Search

Abstract Background The Great Mekong Subregion has attained a major decline in malaria cases and fatalities over the last years, but residual transmission hotspots remain, supposedly fueled by forest workers and migrant populations. This study aimed to: (i) characterize the fine-scale mobility of forest-goers and understand links between their daily movement patterns and malaria transmission, using parasites detection via real time polymerase chain reaction (RT PCR) and the individual exposure to Anopheles bites by quantification of anti-Anopheles saliva antibodies via enzyme-linked immunosorbent assay; (ii) assess the concordance of questionnaires and Global Positioning System (GPS) data loggers for measuring mobility. Methods Two 28 day follow-ups during dry and rainy seasons, including a GPS tracking, questionnaires and health examinations, were performed on male forest goers representing the population at highest risk of infection. Their time spent in different land use categories and demographic data were analyzed in order to understand the risk factors driving malaria in the study area. Results Malaria risk varied with village forest cover and at a resolution of only a few kilometers: participants from villages outside the forest had the highest malaria prevalence compared to participants from forest fringe’s villages. The time spent in a specific environment did not modulate the risk of malaria, in particular the time spent in forest was not associated with a higher probability to detect malaria among forest-goers. The levels of antibody response to Anopheles salivary peptide among participants were significantly higher during the rainy season, in accordance with Anopheles mosquito density variation, but was not affected by sociodemographic and mobility factors. The agreement between GPS and self-reported data was only 61.9% in reporting each kind of visited environment. Conclusions In a context of residual malaria transmission which was mainly depicted by P. vivax asymptomatic infections, the implementation of questionnaires, GPS data-loggers and quantification of anti-saliva Anopheles antibodies on the high-risk group were not powerful enough to detect malaria risk factors associated with different mobility behaviours or time spent in various environments. The joint implementation of GPS trackers and questionnaires allowed to highlight the limitations of both methodologies and the benefits of using them together. New detection and follow-up strategies are still called for.

Abstract Malaria remains a global health challenge, disproportionately affecting vulnerable communities. Despite substantial progress, the emergence of anti-malarial drug resistance poses a constant threat. The Greater Mekong Subregion (GMS), which includes Cambodia, China’s Yunnan province, Lao People's Democratic Republic, Myanmar, Thailand, and Viet Nam has been the epicentre for the emergence of resistance to successive generations of anti-malarial therapies. From the perspective of the World Health Organization (WHO), this article considers the collaborative efforts in the GMS, to contain Plasmodium falciparum artemisinin partial resistance and multi-drug resistance and to advance malaria elimination. The emergence of artemisinin partial resistance in the GMS necessitated urgent action and regional collaboration resulting in the Strategy for Malaria Elimination in the Greater Mekong Subregion (2015–2030), advocating for accelerated malaria elimination interventions tailored to country needs, co-ordinated and supported by the WHO Mekong malaria elimination programme. The strategy has delivered substantial reductions in malaria across all GMS countries, with a 77% reduction in malaria cases and a 97% reduction in malaria deaths across the GMS between 2012 and 2022. Notably, China was certified malaria-free by WHO in 2021. Countries' ownership and accountability have been pivotal, with each GMS country outlining its priorities in strategic and annual work plans. The development of strong networks for anti-malarial drug resistance surveillance and epidemiological surveillance was essential. Harmonization of policies and guidelines enhanced collaboration, ensuring that activities were driven by evidence. Challenges persist, particularly in Myanmar, where security concerns have limited recent progress, though an intensification and acceleration plan aims to regain momentum. Barriers to implementation can slow progress and continuing innovation is needed. Accessing mobile and migrant populations is key to addressing remaining transmission foci, requiring effective cross-border collaboration. In conclusion, the GMS has made significant progress towards malaria elimination, particularly in the east where several countries are close to P. falciparum elimination. New and persisting challenges require sustained efforts and continued close collaboration. The GMS countries have repeatedly risen to every obstacle presented, and now is the time to re-double efforts and achieve the 2030 goal of malaria elimination for the region.

