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Abstract Background Bhutan has achieved a major reduction in malaria incidence amid multiple challenges. This case study seeks to characterize the Bhutan malaria control programme over the last 10 years. Methods A review of the malaria epidemiology, control strategies, and elimination strategies employed in Bhutan was carried out through a literature review of peer-reviewed and grey national and international literature with the addition of reviewing the surveillance and vector control records of the Bhutan Vector-Borne Disease Control Programme (VDCP). Data triangulation was used to identify trends in epidemiology and key strategies and interventions through analysis of the VDCP surveillance and programme records and the literature review. Enabling and challenging factors were identified through analysis of socio-economic and health indicators, corroborated through a review of national and international reports and peer-review articles. Findings Confirmed malaria cases in Bhutan declined by 98.7% from 1994 to 2010. The majority of indigenous cases were due to Plasmodium vivax (59.9%) and adult males are most at-risk of malaria. Imported cases, or those in foreign nationals, varied over the years, reaching 21.8% of all confirmed cases in 2006. Strategies implemented by the VDCP are likely to be related to the decline in cases over the last 10 years. Access to malaria diagnosis in treatment was expanded throughout the country and evidence-based case management, including the introduction of artemisinin-based combination therapy (ACT) for P. falciparum, increasing coverage of high risk areas with Indoor Residual Spraying, insecticide-treated bed nets, and long-lasting insecticidal nets are likely to have contributed to the decline alongside enabling factors such as economic development and increasing access to health services. Conclusion Bhutan has made significant strides towards elimination and has adopted a goal of national elimination. A major challenge in the future will be prevention and management of imported malaria infections from neighbouring Indian states. Bhutan plans to implement screening at border points to prevent importation of malaria and to targeted prevention and surveillance efforts towards at-risk Bhutanese and migrant workers in construction sites.

Abstract Malaria control in Madhya Pradesh is complex because of vast tracts of forest with tribal settlement. Fifty four million individuals of various ethnic origins, accounting for 8% of the total population of India, contributed 30% of total malaria cases, 60% of total falciparum cases and 50% of malaria deaths in the country. Ambitious goals to control tribal malaria by launching "Enhanced Malaria Control Project" (EMCP) by the National Vector Borne Disease Control Programme (NVBDCP), with the World Bank assistance, became effective in September 1997 in eight north Indian states. Under EMCP, the programme used a broader mix of new interventions, i.e. insecticide-treated bed nets, spraying houses with effective residual insecticides, use of larvivorous fishes, rapid diagnostic tests for prompt diagnosis, treatment of the sick with effective radical treatment and increased public awareness and IEC. However, the challenge is to scale up these services. A retrospective analysis of data on malaria morbidity and associated mortality reported under the existing surveillance system of the Madhya Pradesh (Central India) for the years 1996–2007 was carried out to determine the impact of EMCP on malaria morbidity and associated mortality. Analysis revealed that despite the availability of effective intervention tools for the prevention and control of malaria, falciparum malaria remains uncontrolled and deaths due to malaria have increased. Precisely, the aim of this epidemiological analysis is to draw lessons applicable to all international aid efforts, bureaucracy, policy makers and programme managers in assessing its project performance as a new Global Malaria Action Plan is launched with ambitious goal of reducing malaria and its elimination by scaling up the use of existing tools.

Abstract Background Malaria in pregnancy (MiP) is inadequately researched in India, and the burden is probably much higher than current estimates suggest. This paper models the burden of MiP and associated foetal losses and maternal deaths, in rural Madhya Pradesh, India. Methods Number of pregnancies per year was estimated from the number of births and an estimate of pregnancies that end in foetal loss. The prevalence of MiP, risk of foetal loss attributable to MiP and case fatality rate of MiP were obtained from the literature. The estimated total number of pregnancies was multiplied by the appropriate parameter to estimate the number of MiP cases, and foetal loss and maternal deaths attributable to MiP per year. A Monte Carlo simulation sensitivity analysis was done to assess plausibility of various estimates obtained from the literature. The burden of MiP in tribal women was explored by incorporating the variable prevalence of malaria in tribal and non-tribal populations and in forested and non-forested regions within Madhya Pradesh. Results Estimates of MiP cases in rural Madhya Pradesh based on the model parameter values found in the literature ranged from 183,000–1.5 million per year, with 73,000–629,000 lost foetuses and 1,500–12,600 maternal deaths attributable to MiP. The Monte Carlo simulation gave a more plausible estimate of 220,000 MiP cases per year (inter-quartile range (IQR): 136,000–305,000), 95,800 lost foetuses (IQR: 56,800–147,600) and 1,000 maternal deaths (IQR: 650–1,600). Tribal women living in forested areas bore 30% of the burden of MiP in Madhya Pradesh, while constituting 18% of the population. Conclusion Although the estimates are uncertain, they suggest MiP is a significant public health problem in rural Madhya Pradesh, affecting many thousands of women and that reducing the MiP burden should be a priority.

Abstract Objective The main objective of this study was to compare the performance of nested PCR with expert microscopy as a means of detecting Plasmodium parasites during active malaria surveillance in western Thailand. Methods The study was performed from May 2000 to April 2002 in the village of Kong Mong Tha, located in western Thailand. Plasmodium vivax (PV) and Plasmodium falciparum (PF) are the predominant parasite species in this village, followed by Plasmodium malariae (PM) and Plasmodium ovale (PO). Each month, fingerprick blood samples were taken from each participating individual and used to prepare thick and thin blood films and for PCR analysis. Results PCR was sensitive (96%) and specific (98%) for malaria at parasite densities ≥ 500/μl; however, only 18% (47/269) of P. falciparum- and 5% (20/390) of P. vivax-positive films had parasite densities this high. Performance of PCR decreased markedly at parasite densities P. falciparum and 24% for P. vivax at densities Conclusion Although PCR performance appeared poor when compared to microscopy, data indicated that the discrepancy between the two methods resulted from poor performance of microscopy at low parasite densities rather than poor performance of PCR. These data are not unusual when the diagnostic method being evaluated is more sensitive than the reference method. PCR appears to be a useful method for detecting Plasmodium parasites during active malaria surveillance in Thailand.

