Geospatial joint modeling of vector and parasite serology to microstratify malaria transmission.

The World Health Organization identifies a strong surveillance system for malaria and its mosquito vector as an essential pillar of the malaria elimination agenda. Anopheles salivary antibodies are emerging biomarkers of exposure to mosquito bites that potentially overcome sensitivity and logistical constraints of traditional entomological surveys. Using samples collected by a village health volunteer network in 104 villages in Southeast Myanmar during routine surveillance, the present study employs a Bayesian geostatistical modeling framework, incorporating climatic and environmental variables together with Anopheles salivary antigen serology, to generate spatially continuous predictive maps of Anopheles biting exposure. Our maps quantify fine-scale spatial and temporal heterogeneity in Anopheles salivary antibody seroprevalence (ranging from 9 to 99%) that serves as a proxy of exposure to Anopheles bites and advances current static maps of only Anopheles occurrence. We also developed an innovative framework to perform surveillance of malaria transmission. By incorporating antibodies against the vector and the transmissible form of malaria (sporozoite) in a joint Bayesian geostatistical model, we predict several foci of ongoing transmission. In our study, we demonstrate that antibodies specific for Anopheles salivary and sporozoite antigens are a logistically feasible metric with which to quantify and characterize heterogeneity in exposure to vector bites and malaria transmission. These approaches could readily be scaled up into existing village health volunteer surveillance networks to identify foci of residual malaria transmission, which could be targeted with supplementary interventions to accelerate progress toward elimination.

Key factors associated with malaria infection among patients seeking care through the public sector in endemic townships of Ayeyarwady Region, Myanmar.

BACKGROUND: Ayeyarwady Region in Myanmar has made significant progress towards malaria elimination, with cases decreasing from 12,312 in 2015 to 122 in 2019. As transmission declines, malaria becomes increasingly focalized both in geographic hotspots and among population groups sharing certain risk factors. Developing a thorough profile of high-risk activities associated with malaria infections is critical to ensure intervention approaches are evidence-based. METHODS: A test-negative study was conducted from September 2017 to May 2018 in Ngaputaw, Pathein and Thabaung townships in Ayeyarwady Region. Patients that presented to selected public facilities or community health volunteers with fever answered survey questions on demographic and behavioural risk factors, including exposure to malaria interventions, and were assigned to case and control groups based on the result of a malaria rapid diagnostic test. A random-effects logistic regression model adjusted for clustering at the facility level, as well as any variables along the causal pathway described by a directed acyclic graph, was used to determine odds ratios and association with malaria infections. RESULTS: A total of 119 cases and 1744 controls were recruited from 41 public facilities, with a mean age of 31.3 and 63.7% male. Higher risk groups were identified as males (aOR 1.8, 95% CI 1.2-2.9) and those with a worksite located within the forest (aOR 2.8, 95% CI 1.4-5.3), specifically working in the logging (aOR 2.7, 95% CI 1.5-4.6) and rubber plantation (aOR 3.0, 95% CI 1.4-6.8) industries. Additionally, links between forest travel and malaria were observed, with risk factors identified to be sleeping in the forest within the past month (aOR 2.6, 95% CI 1.1-6.3), and extended forest travel with durations from 3 to 14 days (aOR 8.6, 95% CI 3.5-21.4) or longer periods (aOR 8.4, 95% CI 3.2-21.6). CONCLUSION: Malaria transmission is highly focalized in Ayeyarwady, and results illustrate the need to target interventions to the most at-risk populations of working males and forest goers. It will become increasingly necessary to ensure full intervention coverage of at-risk populations active in forested areas as Myanmar moves closer to malaria elimination goals.

Spatiotemporal dynamics of malaria in Banmauk Township, Sagaing region of Northern Myanmar: characteristics, trends, and risk factors.

BACKGROUND: While national malaria incidence has been declining in Myanmar, some subregions within the nation continue to have high burdens of malaria morbidity and mortality. This study assessed the malaria situation in one of these regions, Banmauk Township, located near the Myanmar-India border. Our goal was to provide a detailed description of the malaria epidemiology in this township and to provide some evidence-based recommendations to formulate a strategy for reaching the national malaria elimination plan. Banmauk consistently has one of the highest malaria burdens in Myanmar. METHODS: With the implementation of strengthened malaria control and surveillance activities after the endorsement of a national malaria elimination plan in 2015, detailed incidence data were obtained for 2016-2018 for Banmauk Township. The data include patient demographics, parasite species, disease severity, and disease outcome. Data were analyzed to identify characteristics, trends, distribution, and risk factors. RESULTS: During 2016-2018, 2,402 malaria cases were reported, with Plasmodium falciparum accounting for 83.4% of infections. Both P. falciparum and P. vivax were transmitted more frequently during the rainy season (May-October). Despite intensified control, the annual parasite incidence rate (API) in 2017 (11.0) almost doubled that in 2016 (6.5). In total, 2.5% (59/2042) of the cases, of which 54 P. falciparum and 5 P. vivax, were complicated cases, resulting in 5 deaths. Malaria morbidity was high in children < 15 years and accounted for 33.4% of all cases and about 47% of the complicated cases. Older age groups and males living with poor transportation conditions were more likely to test positive especially in rainy and cold seasons. Despite the clear seasonality of malaria, severe cases were found among young children even more common in the dry season, when malaria incidence was low. CONCLUSIONS: Despite the declining trend, the malaria burden remained high in Banmauk Township. Our study also documented severe cases and deaths from both falciparum and vivax malaria. P. falciparum remained the predominant parasite species, demanding increased efforts to achieve the goal of elimination of P. falciparum by 2025. As P. falciparum cases decreased, the proportion of cases attributable to P. vivax increased. In order to eliminate malaria, it will likely be important to increasingly target this species as well.

