-malarial chemoprophylaxis among forest goers: findings from a qualitative study in Thailand.

BACKGROUND: Across the Greater Mekong Subregion, malaria remains a dangerous infectious disease, particularly for people who visit forested areas where residual transmission continues. Because vector control measures offer incomplete protection to forest goers, chemoprophylaxis has been suggested as a potential supplementary measure for malaria prevention and control. To implement prophylaxis effectively, additional information is needed to understand forest goers' activities and their willingness to use malaria prevention measures, including prophylaxis, and how it could be delivered in communities. Drawing on in-depth interviews with forest goers and stakeholders, this article examines the potential acceptability and implementation challenges of malaria prophylaxis for forest goers in northeast Thailand. METHODS: In-depth interviews were conducted with forest goers (n = 11) and stakeholders (n = 16) including healthcare workers, community leaders, and policymakers. Interviews were audio-recorded, transcribed and coded using NVivo, employing an inductive and deductive approach, for thematic analysis. RESULTS: Forest goers were well aware of their (elevated) malaria risk and reported seeking care for malaria from local health care providers. Forest goers and community members have a close relationship with the forest but are not a homogenous group: their place and time-at-risk varied according to their activities and length of stay in the forest. Among stakeholders, the choice and cost of anti-malarial prophylactic regimen-its efficacy, length and complexity, number of tablets, potential side effects, and long-term impact on users-were key considerations for its feasibility. They also expressed concern about adherence to the preventive therapy and potential difficulty treating malaria patients with the same regimen. Prophylaxis was considered a low priority in areas with perceived accessible health system and approaching malaria elimination. CONCLUSIONS: In the context of multi-drug resistance, there are several considerations for implementing malaria prophylaxis: the need to target forest goers who are at-risk with a clear period of exposure, to ensure continued use of vector control measures and adherence to prophylactic anti-malarials, and to adopt an evidence-based approach to determine an appropriate regimen. Beyond addressing current intervention challenges and managing malaria incidence in low-transmission setting, it is crucial to keep malaria services available and accessible at the village level especially in areas home to highly mobile populations.

Forest malaria and prospects for anti-malarial chemoprophylaxis among forest goers: findings from a qualitative study in Lao PDR.

BACKGROUND: Despite significant decline in malarial incidence and mortality in countries across the Greater Mekong Subregion, the disease remains a public health challenge in the region; transmission continues mainly among people who visit forests in remote areas, often along international borders, where access to primary healthcare is limited. In the absence of effective vector-control measures and limited exposure periods, malaria chemoprophylaxis has been proposed as a strategy to protect forest goers. As a rarely used approach for indigenous populations, questions remain about its feasibility and acceptability. Drawing on in-depth interviews with forest goers and stakeholders, this article examines opportunities and challenges for implementation of anti-malarial chemoprophylaxis for forest goers in Lao PDR. METHODS: In-depth interviews were conducted with 16 forest goers and 15 stakeholders in Savannakhet province, Lao PDR. Interview topics included experience of malaria prevention and health services, and perceptions of prophylaxis as a potential component of malaria elimination strategy. The interviews were transcribed and coded using inductive and deductive approaches for qualitative thematic analysis. RESULTS: In ethnically and geographically diverse villages, awareness of malaria risk prompts forest goers to protect themselves, albeit sub-optimally using available preventive measures. Stakeholders highlighted challenges for targeting at-risk populations and approaches to address forest malaria in southern Lao PDR. Among policymakers, choice and cost of anti-malarials, particularly their efficacy and source of funding, were key considerations for the feasibility of malaria prophylaxis. Acceptability of prophylaxis among forest goers was also influenced by the complexity of the regimen, including the number of tablets and timing of doses. Implementation of prophylaxis may be affected by a lack of transportation and communication barriers in remote communities. CONCLUSION: Adding prophylaxis to existing malaria control activities requires strengthening the capacity of local health workers in Lao PDR. Ideally, this would be part of an integrated approach that includes strategies to address the other febrile illnesses that forest goers describe as priority health concerns. The prophylactic regimen also requires careful consideration in terms of effectiveness and simplicity of dosing.