Thailand's National Malaria Elimination Strategy 2017-2026 introduced the 1-3-7 strategy as a robust surveillance and response approach for elimination that would prioritize timely, evidence-based action. Under this strategy, cases are reported within 1 day, cases are investigated within 3 days, and foci are investigated and responded to within 7 days, building on Thailand's long history of conducting case investigation since the 1980s. However, the hallmark of the 1-3-7 strategy is timeliness, with strict deadlines for reporting and response to accelerate elimination. This paper outlines Thailand's experience adapting and implementing the 1-3-7 strategy, including success factors such as a cross-sectoral Steering Committee, participation in a collaborative regional partnership, and flexible local budgets. The programme continues to evolve to ensure prompt and high-quality case management, capacity maintenance, and adequate supply of lifesaving commodities based on surveillance data. Results from implementation suggest the 1-3-7 strategy has contributed to Thailand's decline in malaria burden; this experience may be useful for other countries aiming to eliminate malaria.

Background: Malaria Clinics (MCs) have served communities in Thailand since 1965 and are still playing a critical role in providing early diagnosis and effective treatment of malaria. Methods: We reviewed six decades of published manuscripts, articles, strategies, and plans regarding MC operations in Thailand;,and analyzed national program surveillance data in both malaria control and malaria elimination phases. Results: MCs accounted for 39.8% of malaria tests and 54.8% of positive cases by the end of the 1980s. The highest number of MCs established was 544 in 1997. MCs contributed to 6.7% of all tests and 30% of all positive cases over the 2015-2017 period. Between 2017 and June 2019, during the malaria elimination phase, MCs continued to test an average of 67% of all persons tested for malaria, and confirmed 38.3% of all positive cases detected in the country. Conclusions: Testing and positive rates of MCs are on a gradual decline as the overall burden of malaria declines annually, which may reflect decreasing transmission intensity. Although the number of MCs in the last three years has been stable ( n = 240), the attrition of MC staff poses a real challenge to the longevity of MCs in the absence of a human resource plan to support the elimination phase. It is necessary to identify and support capacity gaps and needs as MCs are absorbed into an integrated and decentralized program, while ensuring that the Division of Vector Borne Diseases (DVBD) maintains its necessary technical and advisory role.

Following progressive success in reducing the burden of malaria over the past two decades, countries of the Asia Pacific are now aiming for elimination of malaria by 2030. Plasmodium falciparum and Plasmodium vivax are the two main malaria species that are endemic in the region. P. vivax is generally perceived to be less severe but will be harder to eliminate, owing partly to its dormant liver stage (known as a hypnozoite) that can cause multiple relapses following an initial clinical episode caused by a mosquito-borne infection. Primaquine is the only anti-hypnozoite drug against P. vivax relapse currently available, with tafenoquine in the pipeline. However, both drugs may cause severe haemolysis in individuals with deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), a hereditary defect. The overall incidence of malaria has significantly declined in both Thailand and Cambodia over the last 15 years. However, P. vivax has replaced P. falciparum as the dominant species in large parts of both countries. This paper presents the experience of the national malaria control programmes of the two countries, in their efforts to implement safe primaquine therapy for the radical cure, i.e. relapse prevention, of P. vivax malaria by introducing a rapid, point-of-care test to screen for G6PD deficiency.

Background: Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2., Methods: A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples., Results: True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively)., Conclusions: Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.

This is the first in a series of papers describing the epidemiology of malaria in an isolated village in western Thailand. The study site was the village of Kong Mong Tha, located in Sangkhla Buri District, Kanchanaburi Province, Thailand. In this paper we present an overview of the study site and results from our adult anopheline mosquito surveillance conducted over 56 consecutive months from June 1999 until January 2004. The collection site, indoor/outdoor location, parity, biting activity and Plasmodiumfalciparum (Pf) and P. vivax (Pv) infection rates were used to calculate seasonal entomological inoculation rates for the predominant four Anopheles species. A total of 21,566 anophelines representing 28 distinct species and 2 groups that were not identified to species were collected using human bait, with almost 95% of the collection consisting of Anopheles minimus, An. maculatus, An. sawadwongporni and An. barbirostris/campestris. Mosquitoes generally peaked during the wet season, were collected throughout the night, and were collected most often outside (ca. 75%) versus inside (ca. 25%) of houses. Approximately 50% of collected mosquitoes were parous. Overall Plasmodium infection rates were 0.27%, with a total of 16 and 42 pools of Pf- and Pv-positive mosquitoes, respectively. Annual EIRs were 2.3 times higher for Pv than for Pf, resulting in approximately 5.5 and 2.6 infective bites per person per year, respectively. The results suggest An. minimus and An. maculatus are the primary and secondary vectors of Pf and Pv transmission in Kong Mong Tha, while An. sawadwongporni and An. barbirostris/campestris also appear to play a role based on the presence of circumsporozoite protein (CSP) in the head/thorax of the specimens tested.

Asymptomatic infection is an important obstacle for controlling disease in countries where malaria is endemic. Because asymptomatic carriers do not seek treatment for their infections, they can have high levels of gametocytes and constitute a reservoir available for new infection. We employed a sample pooling/PCR-based molecular detection strategy for screening malaria infection in residents from areas of Myanmar where malaria is endemic. Blood samples (n = 1,552) were collected from residents in three areas of malaria endemicity (Kayin State, Bago, and Tanintharyi regions) of Myanmar. Two nested PCR and real-time PCR assays showed that asymptomatic infection was detected in about 1.0% to 9.4% of residents from the surveyed areas. The sensitivities of the two nested PCR and real-time PCR techniques were higher than that of microscopy examination (sensitivity, 100% versus 26.4%; kappa values, 0.2 to 0.5). Among the three regions, parasite-positive samples were highly detected in subjects from the Bago and Tanintharyi regions. Active surveillance of residents from regions of intense malaria transmission would reduce the risk of morbidity and mitigate transmission to the population in these areas of endemicity. Our data demonstrate that PCR-based molecular techniques are more efficient than microscopy for nationwide surveillance of malaria in countries where malaria is endemic., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Artemisinin resistance is a major threat to global malaria control and elimination efforts. Myanmar detected the first indication of the resistance in 2009 in the eastern part of the country, bordering Thailand. Since 2010, WHO has played a vital role in ensuring that a comprehensive programme on the containment of the resistance is in place. This paper documents achievement made in terms of output, outcomes and early impact on malaria from July 2011 to December 2013. It also identifies enabling factors to success and, most importantly, challenges awaiting the national programme and its partners.

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.