Community-based molecular and serological surveillance of subclinical malaria in Myanmar.

BACKGROUND: In the Greater Mekong Subregion (GMS), current malaria surveillance strategies rely on a network of village health volunteers (VHVs) reporting the results of rapid diagnostic tests (RDTs), known to miss many asymptomatic infections. Integration of more sensitive diagnostic molecular and serological measures into the VHV network may improve surveillance of residual malaria transmission in hard-to-reach areas in the region and inform targeted interventions and elimination responses. However, data on residual malaria transmission that would be captured by these measures in the VHV-led testing and treatment surveillance network in the GMS is unknown. METHODS: A total of 114 VHVs were trained to collect dried blood spots from villagers undergoing routine RDTs as part of VHV-led active and passive case detection from April 2015 to June 2016. Samples were subjected to molecular testing (quantitative polymerase chain reaction [qPCR]) to determine Plasmodium falciparum and P. vivax infection and serological testing (against P. falciparum and P. vivax antigens) to determine exposure to P. falciparum and P. vivax. RESULTS: Over 15 months, 114 VHVs performed 32,194 RDTs and collected samples for molecular (n = 13,157) and serological (n = 14,128) testing. The prevalence of molecular-detectable P. falciparum and P. vivax infection was 3.2% compared to the 0.16% prevalence of Plasmodium spp. by RDT, highlighting the large burden of infections undetected by standard surveillance. Peaks in anti-P. falciparum, but not P. vivax, merozoite IgG seroprevalence coincided with seasonal P. falciparum transmission peaks, even in those with no molecularly detectable parasites. At the individual level, antibody seropositivity was associated with reduced odds of contemporaneous P. falciparum (OR for PfCSP 0.51 [95%CI 0.35, 0.76], p = 0.001, PfAMA1 0.70 [95%CI 0.52, 0.93], p = 0.01, and PfMSP2 0.81 [95%CI 0.61, 1.08], p = 0.15), but not P. vivax infection (OR PvAMA1 1.02 [95%CI 0.73, 1.43], p = 0.89) indicating a potential role of immunity in protection against molecular-detectable P. falciparum parasitaemia. CONCLUSIONS: We demonstrated that integration and implementation of sample collection for molecular and serological surveillance into networks of VHV servicing hard-to-reach populations in the GMS is feasible, can capture significant levels of ongoing undetected seasonal malaria transmission and has the potential to supplement current routine RDT testing. Improving malaria surveillance by advancing the integration of molecular and serological techniques, through centralised testing approaches or novel point-of-contact tests, will advance progress, and tracking, towards malaria elimination goals in the GMS.

Residual malaria among migrant workers in Myanmar: why still persistent and how to eliminate it?

BACKGROUND: Residual malaria is probably an important source for the re-emergence of malaria infection in the elimination era. Assessment to identify the factors influencing residual malaria in high-risk groups is needed to develop evidence-based decisions by stakeholders and policymakers. METHODS: This study was conducted to explore the factors influencing the residual malaria infection among migrant workers in two sentinel sites (endemic vs. pre-elimination areas) in Myanmar using the mixed-model method. RESULTS: A total of 102 migrant respondents (65 in Bamauk and 37 in Shwegyin) were included for the quantitative assessment using pretested questionnaires during household visits. Although 87.3% of them had insecticidal bed nets (ITNs/LLINs), only 68.3% of the migrants in Bamauk and 57.9% in Shwegyin used it regularly. The use of any bed net was high (79.9% in Bamauk vs. 91.0% in Shwegyin). The mean LLINs in their families were 1.64 (95%CI: 1.48-1.81) in Bamauk and 2.89 (95%CI: 2.67-3.11) in Shwegyin. Most of them received no health information for malaria prevention within the last year and their knowledge about malaria was low. Their working nature was a challenge for control measures against malaria in migrants. CONCLUSION: The strategy for distributing LLINs and health promotion activities for mobile/migrant populations should be reviewed, and an appropriate action plan should be developed for the specific migrant group. Moreover, health promotion activities for behavior change communication should be strengthened in the migrant population in Myanmar.

