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BackgroundWith the goal for malaria elimination in Thailand set for 2024, increased coverage and utilization of bed net, especially insecticide-treated net (ITN) or long-lasting insecticidal net (LLIN) is a key strategy. This study aims to provide the necessary information about bed net ownership and utilization among the population at risk of malaria living along the Thai-Myanmar border in Tak province.MethodsA cross-sectional study was conducted using a mixed-method approach in 331 households from 5 hamlets in the villages of the Thai-Myanmar border. The research tools included a questionnaire, bed net inspection, and semi-structured interviews. Logistic regression was used to explore the sociodemographic factors associated with bed net utilization. The qualitative analysis employed a thematic analysis approach.ResultsThis survey found that 98.5% of households had at least one bed net per household, and 74.3% had at least one ITN/LLIN. However, only 30.8% of households reached the standard policy set by the Minister of Public Health of one ITN/LLINs per two persons. Most residents used bed net (92.1% used in the previous night and 80.9% used every day). For those using bed nets, however, 61.9% used ITNs or LLINs the night before and 53.1% used them every day. Nonetheless, the usage rates of bed nets (any type) in the previous night among children and pregnant women were high, reaching 95.3% and 90.0%, respectively. Seven explanatory variables showed statistically significant associations with bed net use every day, including: "not staying overnight in the forest or the field", "sleeping pattern based on gender", "sufficient numbers of bed nets to cover all sleeping spaces", "preference for free bed nets", "age", "gender", and "SES score" showed statistically significant association with bed net use every day. The major reasons for the regular use of bed nets in both household and the forest were to prevent mosquito biting. The reasons for not using bednets in the household were discomfort feelings from heat, perception of unnecessity due to low mosquito density, whereas the reason for not using bed nets in the forest was inconvenience.ConclusionDespite that overall coverage and usage of bed nets was high, only one third reached the standard level specified by the policy. Overnight in the forest, the dissatisfaction with the quality of free bed nets, insufficient number of bed nets, sleeping alone, male gender, age more than 10 years, low socioeconomic status, discomfort from heat, perception of no benefits of bed nets due to low mosquito density, and inconvenience were factors influencing bed net use. Maintaining high coverage and utility rate of bed nets should be a priority for the malaria high-risk population.

Abstract Background There is increasing perception that countries cannot work in isolation to militate against the threat of pandemic influenza. In the Greater Mekong Subregion (GMS) of Asia, high socio-economic diversity and fertile conditions for the emergence and spread of infectious diseases underscore the importance of transnational cooperation. Investigation of healthcare resource distribution and inequalities can help determine the need for, and inform decisions regarding, resource sharing and mobilisation. Methods We collected data on healthcare resources deemed important for responding to pandemic influenza through surveys of hospitals and district health offices across four countries of the GMS (Cambodia, Lao PDR, Thailand, Vietnam). Focusing on four key resource types (oseltamivir, hospital beds, ventilators, and health workers), we mapped and analysed resource distributions at province level to identify relative shortages, mismatches, and clustering of resources. We analysed inequalities in resource distribution using the Gini coefficient and Theil index. Results Three quarters of the Cambodian population and two thirds of the Laotian population live in relatively underserved provinces (those with resource densities in the lowest quintile across the region) in relation to health workers, ventilators, and hospital beds. More than a quarter of the Thai population is relatively underserved for health workers and oseltamivir. Approximately one fifth of the Vietnamese population is underserved for beds and ventilators. All Cambodian provinces are underserved for at least one resource. In Lao PDR, 11 percent of the population is underserved by all four resource items. Of the four resources, ventilators and oseltamivir were most unequally distributed. Cambodia generally showed higher levels of inequalities in resource distribution compared to other countries. Decomposition of the Theil index suggests that inequalities result principally from differences within, rather than between, countries. Conclusions There is considerable heterogeneity in healthcare resource distribution within and across countries of the GMS. Most inequalities result from within countries. Given the inequalities, mismatches, and clustering of resources observed here, resource sharing and mobilization in a pandemic scenario could be crucial for more effective and equitable use of the resources that are available in the GMS.

