Letters to the editors

Dear Sirs,

In their report in the February issue of TMIHVijaykadga et al. (2006) described poor performance of mefloquine monotherapy and artesunate–mefloquine combination observed in several sites in Thailand in 2003. They concluded that mefloquine monotherapy should be replaced urgently in some areas and also raised concerns that the artesunate–mefloquine (AS–MQ) combination could be nearing the end of its useful therapeutic life on the Thai-Cambodian border.

Their finding of low efficacy of mefloquine monotherapy in Mae Hong Son Province mirrors the observations reported from further south along the border in the 1980s when a dose of 15 mg/kg mefloquine combined with sulfadoxine–pyrimethamine was adopted as first line treatment for falciparum malaria. Levels of resistance reached 30% within 6 years (Nosten et al. 1991). A change in treatment policy to 25 mg/kg mefloquine saw a short-lived improvement in efficacy. This evidence, from very large clinical trials and mathematical modelling (Nosten et al. 1994, Simpson et al. 2000) led to the conclusion that low dose mefloquine should never be introduced and that monotherapy should be abandoned, as recommended by WHO (2006), in the recently published treatment guidelines.

We would hesitate to draw hasty conclusions about the declining usefulness of artesunate and mefloquine combination therapy from the data shown in this report. The sample sizes at each site were small and confidence intervals wide. Although failure rates in Trat reached 21% by day 28, PCR genotyping to adjust for reinfections was not performed. In Mae Sot where endemicity is similarly low, only 44% of parasites recurring by day 28 are truly recrudescent infections. Furthermore, two patients in the Trat site suffered early treatment failures. No clinical details are given; however, in the presence of artesunate these are unlikely to be due to resistance.

Around Mae Sot District, along the North Western border of Thailand, where the AS–MQ combination has been used intensively for 12 years, sustained efficacy rates of >90% have been observed in trials involving >4000 patients with extended (9 weeks) follow-up and PCR genotyping to confirm true recrudescences (Myint et al. 2004). The regimen used is the same total dose of drugs as described by Vijaykadga et al. (25 mg/kg mefloquine and 12 mg/kg artesunate) but with the artesunate dose divided over 3 days. This is the regimen used by Thailand's neighbouring countries and recommended by WHO. It is more effective but not more expensive than the 2 day regimen used in the Thai National Programme. The 2 day regimen increases the drug pressure on the parasite population and selects for mefloquine resistant strains of P. falciparum (Nosten et al. 2005). In addition, the use of mefloquine in isolation in some parts of the country could jeopardize the combination in neighbouring areas.

We certainly agree that vigilance and ongoing surveillance are critical to monitor any decline in efficacy of the combination. However, we do not agree that there is conclusive evidence that AS–MQ is no longer useful in the region. The 3 day combination of mefloquine and artesunate should be used in all areas of Thailand. In the event that mefloquine resistance should worsen and the cure rates of AS–MQ fall below 90%, there is a practical and affordable alternative in the form of dihydroartemisinin–piperaquine, a fixed combination antimalarial drug of proven high efficacy in Thailand (Tangpukdee et al. 2005), which is registered in neighbouring Cambodia and Vietnam.