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.

Cambodia malaria indicator survey 2020: Implications for malaria elimination.

BACKGROUND: Cambodia has made significant progress in controlling malaria in the past decade. It now aims to eliminate malaria from the country by 2025. It launched the Malaria Elimination Action Framework (MEAF 2016-2020) in 2015 with strong political commitment targeting appropriate interventions on high-risk populations, particularly mobile and migrant groups. METHODS: In 2020, the household-level Cambodia Malaria Survey 2020 (CMS 2020) was conducted with the objective to assess the performance of malaria control activities using the indicators outlined in MEAF 2016-2020. The survey used a cross-sectional probability proportional to size approach drawing 4,000 households from 100 villages across the malaria-endemic districts of the country. RESULTS: A total of 3,996 households with 17,415 inhabitants were interviewed. Of the surveyed households, 98.4% owned a long-lasting insecticide-treated bednet or hammock (LLIN/LLIHN). However, only 79.5% of these reported sleeping under a net the previous night, with only 45.7% sleeping under an insecticide treated net (ITN). Given that forest visitors are at the highest risk of getting malaria, the survey also targeted this group. Of the forest visitor respondents, 89.3% brought an ITN along and 88.9% reported to have used a net during their forest stay. About 10.8% of forest goers had received a forest kit for malaria prevention from mobile malaria workers the last time they went to the forest. Knowledge about mosquito repellents was high among forest goers (62.5%) but the actual use thereof during the last visit to the forest was low (22%). While awareness about malaria prevention with LLINs remained high among most respondents, knowledge about malaria diagnosis and treatment was not universal. Source of malaria knowledge and its treatment was usually from a household member, followed by a village malaria worker or a primary health care center staff. Of those who had fever during the previous two weeks, 93.6% sought advice or treatment outside the home, and the most commonly reported source for advice or treatment was private providers (39.4%) followed by health center/district hospital (31.3%). CONCLUSIONS: ITN distribution and other malaria prevention interventions have largely benefited the high-risk groups including the forest visitors. Comparing the CMS 2020 results with the 2017 CMS results, it is clear that forest visitors' use of LLIN/LLIHN has improved considerably. However, more needs to be done to ensure forest visitors be protected either through using LLINs or repellents while working and staying in the forest areas. Also, given that sleeping under LLINs has decreased over the past several years among the at-risk populations, the programme will have to develop strategies to ensure that the communities do not lower their guard against malaria as cases further dwindle in malaria prone areas. Heightened awareness amongst the general population will be critical for eliminating malaria in Cambodia without any possibility of malaria re-emergence or re-establishment.

Strategic priorities for TB control in Bangladesh, Indonesia, and the Philippines - comparative analysis of national TB prevalence surveys.

BACKGROUND: Philippines, Indonesia, and Bangladesh are three high tuberculosis (TB) burden countries in Asia which account for 18% of the estimated global TB incidence (1.8 million) and 15% of TB related deaths (192,000). In 2017 alone, approximately 785,000 of the incident TB cases in these countries remained missing, including diagnosed but not notified. METHODS: We reviewed the published data from the most recent TB prevalence surveys conducted in Bangladesh, Indonesia, and the Philippines. The prevalence rates established by the surveys were used to estimate the disease burden of these countries for 2017. The Global TB Report 2017 and World Health Organization's (WHO) global TB database were sourced for collection of incidence and notification data by age groups and types of TB to estimate prevalence to notification gaps 2017. RESULTS: According to the surveys, the estimated prevalence rates of bacteriologically confirmed TB and smear-positive TB are 287 and 113 for Bangladesh (2015-16), 759 and 256 for Indonesia (2013-14) and 1159 and 434 for the Philippines (2016) per 100,000 population over the age of 15 years. The overall national TB prevalence estimates for all forms is 260 for Bangladesh, 660 for Indonesia, and 970 for the Philippines (2016). Compared with the incidence rate, the proportion of total notified cases is 67% for Bangladesh, 52% for Indonesia, and 55% for the Philippines. Bangladesh has been able to detect almost 100% of the prevalent pulmonary TB, while Indonesia and Philippines have detected only 30 and 22% of these infectious cases respectively. Although notification has been improving over the years, there is no impact on the incidence rate since a large proportion of the undiagnosed cases, and delayed diagnosis continue to feed the transmission process. CONCLUSION: The surveys have provided data that is critical for developing realistic strategies for these countries to eliminate TB. In general, this paper recommends interventions for strengthening diagnosis of pulmonary TB, implementing targeted communication programs and active case finding to reduce patient level delays, expanding public-private partnership to increase access to TB services, using rapid diagnostics, and providing social protection for vulnerable populations. These measures can accelerate these countries' progress towards achieving End TB goals.