Malaria control in Madhya Pradesh is complex because of vast tracts of forest with tribal settlement. Fifty four million individuals of various ethnic origins, accounting for 8% of the total population of India, contributed 30% of total malaria cases, 60% of total falciparum cases and 50% of malaria deaths in the country. Ambitious goals to control tribal malaria by launching "Enhanced Malaria Control Project" (EMCP) by the National Vector Borne Disease Control Programme (NVBDCP), with the World Bank assistance, became effective in September 1997 in eight north Indian states. Under EMCP, the programme used a broader mix of new interventions, i.e. insecticide-treated bed nets, spraying houses with effective residual insecticides, use of larvivorous fishes, rapid diagnostic tests for prompt diagnosis, treatment of the sick with effective radical treatment and increased public awareness and IEC. However, the challenge is to scale up these services.A retrospective analysis of data on malaria morbidity and associated mortality reported under the existing surveillance system of the Madhya Pradesh (Central India) for the years 1996-2007 was carried out to determine the impact of EMCP on malaria morbidity and associated mortality. Analysis revealed that despite the availability of effective intervention tools for the prevention and control of malaria, falciparum malaria remains uncontrolled and deaths due to malaria have increased. Precisely, the aim of this epidemiological analysis is to draw lessons applicable to all international aid efforts, bureaucracy, policy makers and programme managers in assessing its project performance as a new Global Malaria Action Plan is launched with ambitious goal of reducing malaria and its elimination by scaling up the use of existing tools.

Background: Malaria in pregnancy (MiP) is inadequately researched in India, and the burden is probably much higher than current estimates suggest. This paper models the burden of MiP and associated foetal losses and maternal deaths, in rural Madhya Pradesh, India., Methods: Number of pregnancies per year was estimated from the number of births and an estimate of pregnancies that end in foetal loss. The prevalence of MiP, risk of foetal loss attributable to MiP and case fatality rate of MiP were obtained from the literature. The estimated total number of pregnancies was multiplied by the appropriate parameter to estimate the number of MiP cases, and foetal loss and maternal deaths attributable to MiP per year. A Monte Carlo simulation sensitivity analysis was done to assess plausibility of various estimates obtained from the literature. The burden of MiP in tribal women was explored by incorporating the variable prevalence of malaria in tribal and non-tribal populations and in forested and non-forested regions within Madhya Pradesh., Results: Estimates of MiP cases in rural Madhya Pradesh based on the model parameter values found in the literature ranged from 183,000-1.5 million per year, with 73,000-629,000 lost foetuses and 1,500-12,600 maternal deaths attributable to MiP. The Monte Carlo simulation gave a more plausible estimate of 220,000 MiP cases per year (inter-quartile range (IQR): 136,000-305,000), 95,800 lost foetuses (IQR: 56,800-147,600) and 1,000 maternal deaths (IQR: 650-1,600). Tribal women living in forested areas bore 30% of the burden of MiP in Madhya Pradesh, while constituting 18% of the population., Conclusion: Although the estimates are uncertain, they suggest MiP is a significant public health problem in rural Madhya Pradesh, affecting many thousands of women and that reducing the MiP burden should be a priority.

Objective: The main objective of this study was to compare the performance of nested PCR with expert microscopy as a means of detecting Plasmodium parasites during active malaria surveillance in western Thailand., Methods: The study was performed from May 2000 to April 2002 in the village of Kong Mong Tha, located in western Thailand. Plasmodium vivax (PV) and Plasmodium falciparum (PF) are the predominant parasite species in this village, followed by Plasmodium malariae (PM) and Plasmodium ovale (PO). Each month, fingerprick blood samples were taken from each participating individual and used to prepare thick and thin blood films and for PCR analysis., Results: PCR was sensitive (96%) and specific (98%) for malaria at parasite densities > or = 500/microl; however, only 18% (47/269) of P. falciparum- and 5% (20/390) of P. vivax-positive films had parasite densities this high. Performance of PCR decreased markedly at parasite densities <500/microl, with sensitivity of only 20% for P. falciparum and 24% for P. vivax at densities <100 parasites/microl., Conclusion: Although PCR performance appeared poor when compared to microscopy, data indicated that the discrepancy between the two methods resulted from poor performance of microscopy at low parasite densities rather than poor performance of PCR. These data are not unusual when the diagnostic method being evaluated is more sensitive than the reference method. PCR appears to be a useful method for detecting Plasmodium parasites during active malaria surveillance in Thailand.

A malaria epidemic warning system was established in Thailand in 1984 using graphs displaying the median or mean incidence of malaria over the previous five years compiled from malaria surveillance data throughout the country. This reporting mechanism is not timely enough to detect the occurrence of a malaria epidemic which usually occurs at the district level over a short period of time. An alternative method for early detection of a malaria epidemic employing the Poisson model has been proposed. The development of this early malaria epidemic detection model involved 3 steps: model specification, model validation and model testing. The model was based on data collected at the Vector Borne Disease Control Unit (VBDU) Level. The results of model testing reveal the model can detect increasing numbers of cases earlier, one to two weeks prior to reaching their highest peak of transmission. The system was tested using data from Kanchanaburi Province during 2000 to 2001. Results from model testing show the model may be used for monitoring the weekly malaria situation at the district level. The Poisson model was able to detect malaria early in a highly endemic province with a satisfactory level of prediction. As the application is essential for the malaria officers in monitoring of malaria epidemics, this early detection system was introduced into malaria epidemiological work. The model may be helpful in the decision making process, planning and budget allocation for the Malaria Control Program. The software for early malaria detection is currently implemented in several endemic areas throughout Thailand.

Substandard and counterfeit pharmaceutical products, including antimalarial drugs, appear to be widespread internationally and affect both the developing and developed countries. The aim of the study was to investigate the quality of antimalarial drugs, ie, artesunate (ART), chloroquine (CHL), mefloquine (MEF), quinine (QUI), sulfadoxine/pyrimethamine (S/P) and tetracycline (TT) obtained from the government sector and private pharmacies in 4 Thai provinces: Mae Hong Son, Kanchanaburi, Ranong, and Chanthaburi. Three hundred sixty-nine samples of 6 antimalarial drugs from 27 government hospitals, 27 malaria clinics, and 53 drugstores, were collected. Drug quality was assessed by simple disintegration test and semi-quantitative thin-layer chromatography in each province; 10% passed, 100% failed and doubtful samples were sent to be verified by high performance liquid chromatography (HPLC) at the Thai National Drug Analysis Laboratory, (NL). Fifteen point four percent of ART, 11.1% of CHL and 29.4% of QUI were substandard. Based on the finding, drug regulatory authorities in the country took appropriate action against violators to ensure that antimalarial drugs consumed by malaria patients are of good quality.