Evaluation of the effectiveness of topical repellent distributed by village health volunteer networks against Plasmodium spp. infection in Myanmar: A stepped-wedge cluster randomised trial.

BACKGROUND: The World Health Organization has yet to endorse deployment of topical repellents for malaria prevention as part of public health campaigns. We aimed to quantify the effectiveness of repellent distributed by the village health volunteer (VHV) network in the Greater Mekong Subregion (GMS) in reducing malaria in order to advance regional malaria elimination. METHODS AND FINDINGS: Between April 2015 and June 2016, a 15-month stepped-wedge cluster randomised trial was conducted in 116 villages in Myanmar (stepped monthly in blocks) to test the effectiveness of 12% N,N-diethylbenzamide w/w cream distributed by VHVs, on Plasmodium spp. infection. The median age of participants was 18 years, approximately half were female, and the majority were either village residents (46%) or forest dwellers (40%). No adverse events were reported during the study. Generalised linear mixed modelling estimated the effect of repellent on infection detected by rapid diagnostic test (RDT) (primary outcome) and polymerase chain reaction (PCR) (secondary outcome). Overall Plasmodium infection detected by RDT was low (0.16%; 50/32,194), but infection detected by PCR was higher (3%; 419/13,157). There was no significant protection against RDT-detectable infection (adjusted odds ratio [AOR] = 0.25, 95% CI 0.004-15.2, p = 0.512). In Plasmodium-species-specific analyses, repellent protected against PCR-detectable P. falciparum (adjusted relative risk ratio [ARRR] = 0.67, 95% CI 0.47-0.95, p = 0.026), but not P. vivax infection (ARRR = 1.41, 95% CI 0.80-2.47, p = 0.233). Repellent effects were similar when delayed effects were modelled, across risk groups, and regardless of village-level and temporal heterogeneity in malaria prevalence. The incremental cost-effectiveness ratio was US$256 per PCR-detectable infection averted. Study limitations were a lower than expected Plasmodium spp. infection rate and potential geographic dilution of the intervention. CONCLUSIONS: In this study, we observed apparent protection against new infections associated with the large-scale distribution of repellent by VHVs. Incorporation of repellent into national strategies, particularly in areas where bed nets are less effective, may contribute to the interruption of malaria transmission. Further studies are warranted across different transmission settings and populations, from the GMS and beyond, to inform WHO public health policy on the deployment of topical repellents for malaria prevention. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482).

Utilization of insecticide-treated bed nets and care-seeking for fever and its associated socio-demographic and geographical factors among under-five children in different regions: evidence from the Myanmar Demographic and Health Survey, 2015-2016.

BACKGROUND: Malaria is one of the top-five contributors to under-5 deaths in Myanmar. Use of insecticide-treated nets (ITN) and receiving early appropriate care in case of fever are the core interventions to prevent malaria and its complications and thereby deaths. This study aimed to assess among the under-five children, (a) utilization of ITNs and its associated factors, (b) care-seeking behaviour among their caregivers and its associated factors and uptake of malaria testing among those with fever in the last 2 weeks. METHODS: This was a cross sectional study using secondary analysis of Myanmar Demographic and Health Survey (MDHS) conducted in 2015-2016. Multivariable logistic regression was used to explore the factors associated with non-utilization of ITNs and not seeking care for fever. Effect sizes have been presented using odds ratios with 95% confidence intervals. Data analysis was done using svyset command in STATA to account for the multi-stage sampling design of the survey. RESULTS: Of 4597 alive under-five children, 80.5% did not sleep under an ITN last night. The factors significantly associated with non-utilization of ITNs were residing in malaria elimination regions (aOR = 2.0, 1.3-3.2), urban residence (aOR = 1.8, 1.2-2.9), staying in delta region (aOR = 8.7, 4.7-12.2), hilly region (aOR = 3.0, 2.0-4.6, and having highest wealth quintile (aOR = 1.8, 1.1-3.0). Around 16% had fever in the last 2 weeks, of whom 66.7% sought care for fever and 3% got tested for malaria. Nearly half (50.9%) of the caregivers sought care from a government health facility, followed by private hospital/doctor (27.8%), shop (8.0%), village health worker (4.4%) and pharmacy (3.1%). The factors associated with not seeking care for fever were residing in specific geographical locations (hilly, delta and central plains compared to coastal region) and having lowest wealth quintile (aOR = 2.3, 1.1-5.7). CONCLUSIONS: This study highlighted that ownership and utilization of ITNs was very poor among under-5children. Care-seeking behaviour of the caregivers of under-5 children in case of fever was dismal with two-thirds not seeking care. The programme should seriously consider addressing these barriers if Myanmar is to achieve zero malaria deaths by 2030.

Barriers in distribution, ownership and utilization of insecticide-treated mosquito nets among migrant population in Myanmar, 2016: a mixed methods study.

