An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria.

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.

Determining cost-effectiveness and cost component of three malaria diagnostic models being used in remote non-microscope 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.

Sensitivity of Plasmodium vivax to chloroquine in Sa Kaeo Province, Thailand.

Following a recent, abrupt local increase in the incidence of vivax malaria, a study was conducted in order to evaluate the efficacy of chloroquine for the treatment of 26 adult patients with acute vivax malaria in Sa Kaeo Province, Thailand. The chloroquine sensitivity of Plasmodium vivax has been assessed in parallel, using a growth inhibition method. Blood samples for the in vitro tests were taken prior to the administration of the standard treatment with chloroquine--in total 25 mg base/kg over 3 days--and primaquine 0.25 mg base/kg once daily for 14 days. The efficacy has been assessed according to the WHO standard in vivo test. The cure rate was 100%. No recrudescence was observed during the follow-up period of 28 days. The mean fever clearance time (FCT) was 40 h, the mean parasite clearance time (PCT) was 49 h. Mean IC(50) and IC(90) of the parasites were 28 and 171 nM, respectively. These results show that local P. vivax is still sensitive to chloroquine. The epidemic outbreak was therefore obviously not due to the presence of chloroquine-resistant P. vivax.

Drug resistant malaria on the Thai-Myanmar and Thai-Cambodian borders.

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.

Antimalarial drug combination policy: a caveat.

PIP: This paper presents facts on malaria epidemiology and historical perspectives of antimalarial drug use in Thailand. It also suggests that the use of an artesunate-mefloquine combination for treating falciparum malaria may be one of the factors responsible for the success of the country's control strategies. It is noted that in Thailand Plasmodium falciparum has evolved resistance to chloroquine, sulfadoxine-pyrimethamine, and mefloquine in succession. In view of this, administration of oral artesunate plus mefloquine became the standard treatment for microscopically confirmed uncomplicated falciparum malaria in 1995. The regimen requires administration of 300 mg/day of artesunate for 2 days plus 750 mg mefloquine on the first day, followed by 500 mg on the second day. Overall, it is too early to assume that the addition of artesunate has halted the progression of mefloquine resistance in Thailand. In terms of applicability of the regimen worldwide, the complexity of the factors involved makes it impossible to predict the useful lifespan of the artesunate-mefloquine combination on the Thai-Myanmar border. Further research is needed into the determination and validation of the most suitable antimalarial regimens for each epidemiologically distinct area and each operationally different circumstance.^ieng

Comparison of a rapid field immunochromatographic test to expert microscopy for the detection of Plasmodium falciparum asexual parasitemia in Thailand.

We assessed a rapid, Plasmodium falciparum histidine rich protein 2 (PfHRP2)-based immunochromatographic test (ICT Malaria Pf Test), for detection of asexual P. falciparum parasitemia in 551 subjects in three groups: (1) symptomatic patients self-referring for diagnosis, (2) villagers in a screening survey, and (3) patients recently treated for P. falciparum malaria. Expert light microscopy was the reference standard. ICT test performance was similar for diagnostic and screening modes. Four findings emerged: (1) test sensitivity correlated directly with parasite density, (2) test band intensity correlated directly with parasite density, (3) persistent test positivity after parasite clearance precludes its use for monitoring early therapeutic responses, and (4) a false negative test at 18,000 parasites/microl is unexplained. We conclude that a strong positive ICT test is highly predictive of falciparum asexual parasitemia for the diagnosis of new cases of falciparum malaria in Thailand, but a negative test result is inadequate to exclude parasitemia < 300/microl, and in some instances, even a higher parasitemia.

Cost-effectiveness analysis of artesunate and quinine + tetracycline for the treatment of uncomplicated falciparum malaria in Chanthaburi, Thailand.

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.

PIP: Findings are presented from a randomized, controlled, malaria clinic-based field trial conducted to compare the cost-effectiveness of a 5-day 700 mg oral artesunate and a 7-day quinine and tetracycline regimen to treat uncomplicated falciparum malaria in Thailand. Cost-effectiveness was determined from the providers' perspective and based upon curative effectiveness. 137 patients, aged 15-60 years, attending a malaria clinic were followed for 28 days. 60 received quinine and tetracycline, while 77 received artesunate. Cure rates were assessed on day 5 (artesunate) and day 7 (quinine and tetracycline). The cure rate with artesunate was 100%, significantly higher than the 77.4% rate with quinine and tetracycline. Artesunate was more cost-effective than quinine and tetracycline, with artesunate costing a maximum of US$0.36 per 50 mg tablet, quinine at US$0.06 per 300 mg tablet, tetracycline at US$0.02 per 250 mg capsule, and services per case found no higher than US$11.49.

Malaria in tree crop plantations in south-eastern and western provinces of Thailand.

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.

Compliance with artesunate and quinine + tetracycline treatment of uncomplicated falciparum malaria in Thailand.

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.

Factors influencing malaria endemicity in Yunnan Province, PR China (analysis of spatial pattern by GIS). Geographical Information System.

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.

Application of geographical information systems to co-analysis of disease and economic resources: dengue and malaria 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.

Two doses of artemether/mefloquine or artesunate/mefloquine combination for multidrug resistant falciparum Malaria.

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.

A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in eastern Thailand.

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.

Artemether or artesunate followed by mefloquine as a possible treatment for multidrug 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.

In vivo study of the response of Plasmodium falciparum to standard mefloquine/sulfadoxine/pyrimethamine (MSP) treatment among gem miners returning from Cambodia.

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.

Epidemiology of Malaria in Thailand.

Background: In spite of significant achievements in malaria control in the past two decades, about 150,000 malaria cases still occur in Thailand each year. Although most short-term visitors to Thailand stay in malaria-free areas, an increasing number of more adventurous travelers are exposed to the disease. Method: Since 1987, the Malaria Division of the Thai Ministry of Public Health has maintained a computerized database that includes all malaria cases recorded at malaria clinics, government health institutions, and private hospitals nationwide. In this article, we analyze the 1992 data. Results: The provinces of Trad, Tak, and Kanchanaburi had the highest incidence of locally transmitted cases. Trad Province was also responsible for the highest number of imported cases. The highest incidence rate was found to be 426.5 per 1000 persons per year in a group of villages in Maesod District, Tak Province. Districts and provinces with >= 20 cases per 1000 persons per year are listed in this report. Peak transmission seasons and species prevalence of different endemic areas are described. Analysis of case investigation, a part of this database, indirectly supported the presence of mefloquine resistant Plasmodium falciparum strains on the Thai-Cambodian border. Conclusions: This paper describes the characteristics of malaria in different parts of Thailand and pinpoints areas with significant transmission. However, in accordance with the present policy of the Thai national malaria control program, we do not recommend chemoprophylaxis, but we do strongly encourage personal protection, early diagnosis, and prompt treatment. (J Travel Med 2:59-65, 1995)