Malaria situation in the Greater Mekong Subregion.

The epidemiology of malaria in the Greater Mekong Subregion is complex and rapidly evolving. Malaria control and elimination efforts face a daunting array of challenges including multidrug-resistant parasites. This review presents secondary data collected by the national malaria control programs in the six countries between 1998 and 2010 and examines trends over the last decade. This data has a number of limitations: it is derived exclusively from public sector health facilities; falciparum-specific and then pan-specific rapid diagnostic tests were introduced during the period under review; and, recently there has been a massive increase in case detection capability as a result of increased funding. It therefore requires cautious interpretation. A series of maps are presented showing trends in incidence, mortality and proportion of cases caused by Plasmodium falciparum over the last decade. A brief overview of institutional and implementation arrangements, historical background, demographics and key issues affecting malaria epidemiology is provided for each country. National malaria statistics for 2010 are presented and their robustness discussed in terms of the public sector's share of cases and other influencing factors such as inter-country variations in risk stratification, changes in diagnostic approach and immigration. Targets are presented for malaria control and where appropriate for elimination. Each country's artemisinin resistance status is described. The epidemiological trends presented reflect the improvement in the malaria situation, however the true malaria burden is as yet unknown. There is a need for continuing strengthening and updating of surveillance and response systems.

Monitoring antimalarial drug efficacy in the Greater Mekong Subregion: an overview of in vivo results from 2008 to 2010.

In vivo Therapeutic Efficacy Studies (TES) have been routinely conducted in the Greater Mekong Subregion (GMS) for decades. Results from the last 10 years have contributed to update national antimalarial drug policies, to identify hotspots of multi-drug resistance and from 2008 onwards, to stimulate ambitious multi-country programs and innovative research projects to contain and eliminate artemisinin resistant Plasmodium falciparum strains in the subregion. This paper describes the results of TES of first-line antimalarials in six countries of the GMS from 2008-2010 using the WHO in vivo standard protocol. A total of 91 studies were conducted at 32 sentinel sites testing dihydroartemisinin-piperaquine (DHA-PIP), artesunate+mefloquine (A+M), and artemether-lumefantrine (AL) against P. falciparum malaria, as well as chloroquine and DHA-PIP against P vivax. Overall, artemisinin-based combination therapies (ACTs) remained efficacious against falciparum malaria with some exceptions. The 42-day adequate clinical and parasitological response (ACPR) for DHA-PIP dropped significantly to 73% (95% CI 53-87) in 2010 in the same hotspot area of western Cambodia known to harbor artemisinin resistant P. falciparum strains. Because P falciparum sensitivity to artemisinin is a major concern, especially on the Cambodia-Thailand border, attempts were also made to strengthen the monitoring of parasite clearance time elsewhere in the region and globally. The proportion of patients still blood-smear positive on Day 3 above 10% is considered a proxy indicator to strongly suspect the appearance of falciparum resistance to artesunate. This has led to substantial extra measures to confirm the suspicion and eventually set up interventions to eliminate artemisinin resistant parasites. Notably, increasing proportions (>10%) of Day 3 positives among falciparum malaria patients treated with DHA-PIP have been observed in western Cambodia, Myanmar, Viet Nam and China from 2008. Percent Day 3 parasitemia associated with A+M has increased along the Thailand-Myanmar border to surpass 10% at several sites, adding to the known pool of sites with 'suspected' artemisinin resistance in the GMS. Chloroquine remains highly effective against P. vivax except for northeastern and north-central Cambodia. TES results from this subregional-wide monitoring of antimalarial efficacy have influenced the changes of 1st line drugs against both P. falciparum and P. vivax in Cambodia, against P. falciparum in selected areas in Thailand, and pinpointed hotspot areas elsewhere that should be closely monitored in order to take action in a timely manner.

Malaria control in the Greater Mekong Subregion: an overview of the current response and its limitations.

The malaria burden in the Greater Mekong Subregion has been dramatically reduced over the last 20 years but the disease remains an important public health issue in all six countries. This chapter introduces the standard tools for malaria control (long lasting insecticidal nets; indoor residual spraying; early diagnosis and appropriate treatment; epidemic surveillance and response; and, communication) and presents the evidence base supporting the use of each of these tools in the Subregion. Targeting approaches and delivery mechanisms for these tools are presented and discussed country by country. The technical limitations of these standard tools and delivery mechanisms are then discussed in the context of local variations in the epidemiology of the disease. The challenges presented by the feeding and resting habits of local vectors, by the characteristics and behavior of different human population groups, and by particular species and drug resistant strains of malaria parasites are considered. A range of innovative tools and delivery mechanism that have been developed to address these problems are presented and moves to bring these various innovations together to provide a comprehensive package of malaria control services for each risk group are discussed. Implementation arrangements are introduced and an overview of the stakeholder landscape at regional and country level is provided. Finally, remaining programmatic gaps (which include limited coverage, declining funds, drug resistance, weak surveillance and weak health systems) are highlighted and areas in need of further action (including the need for continued innovation) are discussed.