Abstract 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.

Abstract 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.

Abstract Background Lumefantrine and atovaquone are highly lipophilic anti-malarial drugs. As a consequence absorption is increased when the drugs are taken together with a fatty meal, but the free fraction of active drug decreases in the presence of triglyceride-rich plasma lipoproteins. In this study, the consequences of lipidaemia on anti-malarial drug efficacy were assessed in vitro. Methods Serum was obtained from non-immune volunteers under fasting conditions and after ingestion of a high fat meal and used in standard Plasmodium falciparum in-vitro susceptibility assays. Anti-malarial drugs, including lumefantrine, atovaquone and chloroquine in five-fold dilutions (range 0.05 ng/ml – 1 ug/mL) were diluted in culture medium supplemented with fasting or post-prandial 10% donor serum. The in-vitro drug susceptibility of parasite isolates was determined using the 3H-hypoxanthine uptake inhibition method and expressed as the concentration which gave 50% inhibition of hypoxanthine uptake (IC50). Results Doubling plasma triglyceride concentrations (from 160 mg/dL to 320 mg/dL), resulted in an approximate doubling of the IC50 for lumefantrine (191 ng/mL to 465 ng/mL, P 50 for atovaquone (0.5 ng/mL to 12 ng/ml; P Conclusions Lipidaemia reduces the anti-malarial activity of lipophilic anti-malarial drugs. This is an important confounder in laboratory in vitro testing and it could have therapeutic relevance.

Abstract Background This study aims to assess the situation of communicable diseases under national surveillance in the Cyclone Nargis-affected areas in Myanmar (Burma) before and after the incident. Methods Monthly data during 2007, 2008 and 2009 from the routine reporting system for disease surveillance of the Myanmar Ministry of Health (MMOH) were reviewed and compared with weekly reporting from the Early Warning and Rapid Response (EWAR) system. Data from some UN agencies, NGOs and Tri-Partite Core Group (TCG) periodic reviews were also extracted for comparisons with indicators from Sphere and the Inter-Agency Standing Committee. Results Compared to 2007 and 2009, large and atypical increases in diarrheal disease and especially dysentery cases occurred in 2008 following Cyclone Nargis. A seasonal increase in ARI reached levels higher than usual in the months of 2008 post-Nargis. The number of malaria cases post-Nargis also increased, but it was less clear if this reflected normal seasonal patterns or was specifically associated with the disaster event. There was no significant change in the occurrence of other communicable diseases in Nargis-affected areas. Except for a small decrease in mortality for diarrheal diseases and ARI in 2008 in Nargis-affected areas, population-based mortality rates for all other communicable diseases showed no significant change in 2008 in these areas, compared to 2007 and 2009. Tuberculosis control programs reached their targets of 70% case detection and 85% treatment success rates in 2007 and 2008. Vaccination coverage rates for DPT 3rd dose and measles remained at high though measles coverage still did not reach the Sphere target of 95% even by 2009. Sanitary latrine coverage in the Nargis-affected area dropped sharply to 50% in the months of 2008 following the incident but then rose to 72% in 2009. Conclusion While the incidence of diarrhea, dysentery and ARI increased post-Nargis in areas affected by the incident, the incidence rate for other diseases and mortality rates did not increase, and normal disease patterns resumed by 2009. This suggests that health services as well as prevention and control measures provided to the Nargis-affected population mitigated what could have been a far more severe health impact.

Abstract Chloroquine (CQ) resistant vivax malaria is spreading. In this case, Plasmodium vivax infections during pregnancy and in the postpartum period were not satisfactorily cleared by CQ, despite adequate drug concentrations. A growth restricted infant was delivered. Poor susceptibility to CQ was confirmed in-vitro and molecular genotyping was strongly suggestive of true recrudescence of P. vivax. This is the first clinically and laboratory confirmed case of two high-grade CQ resistant vivax parasite strains from Thailand.