BACKGROUND: Sleeping under insecticide-treated mosquito nets/long-lasting insecticidal nets (ITNs/LLINs henceforth referred to as ITNs) is one of the core interventions recommended by the World Health Organization to reduce malaria transmission and prevent malaria in high-risk communities, such as migrants, by preventing mosquito bites. The malaria burden among the migrant population is a big challenge for malaria elimination in Myanmar. In this context, this study aimed to assess the ownership and utilization of ITNs and to understand the barriers to distribution and utilization of ITNs among the high-risk migrant communities in the Regional Artemisinin Resistance Initiative (RAI) project areas of Myanmar. METHODS: A sequential mixed methods study (quantitative component: cross-sectional study involving analysis of secondary data available from a survey conducted among migrant households in the RAI project areas of Myanmar in 2016 followed by a descriptive qualitative component in 2018). A total of 17 focus group discussions (involving 121 participants) with different groups of migrants and 17 key-informant interviews with key programme stakeholders were conducted in 4 selected townships of RAI project areas. RESULTS: Of 3230 migrant households, 63.3% had at least one ITN while 36% had sufficient ITNs (i.e., 1 ITN per 2 persons). Regarding ITN utilization, about 52% of household members reported sleeping under an ITN the previous night, which is similar among under-fives and pregnant women. Over half of all bed nets were ITNs, with nearly one-third having holes or already undergone repairs. The qualitative findings revealed that the key challenges for ITN utilization were insufficient ITNs in households and dislike of ITNs. The barriers to ITN distribution were incomplete migrant mapping due to resource constraints (time, money, manpower) and difficulties in transportation and carrying ITNs. CONCLUSION: This study highlights poor ownership and utilization of ITNs among migrants in the RAI project areas of Myanmar and barriers to their ownership and utilization. To achieve universal coverage and utilization, more programmatic support by the programme is needed to carry out complete migrant mapping and continuous ITN distribution in remote locations.

Bayesian spatiotemporal analysis of malaria infection along an international border: Hlaingbwe Township in Myanmar and Tha-Song-Yang District in Thailand.

BACKGROUND: One challenge in moving towards malaria elimination is cross-border malaria infection. The implemented measures to prevent and control malaria re-introduction across the demarcation line between two countries require intensive analyses and interpretation of data from both sides, particularly in border areas, to make correct and timely decisions. Reliable maps of projected malaria distribution can help to direct intervention strategies. In this study, a Bayesian spatiotemporal analytic model was proposed for analysing and generating aggregated malaria risk maps based on the exceedance probability of malaria infection in the township-district adjacent to the border between Myanmar and Thailand. Data of individual malaria cases in Hlaingbwe Township and Tha-Song-Yang District during 2016 were extracted from routine malaria surveillance databases. Bayesian zero-inflated Poisson model was developed to identify spatial and temporal distributions and associations between malaria infections and risk factors. Maps of the descriptive statistics and posterior distribution of predicted malaria infections were also developed. RESULTS: A similar seasonal pattern of malaria was observed in both Hlaingbwe Township and Tha-Song-Yang District during the rainy season. The analytic model indicated more cases of malaria among males and individuals aged ≥ 15 years. Mapping of aggregated risk revealed consistently high or low probabilities of malaria infection in certain village tracts or villages in interior parts of each country, with higher probability in village tracts/villages adjacent to the border in places where it could easily be crossed; some border locations with high mountains or dense forests appeared to have fewer malaria cases. The probability of becoming a hotspot cluster varied among village tracts/villages over the year, and some had close to no cases all year. CONCLUSIONS: The analytic model developed in this study could be used for assessing the probability of hotspot cluster, which would be beneficial for setting priorities and timely preventive actions in such hotspot cluster areas. This approach might help to accelerate reaching the common goal of malaria elimination in the two countries.

Low uptake of malaria testing within 24 h of fever despite appropriate health-seeking among migrants in Myanmar: a mixed-methods study.

BACKGROUND: There is limited information on uptake of malaria testing among migrants who are a 'high-risk' population for malaria. This was an explanatory mixed-methods study. The quantitative component (a cross sectional analytical study-nation-wide migrant malaria survey in 2016) assessed the knowledge; health-seeking; and testing within 24 h of fever and its associated factors. The qualitative component (descriptive design) explored the perspectives of migrants and health care providers [including village health volunteers (VHV)] into the barriers and suggested solutions to increase testing within 24 h. Quantitative data analysis was weighted for the three-stage sampling design of the survey. Qualitative data analysis involved manual descriptive thematic analysis. RESULTS: A total of 3230 households were included in the survey. The mean knowledge score (maximum score 11) for malaria was 5.2 (0.95 CI 5.1, 5.3). The source of information about malaria was 80% from public health facility staff and 21% from VHV. Among 11 193 household members, 964 (8.6%) had fever in last 3 months. Health-seeking was appropriate for fever in 76% (0.95 CI 73, 79); however, only 7% (0.95 CI 5, 9) first visited a VHV while 19% (0.95 CI 16, 22) had self-medication. Of 964, 220 (23%, 0.95 CI 20, 26) underwent malaria blood testing within 24 h. Stable migrants, high knowledge score and appropriate health-seeking were associated with testing within 24 h. Qualitative findings showed that low testing within 24 h despite appropriate health-seeking was due to lack of awareness among migrants regarding diagnosis services offered by VHV, delayed health-seeking at public health facilities and not all cases of fever being tested by VHV and health staff. Providing appropriate behaviour change communication for migrants related to malaria, provider's acceptance for malaria testing for all fever cases and mobile peer volunteer under supervision were suggested to overcome above barriers. CONCLUSIONS: Providers were not testing all migrant patients with fever for malaria. Low uptake within 24 h was also due to poor utilization of services offered by VHV. The programme should seriously consider addressing these barriers and implementing the recommendations if Myanmar is to eliminate malaria by 2030.

