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BACKGROUND: Southeast Asia is undergoing an epidemiological transition with non-communicable illnesses becoming increasingly important, yet infectious diseases (tuberculosis, HIV, hepatitis B, malaria) remain widely prevalent in some populations, while emerging and zoonotic diseases threaten. There are also limited population-level estimates of many important heath conditions. This restricts evidence-based decision-making for disease control and prevention priorities. Cross-sectional surveys can be efficient epidemiological tools to measure the prevalence of a wide range of diseases, but no systematic assessment of their coverage of different health conditions has been produced for the region. METHODS: We conducted a systematic search in Medline, Embase, Global Health, CINAHL, Scopus, Web of Science Core Collection, and Global Index Medicus, and additionally Google Scholar. Our inclusion criteria were cross-sectional surveys conducted with community-based recruitment, in Bangladesh, Cambodia, Laos, Myanmar, and Thailand, published between January 1, 2010 and January 27, 2021, and reporting the prevalence of any health condition. RESULTS: 542 publications from 337 surveys were included. Non-communicable conditions (n = 205) were reported by more surveys than infectious conditions (n = 124). Disability (n = 49), self-report history of any disease or symptoms (n = 35), and self-perceived health status (n = 34), which reflect a holistic picture of health, were studied by many fewer surveys. In addition, 45 surveys studied symptomatic conditions which overlap between non-communicable and infectious conditions. The most surveyed conditions were undernutrition, obesity, hypertension, diabetes, intestinal parasites, malaria, anemia, diarrhea, fever, and acute respiratory infections. These conditions overlap with the most important causes of death and disability in the Global Burden of Disease study. However, other high-burden conditions (e.g. hearing loss, headache disorder, low back pain, chronic liver and kidney diseases, and cancers) were rarely studied. CONCLUSION: There were relatively few recent surveys from which to estimate representative prevalences and trends of health conditions beyond those known to be high burden. Expanding the spectrum of health conditions in cross-sectional surveys could improve understanding of evolving disease patterns in the region.
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Enfermedades no Transmisibles , Humanos , Asia Sudoriental/epidemiología , Enfermedades Transmisibles/epidemiología , Estudios Transversales , Estado de Salud , Encuestas Epidemiológicas , Enfermedades no Transmisibles/epidemiología , PrevalenciaRESUMEN
Investment in community health workers is essential.
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Antimaláricos , Artemisininas , Agentes Comunitarios de Salud , Resistencia a Medicamentos , Malaria Falciparum , Plasmodium falciparum , Humanos , África/epidemiología , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Artemisininas/farmacología , Agentes Comunitarios de Salud/economía , Resistencia a Medicamentos/genética , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genéticaRESUMEN
Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and increased copies of plasmepsin II/III (pm2/3). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) pfcrt allele and a single copy of pm2/3, while KH004 has a chloroquine-resistant (Dd2-like) pfcrt allele with an additional G367C substitution and multiple copies of pm2/3. We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at pfcrt and pm2/3. We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC50. We find that inheritance of the KH004 pfcrt allele is required for reduced PPQ sensitivity, whereas copy number variation in pm2/3 further decreases susceptibility but does not confer resistance in the absence of additional mutations in pfcrt. A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions of pfcrt, pm2/3, and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 pm2/3 was inherited among the progeny clones, allowing us to directly test the role of the pm2/3 copy number on resistance-related phenotypes in the context of a unique pfcrt allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.
