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. 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. 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). 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. UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Background: National Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures.Methods: Samples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs.Results: GenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs.Conclusions: GenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community.Funding: The GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of samples were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Despite decreases in incidence and related mortality, malaria remains a major public health challenge in the Greater Mekong Sub-region (GMS). The emergence of artemisinin resistance threatens these gains and has prompted efforts to accelerate elimination in the region. In the GMS, transmission now clusters in hotspots along international borders and among high-risk populations, including forest-goers. To eliminate malaria in the region, interventions must target such hard-to-reach populations. This review provides a comprehensive overview of the qualitative research on behaviours and perceptions that influence uptake of and adherence to malaria interventions among forest-goers in the GMS. A systematic search strategy was used to identify relevant sources, including database (OVID SP, PubMed, ISI Web of Knowledge) and bibliographic searches. Relevant findings from qualitative research methods were extracted and thematic analysis undertaken. Of 268 sources retrieved in searches twenty-two were reviewed. Most reported studies were conducted in Cambodia (n = 10), and were published after 2014 (n = 16). Four major themes emerged that are particularly relevant to the design of intervention packages targeted at forest-goers: (1) understanding of malaria and perceived risk; (2) preventive measures used when visiting the forest; (3) behaviours that put forest-goers at risk of infection; and, (4) malaria-related treatment seeking. There were notable differences across the reviewed articles that suggest the need for a locally tailored approach. A more detailed characterization of forest activities is needed but research on this topic raises methodological challenges. Current vector control measures have limitations, with use of insecticidal-treated nets, hammocks and repellents influenced by the type of forest activities and the characteristics of these measures. In contrast, anti-malarial drugs, for example, as chemoprophylaxis, hold promise but require further evaluation.

Background: Over the last 20 years, malaria incidence has decreased across the Greater Mekong Sub-region (GMS) and the emergence of artemisinin resistance has stimulated efforts to accelerate regional elimination. In the GMS, the malaria transmission is focused increasingly in forested zones. This article describes forest-going activities and examines forest workers’ attitudes to and experiences of malaria prevention and control in north-eastern Cambodia. Methods: In Stung Treng Province, Cambodia, 19 in-depth interviews were conducted in villages with participants recently diagnosed with uncomplicated falciparum malaria who reported working in forests. Two focus group discussions with respondents’ forest-working peers were held. Interviews and focus groups were audio-recorded transcribed, and translated for thematic analysis. Results: Forest work is an essential source of income for respondents. Many combine it with farming, which influences the timing and duration of forest visits. Forest activities include logging and collecting other forest products, particularly malva nuts. Men log year-round, whereas gathering forest products is seasonal and can involve entire families. Forest workers sleep chiefly in unimpregnated hammock nets in make-shift encampments. Respondents are concerned about symptomatic malaria, but unfamiliar with the concept of asymptomatic infection. They view the forest as an area of potential malaria infection and seek to protect themselves from mosquito bites through wearing long-sleeved clothes, using repellents, and lighting fires. Forest workers express a willingness to self-test and self-administer anti-malarials. Conclusions: Forest workers’ behaviour and perceptions of risk indicate that improvements are needed to current control measures. There is potential to: better target distribution of impregnated hammock nets; offer curative or presumptive treatment while in forests; and expand access to screening. Establishing the efficacy and feasibility of prophylaxis for forest workers in the GMS is a priority.

Mass drug administrations (MDAs) are part of the World Health Organization’s Plasmodium falciparum elimination strategy for the Greater Mekong Subregion (GMS). In Cambodia, a 2015–2017 clinical trial evaluated the effectiveness of MDA. This article explores factors that influence the feasibility and acceptability of MDA, including seasonal timing, financial incentives and the delivery model. Quantitative data were collected through structured questionnaires from the heads of 163 households. Qualitative data were collected through 25 semi-structured interviews and 5 focus group discussions with villagers and local health staff. Calendars of village activities were created and meteorological and malaria treatment records were collected. MDA delivered house-to-house or at a central point, with or without compensation, were equally acceptable and did not affect coverage. People who knew about the rationale for the MDA, asymptomatic infections and transmission were more likely to participate. In western Cambodia, MDA delivered house-to-house by volunteers at the end of the dry season may be most practicable but requires the subsequent treatment of in-migrants to prevent reintroduction of infections. For MDA targeted at individual villages or village clusters it is important to understand local preferences for community mobilisation, delivery and timing, as several models of MDA are feasible.

Background: In Siem Pang, northeastern Cambodia, malaria transmission persists in remote forested areas populated by ethnic minorities. Engaging affected communities in health education campaigns is challenging due to language, access and literacy constraints. During 2018, a newly established medical research station conducted a health education programme in local villages harnessing traditional songs, arts and crafts, along with theatre, comedy and health talks and quizzes. Health education topics were proposed by community leaders and focused on maternal and child health and malaria. This article describes a process evaluation of these activities, the community's response and whether this was an appropriate form of health education in this context. Methods: In-depth interviews were conducted with community members, leaders and performers. Interviews were audio-recorded, transcribed and translated to English for thematic analysis. Results: In total, 65 interviews were conducted; 20 of these were follow-up interviews with respondents interviewed prior to the performances. Respondents were able to recall the key health messages about malaria, antenatal care and infant vaccination. They also showed good awareness of malaria transmission and prevention and described how they enjoyed the events and appreciated the efforts of the project team. Conclusions: In isolated communities in Cambodia, a health education programme harnessing performance and arts engaged the whole community and its messages were readily recalled and prompted reflection.