Artemisinin resistance containment project in Thailand. II: Responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia.

BACKGROUND: The area along the Thai-Cambodian border is considered an epicenter of anti-malarial drug resistance. Recently, parasite resistance to artemisinin-based therapies has been reported in the area. The artemisinin resistance containment project was initiated in November 2008, with the aim to limit resistant parasites and eliminate malaria in this region. This study describes the response to artemisinin-based therapy among falciparum malaria patients in the area, using data from the malaria surveillance programmed under the containment project. METHODS: The study was conducted in seven provinces of Thailand along the Thai-Cambodian border. Data of Plasmodium falciparum-positive patients during January 2009 to December 2011 were obtained from the electronic malaria information system (eMIS) Web-based reporting system. All P. falciparum cases were followed for 42 days, as the routine case follow-up protocol. The demographic characteristics of the patients were described. Statistical analysis was performed to determine the cure rate of the current standard anti-malarial drug regimen--mefloquine-artesunate combination therapy (MAS). The proportion of patients who remained parasite-positive at each follow-up day was calculated. In addition, factors related to the delayed parasite clearance on day-3 post-treatment, were explored. RESULTS: A total of 1,709 P. falciparum-positive cases were reported during the study period. Almost 70% of falciparum cases received MAS therapy (n = 1,174). The majority of cases were males, aged between 31 and 50 years. The overall MAS cure rate was > 90% over the three-year period. Almost all patients were able to clear the parasite within 7 to 14 days post-treatment. Approximately 14% of patients undergoing MAS remained parasite-positive on day-3. Delayed parasite clearance was not significantly associated with patient gender, age, or citizenship. However, delayed parasite clearance varied across the study area. CONCLUSION: Anti-malarial drug-resistant parasites should be closely monitored in the area along the Thai-Cambodian border. Although the MAS cure rate in this study area was above 90%, an increasing trend of treatment failure has been reported in neighboring parts. Effective malaria surveillance is an important component to monitor drug-resistance in the malaria containment project.

Artemisinin resistance containment project in Thailand. (I): Implementation of electronic-based malaria information system for early case detection and individual case management in provinces along the Thai-Cambodian border.

BACKGROUND: The Bureau of Vector-borne Diseases, Ministry of Public Health, Thailand, has implemented an electronic Malaria Information System (eMIS) as part of a strategy to contain artemisinin resistance. The attempt corresponds to the WHO initiative, funded by the Bill & Melinda Gates Foundation, to contain anti-malarial drug resistance in Southeast Asia. The main objective of this study was to demonstrate the eMIS' functionality and outputs after implementation for use in the Thailand artemisinin-resistance containment project. METHODS: The eMIS had been functioning since 2009 in seven Thai-Cambodian border provinces. The eMIS has covered 61 malaria posts/clinics, 27 Vector-borne Disease Units covering 12,508 hamlets at risk of malaria infections. The eMIS was designed as an evidence-based and near real-time system to capture data for early case detection, intensive case investigation, monitoring drug compliance and on/off-site tracking of malarial patients, as well as collecting data indicating potential drug resistance among patients. Data captured by the eMIS in 2008-2011 were extracted and presented. RESULTS: The core functionalities of the eMIS have been utilized by malaria staff at all levels, from local operational units to ministerial management. The eMIS case detection module suggested decreasing trends during 2009-2011; the number of malaria cases detected in the project areas over the years studied were 3818, 2695, and 2566, with sero-positive rates of 1.24, 0.98, and 1.16%, respectively. The eMIS case investigation module revealed different trends in weekly Plasmodium falciparum case numbers, when classified by responsible operational unit, local and migrant status, and case-detection type. It was shown that most Thai patients were infected within their own residential district, while migrants were infected either at their working village or from across the border. The data mapped in the system suggested that P. falciparum-infected cases and potential drug-resistant cases were scattered mostly along the border villages. The mobile technology application has detected different follow-up rates, with particularly low rates among seasonal and cross-border migrants. CONCLUSION: The eMIS demonstrated that it could capture essential data from individual malaria cases at local operational units, while effectively being used for situation and trend analysis at upper-management levels. The system provides evidence-based information that could contribute to the control and containment of resistant parasites. Currently, the eMIS is expanding beyond the Thai-Cambodian project areas to the provinces that lie along the Thai-Myanmar border.

Respondent-driven sampling on the Thailand-Cambodia border. II. Knowledge, perception, practice and treatment-seeking behaviour of migrants in malaria endemic zones.

