Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area.

BACKGROUND: Drug resistance of falciparum malaria is a global problem. Sulphadoxine/pyrimethamine-resistant and mefloquine-resistant strains of falciparum malaria have spread in Southeast Asia at lightning speed in 1980s-1990s, and the Cambodia-Thailand border is one of the malaria epidemic areas with the most severe forms of multi-drug resistant falciparum malaria. METHODS: Artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine phosphate (DHP) and artemether-lumefantrine (AL) were used to treat 110, 55 and 55 uncomplicated malaria patients, respectively. The total dosage for adults is 1,750 mg (four tablets, twice over 24 hours) of AP, 2,880 mg (eight tablets, four times over two days) of DHP, and 3,360 mg (24 tablets, six times over three days) of AL. The 28-day cure rate, parasite clearance time, fever clearance time, and drug tolerance of patients to the three drugs were compared. All of the above methods were consistent with the current national guidelines. RESULTS: The mean parasite clearance time was similar in all three groups (66.7 ± 21.9 hrs, 65.6 ± 27.3 hrs, 65.3 ± 22.5 hrs in AP, DHP and AL groups, respectively), and there was no remarkable difference between them; the fever clearance time was also similar (31.6 ± 17.7 hrs, 34.6 ± 21.8 hrs and 36.9 ± 15.4 hrs, respectively). After following up for 28-days, the cure rate was 95.1%(97/102), 98.2%(54/55) and 82.4%(42/51); and the recrudescence cases was 4.9%(5/102), 1.8%(1/55) and 17.6%(9/51), respectively. Therefore, the statistical data showed that 28-day cure rate in AP and DHP groups was superior to AL group obviously.The patients had good tolerance to all the three drugs, and some side effects (anoxia, nausea, vomiting, headache and dizziness) could be found in every group and they were self-limited; patients in control groups also had good tolerance to DHP and AL, there was no remarkable difference in the three groups. CONCLUSIONS: AP, DHP and AL all remained efficacious treatments for the treatment of falciparum malaria in Cambodia-Thailand border area. However, in this particular setting, the AP regimen turned out to be favourable in terms of efficacy and effectiveness, simplicity of administration, cost and compliance. TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Register under identifier 2005L01041.

Rapid and effective malaria control in Cambodia through mass administration of artemisinin-piperaquine.

BACKGROUND: Previous efforts to eradicate malaria parasites, particularly Plasmodium falciparum, have failed in part due to the emergence of drug resistant parasites and mosquitoes resistant to insecticides. Using an artemisinin-based combination therapy (ACT) that kills parasites quickly, a strategy was designed to eliminate the source of transmission by mass treatment of human populations in malaria-endemic areas Cambodia. METHODS: A combination drug of artemisinin and piperaquine given with low doses of primaquine was used to eliminate all stages of parasites from human carriers. RESULTS: In a pilot study, mass administration of artemisinin-piperaquine (two tablets of 62.5 mg artemisinin and 375 mg piperaquine for adults aged > or =16 years at 0 and 24 hrs; 1.5 tablet for children aged 11-15 years; and one tablet for children aged 6-10 years) and primaquine (9 mg for adults, at 10 day intervals for 6 months) was carried out in 17 villages (3,653 individuals). Parasite rates were dramatically reduced from 52.3% to 2.6% after three years. The P. falciparum rate in children decreased from 37.0% to 1.4%, reaching 0% in eight of 17 villages. In a second field study, that included one additional mass treatment of artemisinin-piperaquine, the P. falciparum rate in children was reduced from 20.8% to 0% within six months. No major adverse effects were observed. CONCLUSIONS: Mass administration of artemisinin-piperaquine and low doses of primaquine can be an effective, safe, and affordable strategy for efficiently eliminating malaria parasites in human carriers and interrupting parasite transmission. This study provides important information for future strategies for the eradication of malaria.

Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs.

Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome; screening for genes under selection may suggest potential drug or immune targets. Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of high-throughput genotyping methods, inadequate knowledge of parasite population history and time-consuming adaptations of parasites to in vitro culture. Here we report the first Plasmodium GWAS, which included 189 culture-adapted P. falciparum parasites genotyped using a custom-built Affymetrix molecular inversion probe 3K malaria panel array with a coverage of approximately 1 SNP per 7 kb. Population structure, variation in recombination rate and loci under recent positive selection were detected. Parasite half-maximum inhibitory concentrations for seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. This study provides valuable tools and insight into the P. falciparum genome.

Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia.

Artesunate and mefloquine combination treatment has been used since 2000 in Cambodia as the first-line drug for the treatment of uncomplicated falciparum malaria. In order to assess its efficacy and safety, the national malaria control programme conducted 14 therapeutic efficacy studies with the drug combination between 2001 and 2004 at nine sites. In 2001 and 2002, co-blister packs of artesunate and mefloquine were used, whereas in 2003 and 2004, drugs were given individually from a bulk pack at a total dose of 12 mg/kg of artesunate and 25 mg/kg of mefloquine over 3 days. A total of 1025 patients were enrolled over the 4 years and 977 were follow-up during the period of 28 days. The PCR-corrected cure rates ranged from 85.7% to 100% with an overall cure rate of 95.8% (920/960). The studies in 2002 showed also that co-blister packs used on the basis of age and not on the basis of weight could lead to underdosed regimens but without any detectable effect on the treatment outcome. The follow-up period was extended from 28 to 42 days in three sites in 2004. A total of 219 among 255 were follow-up until day 42. The cure rate decreased but not significantly from 90.1% (73/81) with 28 days follow-up to 79.3% (46/58) with 42 days follow-up in Pailin, whereas the cure rate remained at 100% in the two other sites. Side effects were common, especially dizziness, but were mild and transient and patients recovered without any medical intervention.