Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. METHODS AND FINDINGS: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. INTERPRETATION: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

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.

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial.

In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. BACKGROUND: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. METHODS: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]), assessed in a modified intention-to-treat population (mITT). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial was registered at ClinicalTrials.gov (NCT05041907) on 13/09/2021. RESULTS: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients given favipiravir and patients receiving no study drug; a -1% (95% credible interval: -14 to 14%) difference. High dose favipiravir was well-tolerated. INTERPRETATION: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19. The viral clearance rate estimated from quantitative measurements of oropharyngeal eluate viral densities assesses the antiviral efficacy of drugs in vivo with comparatively few studied patients.

Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV).

BACKGROUND: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. METHODS: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). RESULTS: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%). CONCLUSIONS: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.

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.

Glucose 6 Phosphate Dehydrogenase (G6PD) quantitation using biosensors at the point of first contact: a mixed method study in Cambodia.

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.

Field evaluation of the diagnostic performance of EasyScan GO: a digital malaria microscopy device based on machine-learning.

BACKGROUND: Microscopic examination of Giemsa-stained blood films remains the reference standard for malaria parasite detection and quantification, but is undermined by difficulties in ensuring high-quality manual reading and inter-reader reliability. Automated parasite detection and quantification may address this issue. METHODS: A multi-centre, observational study was conducted during 2018 and 2019 at 11 sites to assess the performance of the EasyScan Go, a microscopy device employing machine-learning-based image analysis. Sensitivity, specificity, accuracy of species detection and parasite density estimation were assessed with expert microscopy as the reference. Intra- and inter-device reliability of the device was also evaluated by comparing results from repeat reads on the same and two different devices. This study has been reported in accordance with the Standards for Reporting Diagnostic accuracy studies (STARD) checklist. RESULTS: In total, 2250 Giemsa-stained blood films were prepared and read independently by expert microscopists and the EasyScan Go device. The diagnostic sensitivity of EasyScan Go was 91.1% (95% CI 88.9-92.7), and specificity 75.6% (95% CI 73.1-78.0). With good quality slides sensitivity was similar (89.1%, 95%CI 86.2-91.5), but specificity increased to 85.1% (95%CI 82.6-87.4). Sensitivity increased with parasitaemia rising from 57% at < 200 parasite/µL, to ≥ 90% at > 200-200,000 parasite/µL. Species were identified accurately in 93% of Plasmodium falciparum samples (kappa = 0.76, 95% CI 0.69-0.83), and in 92% of Plasmodium vivax samples (kappa = 0.73, 95% CI 0.66-0.80). Parasite density estimates by the EasyScan Go were within ± 25% of the microscopic reference counts in 23% of slides. CONCLUSIONS: The performance of the EasyScan Go in parasite detection and species identification accuracy fulfil WHO-TDR Research Malaria Microscopy competence level 2 criteria. In terms of parasite quantification and false positive rate, it meets the level 4 WHO-TDR Research Malaria Microscopy criteria. All performance parameters were significantly affected by slide quality. Further software improvement is required to improve sensitivity at low parasitaemia and parasite density estimations. Trial registration ClinicalTrials.gov number NCT03512678.

Evolution of Multidrug Resistance in Plasmodium falciparum: a Longitudinal Study of Genetic Resistance Markers in the Greater Mekong Subregion.

Increasing resistance in Plasmodium falciparum to artemisinins and their artemisinin combination therapy (ACT) partner drugs jeopardizes effective antimalarial treatment. Resistance is worst in the Greater Mekong subregion. Monitoring genetic markers of resistance can help to guide antimalarial therapy. Markers of resistance to artemisinins (PfKelch mutations), mefloquine (amplification of P. falciparum multidrug resistance-1 [PfMDR1]), and piperaquine (PfPlasmepsin2/3 amplification and specific P. falciparum chloroquine resistance transporter [PfCRT] mutations) were assessed in 6,722 P. falciparum samples from Vietnam, Lao People's Democratic Republic (PDR), Cambodia, Thailand, and Myanmar between 2007 and 2019. Against a high background prevalence of PfKelch mutations, PfMDR1 and PfPlasmepsin2/3 amplification closely followed regional drug pressures over time. PfPlasmepsin2/3 amplification preceded piperaquine resistance-associated PfCRT mutations in Cambodia and reached a peak prevalence of 23/28 (82%) in 2015. This declined to 57/156 (38%) after first-line treatment was changed from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. The frequency of PfMDR1 amplification increased from 0/293 (0%) between 2012 and 2017 to 12/156 (8%) in 2019. Amplification of PfMDR1 and PfPlasmepsin2/3 in the same parasites was extremely rare (4/6,722 [0.06%]) and was dispersed over time. The mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy.