The combination of artesunate and mefloquine is currently one of the most effective treatments for multidrug-resistant Plasmodium falciparum malaria. Simultaneous, rather than sequential treatment with the two drugs, would allow better patient compliance. We therefore evaluated three-day treatment with artesunate combined with either 2 or 3 days of mefloquine co-administered once a day with artesunate. The study was an open, randomized trial for acute, uncomplicated falciparum malaria and was conducted at the Bangkok Hospital for Tropical Diseases. One hundred and twenty adult patients were randomized to two treatment groups. Group 1 patients received 4 mg/kg/day of artesunate for 3 days and 3 daily doses of 8.0 mg/kg/day mefloquine given with artesunate. Group 2 patients received the same dose of artesunate and the same total dose of mefloquine (25 mg/kg). However, the mefloquine was given as 15 mg/kg on the first day and 10 mg/kg/ on the second day, again with artesunate. The baseline demographic and clinical characteristics of the patients in the two groups were similar. The cure rates for the 3-day and 2-day mefloquine regimens were 100% and 99%, respectively. There were no significant differences in either median fever clearance times (group 1=32 hours; group 2=33 hours) or mean parasite clearance times (group 1=42.3 hours; group 2=43.3 hours). Both regimens were well tolerated and there were no significant differences in the incidence of adverse effects. Nausea or vomiting occurred in 3.8% of patients in both groups and transient dizziness occurred in 4% of group 1 and 9% of group 2 patients. These results suggest that a 3-day regimen of mefloquine administered with artesunate is effective and well tolerated. This practical regimen could improve patient compliance.

The occurrence of malaria epidemics in Thailand was reviewed from the malaria surveillance report of the National Malaria Control Program. The literature review revealed that the four epidemic periods recorded during 1980-2000 almost always occurred in the provinces and districts located along international borders. Malaria epidemics are caused by various factors such as: extensive population movement, multi-drug resistance development, low immune status of the population, lack of knowledge and appropriate personal protection against mosquito biting, and the re-emergence of malaria transmission in low malarious areas. Such factors can lead to changes in the parasite ratio and appearance of malaria epidemics throughout the country. Evidence related to the burden of malaria epidemics was also reviewed to identify causal factors that will be helpful in future research.

Due to the deteriorating efficacy of sulfadoxine-pyrimethamine (SP or Fansidar), from the mid-1970s the Thai Malaria Control Program was actively involved in testing potential replacement drugs to be used as the primary therapy for falciparum malaria in Thailand. In 1983, a large-scale field trial of mefloquine, a long-acting antimalarial drug known for its efficacy against chloroquine- and SP-resistant Plasmodium falciparum, was initiated on the Thai-Cambodian border. The study enrolled over 60,000 patients and eventually led to the formal establishment of mefloquine as the first line drug for the treatment of uncomplicated falciparum malaria in the country. Mefloquine has played a significant role in the control of malaria in Thailand for the past two decades, initially in combination with SP, then by itself, and currently in selected areas as a partner drug in the combination therapy with artesunate. Thailand is the country with the most experience in the use of this drug in a malaria control program. We present here a review of mefloquine's pharmacology and usage in Thailand.

Plasmodium falciparum in Thailand is multi-drug resistant. In a previous study it was shown that artesunate and mefloquine were effective, as follow up, we monitored the efficacy of this regimen for six years. During 1997-2002, 516 adult male volunteer patients in Chanthaburi Province were enrolled (50 patients in the first year, 400 patients in 1998-2001 and 66 patients in 2002). The symptom complex and parasite count (thick blood film) were monitored on days 0, 1, 2, 7, 14, 21, 28, 35 and 42. The dosages used were artesunate (ATS) 150 mg and mefloquine (M) 750 mg at hour 0 and ATS 100 mg and M 500 mg at hour 24. Their ages ranged from 30-35 years and their mean body weights were 54-56 kg. The presenting symptoms were fever 100%, headache 97-100%, anorexia 78-90%, and nausea 28-40%. The geometric mean of parasitemia ranged from 7,357-12,750/mm3. Defervescence in one day was found in 42-76% of patients and 85-100% in 2 days. The sensitivity (S) ranged from 87-94% and RI resistance (recrudescence) ranged from 6-13%. Forty patients demonstrated RI type of response, 37 were cured after being retreated with the same dosage and another 3 patients were cured after the third course of treatment. The aggravated adverse effects included vomiting (8-20%), anorexia (1-41%) and diarrhea (0-16%). These side effects were mild and transient. The efficacy of the artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria was high. The RI type of response was possibly due to re-infection or multiple broods and not to drug resistance. The adverse effects of anorexia, nausea, vomiting and diarrhea were mild and transient for mefloquine. The combination can be used as stand by treatment in areas of multi-drug resistant falciparum malaria.

The intercountry border areas of Thailand have high malaria receptivity and vulnerability that present numerous problems in the control of malaria transmission. This study focused on the 30 provinces of Thailand situated next to neighboring countries, which can be divided into 4 groups: the Thai-Myanmar border (10 provinces), the Thai-Cambodia border (6 provinces), the Thai-Lao border (10 provinces) and the Thai-Malaysia border (4 provinces). The purpose of the present study was to describe the pattern and trend of malaria incidence in the highly endemic provinces along the Thai borders for the 11 years from 1991 to 2001. Analysis of trends showed the distribution of malaria parasites to have shifted from a preponderance of Plasmodium falciparum to Plasmodium vivax along the western border with Myanmar, the northern border with Lao PDR and along the eastern border with Cambodia whereas the southern border with Malaysia the pattern changed from a preponderance of P. vivax to P. falciparum, since 1997. There was a significant difference in annual parasite incidence between borders and non-border districts, especially along the Thai-Myanmar and Thai-Cambodia borders. It is thus evident that all border districts should pay more attention to control of malaria transmission and the activities of the malaria surveillance system, and that monitoring and evaluation of the Thai Malaria Control Program needs to be performed consistently, including some areas where a few malaria cases were found as well as in malaria free areas.