Are village health volunteers as good as basic health staffs in providing malaria care? A country wide analysis from Myanmar, 2015.

BACKGROUND: Malaria is one of the major public health problems in Myanmar. Village health volunteers (VHV) are the key malaria diagnosis and treatment service provider at community level in addition to basic health staffs (BHS). This countrywide analysis aimed to assess and compare the accessibility to- and quality of malaria care (treatment initiation, treatment within 24 h and complete treatment delivery) between VHV and BHS in Myanmar. METHODS: This was a retrospective cohort study using record review of routinely collected programme data available in electronic format. All patients with undifferentiated fever screened and diagnosed for malaria in January-December 2015 by VHV and BHS under National Malaria Control Programme in Myanmar were included in the study. Unadjusted and adjusted prevalence ratios (aPR) were calculated to assess the effect of VHV/BHS on receipt of treatment by patients. RESULTS: Of 978,735 undifferentiated fever patients screened in 2015, 11.0% of patients were found malaria positive and the malaria positivity in VHV and BHS group were 11.1 and 10.9% respectively. Access to malaria care: higher proportion of children aged 5-14 years (21.8% vs 17.3%) and females (43.7% vs 41.8%) with fever were screened for malaria by VHV compared to BHS. However, the same for children aged < 5 years was 2.2% lower in VHV group compared to BHS. Quality of malaria care: the proportion of malaria cases that received treatment was 96.6 and 94.9; treatment initiation within 24 h of fever was 44.7 and 34.1; and, complete treatment delivery was 80.9 and 88.2, respectively, in VHV and BHS groups. After adjustment for potential confounders, patients with malaria provided care by VHV had 1.02 times higher chance of receiving treatment compared to BHS [aPR (95% confidence interval) 1.017 (1.015, 1.020)]. CONCLUSIONS: The VHV were more accessible to children and women than BHS in providing malaria screening services. The malaria treatment services provided by VHV was as good as BHS. Further qualitative research to explore and address the challenges on initiation and delivering complete treatment by VHV including inventory assessment and cost-effectiveness studies on integration of VHV in routine health system are needed.

Anti-malarial landscape in Myanmar: results from a nationally representative survey among community health workers and the private sector outlets in 2015/2016.

BACKGROUND: In 2015/2016, an ACTwatch outlet survey was implemented to assess the anti-malarial and malaria testing landscape in Myanmar across four domains (Eastern, Central, Coastal, Western regions). Indicators provide an important benchmark to guide Myanmar's new National Strategic Plan to eliminate malaria by 2030. METHODS: This was a cross-sectional survey, which employed stratified cluster-random sampling across four regions in Myanmar. A census of community health workers (CHWs) and private outlets with potential to distribute malaria testing and/or treatment was conducted. An audit was completed for all anti-malarials, malaria rapid diagnostic tests. RESULTS: A total of 28,664 outlets were approached and 4416 met the screening criteria. The anti-malarial market composition comprised CHWs (41.5%), general retailers (27.9%), itinerant drug vendors (11.8%), pharmacies (10.9%), and private for-profit facilities (7.9%). Availability of different anti-malarials and diagnostic testing among anti-malarial-stocking CHWs was as follows: artemisinin-based combination therapy (ACT) (81.3%), chloroquine (67.0%), confirmatory malaria test (77.7%). Less than half of the anti-malarial-stocking private sector had first-line treatment in stock: ACT (41.7%) chloroquine (41.8%), and malaria diagnostic testing was rare (15.4%). Oral artemisinin monotherapy (AMT) was available in 27.7% of private sector outlets (Western, 54.1%; Central, 31.4%; Eastern; 25.0%, Coastal; 15.4%). The private-sector anti-malarial market share comprised ACT (44.0%), chloroquine (26.6%), and oral AMT (19.6%). Among CHW the market share was ACT (71.6%), chloroquine (22.3%); oral AMT (3.8%). More than half of CHWs could correctly state the national first-line treatment for uncomplicated falciparum and vivax malaria (59.2 and 56.9%, respectively) compared to the private sector (15.8 and 13.2%, respectively). Indicators on support and engagement were as follows for CHWs: reportedly received training on malaria diagnosis (60.7%) or national malaria treatment guidelines (59.6%), received a supervisory or regulatory visit within 12 months (39.1%), kept records on number of patients tested or treated for malaria (77.3%). These indicators were less than 20% across the private sector. CONCLUSION: CHWs have a strong foundation for achieving malaria goals and their scale-up is merited, however gaps in malaria commodities and supplies must be addressed. Intensified private sector strategies are urgently needed and must be scaled up to improve access and coverage of first-line treatments and malaria diagnosis, and remove oral AMT from the market place. Future policies and interventions on malaria control and elimination in Myanmar should take these findings into consideration across all phases of implementation.