Abstract Background At the verge of elimination of malaria in Bhutan, this study was carried out to analyse the trend of malaria in the endemic districts of Bhutan and to identify malaria clusters at the sub-districts. The findings would aid in implementing the control activities. Poisson regression was performed to study the trend of malaria incidences at district level from 1994 to 2008. Spatial Empirical Bayesian smoothing was deployed to identify clusters of malaria at the sub-district level from 2004 to 2008. Results Trend of the overall districts and most of the endemic districts have decreased except Pemagatshel, which has an increase in the trend. Spatial cluster-outlier analysis showed that malaria clusters were mostly concentrated in the central and eastern Bhutan in three districts of Dagana, Samdrup Jongkhar and Sarpang. The disease clusters were reported throughout the year. Clusters extended to the non-transmission areas in the eastern Bhutan. Conclusions There is significant decrease in the trend of malaria with the elimination at the sight. The decrease in the trend can be attributed to the success of the control and preventive measures. In order to realize the target of elimination of malaria, the control measure needs to be prioritized in these high-risk clusters of malaria.

Abstract Background To assess the application of cell phone integrating into the healthcare system to improve antenatal care (ANC) and expanded programme on immunization (EPI) services for the under-served population in border area. Methods A module combining web-based and mobile technology was developed to generate ANC/EPI visit schedule dates in which the healthcare personnel can cross-check, identify and update the mother's ANC and child's EPI status at the healthcare facility or at the household location when performing home visit; with additional feature of sending appointment reminder directly to the scheduled mother in the community. Results The module improved ANC/EPI coverage in the study area along the country border including for both Thai and non-Thai mothers and children who were either permanent resident or migrants; numbers of ANC and EPI visit on-time as per schedule significantly increased; there was less delay of antenatal visits and immunizations. Conclusions The module integrated and functioned successfully as part of the healthcare system; it is proved for its feasibility and the extent to which community healthcare personnel in the low resource setting could efficiently utilize it to perform their duties.

Abstract Background Plasmodium vivax has a dormant hepatic stage, called the hypnozoite, which can cause relapse months after the initial attack. For 50 years, primaquine has been used as a hypnozoitocide to radically cure P. vivax infection, but major concerns remain regarding the side-effects of the drug and adherence to the 14-day regimen. This study examined the effectiveness of using the directly-observed therapy (DOT) method for the radical treatment of P. vivax malaria infection, to prevent reappearance of the parasite within the 90-day follow-up period. Other potential risk factors for the reappearance of P. vivax were also explored. Methods A randomized trial was conducted from May 2007 to January 2009 in a low malaria transmission area along the Thai-Myanmar border. Patients aged ≥ 3 years diagnosed with P. vivax by microscopy, were recruited. All patients were treated with the national standard regimen of chloroquine for three days followed by primaquine for 14 days. Patients were randomized to receive DOT or self-administered therapy (SAT). All patients were followed for three months to check for any reappearance of P. vivax. Results Of the 216 patients enrolled, 109 were randomized to DOT and 107 to SAT. All patients recovered without serious adverse effects. The vivax reappearance rate was significantly lower in the DOT group than the SAT group (3.4/10,000 person-days vs. 13.5/10,000 person-days, p = 0.021). Factors related to the reappearance of vivax malaria included inadequate total primaquine dosage received (< 2.75 mg/kg), duration of fever ≤ 2 days before initiation of treatment, parasite count on admission ≥ 10,000/µl, multiple P. vivax-genotype infection, and presence of P. falciparum infection during the follow-up period. Conclusions Adherence to the 14-day primaquine regimen is important for the radical cure of P. vivax malaria infection. Implementation of DOT reduces the reappearance rate of the parasite, and may subsequently decrease P. vivax transmission in the area.