This cross-sectional experimental study developed a methodology to analyze the cost-effectiveness of three malaria diagnostic models: microscopy; on-site OptiMAL; and on-site Immunochromatographic Test (on-site ICT), used in remote non-microscope areas in Thailand, from both a public provider and patient perspective. The study covered six areas in two highly malaria-endemic areas of provinces located along the Thai-Myanmar border. The study was conducted between April and October 2000, by purposively recruiting 436 malaria suspected cases attending mobile malaria clinics. Each patient was randomly selected to receive service via the three diagnostic models; their accuracy was 95.17%, 94.48% and 89.04%, respectively. In addition, their true positive rates for all malaria species were 76.19%, 82.61% and 73.83%; for falciparum malaria 85.71%, 80.95% and 80.00%, and for vivax malaria 57.14%, 100% and 50%, respectively, with the parasitemia ranging from 80 to 58,240 microl of blood. Consequently, their costs were determined by dividing into provider and consumer costs, which were consequently classified into internal and external costs. The internal costs were the costs of the public providers, whereas the external costs were those incurred by the patients. The aggregate costs of these three models were 58,500.35, 36,685.91, and 40,714.01 Baht, respectively, or 339.53, 234.39, and 243.93, in terms of unit costs per actual case. In the case of microscopy, if all suspected malaria cases incurred forgone opportunity costs of waiting for treatment, the aggregate cost and unit cost per actual case were up to 188,110.89 and 944.03 Baht, respectively. Accordingly, the cost-effectiveness for all malaria species, using their true positive rates as the effectiveness indicator, was 446.75, 282.40, and 343.56 respectively, whereas for falciparum malaria it was 394.80, 289.37 and 304.91, and for vivax malaria 595.67, 234.39 and 487.86, respectively. This study revealed that the on-site OptiMAL was the most cost-effective. It could be used to supplement or even replace microscopy for this criteria in general. This study would be of benefit to malaria control program policy makers to consider using RDT technology to supplement microscopy in remote non-microscope areas.

In an expansion of the first Mekong Malaria monograph published in 1999, this second monograph updates the malaria database in the countries comprising the Mekong region of Southeast Asia. The update adds another 3 years' information to cover cumulative data from the 6 Mekong countries (Cambodia, China/Yunnan, Lao PDR, Myanmar, Thailand, Viet Nam) for the six-year period 1999-2001. The objective is to generate a more comprehensive regional perspective in what is a global epicenter of drug resistant falciparum malaria, in order to improve malaria control on a regional basis in the context of social and economic change. The further application of geographical information systems (GIS) to the analysis has underscored the overall asymmetry of disease patterns in the region, with increased emphasis on population mobility in disease spread. Of great importance is the continuing expansion of resistance of P. falciparum to antimalarial drugs in common use and the increasing employment of differing drug combinations as a result. The variation in drug policy among the 6 countries still represents a major obstacle to the institution of region-wide restrictions on drug misuse. An important step forward has been the establishment of 36 sentinel sites throughout the 6 countries, with the objective of standardizing the drug monitoring process; while not all sentinel sites are fully operational yet, the initial implementation has already given encouraging results in relation to disease monitoring. Some decreases in malaria mortality have been recorded. The disease patterns delineated by GIS are particularly instructive when focused on inter-country distribution, which is where more local collaborative effort can be made to rationalize resource utilization and policy development. Placing disease data in the context of socio-economic trends within and between countries serves to further identify the needs and the potential for placing emphasis on resource rationalization on a regional basis. Despite the difficulties, the 6-year time frame represented in this monograph gives confidence that the now well established collaboration is becoming a major factor in improving malaria control on a regional basis and hopefully redressing to a substantial degree the key problem of spread of drug resistance regionally and eventually globally.

Microscopy of Giemsa-stained thick and thin films by a skilled microscopist has remained the standard laboratory method for the diagnosis of malaria. However, diagnosis of malaria with this method is problematic since interpretation of results requires considerable expertise, particularly at low parasite levels. We compared the efficacy of "field" and "expert laboratory" microscopy for active surveillance of Plasmodium falciparum and P. vivax in western Thailand. Field microscopy consisted of an approximately five-minute read (50-100 fields) of a thick film at x700 using a natural light source, whereas expert laboratory microscopy consisted of a 20-minute read (number of parasites per 500 leukocytes) at x1,000 using a high-quality, well-maintained microscope with an artificial light source. All discordant and 20% of concordant results were cross-checked blindly. A total of 3,004 blood films collected between May and November 2000 were included in the study, of which 156 (5.2%) were positive for P. falciparum, 177 (5.9%) for P. vivax, and 4 (0.1%) for both P. falciparum and P. vivax by expert microscopy. A total of 84.4% (135 of 160) of the P. falciparum-positive slides and 93.9% of the P. vivax-positive slides had a parasitemia of less than 500/microL. Field microscopy was specific (99.3%) but not sensitive (10.0%) for the diagnosis of P. falciparum malaria, with a positive predictive value (PPV) of 43.2% and a negative predictive value (NPV) of 95.1%. The corresponding specificity and sensitivity for the diagnosis of P. vivax malaria were 99.2% and 7.1%, respectively, with a PPV of 38.7% and an NPV of 93.9%. Field microscopy, as defined in this study, is not an effective method for active malaria surveillance in western Thailand, where prevalence and parasitemia rates are low.

Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

Rapid antigen assays provide an effective tool for the detection of malaria in symptomatic patients. However, the efficacy of these devices for detecting asymptomatic malaria, where parasite levels are normally significantly lower than in symptomatic patients, is less well established. We evaluated the efficacy of a new combined Plasmodium falciparum-Plasmodim vivax immunochromatographic test (ICT Malaria Pf/Pv) in a cross-sectional malaria survey of the village of Ban Kong Mong Tha, Kanchanaburi Provice, Thailand, from August to December 2000. A total of 1,976 bleeds were made from 559 individuals over the course of the study. Blinded microscopy of thick and thin blood films was used as the gold standard; all discordant and 10% of concordant results were cross-checked. Of 1,976 ICT Malaria Pf/Pv dipsticks tested, 98.3% (n = 1,943) performed as expected, as evidenced by the appearance of the control line. The ICT Malaria Pf/Pv test was both sensitive (100.0%) and specific (99.7 %) for the diagnosis of falciparum malaria with parasitemias of > or = 500 trophozoites/microL; however, only 15.9% (13/82) of infected individuals had parasitemia rates this high. When P. falciparum parasitemia rates were < 500/microL, the sensitivity of the diagnosis was only 23.3%, with a positive predictive value (PPV) and a negative predictive value (NPV) of 76.2 and 97.2%, respectively. The ICT Malaria Pf/Pv test was specific, but not sensitive, for the diagnosis of vivax malaria with parasite rates of > or = 500 trophozoites/microl, with sensitivity, specificity, PPV, and NPV of 66.7%, 99.9%, 66.7%, and 99.9%, respectively. At parasite rates of < 500/microL, corresponding values were 0.0%, 99.9%, 0%, and 95.1%. Because of the relatively high cost of these assays, low parasite rates found in the majority of asymptomatic individuals, and low sensitivity of this assay with rates of < 500/microl, use of this assay as a tool for active case detection is of limited value in western Thailand.