Abstract Background Cambodia aims to eliminate all forms of malaria by 2025. In 2020, 90% of all malaria cases were Plasmodium vivax. Thus, preventing P. vivax and relapse malaria is a top priority for elimination. 14-day primaquine, a World Health Organization-recommended radical cure treatment regimen, specifically targets dormant hypnozoites in the liver to prevent relapse. Cambodia introduced P. vivax radical cure with primaquine after glucose-6-phosphate dehydrogenase (G6PD) qualitative testing in 2019. This paper presents Cambodia’s radical cure Phase I implementation results and assesses the safety, effectiveness, and feasibility of the programme prior to nationwide scale up. Methods Phase I implementation was carried out in 88 select health facilities (HFs) across four provinces. Males over 20kgs with confirmed P. vivax or mixed (P. vivax and Plasmodium falciparum) infections were enrolled. A descriptive analysis evaluated the following: successful referral to health facilities, G6PD testing results, and self-reported 14-day treatment adherence. P. vivax incidence was compared before and after radical cure rollout and a controlled interrupted time series analysis compared the estimated relapse rate between implementation and non-implementation provinces before and after radical cure. Results In the 4 provinces from November 2019 to December 2020, 3,239 P. vivax/mixed infections were reported, 1,282 patients underwent G6PD deficiency testing, and 959 patients received radical cure, achieving 29.6% radical cure coverage among all P. vivax/mixed cases and 98.8% coverage among G6PD normal patients. Among those who initiated radical cure, 747 patients (78%) completed treatment. Six patients reported side effects. In implementation provinces, an average 31.8 relapse cases per month were estimated signaling a 90% (286 cases) reduction in relapse compared to what would be expected if radical cure was not implemented. Conclusions Plasmodium vivax radical cure is a crucial tool for malaria elimination in Cambodia. The high coverage of radical cure initiation and adherence among G6PD normal patients demonstrated the high feasibility of providing radical cure at point of care in Cambodia. Incomplete referral from community to HFs and limited capacity of HF staff to conduct G6PD testing in high burden areas led to lower coverage of G6PD testing. Phase I implementation informed approaches to improve referral completion and patient adherence during the nationwide expansion of radical cure in 2021.

Abstract Background Southeast Asia is making tremendous progress towards their 2030 malaria elimination goal but needs new interventions to stop forest malaria. This study trials two new vector control tools, a volatile pyrethroid spatial repellent (VPSR) and insecticide-treated clothing (ITC), amongst forest-exposed populations in Mondulkiri Province Cambodia to inform their potential use for eliminating forest malaria. Methods 21 forest-exposed individuals were given a questionnaire on their perceptions of malaria and preventive practices used, after which they trialed two products sequentially. Clothes was treated with ITC by the study team. Mixed methods were used to understand their experience, attitudes, and preferences regarding the products trialed. Quantitative data was summarized and qualitative insights were analysed using thematic analysis, applying the Capability, Opportunity, and Motivation Behaviour Change (COM-B) model and Behaviour Change Wheel Framework to identify intervention functions to support tailored product rollout amongst these populations. Results Study participants reported a need for protection from mosquito bites in outdoor and forest-exposed settings and perceived both products trialed to be effective for this purpose. The VPSR product was preferred when travel was not required, whereas ITC was preferred for ease of use when going to the forest, especially in rainy conditions. COM-B analysis identified that key enablers for use of both products included their perceived efficacy and ease of use, which required no skill or preparation. For barriers to use, the odour of ITC was sometimes perceived as being toxic, as well as its inability to protect uncovered skin from mosquito bites, while the perceived usefulness of the VPSR product trialed was limited by its water sensitivity in rainy forest settings. Intervention components to encourage appropriate and sustained use of these products include education about how to use these products and what to expect, persuasion to use them from community leaders and targeted channels, and enablement to facilitate convenient and affordable access. Conclusion The rollout of VPSRs and ITC amongst forest-exposed populations can be useful for eliminating malaria in Southeast Asia. Study findings can be applied to increase product uptake among forest exposed populations in Cambodia, while manufacturers can aim to develop products that are rainproof, easy to use in forest settings, and have favourable odour profiles to target users.