Abstract Background Malaria still remains a public health problem in some districts of Bhutan despite marked reduction of cases in last few years. To strengthen the country's prevention and control measures, this study was carried out to develop forecasting and prediction models of malaria incidence in the endemic districts of Bhutan using time series and ARIMAX. Methods This study was carried out retrospectively using the monthly reported malaria cases from the health centres to Vector-borne Disease Control Programme (VDCP) and the meteorological data from Meteorological Unit, Department of Energy, Ministry of Economic Affairs. Time series analysis was performed on monthly malaria cases, from 1994 to 2008, in seven malaria endemic districts. The time series models derived from a multiplicative seasonal autoregressive integrated moving average (ARIMA) was deployed to identify the best model using data from 1994 to 2006. The best-fit model was selected for each individual district and for the overall endemic area was developed and the monthly cases from January to December 2009 and 2010 were forecasted. In developing the prediction model, the monthly reported malaria cases and the meteorological factors from 1996 to 2008 of the seven districts were analysed. The method of ARIMAX modelling was employed to determine predictors of malaria of the subsequent month. Results It was found that the ARIMA (p, d, q) (P, D, Q)s model (p and P representing the auto regressive and seasonal autoregressive; d and D representing the non-seasonal differences and seasonal differencing; and q and Q the moving average parameters and seasonal moving average parameters, respectively and s representing the length of the seasonal period) for the overall endemic districts was (2,1,1)(0,1,1)12; the modelling data from each district revealed two most common ARIMA models including (2,1,1)(0,1,1)12 and (1,1,1)(0,1,1)12. The forecasted monthly malaria cases from January to December 2009 and 2010 varied from 15 to 82 cases in 2009 and 67 to 149 cases in 2010, where population in 2009 was 285,375 and the expected population of 2010 to be 289,085. The ARIMAX model of monthly cases and climatic factors showed considerable variations among the different districts. In general, the mean maximum temperature lagged at one month was a strong positive predictor of an increased malaria cases for four districts. The monthly number of cases of the previous month was also a significant predictor in one district, whereas no variable could predict malaria cases for two districts. Conclusions The ARIMA models of time-series analysis were useful in forecasting the number of cases in the endemic areas of Bhutan. There was no consistency in the predictors of malaria cases when using ARIMAX model with selected lag times and climatic predictors. The ARIMA forecasting models could be employed for planning and managing malaria prevention and control programme in Bhutan.

Abstract Background The main objective of this study was to assess the effectiveness of integrating the use of cell-phones into a routine malaria prevention and control programme, to improve the management of malaria cases among an under-served population in a border area. The module for disease and treatment monitoring of malaria (DTMM) consisted of case investigation and case follow-up for treatment compliance and patients' symptoms. Methods The module combining web-based and mobile technologies was developed as a proof of concept, in an attempt to replace the existing manual, paper-based activities that malaria staff used in treating and caring for malaria patients in the villages for which they were responsible. After a patient was detected and registered onto the system, case-investigation and treatment details were recorded into the malaria database. A follow-up schedule was generated, and the patient's status was updated when the malaria staff conducted their routine home visits, using mobile phones loaded with the follow-up application module. The module also generated text and graph messages for a summary of malaria cases and basic statistics, and automatically fed to predetermined malaria personnel for situation analysis. Following standard public-health practices, access to the patient database was strictly limited to authorized personnel in charge of patient case management. Results The DTMM module was developed and implemented at the trial site in late November 2008, and was fully functioning in 2009. The system captured 534 malaria patients in 2009. Compared to paper-based data in 2004-2008, the mobile-phone-based case follow-up rates by malaria staff improved significantly. The follow-up rates for both Thai and migrant patients were about 94-99% on Day 7 (Plasmodium falciparum) and Day 14 (Plasmodium vivax) and maintained at 84-93% on Day 90. Adherence to anti-malarial drug therapy, based on self-reporting, showed high completion rate for P. falciparum-infected cases, but lower rate for P. vivax cases. Patients' symptoms were captured onto the mobile phone during each follow-up visit, either during the home visit or at Malaria Clinic; most patients had headache, muscle pain, and fatigue, and some had fever within the first follow-up day (day7/14) after the first anti-malarial drug dose. Conclusions The module was successfully integrated and functioned as part of the malaria prevention and control programme. Despite the bias inherent in sensitizing malaria workers to perform active case follow-up using the mobile device, the study proved for its feasibility and the extent to which community healthcare personnel in the low resource settings could potentially utilize it efficiently to perform routine duties, even in remote areas. The DTMM has been modified and is currently functioning in seven provinces in a project supported by the WHO and the Bill & Melinda Gates Foundation, to contain multi-drug resistant malaria on the Thai-Cambodian border.