Making data map-worthy-enhancing routine malaria data to support surveillance and mapping of Plasmodium falciparum anti-malarial resistance in a pre-elimination sub-Saharan African setting: a molecular and spatiotemporal epidemiology study.

BACKGROUND: Independent emergence and spread of artemisinin-resistant Plasmodium falciparum malaria have recently been confirmed in Africa, with molecular markers associated with artemisinin resistance increasingly detected. Surveillance to promptly detect and effectively respond to anti-malarial resistance is generally suboptimal in Africa, especially in low transmission settings where therapeutic efficacy studies are often not feasible due to recruitment challenges. However, these communities may be at higher risk of anti-malarial resistance. METHODS: From March 2018 to February 2020, a sequential mixed-methods study was conducted to evaluate the feasibility of the near-real-time linkage of individual patient anti-malarial resistance profiles with their case notifications and treatment response reports, and map these to fine scales in Nkomazi sub-district, Mpumalanga, a pre-elimination area in South Africa. RESULTS: Plasmodium falciparum molecular marker resistance profiles were linked to 55.1% (2636/4787) of notified malaria cases, 85% (2240/2636) of which were mapped to healthcare facility, ward and locality levels. Over time, linkage of individual malaria case demographic and molecular data increased to 75.1%. No artemisinin resistant validated/associated  Kelch-13 mutations were detected in the 2385 PCR positive samples. Almost all 2812 samples assessed for lumefantrine susceptibility carried the wildtype mdr86ASN and crt76LYS alleles, potentially associated with decreased lumefantrine susceptibility. CONCLUSION: Routine near-real-time mapping of molecular markers associated with anti-malarial drug resistance on a fine spatial scale provides a rapid and efficient early warning system for emerging resistance. The lessons learnt here could inform scale-up to provincial, national and regional malaria elimination programmes, and may be relevant for other antimicrobial resistance surveillance.

Surveillance to achieve malaria elimination in eastern Myanmar: a 7-year observational study.

BACKGROUND: The collection and utilization of surveillance data is essential in monitoring progress towards achieving malaria elimination, in the timely response to increases in malaria case numbers and in the assessment of programme functioning. This paper describes the surveillance activities used by the malaria elimination task force (METF) programme which operates in eastern Myanmar, and provides an analysis of data collected from weekly surveillance, case investigations, and monitoring and evaluation of programme performance. METHODS: This retrospective analysis was conducted using data collected from a network of 1250 malaria posts operational between 2014 and 2021. To investigate changes in data completeness, malaria post performance, malaria case numbers, and the demographic details of malaria cases, summary statistics were used to compare data collected over space and time. RESULTS: In the first 3 years of the METF programme, improvements in data transmission routes resulted in a 18.9% reduction in late reporting, allowing for near real-time analysis of data collected at the malaria posts. In 2020, travel restrictions were in place across Karen State in response to COVID-19, and from February 2021 the military coup in Myanmar resulted in widescale population displacement. However, over that period there has been no decline in malaria post attendance, and the majority of consultations continue to occur within 48 h of fever onset. Case investigations found that 43.8% of cases travelled away from their resident village in the 3 weeks prior to diagnosis and 36.3% reported never using a bed net whilst sleeping in their resident village, which increased to 72.2% when sleeping away from their resident village. Malaria post assessments performed in 82.3% of the METF malaria posts found malaria posts generally performed to a high standard. CONCLUSIONS: Surveillance data collected by the METF programme demonstrate that despite significant changes in the context in which the programme operates, malaria posts have remained accessible and continue to provide early diagnosis and treatment contributing to an 89.3% decrease in Plasmodium falciparum incidence between 2014 and 2021.