Abstract Background Malaria is a mosquito-borne disease that is one of the most serious public health issues globally and a leading cause of mortality in many developing countries worldwide. Knowing the prevalence of both symptomatic and asymptomatic malaria on a subnational scale allows for the estimation of the burden of parasitaemia present in the transmission system, enabling targeting and tailoring of resources towards greater impact and better use of available capacity. This study aimed to determine the PCR-based point prevalence of malaria infection, by parasite species, among three high-risk populations in Mondulkiri province, Cambodia: forest rangers, forest dwellers, and forest goers. Methods A cross-sectional survey was performed during the transmission season in November and December 2021. Blood samples collected on filter paper from participants (n = 1301) from all target groups were screened for Plasmodium spp using PCR. Results Malaria prevalence among all study participants was 6.7% for any Plasmodium species. Malaria prevalence in the forest ranger group was 8.1%, was 6.8% in forest goers, and 6.4% in forest dwellers; all infections were asymptomatic. Plasmodium vivax was detected in all participant groups, while the few Plasmodium falciparum infections were found in goers and dwellers. 81% of all infections were due to P. vivax, 9% were due to P. falciparum, 3% due to Plasmodium cynomolgi, and the rest (7%) remained undefined. Gender was associated with malaria infection prevalence, with male participants having higher odds of malaria infection than female participants (OR = 1.69, 95% CI 1.08–2.64). Passively collected malaria incidence data from the Cambodian government were also investigated. Health facility-reported malaria cases, based on rapid diagnostic tests, for the period Jan-Dec 2021 were 521 Plasmodium vivax (0.89% prevalence), 34 P. falciparum (0.06%) and four P. falciparum + mixed (0.01%)—a total of 559 cases (0.95%) for all of Mondulkiri. Conclusion This reservoir of asymptomatic parasitaemia may be perpetuating low levels of transmission, and thus, new strategies are required to realize the goal of eliminating malaria in Cambodia by 2025.

Abstract 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.

Abstract Background Malaria in Cambodia has decreased by 90.8% between 2010 and 2020, driven by the commitment of the National Center for Parasitology, Entomology and Malaria (CNM) and the achievements of the roll-out of a village malaria worker programme. However, in the first seven months of 2018, CNM identified a 207% increase (11,969 to 36,778) in confirmed malaria cases compared to the same months in the previous year. To address this increase, CNM developed the “Intensification Plan” (IP), implemented between October 2018 and December 2020. Methods The structure of the IP was summarized, including the selection of sites, the interventions implemented in the selected health facility catchment areas (HFCAs) and the monitoring and evaluation process. Data on IP interventions were collected by CNM and civil society organisations. Data on malaria cases and tests from all HFCAs in Cambodia from January 2018 to December 2020 were sourced from the Cambodia Malaria Information System (MIS) and WHO Malaria Elimination Database. Malaria data from IP HFCAs and non-IP HFCAs was analysed and compared to present the changes in malaria testing and confirmed cases before and during implementation of the IP. Results Between October 2018 and December 2020, through the IP 16,902 forest packs and 293,090 long-lasting insecticide treated nets were distributed. In the 45 HFCAs included in the IP, 431,143 malaria tests were performed and 29,819 malaria cases were diagnosed, 5364 (18%) of which were Plasmodium falciparum/mixed cases. During the intervention period, over all HFCAs included in IP, P. falciparum/mixed cases declined from 1029 to 39, a 96.2% decrease, and from 25.4 P. falciparum/mixed cases per HFCA to 0.9. HFCAs not included in IP declined from 468 to 43 cases, a 90.8% decrease, showing that routine malaria activities in Cambodia were also playing an important contribution to malaria control. Conclusions Over the course of IP implementation there was a substantial increase in malaria testing and both overall malaria cases and P. falciparum/mixed cases decreased month on month. The initiative yields lessons learned for Cambodia to reach the final stage of elimination as well as for other countries aiming to accelerate their malaria control programmes.

Abstract 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.