Abstract Background The probability of contracting malaria in a given individual is determined not only by the individual's characteristics, but also the ecological factors that characterize the level of human-vector contact in the population. Examination of the relationship between "individual" and "supra-individual" variables over time is important for understanding the local malaria epidemiology. This is essential for planning effective intervention strategies specifically for each location. Methods A retrospective cohort study was conducted, which followed a community-cohort of about 3,500 residents in seven hamlets along the Thai-Myanmar border between 1999 and 2006. Potential malaria determinants measured at different levels (temporal variables, individual variables, and hamlet variables) were incorporated into multilevel models to estimate their effects on an individual's risk of malaria attack. Results The monthly minimum temperature was significantly associated with the seasonal variation of malaria risk. An individual risk of malaria attack decreased by about 50% during the period that active surveillance was conducted; an additional 15% and 25% reduction of Plasmodium falciparum and Plasmodium vivax incidence, respectively, was observed after the use of artesunate-mefloquine combination therapy (ACT) for treatment of P. falciparum. Male children (age < 16 years old) were at highest risk of both P. falciparum and P. vivax attack. An increase in the hamlet's incidence of P. falciparum and P. vivax by 1 per 100 persons in a previous month resulted in 1.14 and 1.34 times increase in the risk of P. falciparum and P. vivax, respectively, among individuals in a particular hamlet. Conclusion In a small area with low malaria transmission intensity, the variation in mosquito abundance is relatively similar across the residential areas; incidence of malaria between hamlets, which reflects the community level of human infectious reservoirs, is an important predictor for the malaria risk among individuals within these hamlets. Therefore, local malaria control strategies should focus on interventions that aim to reduce the gametocyte carriage in the population, such as early detection and treatment programmes and the use of ACT for P. falciparum.

Abstract Background Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail. Methods Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Δ = 5% difference in proportion of failures). Results Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported. Conclusions Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be administered, dihydroartemisinin-piperaquine provides additional benefit in terms of post-treatment prophylaxis, reducing the incidence of recurrence from 4-8 weeks after treatment. Trial Registration The trial was registered at ClinicalTrials.gov under identifier NCT00682578.

Abstract Background Mefloquine and artesunate combination therapy is the recommended first-line treatment for uncomplicated malaria throughout much of south-east Asia. Concerns have been raised about the potential central nervous system (CNS) effects of both drug components and there are no detailed reports in very young children. Methods Children, aged between three months and five years, with acute uncomplicated Plasmodium falciparum malaria were randomized to either 7 days of artesunate monotherapy or the same schedule of artesunate plus mefloquine on day 7 and 8. Neurological testing targeting coordination and behaviour was carried out at day 0, 7, 9, 10, 14 and 28. Non-febrile healthy control children from the same population were tested on days 0, 7, 14 and 28. Results From December 1994 to July 1997, 91 children with uncomplicated P. falciparum, 45 treated with artesunate monotherapy, 46 treated with mefloquine and artesunate combination therapy and 36 non-febrile controls, underwent neurological testing. Malaria and fever had a significant negative impact on testing performance. By contrast, the anti-malarial treatments were not associated with worsening performances in the various components of the test. Artesunate and mefloquine do not appear to have a significant influence on coordination and behaviour. Children treated with mefloquine were significantly less likely to suffer recurrent malaria infection during follow-up compared to those treated with artesunate alone (P = 0.033). Conclusion In keeping with the results of randomized controlled trials in adults, mefloquine was not associated with a decrease in specific items of neurological performance. Likewise, children treated with artesunate did not perform significantly differently to control children. This study does not exclude subtle or rare treatment CNS effects of artesunate or mefloquine. Treatment of acute uncomplicated malaria results in a significant improvement on items of neurological performance.