Insights into the availability and distribution of oral artemisinin monotherapy in Myanmar: evidence from a nationally representative outlet survey.

BACKGROUND: The containment of artemisinin resistance in Myanmar, historically an important probable origin and route of anti-malarial resistance to the India sub-continent and beyond, is crucial to global malaria control and elimination. This paper describes what is currently known about the sale and distribution of oral artemisinin monotherapy (AMT) across Myanmar, where this medicine is commonly found. METHODS: A nationally representative 2015 outlet survey was conducted in the private sector, and among community health workers across four geographical domains. A national sample of outlets was screened for availability of malaria testing and treatment, and an audit was completed for all anti-malarials. RESULTS: A total of 3859 outlets across Myanmar had an anti-malarial in stock on the day of survey. Of the 3859 anti-malarial stocking outlets, 988 outlets stocked oral AMT. Availability of oral AMT was highest among outlets in the Western border (36.8%) versus other domains (Eastern, 15.0%; Central, 19.3% Coastal, 10.7%). Over 90% of the oral AMT service delivery points were private sector outlets: general retailers (49.4%), pharmacies (23.5%), and itinerant drug vendors (14.2%). Eleven unique oral AMT products were audited. The most common product audited was Artesunate®, manufactured by Mediplantex in Vietnam, which accounted for 79.9% of the oral AMT market share. Other oral AMT products were manufactured in China and in Myanmar. Over 60% of oral AMT products had a shelf life at purchase of greater than 2 years and only 14.7% were expired. The median number of oral AMT tablets typically dispensed to treat malaria was two tablets, approximately one tenth of a full adult course. The median price of a 50 mg tablet was $0.16. CONCLUSIONS: Given the high availability and distribution of oral AMT, it is possible that Myanmar has become the last remaining viable market for any oral AMT in the region for manufacturers. National and international organizations need to act quickly and effectively to stop the production and distribution to both improve malaria control within Myanmar and reduce risk of artemisinin resistance spreading to India and Africa.

Therapeutic efficacy and artemisinin resistance in northern Myanmar: evidence from in vivo and molecular marker studies.

BACKGROUND: In Myanmar, three types of artemisinin-based combination therapy (ACT) are recommended as first-line treatment of uncomplicated falciparum malaria: artemether-lumefantrine (AL), artesunate-mefloquine (AS + MQ), and dihydroartemisinin-piperaquine (DP). Resistance to both artemisinins and ACT partner drugs has been reported from the Greater Mekong Sub-region, and regular efficacy monitoring of the recommended ACT is conducted in Myanmar. This paper reports on results from studies to monitor the efficacy of the three forms of ACT in sentinel sites in northern Myanmar, and investigations of mutations in the Kelch13 (k13) propeller domain. METHODS: Seven therapeutic efficacy studies were conducted in 2011-12 and 2014 in three sentinel sites in Myanmar (Tamu, Muse, Tabeikkyin). Three studies were done for the evaluation of AL (204 patients), two studies for AS + MQ (119 patients) and two studies for DP (147 patients). These studies were done according to 2009 standard WHO protocol. Polymorphisms in the k13 propeller domain were examined in dried blood spots collected on day 0. The primary endpoint was adequate clinical and parasitological response (ACPR) on day 28 for AL and on day 42 for DP and AS + MQ, corrected to exclude re-infection using polymerase chain reaction (PCR) genotyping. Safety data were collected through self-reporting. RESULTS: PCR-corrected ACPR was 97.2-100% for AL, 98.6-100% for AS + MQ and 100% for DP across the study sites and years. All studies found a prevalence of k13 mutations (>440) above 23% in the day-0 samples. The F446I mutation was the most common mutation, making up 66.0% of the mutations found. Seven out of nine day-3 positive patients were infected with k13 wild type parasites. The remaining two cases with day-3 parasitaemia had the P574L mutation. CONCLUSIONS: The efficacy of AL, AS + MQ and DP remains high in northern Myanmar despite widespread evidence of k13 mutations associated with delayed parasite clearance. This study showed that already in 2012 there was a high frequency of k13 mutations in Myanmar on the border with India. The high efficacy of the recommended ACT gives confidence in the continued recommendation of the use of these treatments in Myanmar. Trial registration numbers ACTRN12611001245987 (registered 06-12-2011) and ACTRN12614000216617 (registered 28-02-2014).