Abstract Background Remaining Plasmodium falciparum cases in Cambodia are concentrated in forested border areas and in remote populations who are hard to reach through passive case detection. A key approach to reach these populations is active case detection by mobile malaria workers (MMWs). However, this is operationally challenging because of changing movement patterns of the target population moving into less accessible areas. From January 2018 to December 2020, a tailored package of active case detection approaches was implemented in forested border areas of three provinces in north-eastern Cambodia to reach remote populations and support the elimination of falciparum malaria. Methods Key elements of this project were to tailor approaches to local populations, use responsive monitoring systems, maintain operational flexibility, build strong relationships with local communities, and implement close supervision practices. MMWs were recruited from local communities. Proactive case detection approaches included mobile malaria posts positioned at frequented locations around and within forests, and locally informed outreach activities targeting more remote locations. Reactive case detection was conducted among co-travellers of confirmed cases. Testing for malaria was conducted independent of fever symptoms. Routine monitoring of programmatic data informed tactical adaptations, while supervision exercises ensured service quality. Results Despite operational challenges, service delivery sites were able to maintain consistently high testing rates throughout the implementation period, with each of 45 sites testing a monthly average of 64 (SD 6) people in 2020. In 2020, project MMWs detected only 32 P. falciparum cases. Over the project period, the P. falciparum/P. vivax ratio steadily inversed. Including data from neighbouring health centres and village malaria workers, 45% (80,988/180,732) of all people tested and 39% (1280/3243) of P. falciparum cases detected in the area can be attributed to project MMWs. Remaining challenges of the last elimination phase include maintaining intensified elimination efforts, addressing the issue of detecting low parasitaemia cases and shifting focus to P. vivax malaria. Conclusions Reaching remote populations through active case detection should remain a key strategy to eliminate P. falciparum malaria. This case study presented a successful approach combining tailored proactive and reactive strategies that could be transferred to similar settings in other areas of the Greater Mekong Subregion.

Abstract Background Cambodia has targeted malaria elimination within its territory by 2025 and is developing a model elimination package of strategies and interventions designed to achieve this goal. Methods Cambodia adopted a simplified 1-3-7 surveillance model in the Sampov Loun operational health district in western Cambodia beginning in July 2015. The 1-3-7 approach targets reporting of confirmed cases within one day, investigation of specific cases within three days, and targeted control measures to prevent further transmission within seven days. In Sampov Loun, response measures included reactive case detection (testing of co-travelers, household contacts and family members, and surrounding households with suspected malaria cases), and provision of health education, and insecticide-treated nets. Day 28 follow up microscopy was conducted for all confirmed P. falciparum and P. falciparum-mixed-species malaria cases to assess treatment efficacy. Results The number of confirmed malaria cases in the district fell from 519 in 2015 to 181 in 2017, and the annual parasite incidence (API) in the district fell from 3.21 per 1000 population to 1.06 per 1000 population. The last locally transmitted case of malaria in Sampov Loun was identified in March 2016. In response to the 408 index cases identified, 1377 contacts were screened, resulting in the identification of 14 positive cases. All positive cases occurred among index case co-travelers. Conclusion The experience of the 1-3-7 approach in Sampov Loun indicates that the basic essential malaria elimination package can be feasibly implemented at the operational district level to achieve the goal of malaria elimination in Cambodia and has provided essential information that has led to the refinement of this package.

Abstract Cambodia targets malaria elimination by 2025. Rapid elimination will depend on successfully identifying and clearing malaria foci linked to forests. Expanding and maintaining universal access to early diagnosis and effective treatment remains the key to malaria control and ultimately malaria elimination in the Greater Mekong Subregion (GMS) in the foreseeable future. Mass Drug Administration (MDA) holds some promise in the rapid reduction of Plasmodium falciparum infections, but requires considerable investment of resources and time to mobilize the target communities. Furthermore, the most practical drug regimen for MDA in the GMS—three rounds of DHA/piperaquine—has lost some of its efficacy. Mass screening and treatment benefits asymptomatic P. falciparum carriers by clearing chronic infections, but in its current form holds little promise for malaria elimination. Hopes that “highly sensitive” diagnostic tests would provide substantial advances in screen and treat programmes have been shown to be misplaced. To reduce the burden on P. falciparum and Plasmodium vivax infections in people working in forested areas novel approaches to the use of malaria prophylaxis in forest workers should be explored. During an October 2019 workshop in Phnom Penh researchers and policymakers reviewed evidence of acceptability, feasibility and effectiveness of interventions to target malaria foci and interrupt P. falciparum transmission and discussed operational requirements and conditions for programmatic implementation.