Abstract Background Effective malaria control has successfully reduced the malaria burden in many countries, but to eliminate malaria, these countries will need to further improve their control efforts. Here, a malaria control programme was critically evaluated in a very low-endemicity Thai-Myanmar border population, where early detection and prompt treatment have substantially reduced, though not ended, Plasmodium falciparum transmission, in part due to carriage of late-maturing gametocytes that remain post-treatment. To counter this effect, the WHO recommends the use of a single oral dose of primaquine along with an effective blood schizonticide. However, while the effectiveness of primaquine as a gametocidal agent is widely documented, the mismatch between primaquine's short half-life, the long-delay for gametocyte maturation and the proper timing of primaquine administration have not been studied. Methods Mathematical models were constructed to simulate 8-year surveillance data, between 1999 and 2006, of seven villages along the Thai-Myanmar border. A simple model was developed to consider primaquine pharmacokinetics and pharmacodynamics, gametocyte carriage, and infectivity. Results In these populations, transmission intensity is very low, so the P. falciparum parasite rate is strongly linked to imported malaria and to the fraction of cases not treated. Given a 3.6-day half-life of gametocyte, the estimated duration of infectiousness would be reduced by 10 days for every 10-fold reduction in initial gametocyte densities. Infectiousness from mature gametocytes would last two to four weeks and sustain some transmission, depending on the initial parasite densities, but the residual mature gametocytes could be eliminated by primaquine. Because of the short half-life of primaquine (approximately eight hours), it was immediately obvious that with early administration (within three days after an acute attack), primaquine would not be present when mature gametocytes emerged eight days after the appearance of asexual blood-stage parasites. A model of optimal timing suggests that primaquine follow-up approximately eight days after a clinical episode could further reduce the duration of infectiousness from two to four weeks down to a few days. The prospects of malaria elimination would be substantially improved by changing the timing of primaquine administration and combining this with effective detection and management of imported malaria cases. The value of using primaquine to reduce residual gametocyte densities and to reduce malaria transmission was considered in the context of a malaria transmission model; the added benefit of the primaquine follow-up treatment would be relatively large only if a high fraction of patients (>95%) are initially treated with schizonticidal agents. Conclusion Mathematical models have previously identified the long duration of P. falciparum asexual blood-stage infections as a critical point in maintaining malaria transmission, but infectiousness can persist for two to four weeks because of residual populations of mature gametocytes. Simulations from new models suggest that, in areas where a large fraction of malaria cases are treated, curing the asexual parasitaemia in a primary infection, and curing mature gametocyte infections with an eight-day follow-up treatment with primaquine have approximately the same proportional effects on reducing the infectious period. Changing the timing of primaquine administration would, in all likelihood, interrupt transmission in this area with very good health systems and with very low endemicity.

Abstract Background The use of artemisinin derivatives has increased exponentially with the deployment of artemisinin combination therapy (ACT) in all malarious areas. They are highly effective and are considered safe, but in animal studies artemisinin derivatives produce neurotoxicity targeting mainly the auditory and vestibular pathways. The debate remains as to whether artemisinin derivatives induce similar toxicity in humans. Methods This prospective study assessed the effects on auditory function of a standard 3-day oral dose of artesunate (4 mg/kg/day) combined with mefloquine (25 mg/kg) in patients with acute uncomplicated falciparum malaria treated at the Shoklo Malaria Research Unit, on the Thai-Burmese border. A complete auditory evaluation with tympanometry, audiometry and auditory brainstem responses (ABR) was performed before the first dose and seven days after initiation of the antimalarial treatment. Results Complete auditory tests at day 0 (D0) and day 7 (D7) were obtained for 93 patients. Hearing loss (threshold > 25 dB) on admission was common (57%) and associated with age only. No patient had a threshold change exceeding 10 dB between D0 and D7 at any tested frequency. No patient showed a shift in Wave III peak latency of more than 0.30 msec between baseline and D7. Conclusion Neither audiometric or the ABR tests showed clinical evidence of auditory toxicity seven days after receiving oral artesunate and mefloquine.