BACKGROUND: Population movements along the Thailand-Cambodia border, particularly among highly mobile and hard-to-access migrant groups from Cambodia and Myanmar, are assumed to play a key role in the spread of artemisinin resistance. Data on treatment-seeking behaviours, knowledge and perceptions about malaria, and use of preventive measures is lacking as characteristics of this population prevent them from being represented in routine surveillance and the lack of a sampling frame makes reliable surveys challenging. METHODS: A survey of migrant populations from Cambodia and Myanmar was implemented in five selected rural locations in Thailand along the Thai-Cambodian border using respondent driven sampling (RDS) to determine demographic characteristics of the population, migratory patterns, knowledge about malaria, and health-care -seeking behaviours. RESULTS: The majority of migrants from Myanmar are long-term residents (98%) with no plans to move back to Myanmar, understand spoken Thai (77%) and can therefore benefit from health messages in Thai, have Thai health insurance (99%) and accessed public health services in Thailand (63%) for their last illness. In comparison, the majority of Cambodian migrants are short-term (72%). Of the short-term Cambodian migrants, 92% work in agriculture, 18% speak Thai, 3.4% have Thai health insurance, and the majority returned to Cambodia for treatment (45%), self-treated (11%), or did not seek treatment for their last illness (27%). CONCLUSION: Most highly mobile migrants along the Thai-Cambodia border are not accessing health messages or health treatment in Thailand, increasing their risk of malaria and facilitating the spread of potentially resistant Plasmodium falciparum as they return to Cambodia to seek treatment. Reaching out to highly mobile migrants with health messaging they can understand and malaria diagnosis and treatment services they can access is imperative in the effort to contain the spread of artemisinin-resistant P. falciparum.

Respondent-driven sampling on the Thailand-Cambodia border. I. Can malaria cases be contained in mobile migrant workers?

BACKGROUND: Reliable information on mobility patterns of migrants is a crucial part of the strategy to contain the spread of artemisinin-resistant malaria parasites in South-East Asia, and may also be helpful to efforts to address other public health problems for migrants and members of host communities. In order to limit the spread of malarial drug resistance, the malaria prevention and control programme will need to devise strategies to reach cross-border and mobile migrant populations. METHODOLOGY: The Respondent-driven sampling (RDS) method was used to survey migrant workers from Cambodia and Myanmar, both registered and undocumented, in three Thai provinces on the Thailand-Cambodia border in close proximity to areas with documented artemisinin-resistant malaria parasites. 1,719 participants (828 Cambodian and 891 Myanmar migrants) were recruited. Subpopulations of migrant workers were analysed using the Thailand Ministry of Health classification based on length of residence in Thailand of greater than six months (long-term, or M1) or less than six months (short-term, or M2). Key information collected on the structured questionnaire included patterns of mobility and migration, demographic characteristics, treatment-seeking behaviours, and knowledge, perceptions, and practices about malaria. RESULTS: Workers from Cambodia came from provinces across Cambodia, and 22% of Cambodian M1 and 72% of Cambodian M2 migrants had been in Cambodia in the last three months. Less than 6% returned with a frequency of greater than once per month. Of migrants from Cambodia, 32% of M1 and 68% of M2 were planning to return, and named provinces across Cambodia as their likely next destinations. Most workers from Myanmar came from Mon state (86%), had never returned to Myanmar (85%), and only 4% stated plans to return. CONCLUSION: Information on migratory patterns of migrants from Myanmar and Cambodia along the malaria endemic Thailand-Cambodian border within the artemisinin resistance containment zone will help target health interventions, including treatment follow-up and surveillance.

Malaria trends and challenges in the Greater Mekong Subregion.

This report provides an overview of the epidemiological patterns of malaria in the Greater Mekong Subregion (GMS) from 1998 to 2007, and highlights critical challenges facing national malaria control programs and partners in effort to build on their successes as they move towards malaria pre-elimination and elimination as a programmatic goal. Epidemiological data provided by malaria programs show a drastic decline in malaria deaths and confirmed malaria positive cases over the last 10 years in the GMS. More than half of confirmed malaria cases and deaths recorded in the GMS occur in Myanmar, however, reporting methods and data management are not comparable between countries despite effort made by WHO to harmonize data collection, analysis and reporting among WHO Member States. Malaria is concentrated in forested/forest-fringe areas of the region mainly along international borders providing strong rationale to develop harmonized cross-border pre-elimination programs in conjunction with national efforts. Across the Mekong Region, the declining efficacy of recommended first-line antimalarials, eg artemisinin-based combination therapies (ACTs) against falciparum malaria on the Cambodia-Thailand border, the prevalence of counterfeit and substandard antimalarial drugs, the lack of health services in general and malaria services in particular in remote settings, and the lack of information and services targeting migrants and mobile population present important barriers to reach or maintain malaria pre-elimination programmatic goals. Strengthening networking between research institutions and non-government organizations will increase knowledge-based decision and action.