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Antimaláricos , Ácido Aspártico Endopeptidasas , Resistencia a Medicamentos , Proteínas de Transporte de Membrana , Plasmodium falciparum , Proteínas Protozoarias , Quinolinas , Plasmodium falciparum/genética , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Resistencia a Medicamentos/genética , Antimaláricos/farmacología , Quinolinas/farmacología , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Proteínas de Transporte de Membrana/genética , Malaria Falciparum/parasitología , Malaria Falciparum/tratamiento farmacológico , Humanos , Alelos , Cambodia , Mutación , PiperazinasRESUMEN
INTRODUCTION: The national malaria programme of Cambodia targets the rapid elimination of all human malaria by 2025. As clinical cases decline to near-elimination levels, a key strategy is the rapid identification of malaria outbreaks triggering effective action to interrupt local transmission. We report a comprehensive, multipronged management approach in response to a 2022 Plasmodium falciparum outbreak in Kravanh district, western Cambodia. METHODS: The provincial health department of Pursat in conjunction with the Center for Parasitology, Entomology and Malaria Control (CNM) identified villages where transmission was occurring using clinical records, and initiated various interventions, including the distribution of insecticide-treated bed nets, running awareness campaigns, and implementing fever screening with targeted drug administration. Health stations were set up at forest entry points, and later, targeted drug administrations with artesunate-pyronaridine (Pyramax) and intermittent preventive treatment for forest goers (IPTf) were implemented in specific village foci. Data related to adherence and adverse events from IPTf and TDA were collected. The coverage rates of interventions were calculated, and local malaria infections were monitored. RESULTS: A total of 942 individuals were screened through active fever surveillance in villages where IPTf and TDA were conducted. The study demonstrated high coverage and adherence rates in the targeted villages, with 92% (553/600) coverage in round one and 65% (387/600) in round two. Adherence rate was 99% (551/553) in round one and 98% (377/387) in round two. The study found that forest goers preferred taking Pyramax over repeated testing consistent with the coverage rates: 92% in round one compared to 65% in round two. All individuals reachable through health stations or mobile teams reported complete IPTf uptake. No severe adverse events were reported. Only six individuals reported mild adverse events, such as loss of energy, fever, abdominal pain, diarrhoea, and muscle aches. Two individuals attributed their symptoms to heavy alcohol intake following prophylaxis. CONCLUSIONS: The targeted malaria outbreak response demonstrated high acceptability, safety, and feasibility of the selected interventions. Malaria transmission was rapidly controlled using the available community resources. This experience suggests the effectiveness of the programmatic response for future outbreaks.
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Engaging young people in health research has been promoted globally. We explored the outcomes of youth advisory group on health and research engagement (YAGHRE) in rural Cambodia. In May 2021, the Mahidol Oxford Tropical Medicine Research Unit (MORU) partnered with a local health centre and a secondary school to establish a youth engagement group. Ten students underwent training and led health engagement activities in schools and communities. Activities were documented as field notes and audio-visual materials which underwent content analysis using theory of change supplemented by iterative discussions with YAGHRE members and stakeholders. Five major outcomes were identified: 1. Increased respect. Engagement activities developed based on input from students and stakeholders may have fostered greater respect. 2. Built trust and relationships. Frequent visits to MORU's laboratory and interactions with researchers appeared to contribute to the building of trust and relationship. 3. Improved health and research literacy. Learning new health and research topics, through participatory activities may have improved literacy; 4. Improved uptake of health and research interventions. Health promotional activities and communication with research participants potentially increased the uptake of interventions; 5. Improved community health. YAGHRE's health promotional interventions may have contributed in enhancing community's health.
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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.
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Agentes Comunitarios de Salud , Malaria , Embarazo , Humanos , Femenino , Investigación Operativa , Malaria/prevención & control , Malaria/diagnóstico , Cambodia/epidemiología , Encuestas y CuestionariosRESUMEN
The reduction of deaths from malaria in sub-Saharan Africa (SSA) is stalling, whereas many countries in Southeast Asia are approaching malaria elimination. We reviewed the role of community health worker (CHW) programmes in malaria control and elimination between regions, with a more detailed description of the programmes in Tanzania and Cambodia. Compared with Tanzania, Cambodia has a much more developed CHW network, which has been pivotal in the near elimination of malaria. In Tanzania, the malaria burden has remained similar over the last decade and treatment continues to rely on healthcare facilities, which provide more limited access to early diagnosis and treatment. Overall, the proportion of malaria cases treated by CHWs is substantially lower in SSA than in Southeast Asia. Even though networks of CHWs are resource intensive and malaria epidemiology differs substantially between countries, there is a strong case for expanding CHW networks in rural SSA to improve early access to effective malaria treatment and reduce the malaria burden.