We describe the changing epidemiology of drug resistant malaria in Thailand over the past decade. Factors determining the characteristic patterns of the development and spread of resistance to anti-malarial drugs on the Thai-Cambodian border and the Thai-Myanmar border are explored, namely, population dynamics, drug usage and malaria control measures. The introduction of artesunate-mefloquine combination in selected areas along the two borders in 1995 is believed to be one of the multiple factors responsible for stabilizing the multidrug resistance problems in Thailand today. Other control measures and inter-governmental co-operation must continue to be strengthened in order to limit the spread of drug resistance malaria in the Southeast Asian region.

During the past three decades almost half of the existing natural tropical forests in Thailand were destroyed and replaced by cash crops, rubber, coffee, fruit orchards (durian, rambutan, mangosteen) and other commercial plantations. In order to determine the proportion of malaria cases contracted from such commercial plantations, an epidemiological study was conducted between June 1996 to May 1997 in two districts, one in Pong Nam Ron, located in a south-eastern province near the Cambodian border and another in Sai Yok, in a western province along the Myanmar border. Data were collected by passive case detection from patients attending the existing malaria clinics and active case detection by monthly malariometric survey in selected villages. All malaria cases were thoroughly investigated and classified according to exposure to different ecotypes prior to onset of malaria symptoms in the preceding two weeks. Malaria cases acquired from commercial plantations accounted for 35.2% and 11.2% in Pong Nam Ron and in Sai Yok districts respectively. In such plantations, most of the malaria cases were contracted from fruit orchards and to a lesser extent from rubber and teak plantations. From this study it is evident that commercial plantations provide a significant site of malaria transmission in addition to the forest and foothills areas in Southeast Asia where efficient vectors such as An. dirus and An. minimus are prevalent and have adapted to such changed ecosystems.

A randomized, controlled, malaria-clinic-based field trial was carried out to compare the cost-effectiveness of a 5-day 700-mg oral artesunate and a 7-day quinine + tetracycline regimen for the treatment of uncomplicated falciparum malaria in Thailand. Cost-effectiveness was determined from the providers' perspective and based on curative effectiveness. A total of 137 patients, aged 15-60 years, attending a malaria clinic were followed for 28 days, 60 of them received quinine + tetracycline and 77 received artesunate. Cure rates were assessed on day 5 (artesunate) and day 7 (quinine + tetracycline), using the intention-to-treat approach. Cost-effectiveness and sensitivity analyses were performed by varying the day 5/day 7 curative effectiveness and cost of artesunate. The cure rate with artesunate (100%) was significantly higher than with quinine + tetracycline (77.4%) (relative risk adjusted for sex (aRR) = 1.32, 95% confidence interval (CI) = 1.12-1.55; referent quinine + tetracycline). Artesunate was more cost-effective than quinine + tetracycline at the following costs: artesunate, < or = US$0.36 per 50-mg tablet; quinine, US$0.06 per 300-mg tablet; tetracycline, US$0.02 per 250-mg capsule; and services per case found, < or = US$11.49. Because of the higher cure rate and higher cost-effectiveness of the artesunate regimen compared with quinine + tetracycline, we recommend its use for the treatment of uncomplicated falciparum malaria in malaria clinics in Thailand.

Two vector-borne communicable diseases, malaria and dengue, are among a number of diseases of particular importance in relation to economic development in Southeast Asia and thus need to be assessed in relation to economic parameters in the region. Geographical Information Systems (GIS) provide one means of comparing disease and resource data versus time and place, to facilitate rapid visualization by planners and administrators. Given that Thailand is a global epicenter of multidrug resistant falciparum malaria and of dengue hemorrhagic fever, both of which are mosquito-borne, application of GIS methods to these two diseases gives opportunity for comparison of resource needs and allocation in relation to disease epidemiologic patterns. This study examined per capita gross provincial product (GPPpc) and health care resources in relation to geographic distribution of malaria and dengue in Thailand. The two diseases vary greatly in overall seasonal patterns and in relation to provincial economic status, and present differing demands on resource utilization: planned integration of control of malaria and dengue could utilize such analyses in relation to resource sharing and consideration of allocative efficiency. The concentration of malaria (and to a lesser extent dengue) along international border areas underscores the desirability of multi-country coordination of disease management and control programs. Because socio-economic and disease data are collected by quite different means and in different time frames, there are some limitations to the dynamic interpolation of these two broad data sets, but useful inferences can be drawn from this approach for application to overall planning, at both national and multi-country levels.

This study is an initial attempt to apply disease mapping through Geographical Information System (GIS) with multiple regression analysis to determine the nature and extent of factors influencing malaria transmission in Yunnan Province, PR China, particularly in border areas. Secondary county-based data covering the period 1990 to 1996 were collected and analyzed. The malaria situation in Yunnan Province as a whole is influenced mainly by the combined effects of the physical environment, the presence of efficient vector species, and mobile population along international borders with Myanmar, Lao PDR and Vietnam.