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.

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.

Decentralized, Community-Based Treatment for Drug-Resistant Tuberculosis: Bangladesh Program Experience.

BACKGROUND: Bangladesh is a highly populous country where the prevalence of drug-resistant tuberculosis (DR-TB) is growing. With the rapid increase in DR-TB notifications through GeneXpert technology, it was imperative to come up with a new treatment strategy that could keep up with the increase of patients diagnosed. INTERVENTION: Intervention was designed to support national transition of DR-TB management of World Health Organization-approved long course (20-to-24-month regimen) treatment from a hospital-based approach to the decentralized model of community-based programmatic management of DR-TB (cPMDT). In close coordination with the Ministry of Health and Family Welfare and National TB Program, patients were initiated into treatment at hospitals and then transferred to community-based care. A cadre of directly observed therapy providers supported treatment at the household level, supervised by the outpatient DR-TB teams. METHODS: We conducted a descriptive pre- and post-intervention study of all 1,946 DR-TB patients enrolled in treatment nationwide between May 2012 and June 2015. Data were collected from hospitals, patient cards, district records, and diagnostic laboratories through the National TB Program. Intervention results were assessed in comparison with the baseline (2011) indicators. RESULTS: During the intervention period, treatment enrollment of 1,946 diagnosed DR-TB patients through the national program increased from 50% in 2011 to 100% in 2015. The delay between diagnosis and treatment initiation decreased from 69 days in 2011 to 6 days in 2014. Most (95%) of the patients completed all scheduled follow-up smear and culture tests. By the sixth month of treatment, 99% of patients had negative smear conversion and 98% had negative culture conversion. The treatment success rate increased from 70% in 2011 to 76% in 2015 at the end of the intervention period. The results also indicate a decline between baseline and end line from 14% to 9% for patients died, 14% to 10% for loss to follow-up, and 1.7% to 0% for treatment failure. CONCLUSIONS: Community-based management is an effective approach for increasing access to quality-assured DR-TB treatment. Using existing structures and resources, the intervention demonstrated that favorable treatment outcomes can be achieved and sustained by treating patients with DR-TB at their homes.

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.

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.

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.

Self-reported substance use in Iraq: findings from the Iraqi National Household Survey of Alcohol and Drug Use, 2014.

AIMS: To estimate the prevalence of tobacco, alcohol and drug use in Iraq using data from the Iraqi National Household Survey of Alcohol and Drug Use (INHSAD). DESIGN: A cross-sectional survey was conducted using a multi-stage cluster sampling method. Trained surveyors conducted face-to-face household interviews. SETTING: Iraq, from April 2014 to December 2014. PARTICIPANTS: A total of 3200 adult, non-institutionalized Iraqi citizens residing across all 18 governorates of Iraq. MEASUREMENTS: We estimated weighted prevalence and 95% confidence intervals (CIs) for life-time, past-year and past-month use of a variety of substances (tobacco, alcohol, prescription drugs and illicit drugs). For each substance, we also estimated whether individuals knew people who currently use the substance. FINDINGS: Self-reported past-month tobacco use was 23.2% (95% CI = 21.40, 25.19). Past-month alcohol use was 3.2% (95% CI = 2.58, 3.93). Women reported significantly lower prevalence for both tobacco and alcohol use compared with men (P-value < 0.01 for both). Only 1.4% (95% CI = 0.67, 3.02) reported past-month non-medical use of any prescription drugs. None of the women reported using any illicit drugs, and only 0.2% (95% CI = 0.07, 0.49) of men reported using any illicit drugs in the past month. Approximately 90.5% (95% CI = 88.58, 92.11) knew someone who uses tobacco, 42.4% (95% CI = 39.53, 45.24) knew someone who drinks alcohol, 27.9% (95% CI = 25.53, 30.45) knew someone who uses medication outside a doctor's instructions and 9.2% (95% CI = 7.87, 10.75) knew someone who uses an illicit drug. CONCLUSIONS: Psychoactive drug use is generally low in Iraq, tobacco being highest at an estimated 23.2%. Iraqi women report significantly less substance use than Iraqi men, which may be related to cultural gender norms. Discrepancy between self-report and 'knowing someone who uses a substance' suggests under-reporting in this population.

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.