Radical cure for Plasmodium vivax malaria after G6PD qualitative testing in four provinces in Cambodia, results from Phase I implementation.

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.

Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.

BACKGROUND: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. METHODS: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. RESULTS: The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day. CONCLUSION: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Malaria elimination using the 1-3-7 approach: lessons from Sampov Loun, Cambodia.

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.

Prevalence of K13 mutation and Day-3 positive parasitaemia in artemisinin-resistant malaria endemic area of Cambodia: a cross-sectional study.

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.

Correction to: Prevalence of K13 mutation and Day-3 positive parasitaemia in artemisinin-resistant malaria endemic area of Cambodia: a cross-sectional study.

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.

An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia.

BACKGROUND: In 2012, the World Health Organization recommended the addition of single low-dose primaquine (SLDPQ, 0.25 mg base/kg body weight) to artemisinin combination therapies to block the transmission of Plasmodium falciparum without testing for glucose-6-phosphate dehydrogenase deficiency. The targeted group was non-pregnant patients aged ≥ 1 year (later changed to ≥ 6 months) with acute uncomplicated falciparum malaria, primarily in countries with artemisinin-resistant P. falciparum (ARPf). No dosing regimen was suggested, leaving malaria control programmes and clinicians in limbo. Therefore, we designed a user-friendly, age-based SLDPQ regimen for Cambodia, the country most affected by ARPf. METHODS: By reviewing primaquine's pharmacology, we defined a therapeutic dose range of 0.15-0.38 mg base/kg (9-22.5 mg in a 60-kg adult) for a therapeutic index of 2.5. Primaquine doses (1-20 mg) were tested using a modelled, anthropometric database of 28,138 Cambodian individuals (22,772 healthy, 4119 with malaria and 1247 with other infections); age distributions were: 0.5-4 years (20.0 %, n = 5640), 5-12 years (9.1 %, n = 2559), 13-17 years (9.1 %, n = 2550), and ≥ 18 years (61.8 %, n = 17,389). Optimal age-dosing groups were selected according to calculated mg base/kg doses and proportions of individuals receiving a therapeutic dose. RESULTS: Four age-dosing bands were defined: (1) 0.5-4 years, (2) 5-9 years, (3) 10-14 years, and (4) ≥15 years to receive 2.5, 5, 7.5, and 15 mg of primaquine base, resulting in therapeutic doses in 97.4 % (5494/5640), 90.5 % (1511/1669), 97.7 % (1473/1508), and 95.7 % (18,489/19,321) of individuals, respectively. Corresponding median (1st-99th centiles) mg base/kg doses of primaquine were (1) 0.23 (0.15-0.38), (2) 0.29 (0.18-0.45), (3) 0.27 (0.15-0.39), and (4) 0.29 (0.20-0.42). CONCLUSIONS: This age-based SLDPQ regimen could contribute substantially to malaria elimination and requires urgent evaluation in Cambodia and other countries with similar anthropometric characteristics. It guides primaquine manufacturers on suitable tablet strengths and doses for paediatric-friendly formulations. Development of similar age-based dosing recommendations for Africa is needed.

G6PD testing and radical cure for Plasmodium vivax in Cambodia: A mixed methods implementation study.

INTRODUCTION: Cambodia aims to eliminate malaria by 2025, however tackling Plasmodium vivax (P.v) presents multiple challenges. The prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency has prevented the deployment of 8-aminoquinolones for "radical cure", due to the risk of severe haemolysis. Patients with P. vivax have therefore continued to experience recurrent relapses leading to cumulative health and socioeconomic burden. The recent advent of point of care testing for G6PD deficiency has made radical cure a possibility, however at the time of the study lack of operational experience and guidance meant that they had not been introduced. This study therefore aimed to design, implement and evaluate a new care pathway for the radical cure of P.vivax. METHODS: This implementation study took place in Pursat province, Western Cambodia. The interventions were co-developed with key stakeholders at the national, district, and local level, through a continuous process of consultations as well as formal meetings. Mixed methods were used to evaluate the feasibility of the intervention including its uptake (G6PD testing rate and the initiation of primaquine treatment according to G6PD status); adherence (self-reported); and acceptability, using quantitative analysis of primary and secondary data as well as focus group discussions and key informant interviews. RESULTS: The co-development process resulted in the design of a new care pathway with supporting interventions, and a phased approach to their implementation. Patients diagnosed with P.v infection by Village Malaria Workers (VMWs) were referred to local health centres for point-of-care G6PD testing and initiation of radical cure treatment with 14-day or 8-week primaquine regimens depending on G6PD status. VMWs carried out follow-up in the community on days 3, 7 and 14. Supporting interventions included training, community sensitisation, and the development of a smartphone and tablet application to aid referral, follow-up and surveillance. The testing rate was low initially but increased rapidly over time, reflecting the deliberately cautious phased approach to implementation. In total 626 adults received G6PD testing, for a total of 675 episodes. Of these 555 occurred in patients with normal G6PD activity and nearly all (549/555, 98.8%) were initiated on PQ14. Of the 120 with deficient/intermediate G6PD activity 61 (50.8%) were initiated on PQ8W. Self-reported adherence was high (100% and 95.1% respectively). No severe adverse events were reported. The pathway was found to be highly acceptable by both staff and patients. The supporting interventions and gradual introduction were critical to success. Challenges included travel to remote areas and mobility of P.v patients. CONCLUSION: The new care pathway with supporting interventions was highly feasible with high levels of uptake, adherence and acceptability in this setting where high prevalence of G6PD deficiency is high and there is a well-established network of VMWs. Scaling up of the P.v radical cure programme is currently underway in Cambodia and a decline in reduction in the burden of malaria is being seen, bringing Cambodia a step closer to elimination.