A randomized, controlled, malaria-clinic-based field trial was conducted to compare compliance with a 7-day quinine + tetracycline regimen and a 5-day 700-mg artesunate regimen for the treatment of uncomplicated falciparum malaria in a community in Thailand. Of 137 patients, aged 15-60 years attending a malaria clinic, 77 received artesunate and 60 received quinine + tetracycline. Compliance and cure rates were evaluated on days 5 (artesunate) and 7 (quinine + tetracycline) using patient interview/residual pill counts and peripheral blood smear, respectively. Data were analysed using the intention-to-treat approach, and the reasons for compliance and noncompliance were investigated. Compliance was significantly higher (98.4%) with artesunate than with quinine + tetracycline (71.7%) (relative risk adjusted for sex (aRR) = 1.39 (95% C.I. = 1.15-1.68); referent: quinine + tetracycline). Cure rate (100%) was higher in those receiving artesunate than quinine + tetracycline (77.4%) (aRR = 1.32 (95% C.I. = 1.12-1.55)). Reasons for compliance included the desire to be cured and to follow the advice of malaria staff/employer, and the simple dosing regimen. Noncompliance was mostly due to adverse reactions and forgetting to take the drugs. These results can serve as a baseline for designing and evaluating new interventions to improve compliance, as well as for studying cost-effectiveness to help drug policy decision-making. We recommend a strategy which integrates a short-course, once-a-day regimen (with minimal adverse reactions), a better delivery system for antimalarial drugs and health education, and an enhanced advisory role of malaria staff. Considering the higher compliance rate and curative effectiveness of artesunate, we recommend its use instead of quinine + tetracycline for the treatment of uncomplicated malaria in clinics in Thailand.

Plasmodium falciparum in Southeast Asia is highly resistant to chloroquine, sulfadoxine/ pyrimethamine, quinine and even mefloquine. The use of two doses of short course artemether/mefloquine combination has been shown to be effective in a recent study. In the present study, we have assessed the efficacy of short course treatment with artesunate/mefloquine, in comparison with artemether/mefloquine in patients with multidrug resistant falciparum malaria. Ninety-nine Thai male patients who sought consultation at Makham Malaria Clinic, Chantaburi (eastern part of Thailand), were randomized to receive either the combination of artemether (150 and 100 mg; group A) or artesunate (150 and 100 mg; group B) with mefloquine (750 and 500 mg) at 24 hours apart. The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups showed a rapid initial response to treatment; fever and parasite were cleared within 48 hours in 100 and 100% vs 91.8 and 96%, for group A vs B, respectively. All patients in group A had completed the 42 day-follow up; however, two patients in group B did not finish the 42-day follow-up. The cure rate was 100% in either group. No serious adverse effects were found. Artemether or artesunate with mefloquine given two doses at 24 hours apart can be used as effective alternative treatment regimens for multidrug resistant falciparum malaria.

Plasmodium falciparum in Thailand is highly resistant to chloroquine, sulfadoxine-pyrimethamine and there is increasing resistance to quinine and mefloquine. The use of qinghaosu derivatives alone or in combination with mefloquine has been shown successfully effective against multidrug resistant P. falciparum in many clinical trials. However their applications with ambulatory treatment should be assessed. 394 uncomplicated falciparum malaria cases studied at Trat and Chanthaburi malaria clinics, eastern Thailand, were allocated at random to receive either one of the seven following regimens: A) artesunate 600 mg over 2 days and mefloquine 1,250 mg in divided doses. B) artemether 640 mg over 2 days and mefloquine 1,250 mg in divided doses. C) artesunate alone 700 mg over 5 days period. D) artemether alone 800 mg over 5 days period. E) quinine plus tetracycline for 7 days. F) mefloquine 1,250 mg in divided doses and G) artesunate 600 mg over 2 days period and mefloquine 750 mg. The follow-up was on Days 1, 2, 7, 14, 21 and 28. Patients tolerated all regimens very well and there was no serious side effects. The adverse effects did not differ among the seven regimens. The cure rates were 98.7, 97.1, 97.9, 96.7, 92.3, 100 and 95.2%, respectively. There was no significant difference of cure rates among various regimens. A total of 16 P. vivax and 1 P. malariae reinfections were reported among the study groups during the second half of the follow-up period, 14 of which were from the groups administered short action drugs (artesunate, artemether or quinine). The results suggested that either artesunate 600 mg or artemether 640 mg in combination with mefloquine 1,250 mg over a period of two days should be considered as alternative regimens for treating uncomplicated multi-drug resistant falciparum malaria.

Plasmodium falciparum in south-east Asia is highly resistant to chloroquine and sulfadoxine-pyrimethamine. Mefloquine used to be the chemosuppressant drug of choice in areas with chloroquine resistance. However, sensitivity to this drug has recently decreased in Thailand, Cambodia and Myanmar, and there is no suitable single alternative drug. We therefore investigated possible alternative combination therapies for multidrug resistant falciparum malaria. 120 male Thai patients at Makarm Malaria Clinic, Chantaburi, in eastern Thailand were allocated at random to receive either oral artemether (group A) or artesunate (group B) at a single dose of 300 mg on day 1, both followed by mefloquine, 750 and 500 mg at 24 and 30 h, respectively. Follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups had a rapid initial response to treatment; in most cases parasitaemia was cleared within 24 h, and fever was cleared within 24 h in 62% and 76.7% of the patients in groups A and B, respectively. 58 patients in group A and 57 in group B completed follow-up and cure rates were 98% and 97%, respectively. Reinfection could not be excluded for the 3 patients with recrudescences; all were cured with a repeated course of treatment. No serious adverse effect was observed in either group, only mild and transient nausea, vomiting and loss of appetite, with no significant difference between the 2 groups. These results suggest that a single oral dose of 300 mg of either artemether or artesunate followed by 1250 mg of mefloquine in 2 divided doses is effective against multiple drug resistant falciparum malaria. Either regimen can be considered as a suitable 'stand-by' in endemic areas of multiple drug resistant falciparum malaria.

An in vivo study of the response of P. falciparum to the combination drug, MSP, was conducted among gem miners who contracted malaria from Cambodia in 1991-1992. High level resistance (RII, RIII responses) was observed in 22.5% of the 40 cases attending Mae Sot malaria clinic, west Thailand border, and in 28.1% of the 96 cases attending Bo Rai malaria clinic, east Thailand border. The observations on in vitro studies conducted prior to the MSP treatment and after recrudescence, together with the findings on adequate mefloquine blood levels strongly indicated the serious deterioration of mefloquine efficacy. The first line treatment for the malaria control program needs to be revised and the use of qinghaosu derivatives considered. Intensive measures to combat spreading of the highly resistant strains to other parts of the country should be taken into account.

