In vivo sensitivity monitoring of mefloquine ... - Wiley Online Library

Tropical Medicine and International Health

doi:10.1111/j.1365-3156.2005.01557.x

volume 11 no 2 pp 211–219 february 2006

In vivo sensitivity monitoring of mefloquine monotherapy and artesunate–mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003 Saowanit Vijaykadga1, Chaiporn Rojanawatsirivej1, Sawat Cholpol1, Duangduen Phoungmanee1, Argat Nakavej1 and Chansuda Wongsrichanalai2 1 Disease Control Department, Ministry of Public Health, Nonthaburi, Thailand 2 US Naval Medical Research Unit No. 2 (NAMRU-2), Jakarta, Indonesia

Summary

objective To monitor the efficacy of anti-malarial treatments in Thailand. method A 28-day in vivo study in nine provinces along international borders in 2003. The first group comprised 164 patients from four provinces: Mae Hong Son, Chiang Mai, Ratchaburi and Ubon Ratchathani. These patients received 15 mg/kg mefloquine as a single dose. The second group, 58 patients from Kanchanaburi, were treated with 15 mg/kg mefloquine plus artesunate (12 mg/kg). The third group, 196 patients from provinces with high-level mefloquine resistance (Tak, Ranong, Chanthaburi and Trat), received 25 mg/kg of mefloquine plus 12 mg/kg artesunate. In all arms, follow-up blood smears were scheduled for days 1, 2, 3, 7, 14, 21 and 28. All patients tolerated the regimens well. results The percentage of adequate clinical and parasitological response to mefloquine monotherapy was 62.0% in Mae Hong Son, 75.0% in Chiang Mai, 94.0% in Ratchaburi and 89.7% in Ubon Ratchathani. In Kanchanaburi, the percentage of adequate clinical and parasitological response to the artesunate–mefloquine combination was 94.2%. In the third group, this response exceeded 90%, except in Trat, where it was only 78.6% (44 patients). conclusion Mefloquine monotherapy must urgently be replaced in Mae Hong Son and Chiang Mai. The markedly reduced efficacy of the artesunate–mefloquine combination used in Trat raises questions about the future of this therapy on the southeastern border of Thailand with Cambodia. It is very worrying because no practical and affordable alternative is yet available. keywords artesunate, mefloquine, plasmodium falciparum, Thailand, ACT

Introduction The malaria situation in Thailand has significantly improved over the past few decades. Total microscopyconfirmed cases in 2003 were 37 355, with an Annual Parasite Incidence (API) of 0.62/1000 people compared with 395 442 cases and an API of 8.94/1000 people in 1980. Malaria mortality rates decreased significantly from 8.1/100 000 in 1980 to 0.58/100 000 in 2002. However, malaria remains a public health threat and it is possible that the situation could worsen any time should an outbreak of drug resistant malaria occur. Thai–Cambodian and Thai– Myanmar borders are known as the major foci of multidrug resistant malaria (Thimasarn et al. 1997; Wongsrichanalai et al. 2001). Fighting drug resistance is the most difficult task faced by the Thai malaria control programme today.

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Since 1995, artesunate in combination with mefloquine for the treatment of uncomplicated falciparum malaria has been used at malaria clinics in Trat, Chanthaburi and Sakaeo provinces on the Cambodian border and Tak, on the northwestern border with Myanmar. Use of mefloquine (15 mg/kg) alone continued in all other endemic areas in the country. Declining efficacy of mefloquine monotherapy led to a change in the national anti-malarial drug policy in Nakorn Nayok province (Thai–Cambodian border) to artesunate (12 mg/kg) in combination with mefloquine 15 mg/kg in 2000. Artesunate–mefloquine combination replaced mefloquine alone in two provinces along the Myanmar border, namely: Ranong in May 2003 (artesunate 12 mg/kg plus mefloquine 25 mg/kg) and Kanchanaburi in July 2002 (artesunate 12 mg/kg plus mefloquine 15 mg/kg). 211



S. Vijaykadga et al. Sensitivity monitoring of MQ and MQ + Art

The Thai national malaria treatment guidelines are revised periodically according to evidence gained from therapeutic monitoring studies, in vitro drug sensitivity, information from malaria surveillance and findings from research projects conducted by local universities and other institutes (Rojanawatsirivej et al. 2003). With technical support from the World Health Organization (WHO), the Thai malaria control programme has monitored drug resistance in six sentinel sites since the early 1980s. In 2000, the programme was expanded to include three additional sites with financial support from Kenan Institute Asia. These nine sentinel sites lie along Thailand’s international borders (Figure 1). The purpose of this study was to ascertain the therapeutic efficacy of

first line therapies for uncomplicated falciparum malaria at these sites. Patients and methods Study sites and data collection This study was conducted from May to December 2003 in nine provinces grouped geographically as follows (Figure 1): • Thai–Myanmar border: Mae Hong Son, Chiang Mai, Tak, Kanchanaburi, Ratchaburi and Ranong. • Thai–Laotian–Cambodian border: Ubon Ratchathani. • Thai–Cambodian border: Chanthaburi and Trat.

N

MYANMAR

Chiang Mai M:n = 24 ACPR = 75% LAOS PDR

Mae Hong Son M:n = 50 ACPR = 62% Ubon Ratchathani M:n = 39 ACPR = 89.7%,

Tak M5AS:n = 58 ACPR = 96.6%

Kanchanaburi M3AS:n = 52 ACPR = 94.2% CAMBODIA Ratchaburi M:n = 49 ACPR = 94%

Chanthaburi M5AS:n = 43 ACPR = 97.7%

Trat M5AS:n = 42 ACPR = 78.6%

Ranong M5AS:n = 32 ACPR = 93.8%

MALAYSIA

Figure 1 Map of Thailand showing the location of the nine study sites for the anti-malarial in vivo monitoring, 2003. Therapeutic regimen evaluated for each site with the number of volunteers and adequate clinical and parasitological response (ACPR) is also indicated.

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Malaria in these areas is endemic and usually with seasonal peaks and forest-related. Anopheles minimus and An. dirus are the principal vectors. Reported cases in these nine provinces account for nearly 56% of the total number of malaria cases in the country. In regard to species composition, the ratio of Plasmodium falciparum to P. vivax is about 1:1 (Ministry of Public Health 2003). Patients aged ‡10 years presenting to malaria clinics of the Thai malaria control programme and, in the case of Tak province, to the outpatient clinics of Mae Sot District Hospital and Ta Song Yang District Hospital, who were found positive for falciparum malaria by Giemsa microscopy were potentially eligible. The patients were residents of Thailand. Adult patients from the Thai–Myanmar border, especially those from Tak province, tended to have had multiple malaria attacks previously as a result of occupational exposure in the jungles in that part of the border, where transmission was higher than other border areas. Only acute, uncomplicated cases of falciparum malaria, i.e. presence of P. falciparum asexual forms on a thick blood film with a density of