Abstract Background Malaria transmission is highly heterogeneous, especially in low endemic countries, such as Cambodia. This results in geographical clusters of residual transmission in the dry, low transmission season, which can fuel the transmission to wider areas or populations during the wet season. A better understanding of spatial clustering of malaria can lead to a more efficient, targeted strategy to reduce malaria transmission. This study aims to evaluate the potential of the use of serological markers to define spatial patterns in malaria exposure. Methods Blood samples collected in a community-based randomized trial performed in 98 high endemic communities in Ratanakiri province, north-eastern Cambodia, were screened with a multiplex serological assay for five serological markers (three Plasmodium falciparum and two Plasmodium vivax). The antibody half-lives range from approximately six months until more than two years. Geographical heterogeneity in malaria transmission was examined using a spatial scan statistic on serology, PCR prevalence and malaria incidence rate data. Furthermore, to identify behavioural patterns or intrinsic factors associated with malaria exposure (antibody levels), risk factor analyses were performed by using multivariable random effect logistic regression models. The serological outcomes were then compared to PCR prevalence and malaria incidence data. Results A total of 6502 samples from two surveys were screened in an area where the average parasite prevalence estimated by PCR among the selected villages is 3.4 %. High-risk malaria pockets were observed adjacent to the ‘Tonle San River’ and neighbouring Vietnam for all three sets of data (serology, PCR prevalence and malaria incidence rates). The main risk factors for all P. falciparum antigens and P. vivax MSP1.19 are age, ethnicity and staying overnight at the plot hut. Conclusion It is possible to identify similar malaria pockets of higher malaria transmission together with the potential risk factors by using serology instead of PCR prevalence or malaria incidence data. In north-eastern Cambodia, the serological markers show that malaria transmission occurs mainly in adults staying overnight in plot huts in the field. Pf.GLURP.R2 showed a shrinking pocket of malaria transmission over time, and Pf.MSP1.19, CSP, PvAMA1 were also informative for current infection to a lesser extent. Therefore, serology could contribute in future research. However, further in-depth research in selecting the best combination of antigens is required.

Abstract Background The presence of artemisinin-resistant malaria parasites was confirmed in western Cambodia in 2009. In 2013, mutations in the propeller domain of the kelch protein K13 was found to be associated with artemisinin resistance. A cross-sectional study was conducted to determine the prevalence of Day-3 parasitaemia, estimate the frequency of k13 molecular marker and assess their relationship in the context of operational research. Methods Blood smears and filter paper blood spots were collected from febrile patients in Kravanh District, Pursat Province. The blood smears were examined by microscopy, and blood spots by a k13 mutation assay. Results Data from 92 patients were analysed. Only one was positive for Day-3 parasitaemia. Results of the k13 assay were interpretable for 76 of the 92 samples. The findings were: wild type: 9 (12%), C580Y: 64 (84%), Y493H: 3 (4%). Therefore, despite the high prevalence of k13 mutants (67/76: 88%), only 1 of the 92 patients remained blood smear positive for Plasmodium falciparum on Day-3. Conclusions These preliminary findings suggest good potency of artemisinin despite the dominance of k13 mutation in Kravanh, but the result is not necessarily representative of the western part of Cambodia. Further investigation should be made to determine if k13 marker remains useful as a tool for tracking artemisinin resistance and predicting the trend of the efficacy of artemisinin combination therapy once the mutant alleles have been well established in the population.

After publication of the article [1], it has been brought to our attention that the funding acknowledgements for this article are incomplete. The authors would like to also include the following.