Understanding malaria treatment-seeking preferences within the public sector amongst mobile/migrant workers in a malaria elimination scenario: a mixed-methods study.

BACKGROUND: Migration flows and the emerging resistance to artemisinin-based combination therapy in the Greater Mekong Sub-region (GMS) create programmatic challenges to meeting the AD 2030 malaria elimination target in Myanmar. The National Malaria Control Programme (NMCP) targeted migrant workers based mainly on the stability of their worksites (categories 1: permanent work-setting; categories 2 and 3: less stable work-settings). This study aims to assess the migration patterns, malaria treatment-seeking preferences, and challenges encountered by mobile/migrant workers at remote sites in a malaria-elimination setting. METHODS: A mixed-methods explanatory sequential study retrospectively analysed the secondary data acquired through migrant mapping surveys (2013-2015) in six endemic regions (n = 9603). A multivariate logistic regression model was used to ascertain the contributing factors. A qualitative strand (2016-2017) was added by conducting five focus-group discussions (n = 50) and five in-depth interviews with migrant workers from less stable worksites in Shwegyin Township, Bago Region. The contiguous approach was used to integrate quantitative and qualitative findings. RESULTS: Among others, migrant workers from Bago Region were significantly more likely to report the duration of stay ≥ 12 months (63% vs. 49%) and high seasonal mobility (40% vs. 35%). Particularly in less stable settings, a very low proportion of migrant workers (17%) preferred to seek malaria treatment from the public sector and was significantly influenced by the worksite stability (adjusted OR = 1.4 and 2.3, respectively for categories 2 and 1); longer duration of stay (adjusted OR = 3.5); and adjusted OR < 2 for received malaria messages, knowledge of malaria symptoms and awareness of means of malaria diagnosis. Qualitative data further elucidated their preference for the informal healthcare sector, due to convenience, trust and good relations, and put migrant workers at risk of substandard care. Moreover, the availability of cheap anti-malarial in unregistered small groceries encouraged self-medication. Infrequent or no contact with rural health centres and voluntary health workers worsened the situation. CONCLUSIONS: Mitigating key drivers that favour poor utilization of public-sector services among highly mobile migrant workers in less stable work-settings should be given priority in a malaria-elimination setting. These issues are challenging for the NMCP in Myanmar and might be generalized to other countries in the GMS to achieve malaria-elimination goals. Further innovative out-reach programmes designed and implemented specific to the nature of mobile/migrant workers is crucial.

Oral artemisinin monotherapy removal from the private sector in Eastern Myanmar between 2012 and 2014.

BACKGROUND: In 2012 the Artemisinin Monotherapy Therapy Replacement (AMTR) project was implemented in Eastern Myanmar to increase access to subsidized, quality-assured artemisinin combination therapy (ACT) and to remove oral artemisinin monotherapy (AMT) from the private sector. The aim of this paper is to examine changes over time in the private sector anti-malarial landscape and to illustrate the value of complementary interventions in the context of a national ACT subsidy. METHODS: Three rounds of cross-sectional malaria medicine outlet surveys were conducted, in 2012, 2013 and 2014. Project intervention areas were selected from the Myanmar Artemisinin Resistance Containment (MARC) area. Provider detailing was implemented in these selected areas. Comparison areas were selected outside of this catchment area, from townships in close proximity to the MARC framework. Within each domain, multi-staged sampling was used to select areas for the survey. Outlets with the potential to sell or distribute anti-malarials in the private sector were screened for eligibility. RESULTS: The total number of outlets approached for an interview was as follows in the intervention and comparison areas, respectively: 2012, N = 2046 and 1612; 2013, N = 1636 and 1884; 2014, N = 2939 and 2941. The percentage of pharmacies, general retailers and mobile providers (classed as 'priority outlets') with oral AMT in stock on the day of the survey decreased over time in the intervention areas (2012 = 68 %; 2013 = 48 %; 2014 = 10 %). Conversely, quality-assured ACT availability increased among these outlets (2012 = 4 %; 2013 = 62 %; 2014 = 79 %). Relative oral AMT market share among priority outlets also decreased over time (2012 = 44 %; 2013 = 18 %; 2014 = 14 %), while market share of quality-assured ACT increased (2012 = 3 %; 2013 = 59 %; 2014 = 51 %). Among priority outlets in the comparison area, similar trends were observed, though changes over time were less substantial compared to the intervention area. Other outlet types (community health workers and health facilities) performed relatively well over time though modest improvements were also observed. CONCLUSION: The findings point to the successful design and implementation of a strategy to rapidly remove oral AMT from pharmacies, general retailers and mobile providers and to replace its use with quality-assured ACT. The evidence also highlights the importance of supporting interventions in the context of a high-level subsidy.