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Agentes Comunitarios de Salud , Malaria , Humanos , Cambodia/epidemiología , Tanzanía/epidemiología , Malaria/epidemiología , Malaria/prevención & control , Población RuralRESUMEN
INTRODUCTION: Causes of deaths often go unrecorded in lower income countries, yet this information is critical. Verbal autopsy is a questionnaire interview with a family member or caregiver to elicit the symptoms and circumstances preceding a death and assign a probable cause. The social and cultural aspects of verbal autopsy have gotten less attention than the technical aspects and have not been widely explored in South and Southeast Asia settings. METHODS: Between October 2021 and March 2023, prior to implementing a verbal autopsy study at rural sites in Bangladesh, Cambodia, Laos, Myanmar and Thailand, focus group discussions were conducted with village heads, religious leaders and community members from varied demographic backgrounds. Thematic analysis elucidated customs and traditional views surrounding death to understand local ethnocultural sensitivities. RESULTS: We found that death rituals varied greatly among religions, ethnicities and by socioeconomic status. Mourning periods were reported to last 3-100 days and related to the cause of death, age and how close the deceased person was to the family. Participants advised that interviews should happen after mourning periods to avoid emotional distress, but not long after so as to avoid recall bias. Interviewers should be introduced to respondents by a trusted local person. To provide reassurance and confidentiality, a family's residence is the preferred interview location. Interview questions require careful local language translation, and community sensitisation is important before data collection. CONCLUSION: Verbal autopsy is acceptable across a wide range of cultural settings in Southeast Asia, provided that local norms are preidentified and followed.
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Familia , Humanos , Causas de Muerte , Autopsia , Encuestas y Cuestionarios , Asia SudorientalRESUMEN
In this Policy Forum article, James A. Watson and colleagues discuss recent guidelines relating to pre-referral treatment of suspected severe malaria with rectal artesunate suppositories in remote areas.
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Antimaláricos , Artemisininas , Malaria , Humanos , Artesunato/uso terapéutico , Antimaláricos/uso terapéutico , Supositorios , Artemisininas/uso terapéutico , Malaria/tratamiento farmacológico , Derivación y ConsultaRESUMEN
BACKGROUND: Early access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant. METHODS: During 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis. RESULTS: VMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities. CONCLUSIONS: The transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs.
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Educación en Salud , Malaria , Femenino , Embarazo , Humanos , Cambodia/epidemiología , Atención Prenatal , Agentes Comunitarios de Salud , Malaria/epidemiología , Malaria/prevención & controlRESUMEN
In Cambodia, malaria cases are on a trajectory towards the goal of malaria elimination by 2025. Vivax malaria is difficult to eliminate because of hypnozoites that can cause relapse. Primaquine, an 8-aminoquinoline, clears hypnozoites but requires testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Routine primaquine treatment of vivax malaria has recently been implemented in Cambodia in which Village Malaria Workers (VMWs) diagnose vivax malaria by rapid diagnostic test and refer patients to health centres for G6PD testing and further treatment. Patients are referred back to the VMWs for monitoring adverse symptoms and treatment adherence. This article explores how VMWs' roles might be optimized for the community-based management of vivax malaria. With sufficient training and supervision, the role of VMWs might be expanded to include G6PD testing, making referral to the health centre superfluous. Community-based management of vivax malaria could increase the coverage of radical cure and accelerate vivax malaria elimination.
