Efficacy and Safety of Dihydroartemisinin-Piperaquine (Artekin) in Cambodian Children and Adults with Uncomplicated Falciparum Malaria

0 Institut Pasteur du Cambodge , Phnom Penh, Cambodia 1 Received 16 May 2002; accepted 15 August 2002; electronically published 2 December 2002. Financial support: European Commission; Cambodia Malaria Control Programme; Institut Pasteur du Cambodge. Dept. of Medicine, Fremantle Hospital , PO Box 480, Fremantle, Western Australia 6959, Australia 2 National Malaria Centre 3 European Commission, Cambodia Malaria Control Programme 4 University of Western Australia, Department of Medicine, Fremantle Hospital , Fremantle, Western Australia, Australia The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children. - Artemisinin derivatives are rapidly effective antimalarial drugs [1]. Their main drawback is that conventional courses (35 days) are associated with a high rate of recrudescence, typically 125% [1, 2]. In addition, there is the risk that parasite resistance will develop when antimalarial drugs are used alone [3]. Because artemisinin derivatives are now the first-line treatment for multidrug-resistant falciparum malaria in many tropical countries, the appearance of artemisinin-resistant Plasmodium falciparum would have serious implications. The development of suitable combinations of an artemisinin compound with a second drug is therefore a priority [4]. Recent data on the use of sequential artesunate and mefloquine treatment suggest that this approach cures the individual and safeguards against resistance [5]. The choice of a suitable partner for the artemisinins has, however, proved problematic. Mefloquine can have unpleasant adverse effects, especially neurological effects [6], and is expensive. Atovaquone-proguanil is more costly than mefloquine. Pyrimethamine-sulfadoxine and chloroquine can be unsuitable in patients infected with parasites with high-grade antimalarial resistance. Other candidates are being developed, including piperaquine, pyronaridine, and naphthoquinone [4, 7]. Piperaquine (1,3-bis[1-(7-chloro-4 quinolyl)-4 -piperazinyl]-propane) is a member of the 4-aminoquinoline group that includes chloroquine. The first human studies of piperaquine were carried out in the 1970s and involved its prophylactic use in several thousand adults and children [8]. Piperaquine proved to be effective and well tolerated, and no cross-resistance with chloroquine was observed [8]. More recently, piperaquine has been used as part of short-course artemisininbased combination oral therapies designed to have a high cure rate, to have few side effects, and to reduce malaria transmission. The first such combination was China-Vietnam 8 (CV8; Tonghe Pharmaceutical), which included dihydroartemisinin (DHA), piperaquine, primaquine, and trimethoprim. Although CV8 seems to be effective [4, 9], the role of trimethoprim is questionable because of its weak antimalarial activity. In addition, the high prevalence of glucose-6-phosphate dehydrogenase deficiency among Asians means that primaquine-induced RBC hemolysis is of concern. The total DHA dose in a course of CV8 given under the manufacturers recommendations (80 mg over the course of 2 days) was lower than that given in the form of DHA monotherapy for acute malaria (480 mg over the course of 7 days) [10]. The piperaquine-based formulation most recently made available, Artekin (Holleykin Pharmaceuticals), contains neither trimethoprim nor primaquine, and its DHA content is higher than that of CV8. Although Artekin is the simplest and least expensive drug of the CV8 group, there are no published safety and efficacy data for its use in humans. We therefore carried out safety and efficacy studies of the use of Artekin to treat Cambodian children and adults with uncomplicated falciparum malaria. PATIENTS AND METHODS Study sites. Patients were recruited from the Anlong Veng district, Oddor Meanchey Province, in northwestern Cambodia and from the Snoul district, Kratie Province, in eastern Cambodia between October 2001 and February 2002. Both areas are covered in secondary mixed deciduous mosaic forest, and Anopheles dirus mosquitoes are thought to be the primary malaria vector. Transmission is seasonal, peaking in October at the end of the rains. In Anlong Veng, most patients were recruited from roadside settlements newly established by economic migrants from areas of central Cambodia in which malaria is not endemic. There is limited immunity to malaria in these communities. In Snoul, patients were from long-established forestfringe communities in which the level of transmission is greater (between meso- and hyperendemic) and in which the rate of adult immunity is relatively high. Both districts are now served by health centers, but access is difficult, and reliance on the private health sector is high. Under these circumstances, patients often receive inappropriate or incomplete antimalarial therapy. Most patients recruited in Anlong Veng were detected through routine outreach, and most patients in Snoul were recruited through arranged village visits. Eligibility and recruitment of subjects. Patients with a recent history of fever were screened for falciparum malaria by use of Paracheck-Pf (Orchid Biomedical Systems). All patients with positive results who had no clinical evidence of complications were transferred to the health center within 3 h for further assessment, including blood film microscopic examination. Transferred patients were eligible to participate in the study if they were 160 years old and had uncomplicated falciparum malaria with a parasite density 11000 parasites/mL of whole blood. Informed consent was obtained from each patient or, in the case of those !18 years old, from a parent or guardian. Exclusion criteria included mixed malarial infection, concomitant illness, pregnancy, and previous antimalarial therapy (receipt of quinine or an artemisinin drug within 7 days of study entry, of a 4-aminoquinoline within 14 days, or of pyrimethamine, sulfonamide, or both within 28 days). The study protocol was approved by and the research was performed in accordance with the ethical standards of the Ministry of Health, Phnom Penh, Cambodia, (...truncated)