Abstract Background Haematological changes associated with malaria in pregnancy are not well documented, and have focused predominantly on anaemia. Examined here is thrombocytopaenia in pregnant women infected with Plasmodium falciparum or Plasmodium vivax in a low transmission area on the north-western border of Thailand. Methods In this observational study we reviewed the platelet counts from routine complete blood count (CBC) in a cohort of healthy and malaria infected Karen pregnant women attending weekly antenatal clinics. A platelet count of 75,000/μL was the threshold at 2 standard deviations below the mean for healthy pregnant women used to indicate thrombocytopenia. Differences in platelet counts in non-pregnant and pregnant women were compared after matching for age, symptoms, malaria species and parasitaemia. Results In total 974 pregnant women had 1,558 CBC measurements between February 2004 and September 2006. The median platelet counts (/μL) were significantly lower in patients with an episode of falciparum 134,000 [11,000–690,000] (N = 694) or vivax malaria 184,000 [23,000–891,000] (N = 523) compared to healthy pregnant women 256,000 [64,000–781,000] (N = 255), P < 0.05 for both comparisons. Plasmodium falciparum and P. vivax caused a 34% (95% CI 24–47) and 22% (95% CI 8–36) reduction in platelet count, respectively. Pregnant compared to non pregnant women were at higher risk OR = 2.27 (95%CI 1.16–4.4) P = 0.017, for thrombocytopaenia. Platelets counts were higher in first compared with subsequent malaria infections within the same pregnancy. Malaria associated thrombocytopaenia had a median [range] time for recovery of 7 234567891011121314 days which did not differ by antimalarial treatment (P = 0.86), or species (P = 0.63) and was not associated with active bleeding. Conclusion Pregnant women become more thrombocytopenic than non-pregnant women with acute uncomplicated malaria. Uncomplicated malaria associated thrombocytopaenia is seldom severe. Prompt antimalarial treatment resulted in normalization of platelet counts within a week.

Abstract Background Clinical case treatment of malaria infections where Plasmodium falciparum and Plasmodium vivax are sympatric has achieved effective reductions in P. falciparum prevalence and incidence rates, but has been less successful for P. vivax. The high transmissibility of P. vivax and its capacity to relapse have been suggested to make it a harder parasite species to control. Methods A clinical malaria case treatment programme was carried out over a decade in a Karen community composed of seven hamlets on the Thai-Myanmar border. Results From 1994 to 2004, prevalence rates of both P. falciparum and P. vivax decreased by 70–90% in six of the seven study hamlets, but were unchanged in one hamlet. Overall, incidence rates decreased by 72% and 76% for P. falciparum and P. vivax respectively over the period 1999–2004. The age-incidence and prevalence curves suggested that P. vivax was more transmissible than P. falciparum despite a greater overall burden of infection with P. falciparum. Male gender was associated with increased risk of clinical presentation with either parasite species. Children (< 15 years old) had an increased risk of presenting with P. vivax but not P. falciparum. Conclusion There was a considerable reduction in incidence rates of both P. vivax and P. falciparum over a decade following implementation of a case treatment programme. The concern that intervention methods would inadvertently favour one species over another, or even lead to an increase in one parasite species, does not appear to be fulfilled in this case.