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BACKGROUND: The decline of malaria in Southeast Asia means other causes of fever are increasingly relevant, but often undiagnosed. The objective of this study was to assess the feasibility of point-of-care tests to diagnose acute febrile illnesses in primary care settings. METHODS: A mixed-methods study was conducted at nine rural health centres in western Cambodia. Workshops introduced health workers to the STANDARD(TM) Q Dengue Duo, STANDARD(TM) Q Malaria/CRP Duo and a multiplex biosensor detecting antibodies and/or antigens of eight pathogens. Sixteen structured observation checklists assessed users' performances and nine focus group discussions explored their opinions. RESULTS: All three point-of-care tests were performed well under assessment, but sample collection was difficult for the dengue test. Respondents expressed that the diagnostics were useful and could be integrated into routine clinical care, but were not as convenient to perform as standard malaria rapid tests. Health workers recommended that the most valued point-of-care tests would directly inform clinical management (e.g. a decision to refer a patient or to provide/withhold antibiotics). CONCLUSIONS: Deployment of new point-of-care tests to health centres could be feasible and acceptable if they are user-friendly, selected for locally circulating pathogens and are accompanied by disease-specific education and simple management algorithms.
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Dengue , Malaria , Humanos , Estudios de Factibilidad , Pruebas en el Punto de Atención , Asia Sudoriental , Fiebre/diagnóstico , Fiebre/etiología , Malaria/diagnóstico , Malaria/complicaciones , Dengue/diagnóstico , Dengue/complicacionesRESUMEN
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.
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Antimaláricos , Malaria , Femenino , Humanos , Antimaláricos/uso terapéutico , Arteméter/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Bosques , Malaria/epidemiologíaRESUMEN
Vivax malaria can relapse after an initial infection due to dormant liver stages of the parasite. Radical cure can prevent relapses but requires the measurement of glucose-6-phosphate dehydrogenase enzyme (G6PD) activity to identify G6PD-deficient patients at risk of drug-induced haemolysis. In the absence of reliable G6PD testing, vivax patients are denied radical curative treatment in many places, including rural Cambodia. A novel Biosensor, 'G6PD Standard' (SD Biosensor, Republic of Korea; Biosensor), can measure G6PD activity at the point of care. The objectives of this study were to compare the G6PD activity readings using Biosensors by village malaria workers (VMWs) and hospital-based laboratory technicians (LTs), and to compare the G6PD deficiency categorization recommended by the Biosensor manufacturer with categories derived from a locally estimated adjusted male median (AMM) in Kravanh district, Cambodia. Participants were enrolled between 2021 and 2022 in western Cambodia. Each of the 28 VMWs and 5 LTs received a Biosensor and standardized training on its use. The G6PD activities of febrile patients identified in the community were measured by VMWs; in a subset, a second reading was done by LTs. All participants were tested for malaria by rapid diagnostic test (RDT). The adjusted male median (AMM) was calculated from all RDT-negative participants and defined as 100% G6PD activity. VMWs measured activities in 1344 participants. Of that total, 1327 (98.7%) readings were included in the analysis, and 68 of these had a positive RDT result. We calculated 100% activity as 6.4 U/gHb (interquartile range: 4.5 to 7.8); 9.9% (124/1259) of RDT-negative participants had G6PD activities below 30%, 15.2% (191/1259) had activities between 30% and 70%, and 75.0% (944/1259) had activities greater than 70%. Repeat measurements among 114 participants showed a significant correlation of G6PD readings (rs = 0.784, p < 0.001) between VMWs and LTs. Based on the manufacturer's recommendations, 285 participants (21.5%) had less than 30% activity; however, based on the AMM, 132 participants (10.0%) had less than 30% activity. The G6PD measurements by VMWs and LTs were similar. With the provisions of training, supervision, and monitoring, VMWs could play an important role in the management of vivax malaria, which is critical for the rapid elimination of malaria regionally. Definitions of deficiency based on the manufacturer's recommendations and the population-specific AMM differed significantly, which may warrant revision of these recommendations.
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CARAMAL was a large observational study which recorded mortality in children with suspected severe malaria before and after the roll-out of rectal artesunate in Nigeria, Uganda and the Democratic Republic of the Congo. The results of CARAMAL have had a huge impact on public health policy leading to a World Health Organization moratorium on the roll-out of rectal artesunate. The conclusion reported in the abstract uses strong causal language, stating that "pre-referral RAS [rectal artesunate suppositories] had no beneficial effect on child survival". We argue that this causal interpretation of the study results is not justified. Data from the CARAMAL study inform chiefly on the strengths and weaknesses of referral systems in these three countries and do not inform reliably as to the beneficial effect of providing access to a known life-saving treatment.