Increasing access to early malaria diagnosis and prompted treatment in remote cambodian villages.

Malaria poses a significant public health burden in the remote areas of western Cambodia, where access to health services and information is limited. Recognizing the potential of village malaria workers to reach these communities, the US Agency for International Development-funded Malaria Control in Cambodia project used a multipronged approach to strengthen the village malaria workers network. As a result, the proportion of confirmed malaria cases treated by village malaria workers has doubled during the past 2 years, significantly increasing the numbers being properly diagnosed and treated. Key to the program's success has been the integration of village malaria workers with public health facilities, improved patient access to prompt diagnosis and treatment, and resolution of systemic barriers such as logistics for rapid diagnostic tests.

Performance of Ultrasensitive Rapid Diagnostic Tests for Detecting Asymptomatic Plasmodium falciparum.

Proposed interventions for eliminating drug-resistant Plasmodium falciparum malaria include the targeting of asymptomatic carriers through screening and treatment. We report on the diagnostic performance of the recently developed ultrasensitive rapid diagnostic test (uRDT) compared with screening with conventional RDTs (cRDT) and polymerase chain reaction (PCR) under field conditions in Cambodia in a total of 2,729 individuals. The P. falciparum positivity by quantitative PCR (qPCR) was 3.8% (26/678) in those screened during active case detection and 0.5% (10/2,051) in the cross-sectional survey. Compared with qPCR, the sensitivity of the uRDTs was 53.8% (95% CI: 33.4-73.4%) when used in active case detection and 60.0% (95% CI: 26.2-87.8%) in the cross-sectional survey. The uRDTs did not show a significant improvement in diagnostic performance over cRDTs when used for active case detection and for a malaria prevalence survey in the context of this low-transmission setting.

Cost-effectiveness of malaria elimination in Sampov Loun Operational District, Cambodia.

BACKGROUND: Over the past decade, Cambodia has seen a significant decline in its malaria burden. The government has established the goal of eliminating malaria in the country by 2025. With PMI/USAID support, Cambodia is implementing a package of interventions as part of its efforts. This assessment aimed to describe the cost of malaria elimination activities in Sampov Loun Operational District (OD) between July 2015 and March 2018, to describe the cost per malaria case detected under PMI programming, and to estimate the incremental cost-effectiveness of the elimination programme per Plasmodium falciparum (Pf) or P. vivax (Pv)/Pf mixed case averted under the Cambodia Malaria Elimination Programme (CMEP) and the U.S. President's Malaria Initiative. Opportunity costs of government workers were also assessed to understand the theoretical cost of sustaining this programme through government efforts alone. MATERIALS AND METHODS: We conducted an empirical micro-costing analysis based on elimination activities alone using CMEP internal project implementation data and corresponding epidemiologic data from July 2015 to March 2018 and empirical findings from implementation to date. We then constructed a cost model in Microsoft Excel using empirical data and used a cost-effectiveness decision tree to describe programme effectiveness in the first three years of implementation and to estimate efficacy for the subsequent year. RESULTS: The total cost of malaria elimination activities in Sampov Loun OD from July 2015 to March 2018 was $883,096. The cost per case of malaria detected in 2017 was $1,304. Including opportunity costs for government staff from July 2015 to March 2018, the total cost was $926,000. Under continued CMEP implementation, the projected future total cost of the program would be about $110,000 per year, or $0.64 per Sampov Loun resident. The incremental cost-effectiveness of the elimination programme was $28 for every additional Pf or Pv/Pf mix malaria case averted, compared to the no-CMEP proxy. CONCLUSION: CMEP activities are cost effective compared to the no-CMEP proxy, as shown through an incremental cost-effectiveness of $28 for every additional Pf or Pv/Pf mix malaria case averted. The total cost of the project is 0.93% of the total per capita spending on health in Cambodia and about 5% of all government health expenditure. Continuing investments in malaria will be needed at national level for stewardship and governance and at local level for ensuring programme readiness in case of malaria outbreaks.