Using supply side evidence to inform oral artemisinin monotherapy replacement in Myanmar: a case study.

BACKGROUND: In 2012, alarmingly high rates of oral artemisinin monotherapy availability and use were detected along Eastern Myanmar, threatening efforts to halt the spread of artemisinin resistance in the Greater Mekong Subregion (GMS), and globally. The aim of this paper is to exemplify how the use of supply side evidence generated through the ACTwatch project shaped the artemisinin monotherapy replacement malaria (AMTR) project's design and interventions to rapidly displace oral artemisinin monotherapy with subsidized, quality-assured ACT in the private sector. METHODS: The AMTR project was implemented as part of the Myanmar artemisinin resistance containment (MARC) framework along Eastern Myanmar. Guided by outlet survey and supply chain evidence, the project implemented a high-level subsidy, including negotiations with a main anti-malarial distributor, with the aim of squeezing oral artemisinin monotherapy out of the market through price competition and increased availability of quality-assured artemisinin-based combinations. This was complemented with a plethora of demand-creation activities targeting anti-malarial providers and consumers. Priority outlet types responsible for the distribution of oral artemisinin monotherapy were identified by the outlet survey, and this evidence was used to target the AMTR project's supporting interventions. CONCLUSIONS: The widespread availability and use of oral artemisinin monotherapy in Myanmar has been a serious threat to malaria control and elimination in the country and across the region. Practical anti-malarial market evidence was rapidly generated and used to inform private sector approaches to address these threats. The program design approach outlined in this paper is illustrative of the type of evidence generation and use that will be required to ensure effective containment of artemisinin drug resistance and progress toward regional and global malaria elimination goals.

Malaria community health workers in Myanmar: a cost analysis.

BACKGROUND: Myanmar has the highest malaria incidence and attributed mortality in South East Asia with limited healthcare infrastructure to manage this burden. Establishing malaria Community Health Worker (CHW) programmes is one possible strategy to improve access to malaria diagnosis and treatment, particularly in remote areas. Despite considerable donor support for implementing CHW programmes in Myanmar, the cost implications are not well understood. METHODS: An ingredients based micro-costing approach was used to develop a model of the annual implementation cost of malaria CHWs in Myanmar. A cost model was constructed based on activity centres comprising of training, patient malaria services, monitoring and supervision, programme management, overheads and incentives. The model takes a provider perspective. Financial data on CHWs programmes were obtained from the 2013 financial reports of the Three Millennium Development Goal fund implementing partners that have been working on malaria control and elimination in Myanmar. Sensitivity and scenario analyses were undertaken to outline parameter uncertainty and explore changes to programme cost for key assumptions. RESULTS: The range of total annual costs for the support of one CHW was US$ 966-2486. The largest driver of CHW cost was monitoring and supervision (31-60% of annual CHW cost). Other important determinants of cost included programme management (15-28% of annual CHW cost) and patient services (6-12% of annual CHW cost). Within patient services, malaria rapid diagnostic tests are the major contributor to cost (64% of patient service costs). CONCLUSION: The annual cost of a malaria CHW in Myanmar varies considerably depending on the context and the design of the programme, in particular remoteness and the approach to monitoring and evaluation. The estimates provide information to policy makers and CHW programme planners in Myanmar as well as supporting economic evaluations of their cost-effectiveness.

Temporal Dynamics of Subclinical Malaria in Different Transmission Zones of Myanmar.

Countries in the Greater Mekong Subregion have committed to eliminate Plasmodium falciparum malaria by 2025. Subclinical malaria infections that can be detected by highly sensitive polymerase chain reaction (PCR) testing in asymptomatic individuals represent a potential impediment to this goal, although the extent to which these low-density infections contribute to transmission is unclear. To understand the temporal dynamics of subclinical malaria in this setting, a cohort of 2,705 participants from three epidemiologically distinct regions of Myanmar was screened for subclinical P. falciparum and P. vivax infection using ultrasensitive PCR (usPCR). Standard rapid diagnostic tests (RDTs) for P. falciparum were also performed. Individuals who tested positive for malaria by usPCR were followed for up to 12 weeks. Regression analysis was performed to estimate whether the baseline prevalence of infection and the count of repeated positive tests were associated with demographic, behavioral, and clinical factors. At enrollment, the prevalence of subclinical malaria infection measured by usPCR was 7.7% (1.5% P. falciparum monoinfection, 0.3% mixed P. falciparum and P. vivax, and 6.0% P. vivax monoinfection), while P. falciparum prevalence measured by RDT was just 0.2%. Prevalence varied by geography and was higher among older people and in those with outdoor exposure and travel. No difference was observed in either the prevalence or count of subclinical infection by time of year, indicating that even in low-endemicity areas, a reservoir of subclinical infection persists year-round. If low-density infections are shown to represent a significant source of transmission, identification of high-risk groups and locations may aid elimination efforts.