Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border

Abstract

BackgroundDeclining in clinical efficacy of artesunate-mefloquine combination has been documented in areas along the eastern border (Thai-Cambodian) of Thailand. In the present study, the clinical efficacy of the three-day combination regimen of artesunate-mefloquine as first-line treatment for acute uncomplicated falciparum malaria in Thailand was monitored in an area along the western border (Thai-Myanmar) of the country.MethodsA total of 150 Burmese patients (85 males and 65 females) aged between 16 and 50 years who were attending the Mae Tao clinic, Mae-Sot, Tak Province, and presenting with symptomatic acute uncomplicated Plasmodium falciparum malaria were included into the study. Patients were treated initially (day 0) with 4 mg/kg body weight artesunate and 15 mg/kg body weight mefloquine. The dose regimen on day 2 was 4 mg/kg body weight artesunate and 10 mg/kg body weight mefloquine. On day 3, artesunate at the dose of 4 mg/kg body weight was given with 0.6 mg/kg body weight primaquine. Whole blood mefloquine and plasma artesunate and dihydroartemisinin (active plasma metabolite of artesunate) concentrations following treatment were determined by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS), respectively.ResultsThirty-four cases had recrudescence during days 7 and 42. Five and 5 cases, respectively had reinfection with P. falciparum and reappearance of Plasmodium vivax in their peripheral blood during follow-up. The Kaplan-Meier estimate of the 42-and 28-day efficacy rates of this combination regimen were 72.58% (95% CI: 63.20-79.07%) and 83.06 (95% CI 76.14-94.40%), respectively. Parasite clearance time (PCT) and fever clearance time (FCT) were significantly prolonged in patients with treatment failure compared with those with sensitive response [median (95% CI) values for PCT 32.0 (20.0-48.0) vs 24.0 (14.0-32.0) hr and FCT 30.0 (22.0-42.0) vs 26.0 (18.0-36.0) hr; p < 0.005]. Whole blood mefloquine concentrations on days 1, 7 and 14 in patients with sensitive and recrudescence response were comparable. Although plasma concentration of dihydroartemisinin at 1 hour of treatment was significantly lower in patients with recrudescence compared with sensitive response [mean (95% CI) 456 (215-875) vs 525 (452-599) ng/ml; p < 0.001], the proportion of patients with recrudescence who had relatively low (compared with the lower limit of 95% CI defined in the sensitive group) was significantly smaller than that of the sensitive group.ConclusionsAlthough pharmacokinetic (ethnic-related) factors including resistance of P. falciparum to mefloquine contribute to some treatment failure following treatment with a three-day combination regimen of artesunate-mefloquine, results suggest that artesunate resistance may be emerging at the Thai-Myanmar border.

Polymorphisms of Molecular Markers of Antimalarial Drug Resistance and Relationship with Artesunate-Mefloquine Combination Therapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Thailand

“…Baseline demographic and clinical data have been reported. 14 Association between treatment response and mutations of pfcrt , pfmdr1 , or pfatp6 . The mutation of pfcrt was found in all isolates (100%), whereas no mutation of pfmdr1 and pfatp6 was observed at any amino acid codons under investigation ( Table 1 ).…”

“…28,29 Artesunatemefloquine has been used for treatment of uncomplicated P. falciparum malaria in Thailand since 1996, but the decrease in treatment efficacy has been reported in areas along the Thailand-Myanmar and Thailand-Cambodia borders. 4,5,14,30 Our study, which was conducted 30 years after chloroquine had been withdrawn from clinical use, still showed a pfcrt mutation frequency of virtually 100%. This finding may be caused by the continued use of chloroquine as first-line treatment for P. vivax malaria in Thailand for almost six decades.…”

“…The study was a part of a clinical trial to monitor the clinical efficacy of the three-day artesunatemefloquine combination therapy conducted during March 2009-December 2009 at Mae Tao Clinic for migrant workers located along the Thailand-Myanmar border in Tak Province. 14 The study protocol was approved by the Ethics Committee of the Ministry of Public Health of Thailand. A total of 134 Burmese patients greater 15 years of age who came to the clinic with typical symptoms of malaria and had a blood smear positive for P. falciparum were included into this study.…”

Population Pharmacokinetics and Clinical Response for Artemether-Lumefantrine in Pregnant and Nonpregnant Women with Uncomplicated Plasmodium falciparum Malaria in Tanzania

“…We have reason to believe that AL is more efficacious in Africa than in Southeast Asia where resistance to other antimalarial drugs, such as quinine, mefloquine, and artesunate, has increased (14,49).…”

Novel Potent Metallocenes against Liver Stage Malaria

“…esistance to antimalarials, especially in Plasmodium falciparum, is a serious problem that threatens to undermine the efficacy of even the artemisinin components of new first-line artemisinin-based combination therapies (ACTs) (5,7,24). In addition to P. falciparum, Plasmodium vivax malaria is an increasing source of concern (1,3,11,12,14,21,23,28,32,34).…”