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.

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.

Tools to accelerate falciparum malaria elimination in Cambodia: a meeting report.

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.

Forest work and its implications for malaria elimination: a qualitative study.

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.

A youth advisory group on health and health research in rural Cambodia.

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.

Artemisinin-resistant malaria in Africa demands urgent action.

Investment in community health workers is essential.

Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial.

BACKGROUND: Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their antiviral activities in patients have not been compared directly. The aim of this ongoing platform trial is to compare different antiviral treatments using the rate of viral clearance as the measure of antiviral effect. METHODS: PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. The component of the trial reported here was conducted in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. We recruited low-risk adult patients aged 18-50 years with early symptomatic COVID-19 (<4 days of symptoms). Eligible patients were randomly assigned using block randomisation via a centralised web app to one of seven treatment groups: molnupiravir, ritonavir-boosted nirmatrelvir, casirivimab-imdevimab, tixagevimab-cilgavimab, favipiravir, fluoxetine, or no study drug. The no study drug group comprised a minimum proportion of 20% of patients at all times, with uniform randomisation ratios applied across the active treatment groups. Results for the concurrently randomised molnupiravir, ritonavir-boosted nirmatrelvir, and no study drug groups are reported here. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population, defined as patients with more than 2 days of follow-up. Safety was assessed in all participants who took at least one dose of the medication. The viral clearance rate was derived under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 1 week (18 measurements). Treatment groups with a probability of more than 0·9 that viral clearance was accelerated by more than 20% compared with no drug entered a non-inferiority comparison (with a 10% non-inferiority margin) compared with the platform's current most effective drug. This ongoing trial is registered at ClinicalTrials.gov, NCT05041907. FINDINGS: Between June 6, 2022, and Feb 23, 2023, 209 patients in Thailand were enrolled and concurrently randomly assigned to molnupiravir (n=65), ritonavir-boosted nirmatrelvir (n=59), or no study drug (n=85). 129 (62%) of the patients were female and 80 (38%) were male. Relative to the no study drug group, the rates of viral clearance were 37% (95% credible interval 16-65) faster with molnupiravir and 84% (54-119) faster with ritonavir-boosted nirmatrelvir. In the non-inferiority comparison, viral clearance was 25% (10-38) slower with molnupiravir than ritonavir-boosted nirmatrelvir. Molnupiravir was removed from the study platform when it reached the prespecified inferiority margin of 10% compared with ritonavir-boosted nirmatrelvir. Median estimated viral clearance half-lives were 8·5 h (IQR 6·7-10·1) with ritonavir-boosted nirmatrelvir, 11·6 h (8·6-15·4) with molnupiravir, and 15·5 h (11·9-21·2) with no study drug. Viral rebound occurred more frequently following nirmatrelvir (six [10%] of 58) compared with the no study drug (one [1%] of 84; p=0·018) or the molnupiravir (one [2%] of 65; p=0·051) groups. Persistent infections following molnupiravir had more viral mutations (three of nine patients had an increased number of single nucleotide polymorphisms in samples collected at 7 or more days compared with those at baseline) than after nirmatrelvir (zero of three) or no study drug (zero of 19). There were no adverse events of grade 3 or worse, or serious adverse events in any of the reported treatment groups. INTERPRETATION: Both molnupiravir and ritonavir-boosted nirmatrelvir accelerate oropharyngeal SARS-CoV-2 viral clearance in patients with COVID-19, but the antiviral effect of ritonavir-boosted nirmatrelvir was substantially greater. Measurement of oropharyngeal viral clearance rates provides a rapid and well tolerated approach to the assessment and comparison of antiviral drugs in patients with COVID-19. It should be evaluated in other acute viral respiratory infections. FUNDING: Wellcome Trust through the COVID-19 Therapeutics Accelerator.

Comparing the roles of community health workers for malaria control and elimination in Cambodia and Tanzania.

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.

Village malaria workers for the community-based management of vivax malaria.

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.

Glucose-6-Phosphate Dehydrogenase (G6PD) Measurement Using Biosensors by Community-Based Village Malaria Workers and Hospital Laboratory Staff in Cambodia: A Quantitative Study.

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.

The feasibility of novel point-of-care diagnostics for febrile illnesses at health centres in Southeast Asia: a mixed-methods study.

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.

Expanding the role of village malaria workers in Cambodia: Implementation and evaluation of four health education packages.

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.