Estimated global resources needed to attain international malaria control goals.

OBJECTIVE: To provide the international community with an estimate of the amount of financial resources needed to scale up malaria control to reach international goals, including allocations by country, year and intervention as well as an indication of the current funding gap. METHODS: A costing model was used to estimate the total costs of scaling up a set of widely recommended interventions, supporting services and programme strengthening activities in each of the 81 most heavily affected malaria-endemic countries. Two scenarios were evaluated, using different assumptions about the effect of interventions on the needs for diagnosis and treatment. Current health expenditures and funding for malaria control were compared to estimated needs. FINDINGS: A total of US$ 38 to 45 billion will be required from 2006 to 2015. The average cost during this period is US$ 3.8 to 4.5 billion per year. The average costs for Africa are US$ 1.7 billion and US$ 2.2 billion per year in the optimistic and pessimistic scenarios, respectively; outside Africa, the corresponding costs are US$ 2.1 billion and US$ 2.4 billion. CONCLUSION: While these estimates should not be used as a template for country-level planning, they provide an indication of the scale and scope of resources required and can help donors to collaborate towards meeting a global benchmark and targeting funding to countries in greatest need. The analysis highlights the need for much greater resources to achieve the goals and targets for malaria control set by the international community.

Estimating trends in the burden of malaria at country level.

National disease burdens are often not estimated at all or are estimated using inaccurate methods, partly because the data sources for assessing disease burden-nationally representative household surveys, demographic surveillance sites, and routine health information systems-each have their limitations. An important step forward would be a more consistent quantification of the population at risk of malaria. This is most likely to be achieved by delimiting the geographical distribution of malaria transmission using routinely collected data on confirmed cases of disease. However, before routinely collected data can be used to assess trends in the incidence of clinical cases and deaths, the incompleteness of reporting and variation in the utilization of the health system must be taken into account. In the future, sentinel surveillance from public and private health facilities, selected according to risk stratification, combined with occasional household surveys and other population-based methods of surveillance, may provide better assessments of malaria trends.

The burden of malaria epidemics and cost-effectiveness of interventions in epidemic situations in Africa.

Attempts to quantify the epidemiologic and economic burden of malaria have so far neglected to specifically address the burden of epidemic malaria. Moreover, the data on the effectiveness and cost-effectiveness of interventions in epidemics is extremely limited. Answering such key questions in an epidemic prone context is more challenging than doing so in endemic areas. Using the limited data available, we estimate that in Africa, there are more than 12 million malaria episodes and 155,000-310,000 malaria deaths per year attributable to epidemics if control options are not implemented or well timed, which is equivalent to some 4% of estimated annual malaria cases worldwide and 12-25% of estimated annual worldwide malaria deaths, including up to 50% of the estimated annual worldwide malaria mortality in persons > 15 years of age. The possible economic impact of malaria epidemics is described and the limited evidence on the effectiveness and cost-effectiveness of interventions in areas of low or seasonal transmission is reviewed.

[Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi]. / Efficacité de combinaisons thérapeutiques avec des dérivés de l'artémisinine dans le traitement de l'accès palustre non-complique au Burundi.

Faced with the problem of resistance to chloroquine and sulfadoxine-pyrimethamine, the Ministry of Public Health of Burundi decided to study the efficacy of two artemisinin-based combinations, the fixed combination of artemether-lumefantrine and the combination of amodiaquine + artesunate. The efficacy of these combinations for the treatment of uncomplicated falciparum malaria was studied in two sites representative of the country, in Kigobe neighbourhood of Bujumbura, the capital city, and in Buhiga, a rural area. The study followed the standardized WHO protocol from October 2001 to November 2002. A total of 295 children under 5 years were included; 153 children were treated with artesunate and amodiaquine (77 at Buhiga and 76 at Kigobe), and 142 children with the combination of artemether-lumefantrine (64 at Buhiga and 78 at Kigobe). Among the 295 children, 290 were followed up to 14 days. In the group of 149 children treated with artesunate and amodiaquine, 142 (95.3%, 95% CI: 91.9-98.7%) presented with adequate clinical and parasitological response, five (3.3%) with late parasitological failure, one (0.7%) with late clinical failure and one (0.7%) with early treatment failure. Among the 141 children treated with artemether-lumefantrine, 140 (99.3%, 95% CI: 97.9-100%) presented with adequate clinical and parasitological response and one (0.7%) with late parasitological failure at Buhiga. Side-effects were comparable in both groups except for the vomiting. Vomiting was more frequent in the artesunate + amodiaquine on D1 and D2. Both treatments decreased the gametocyte carriage but without getting full clearance in all the patients. During a consensus workshop, the Ministry of Public Health agreed on the combination of artesunate and amodiaquine as the first line drug for the treatment of uncomplicated falciparum malaria in Burundi including epidemic outbreak.