Various vector control measures were applied in different endemic areas in two provinces, Saraburi and Chanthaburi, with comparison among different control measures. Application of IGR (insect growth regurator, pyriproxyfen) was introduced at Wat Tam Pra Pothisat, Tab-Kwang District, Saraburi Province. Some integration measures were performed at villages 6 and 8, Patavee, Makham District, Chanthaburi Province. In Tab-Kwang District with low malaria endemicity at the study site predators were not able to be released due to rapid velocity of running water. IGR could effectively control malaria compared to the basin released predators. Another endemic areas villagers 6 and 8, Patavee, Makham, Chanthaburi Province was chosen. Highly endemic multidrug resistant malaria has been prevalent for many years in this area. Integration of Kanda's trapping system, application of IGR, use of both residual spraying and impregnated bed-net methods with etofenprox successfully interrupted malaria infection. The application of these methods as an integrated control system could be adjusted to environmental conditions. The results of this study suggest rapid effective vector control.

Plasmodium falciparum in Thailand is highly resistant to chloroquine and sulfadoxine/pyrimethamine and there is increasing resistance to the alternative antimalarials, quinine and mefloquine. In eastern Thailand, the cure rates of mefloquine at 750 and 1250 mg were 30% and 55%, respectively. The use of drug combinations may be necessary in areas where drug-resistant parasites exist. 159 male Thai patients in Chantaburi, eastern Thailand, were allocated at random to receive either oral artemether at a single dose of 300 mg on the first day followed by mefloquine 750 mg at 24 h and 500 mg at 30 h (group A), or oral artemether at a single dose of 300 mg on the first day, mefloquine 750 mg at 24 h and placebo at 30 h (group B). The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Most patients in both groups had a rapid initial response to treatment, parasitaemia being cleared within 24 h and fever cleared within 48 h in both groups. The cure rates were 97% and 90%, respectively, for groups A and B. No serious adverse effect was seen in either group; mild and transient nausea, vomiting and loss of appetite were noted. The adverse effects did not differ between the 2 groups. The results suggested that a single oral dose of artemether (300 mg) can markedly improve the cure rate of mefloquine at a dose of 750 or 1250 mg in multiple drug-resistant falciparum malaria.

A total of 42 patients with uncomplicated falciparum malaria who attended the malaria clinic in Mae Sot, Tak Province were treated with single oral dose of MSP 3 tablets (Fansimef, equivalent to 750 mg of mefloquine) concurrently with primaquine (30 mg). They all contracted the infection from Cambodia. The aim of the study was to monitor the efficacy of MSP 3 tablets for the treatment of this highly multiple drug resistant strains of Plasmodium falciparum in this area. Of the 39 patients included for efficacy assessment, 13 (33.3%) patients had sensitive responses, whereas 15 (38.5%) and 8 (20.5%) had RI and RII types of response, respectively. Melfoquine concentrations on Day-3 after treatment in patients with sensitive and treatment failure groups were comparable; the respective mean (SD) values were 665 (279) and 772 (264) ng/ml.

A total of 99 patients with uncomplicated falciparum malaria who attended the malaria clinic in Bo Rai, Trat Province were treated with a single oral dose of MSP 3 tablets (Fansimef; equivalent to 750 mg of mefloquine) concurrently with primaquine (30 mg). The aim of the study was to detect RII and RIII types of response with 3 tablets of MSP. Seven (8.1%) and 22 patients (25.3%) had RII and RIII types of response, respectively, and 58 (66.8%) had no parasitemia on Day-7 (S or RI response). Mefloquine concentrations on Day-3 after treatment in patients in the S/RI group were significantly higher than those with early treatment failure (RII, RIII), with the respective mean (SD) values of 1,959 (696) and 1,622 (863) ng/ml. The mean concentrations of mefloquine in these patients with RII and RIII types of response were higher than those with a sensitive response in a previous study. The result suggests that Plasmodium falciparum strains in this part of the country are highly resistant to mefloquine and that blood levels of mefloquine on Day-3 may also be a good indicator of treatment outcome in this particular area.

In order to assess the risk and predictors of mefloquine resistance we monitored a cohort of 113 patients in eastern Thailand who had been treated for uncomplicated falciparum malaria with a single dose of 15 mg/kg of the drug and followed up for 42 days. The overall treatment failure rate at day 42 was 59.1% (95% confidence interval (CI) = 50%, 68%) with only 2.7% of the patients being lost to follow-up. There were 6.4% RIII, 20.9% RII, 31.8% RI, and 40.9% sensitive responses, based on a modified WHO classification. A low haemoglobin level on the day of treatment and diarrhoea during the first two days after treatment were independent predictors of treatment failure. These findings remained statistically significant in a Cox proportional hazards model, after controlling for other baseline characteristics and adverse effects. Although a history of digestive disorders prior to treatment was associated with diarrhoea on day 2 (P = 0.024), it was in itself not a predictor of treatment failure (adjusted hazard ratio = 1.16; 95% CI = 0.35, 2.14). A total of 60 patients with an R response were hospitalized for 7 days to receive supervised treatment with quinine-tetracycline. Only three had a positive thick smear for asexual forms of Plasmodium falciparum 14 days later, and quinine-tetracycline therefore remains a good alternative treatment for mefloquine-resistant falciparum malaria.

Resistance of P. falciparum to mefloquine emerged along the Thai-Cambodian border following the falciparum malaria outbreak in Bo Rai areas in late 1988. Efforts have been made since then to prevent or delay the spread of multi-drug resistant strains by restricting the use of mefloquine, limiting the distribution of the drug for presumptive treatment and chemoprophylaxis, encouraging personal protection, strengthening the case follow-up system, increasing physician awareness, and mass treatment with primaquine of gem miners crossing the borders.

Mefloquine was introduced into Thailand in 1985 for the treatment of Plasmodium falciparum infection. Recently, clinical failure of mefloquine was observed in southeastern Thailand, where an epidemic of falciparum malaria occurred. Beginning in 1984 and continuing until 1989, in vitro monitoring of P. falciparum isolates from Borai, a border district in the southeastern part of the country, showed a progressive decrease in mefloquine sensitivity until 1989; in 1990, the degree and prevalence of resistance accelerated. A similar pattern of resistance was observed for halofantrine, an antimalarial drug not yet commercially available in Thailand. In vitro sensitivity patterns of mefloquine and halofantrine elsewhere in the country remained relatively unchanged. These observations suggest a serious deterioration in available drugs for the treatment of falciparum malaria in southeastern Thailand that is predicted to spread throughout the country and Southeast Asia.