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Antimaláricos , Artemisininas , Malaria , Niño , Humanos , Preescolar , Artesunato/uso terapéutico , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria/tratamiento farmacológico , Derivación y ConsultaRESUMEN
The recent World Health Organization moratorium on rectal artesunate (RAS) for pre-referral treatment of severe childhood malaria is costing young lives. The decision was based on disappointing findings from a large observational study that provided RAS to community health workers with little training and supervision. This non-randomized, operational research has provided useful information to guide the implementation of RAS but is subject to bias and confounding and cannot be used to assess treatment effects. Parenteral artesunate reduces severe malaria mortality and a large body of evidence also shows RAS has lifesaving efficacy. There is now more than a decade of delay in conducting the necessary engagement and training required for successful deployment of RAS. Further delays will result in more preventable deaths.
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Antimaláricos , Artemisininas , Malaria , Humanos , Niño , Artesunato/uso terapéutico , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Administración Rectal , Malaria/tratamiento farmacológico , Derivación y Consulta , Organización Mundial de la SaludRESUMEN
BACKGROUND: Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia. METHODS: We conducted an open-label, individually randomised controlled trial in Cambodia, which recruited participants aged 16-65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether-lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomisation schedule, and randomisation was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1-28, 29-56, or 57-84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete. FINDINGS: Between March 11 and Nov 20, 2020, 1480 individuals were enrolled, of whom 738 were randomly assigned to artemether-lumefantrine and 742 to the multivitamin. 713 participants in the artemether-lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2-4) of 713 participants had parasitaemia or clinical malaria in the artemether-lumefantrine group and 123 (17%, 15-20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12-18; p<0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P vivax were 18 (3%, 95% CI 2-4) in the artemether-lumefantrine group versus 112 (16%, 13-19) in the multivitamin group (absolute risk difference 13%, 95% CI 10-16; p<0·0001). The numbers of participants with P falciparum were two (0·3%, 95% CI 0·03-1·01) in the artemether-lumefantrine group versus 12 (1·7%, 0·9-2·9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0·4-2·4; p=0·013). Overall reported adherence to the full course of medication was 97% (95% CI 96-98; 1797 completed courses out of 1854 courses started) in the artemether-lumefantrine group and 98% (97-98; 1842 completed courses in 1885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1·9% (355 events in 18 806 doses) in the artemether-lumefantrine group and 1·1% (207 events in 19 132 doses) in the multivitamin group (p<0·0001). INTERPRETATION: Antimalarial chemoprophylaxis with artemether-lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust.
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Antimaláricos , Artemisininas , Malaria Falciparum , Malaria , Humanos , Antimaláricos/efectos adversos , Arteméter/uso terapéutico , Artemisininas/uso terapéutico , Fluorenos/uso terapéutico , Etanolaminas/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Lumefantrina/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/prevención & control , Malaria Falciparum/complicaciones , Malaria/tratamiento farmacológico , Malaria/prevención & control , Cambodia/epidemiología , Quimioprevención , Combinación de MedicamentosRESUMEN
BACKGROUND: The amplification of GTP cyclohydrolase 1 (pfgch1) in Plasmodium falciparum has been linked to the upregulation of the pfdhfr and pfdhps genes associated with resistance to the antimalarial drug sulfadoxine-pyrimethamine. During the 1990s and 2000s, sulfadoxine-pyrimethamine was withdrawn from use as first-line treatment in southeast Asia due to clinical drug resistance. This study assessed the temporal and geographic changes in the prevalence of pfdhfr and pfdhps gene mutations and pfgch1 amplification a decade after sulfadoxine-pyrimethamine had no longer been widely used. METHODS: A total of 536 P. falciparum isolates collected from clinical trials in Thailand, Cambodia, and Lao PDR between 