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.

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.

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.

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.

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.

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.

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.

Integration of control measures for malaria vectors in endemic areas of Thailand.

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.

Mefloquine level monitoring in patients with multidrug resistant Plasmodium falciparum on the Thai Myanmar border.

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.

Mefloquine levels in patients with mefloquine resistant Plasmodium falciparum in the eastern part of Thailand.

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.

Current measures of containment of multi-drug resistant falciparum malaria in Thailand.

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.

Comparative trial on the response of Plasmodium falciparum to halofantrine and mefloquine in Trat Province, eastern Thailand.

With the appearance of strains of Plasmodium falciparum in the Trat Province, eastern Thailand, reported to have developed resistance to mefloquine there is a need for an alternative drug. This comparative trial with mefloquine and halofantrine has demonstrated extremely low cure rates with both drugs (33.3% and 28.13% respectively), cross-resistance is suggested.

Phase III double-blind comparative study of Fansimef and Lariam for the curative treatment of Plasmodium falciparum infections in Thailand.

A double-blind comparative study of Fanismef-mefloquine/sulfadoxine/pyrimethamine (MSP) and Lariam-mefloquine (MEF) for the treatment of falciparum malaria, was carried out at malaria clinics in Kanchanaburi, in western Thailand, in the years 1987 and 1988. The cure rates obtained were 96% for the MSP group and 93% for the MEF and there was no significant difference. Vomiting and diarrhea were common side effects in both the MSP and MEF groups. Less common side effects were epigastric pain, minor skin rashes and dizziness. Significant differences in vomiting and epigastric pain only occurred in the patients who did not have these symptoms before treatment: vomiting MSP 23%, MEF 8%, epigastric pain MSP 22% and MEF 11%.

Malaria clinics in Mae Sot, Thailand: factors affecting clinic attendance.

Clinics of the Anti-Malaria Program of Thailand play an important part in the control of malaria morbidity and mortality, treating over 60% of reported cases yearly. Interviews were conducted both with attenders at three clinics in Mae Sot District and among those reporting malaria illness but not attending. Distance travelled to the clinic, costs of travel and frequency of other treatment prior to clinic attendance were all highest among patients at the large centralized clinic, moderate in a peripheral fixed clinic, and lowest in a village-based mobile clinic. Reported length of illness prior to attendance was similar for all three clinics. As many as 91% of villagers interviewed chose not to treat their illness in a malaria clinic. These non-attenders reported longer illness time and higher expenditures on treatment than clinic patients. Provision of village-based clinics can improve access. However, the widespread reliance on non-Program treatment of malaria suggests the need for policies to address these alternative therapeutic modes.