Artemisinin-Piperaquine for Resistant Falciparum Malaria
Abstract and Commentary
By Michele Barry MD, FACP
Professor of Medicine, Co-Director, Tropical Medicine and International Travelers’ Clinic, Yale University School of Medicine.
Dr. Barry is a consultant for the Ford Foundation and receives funds from Johnson & Johnson.
Synopsis: Dihydroartemisinin-piperaquine (DP) is a fixed combination antimalarial drug used for treatment of multidrug falciparum malaria. DP is already part of the national treatment recommendation in Cambodia and Vietnam.
Source: Ashley EA, et al. A Randomized, Controlled Study of a Simple, Once-Daily Regimen of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated, Multidrug-Resistant Falciparum Malaria. Clin Infect Dis. 2005;41:425-432.
This study is a randomized, controlled 3-ARM trial conducted along the northwestern border of Thailand, comparing a once-daily or 4-dose graduated regimen of DP to standard treatment of mefloquine-artesunate (MAS), 4 mg/kg day artesunate, and 8 mg/kg mefloquine per day for 3 days. Four hundred ninety-nine patients, ages 1-65, from 4 clinics along the Thai-Myanmar border, were randomized into the 3 protocols for treatment of symptomatic P. falciparum monoinfection or mixed infection. Pregnant women were excluded. DP4 consisted of a 4-dose regimen of dihydroartemisinin-piperaquine, Artekin (Holleykin Pharmaceuticals). One tablet contained 40 mg of dihydroartemisinin and 320 mg of piperaquine. A weight based regimen of 1.6 and 12.8 mg/kg per dose of dihydroartemisinin and piperaquine, respectively, rounded up or down to the nearest half tablet, was given at 0 hours, 8 hours, 24 hours, and 48 hours. DP3 was given in the same dose at 0 hours, 24 hours, and 48 hours.
Times to fever and parasite clearance were similar in all groups. The PCR genotyping-adjusted cure rates at day 63 after treatment initiation were 95.7% (95% CI = 92.2-98.9%) for MAS3, 100% for DP4, and 99.4% for DP3 (95% CI = 98.1-100%). The DP4 and DP3 regimens had slightly significantly higher cure rates when compared to MAS3. All regimens were well tolerated. Early vomiting, occurring up to 1 hour after dose, occurred in < 3% of patients in all groups. Diarrhea within the first 28 days was reported by 12% of the DP4 group, 5% MAS3, and 8% of the DP3 group. Three deaths occurred during the study, all of which were considered unlikely due to malaria or its treatment. DP treatment did not suppress relapse of P. vivax.
Commentary
Artemisinin combination therapy (ACT) has been proposed as the way forward in confronting malaria resistance.1 Coartem (artemether-lumefantrine [Novartis]), is now the recommended first-line treatment for uncomplicated malaria in several sub-Saharan African countries. DP therapy consists of dihydroartemisinin, which is a highly active artemisinin derivative and the main metabolite of artesunate or artemether, combined with piperaquine, a bisquinoline that has retained activity against chloroquine-resistant P. falciparum. Piperaquine replaced chloroquine as a first line drug for malaria in China in 1978. It is estimated that between 1978 and 1993, 4 million Chinese were treated without serious adverse events; however, piperaquine resistance emerged in the mid-1980s. Combination therapy with dihydroartemisinin and piperaquine was highly effective in this study, and once-daily therapy had the added benefit of easy adherence. Although there was no increased toxicity in children, none < 7 kg were randomized in this study, and pregnant women were excluded (one pregnancy occurred inadvertently and a normal outcome occurred; conception was estimated by ultrasound to have occurred the day after the final dose of DP). Use of the current formulation of DP will mean that dosing children will involve crushing tablets. Given the low cost of DP3, this simple and apparently safe fixed ACT treatment could become the treatment of choice for falciparum malaria. An accompanying editorial calls for confirmatory studies in sub-Saharan Africa.2
References
- White NJ, et al. Averting a Malaria Disaster. Lancet. 1999;353:1965-1967.
- Kokwaro G. Once-Daily Combination Therapy for Uncomplicated Malaria: Is This the Way Forward? Clin Infect Dis. 2005;41:433-434.
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