Development and Validation of an In Silico Decision Tool To Guide Optimization of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients.

Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% of parasites within 24 h (PC24≥99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children (≥20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (<20 kg). The upper limit of the credible intervals for all regimens was below a PC24≥99% of 80%, a threshold achieved on average in clinical studies of severe falciparum malaria infections. In severe falciparum malaria caused by parasites with reduced ring stage susceptibility to artemisinin, parasite clearance is predicted to be slower with both the currently recommended and proposed simplified i.v. artesunate dosing regimens.

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.

BACKGROUND: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. METHODS: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. FINDINGS: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50). INTERPRETATION: Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. FUNDING: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Analysing human population movement data for malaria control and elimination.

BACKGROUND: Human population movement poses a major obstacle to malaria control and elimination. With recent technological advances, a wide variety of data sources and analytical methods have been used to quantify human population movement (HPM) relevant to control and elimination of malaria. METHODS: The relevant literature and selected studies that had policy implications that could help to design or target malaria control and elimination interventions were reviewed. These studies were categorized according to spatiotemporal scales of human mobility and the main method of analysis. RESULTS: Evidence gaps exist for tracking routine cross-border HPM and HPM at a regional scale. Few studies accounted for seasonality. Out of twenty included studies, two studies which tracked daily neighbourhood HPM used descriptive analyses as the main method, while the remaining studies used statistical analyses or mathematical modelling. CONCLUSION: Although studies quantified varying types of human population movement covering different spatial and temporal scales, methodological gaps remain that warrant further studies related to malaria control and elimination.

Risk factors for malaria in high incidence areas of Viet Nam: a case-control study.

BACKGROUND: A key step to advancing the goal of malaria elimination in Viet Nam by 2030 is focusing limited resources for treatment and prevention to groups most at risk for malaria transmission. METHODS: To better understand risk factors for malaria transmission in central Viet Nam, a survey of 1000 malaria positive cases and 1000 malaria negative controls was conducted. Cases and controls were matched for age and gender and self-presented at commune health stations (CHS) in Binh Phuoc, Dak Nong and Dak Lak Provinces. Diagnoses were confirmed with microscopy, rapid diagnostic test and PCR. Participants were interviewed about 50 potential risk factors for malaria, which included information about occupation, forest visitation, travel, healthcare-seeking behaviour and prior use of anti-malaria interventions. Participants were enrolled by trained government health workers and the samples were analysed in Vietnamese government laboratories. Data were analysed by univariable, block-wise and multivariable logistic regression. RESULTS: Among cases, 61.8% had Plasmodium falciparum, 35.2% Plasmodium vivax and 3% mixed species infections. Median (IQR) age was 27 (21-36) years and 91.2% were male. Twenty-five risk factors were associated with being a case and eleven with being a control. Multivariable analysis found that malaria cases correlated with forest workers, recent forest visitation, longer duration of illness, having a recorded fever, number of malaria infections in the past year, having had prior malaria treatment and having previously visited a clinic. CONCLUSIONS: This study demonstrates the benefits of increased statistical power from matched controls in malaria surveillance studies, which allows identification of additional independent risk factors. It also illustrates an example of research partnership between academia and government to collect high quality data relevant to planning malaria elimination activities. Modifiable risk factors and implications of the findings for malaria elimination strategy are presented.

Acceptability and feasibility of malaria prophylaxis for forest goers: findings from a qualitative study in Cambodia.