Malaria Case Detection Among Mobile Populations and Migrant Workers in Myanmar: Comparison of 3 Service Delivery Approaches.

BACKGROUND: Mobile populations and migrant workers are a key population to containing the spread of artemisinin-resistant malaria found in the border areas between Cambodia, Myanmar, and Thailand. Migrants often have limited knowledge of public health, including malaria, services in the area, and many seek care from unregulated, private vendors. METHODS: Between October 2012 and August 2016, we implemented malaria case finding and treatment in Tanintharyi Region, Kayin State, and Rakhine State of Myanmar through 3 entry points: village malaria workers (VMWs), mobile malaria clinics, and screening points. A total of 1,000 VMWs provided passive case detection and treatment services to residents in malaria-endemic villages. Active case finding through mobile malaria clinics was conducted by staff in 354 remote villages and work sites, where regular monitoring and supervision of VMWs would be difficult to maintain. Malaria screening points were a hybrid combination of active and passive case finding in which screening points were set up at fixed locations in Tanintharyi Region and Kayin State, such as bus stops, ferry docks, or informal border crossing points, and migrants entering into or departing from endemic areas could voluntarily receive malaria testing and treatment. Using routine monitoring data, we assessed and compared the malaria positive rate-the number of positive malaria cases out of those tested-across the 3 approaches as an indication of the programmatic effectiveness in identifying malaria cases in the population. Most testing was conducted with rapid diagnostic tests. RESULTS: Mobile teams (169,859) and VMWs (157,048) tested a higher number of community members than screening points (3,676) as they covered a wider geographical area. However, the malaria positive rate was higher among VMWs (7.29%) and screening points (7.10%) than mobile teams (2.64%). VMWs were located in hard-to-access areas that have higher malaria prevalence and are difficult to reach by vehicle while screening points specifically targeted mobile populations and migrant workers. Mobile teams also screened non-fever patients during their visits, which may explain their lower malaria positive rate. CONCLUSIONS: A combination of malaria testing approaches helps achieve both maximum reach and high case finding as it allows access to a range of migrant communities and provides an opportunity for continuity of service delivery as the migrants travel to their destinations.

How labour intensive is a doctor-based delivery model for antiretroviral treatment (ART)? Evidence from an observational study in Siem Reap, Cambodia.

BACKGROUND: Funding for scaling-up antiretroviral treatment (ART) in low-income countries has increased substantially, but the lack of human resources for health (HRH) is increasingly being identified as an important constraint for scaling-up ART. METHODS: In a clinic run by Médecins Sans Frontières in Siem Reap, Cambodia, we documented the use of doctor-time for ART in September 2004 and in August 2005, for different phases in ART (pre-ART, ART initiation, ART follow-up Year 1, & ART follow-up Year 2). Based on these observations and using a variety of assumptions for survival of patients on ART (between 90 and 95% annually) and for further reductions in doctor-time per patient (between 0 and 10% annually), we estimated the need for doctors for the period 2004 till 2013 in the Siem Reap clinic, and in a hypothetical district in sub-Saharan Africa. RESULTS: In the Siem Reap clinic, we found that from 2004 to 2005 the doctor-time needed per patient was reduced by between 14% and 33%, thanks to a reduction in number of visits per patient and shorter consultation times. In 2004, 2.06 full-time equivalent (FTE) doctors were needed for 522 patients on ART, and in 2005 this was slightly reduced to 1.97 FTE doctors for 911 patients on ART. By 2013, Siem Reap clinic will need between 2 and 5 FTE doctors for ART. In a district in sub-Saharan Africa with 200,000 inhabitants and 20% adult HIV prevalence, using a similar doctor-based ART delivery model, between 4 and 11 FTE doctors would be needed to cover 50% of ART needs. CONCLUSION: ART is labour intensive. Important reductions in doctor-time per patient can be realized during scaling-up. The doctor-based ART delivery model analysed seems adequate for Cambodia. However, for many districts in sub-Saharan Africa a doctor-based ART delivery model may be incompatible with their HRH constraints.