2008 and 2018 were assayed. Single nucleotide polymorphisms of the pfdhfr and pfdhps genes were analyzed using nested PCR and Sanger sequencing. Gene copy number variations of pfgch1 were investigated using real-time polymerase chain reaction assay. RESULTS: Sequences of the pfdhfr and pfdhps genes were obtained from 96% (517/536) and 91% (486/536) of the samples, respectively. There were 59 distinct haplotypes, including single to octuple mutations. The two major haplotypes observed included IRNI-AGEAA (25%) and IRNL-SGKGA (19%). The sextuple mutation IRNL-SGKGA increased markedly over time in several study sites, including Pailin, Preah Vihear, Ratanakiri, and Ubon Ratchathani, whereas IRNI-AGEAA decreased over time in Preah Vihear, Champasak, and Ubon Ratchathani. Octuple mutations were first observed in west Cambodia in 2011 and subsequently in northeast Cambodia, as well as in southern Laos by 2018. Amplification of the pfgch1 gene increased over time across the region, particularly in northeast Thailand close to the border with Laos and Cambodia. CONCLUSION: Despite the fact that SP therapy was discontinued in Thailand, Cambodia, and Laos decades ago, parasites retained the pfdhfr and pfdhps mutations. Numerous haplotypes were found to be prevalent among the parasites. Frequent monitoring of pfdhfr and pfdhps in these areas is required due to the relatively rapid evolution of mutation patterns.
Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Malaria Falciparum , Humanos , Plasmodium falciparum , Antagonistas del Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/uso terapéutico , Dihidropteroato Sintasa/genética , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Variaciones en el Número de Copia de ADN , Tetrahidrofolato Deshidrogenasa/genética , Tailandia , Sulfadoxina/farmacología , Sulfadoxina/uso terapéutico , Pirimetamina/farmacología , Pirimetamina/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Resistencia a Medicamentos/genética , Sulfanilamida , Combinación de MedicamentosRESUMEN
BACKGROUND: Quantitative measurement of Glucose-6-Phosphate Dehydrogenase (G6PD) enzyme activity is critical to decide on appropriate treatment and provision of radical cure regimens for vivax malaria. Biosensors are point-of-care semi-quantitative analysers that measure G6PD enzyme activity. The main objective of this study was to evaluate the operational aspects of biosensor deployment in the hands of village malaria workers (VMWs) in Cambodia over a year. METHODS: Following initial orientation and training at Kravanh Referral Hospital, each VMW (n = 28) and laboratory technician (n = 5) was provided a biosensor (STANDARD SD Biosensor, Republic of Korea) with supplies for routine use. Over the next 12 months VMWs convened every month for refresher training, to collect supplies, and to recalibrate and test their biosensors. A quantitative self-administered questionnaire was used to assess the skills necessary to use the biosensor after the initial training. Subsequently, VMWs were visited at their location of work for field observation and evaluation using an observer-administered questionnaire. All quantitative questionnaire-based data were analysed descriptively. Semi-structured interviews (SSIs) were conducted among all participants to explore their experience and practicalities of using the biosensor in the field. SSIs were transcribed and translated into English and underwent thematic analysis. RESULTS: A total of 33 participants completed the training and subsequently used the biosensor in the community. Quantitative assessments demonstrated progressive improvement in skills using the biosensor. VMWs expressed confidence and enthusiasm to use biosensors in their routine work. Providing G6PD testing at the point of first contact avoids a multitude of barriers patients have to overcome when travelling to health centres for G6PD testing and radical cure. Deploying biosensors in routine work of VMWs was also considered an opportunity to expand and strengthen the role of VMWs as health care providers in the community. VMWs reported practical concerns related to the use of biosensor such as difficulty in using two pipettes, difficulty in extracting the code chip from the machine, and the narrow base of buffer tube. CONCLUSIONS: VMWs considered the biosensor a practical and beneficial tool in their routine work. Providing VMWs with biosensors can be considered when followed by appropriate training and regular supervision. Providing community management of vivax malaria at the point of first contact could be key for elimination.