BACKGROUND: In the Greater Mekong Subregion, adults are at highest risk for malaria, particularly those who visit forests. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest goers against malaria. METHODS: Alongside a clinical trial of anti-malarial chemoprophylaxis in northern Cambodia, qualitative research was conducted, including in-depth interviews and observation, to explore the acceptability of malaria prophylaxis for forest goers, the implementation opportunities, and challenges of this strategy. RESULTS: Prophylaxis with artemether-lumefantrine for forest goers was found to be acceptable under trial conditions. Three factors played a major role: the community's awareness and perception of the effectiveness of prophylaxis, their trust in the provider, and malaria as a local health concern. The findings highlight how uptake and adherence to prophylaxis are influenced by the perceived balance between benefits and burden of anti-malarials which are modulated by the seasonality of forest visits and its influence on malaria risk. CONCLUSIONS: The implementation of anti-malarial prophylaxis needs to consider how the preventive medication can be incorporated into existing vector-control measures, malaria testing and treatment services. The next step in the roll out of anti-malarial prophylaxis for forest visitors will require support from local health workers.

Bayesian spatio-temporal distributed lag modeling for delayed climatic effects on sparse malaria incidence data.

BACKGROUND: In many areas of the Greater Mekong Subregion (GMS), malaria endemic regions have shrunk to patches of predominantly low-transmission. With a regional goal of elimination by 2030, it is important to use appropriate methods to analyze and predict trends in incidence in these remaining transmission foci to inform planning efforts. Climatic variables have been associated with malaria incidence to varying degrees across the globe but the relationship is less clear in the GMS and standard methodologies may not be appropriate to account for the lag between climate and incidence and for locations with low numbers of cases. METHODS: In this study, a methodology was developed to estimate the spatio-temporal lag effect of climatic factors on malaria incidence in Thailand within a Bayesian framework. A simulation was conducted based on ground truth of lagged effect curves representing the delayed relation with sparse malaria cases as seen in our study population. A case study to estimate the delayed effect of environmental variables was used with malaria incidence at a fine geographic scale of sub-districts in a western province of Thailand. RESULTS: From the simulation study, the model assumptions which accommodated both delayed effects and excessive zeros appeared to have the best overall performance across evaluation metrics and scenarios. The case study demonstrated lagged climatic effect estimation of the proposed modeling with real data. The models appeared to be useful to estimate the shape of association with malaria incidence. CONCLUSIONS: A new method to estimate the spatiotemporal effect of climate on malaria trends in low transmission settings is presented. The developed methodology has potential to improve understanding and estimation of past and future trends in malaria incidence. With further development, this could assist policy makers with decisions on how to more effectively distribute resources and plan strategies for malaria elimination.

Longitudinal trends in malaria testing rates in the face of elimination in eastern Myanmar: a 7-year observational study.

BACKGROUND: Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. METHODS: A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. RESULTS: In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59-0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). CONCLUSION: Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria.

Reduced Cardiac Index Reserve and Hypovolemia in Severe Falciparum Malaria.

BACKGROUND: Impaired microvascular perfusion is central to the development of coma and lactic acidosis in severe falciparum malaria. Refractory hypotension is rare on admission but develops frequently in fatal cases. We assessed cardiac function and volume status in severe falciparum malaria and its prognostic significance. METHODS: Patients with severe (N = 101) or acute uncomplicated falciparum malaria (N = 83) were recruited from 2 hospitals in India and Bangladesh, and healthy participants (N = 44) underwent echocardiography. RESULTS: Patients with severe malaria had 38% shorter left ventricular (LV) filling times and 25% shorter LV ejection times than healthy participants because of tachycardia; however, stroke volume, LV internal diameter in diastole (LVIDd), and LV internal diameter in systole (LVIDs) indices were similar. A low endocardial fraction shortening (eFS) was present in 17% (9 of 52) of severe malaria patients. Adjusting for preload and afterload, eFS was similar in health and severe malaria. Fatal cases had smaller baseline LVIDd and LVIDs indices, more collapsible inferior vena cavae (IVC), and higher heart rates than survivors. The LVIDs and IVC collapsibility were independent predictors for mortality, together with base excess and Glasgow Coma Scale. CONCLUSIONS: Patients with severe malaria have rapid ejection of a normal stroke volume. Fatal cases had features of relative hypovolemia and reduced cardiac index reserve.