Abstract Background On the borders of Thailand, Plasmodium falciparum has become resistant to nearly all available drugs, and there is an urgent need to find new antimalarial drugs or drug combinations. Ferroquine (SSR97193) is a new 4-aminoquinoline antimalarial active against chloroquine resistant and sensitive P. falciparum strains in vivo and in vitro. This antimalarial organic iron complex (a ferrocenyl group has been associated with chloroquine) is meant to use the affinity of Plasmodium for iron to increase the probability for encountering the anti-malarial molecule. The aim of the present study was to investigate the activity of ferroquine against P. falciparum isolates from an area with a known high multi-drug resistance rate. Methods Parasite isolates were obtained from patients with acute falciparum malaria attending the clinics of SMRU. In vitro cultures of these isolates were set-up in the SMRU-laboratory on pre-dosed drug plates, and grown in culture for 42 hours. Parasite growth was assessed by the double-site enzyme-linked pLDH immunodetection (DELI) assay. Results Sixty-five P. falciparum isolates were successfully grown in culture. The ferroquine mean IC50 (95% CI) was 9.3 nM (95% C.I.: 8.7 – 10.0). The mean IC50 value for the principal metabolite of ferroquin, SR97213A, was 37.0 nM (95% C.I.: 34.3 – 39.9), which is four times less active than ferroquine. The isolates in this study were highly multi-drug resistant but ferroquine was more active than chloroquine, quinine, mefloquine and piperaquine. Only artesunate was more active than ferroquine. Weak but significant correlations were found between ferroquine and its principal metabolite (r2 = 0.4288), chloroquine (r2 = 0.1107) and lumefantrine (r2 = 0.2364). Conclusion The results presented in this study demonstrate that the new ferroquine compound SSR97193 has high anti-malarial activity in vitro against multi-drug resistant P. falciparum.

Abstract Background Maptaphut Industrial Estate (MIE) was established with a single factory in 1988, increasing to 50 by 1998. This development has resulted in undesirable impacts on the environment and the health of the people in the surrounding areas, evidenced by frequent complaints of bad odours making the people living there ill. In 1999, the Bureau of Environmental Health, Department of Health, Ministry of Public Health, conducted a study of the health status of people in Rayong Province and found a marked increase in respiratory diseases over the period 1993–1996, higher than the overall prevalence of such diseases in Thailand. However, the relationship between the pollutants and the respiratory diseases of the people in the surrounding area has still not been quantified. Therefore, this study aimed to determine the spatial distribution of respiratory disease, to estimate pollutants released from the industrial estates, and to quantify the relationship between estimated pollutants and respiratory disease in the Maptaphut Municipality. Results Disease mapping showed a much higher risk of respiratory disease in communities adjacent to the Maptaphut Industrial Estate. Disease occurrence formed significant clusters centred on communities near the estate, relative to the weighted mean centre of chimney stacks. Analysis of the rates of respiratory disease in the communities, categorized by different concentrations of estimated pollutants, found a dose-response effect. Spatial regression analysis found that the distance between community and health providers decreased the rate of respiratory disease (p < 0.05). However, after taking into account distance, total pollutant (p < 0.05), SO2 (p < 0.05) and NOx (p < 0.05) played a role in adverse health effects during the summer. Total pollutant (p < 0.05) and NOx (p < 0.05) played a role in adverse health effects during the rainy season after taking into account distance, but during winter there was no observed relationship between pollutants and rates of respiratory disease after taking into account distance. A 12-month time-series analysis of six communities selected from the disease clusters and the areas impacted most by pollutant dispersion, found significant effects for SO2 (p < 0.05), NOx (p < 0.05), and TSP (p < 0.05) after taking into account rainfall. Conclusion This study employed disease mapping to present the spatial distribution of disease. Excessive risk of respiratory disease, and disease clusters, were found among communities near Maptaphut Industrial Estate. Study of the relationship between estimated pollutants and the occurrence of respiratory disease found significant relationships between estimated SO2, NOx, and TSP, and the rate of respiratory disease.

Abstract Background The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum. The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border. Methods The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis. Results In 2001–2002 a total of 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. Conclusion Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.

BackgroundThe emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, where artemisinin resistance is prevalent.Methods and findingsAfter establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention.ConclusionsAdded to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination.Trial registrationClinicalTrials.gov NCT01872702.

BackgroundThe fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda.Methods and findingsIn total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site).ConclusionsDP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.