A Randomized, Controlled Study of a Simple, Once-Daily Regimen of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated, Multidrug-Resistant Falciparum Malaria

Abstract

Background. Dihydroartemisinin-piperaquine (DP) is a fixed-combination antimalarial drug increasingly deployed in Southeast Asia. The current regimen involves 4 doses given over 3 days. Simplification of the dose regimen should facilitate treatment adherence and thereby increase effectiveness.Methods. In a randomized, controlled, 3-arm trial conducted along the northwestern border of Thailand, the standard 4-dose course of DP (DP4) was compared to an equivalent dose given as a once-daily regimen (DP3) and to the standard treatment of mefloquine-artesunate (MAS3).Results. A total of 499 patients were included in the study. 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% confidence interval [95% CI], 92.2%-98.9%) for MAS3, 100% for DP4, and 99.4% (95% CI, 98.1%-100%) for DP3. The DP4 and DP3 cure rates were significantly higher than that for MAS3 ( and , respectively). P p .008 P p .03 All regimens were well tolerated. There were 3 deaths (1 in the MAS3 group and 2 in the DP3 group), all of which were considered to be unrelated to treatment. Rates of other adverse events were comparable between the groups, except for diarrhea, which was more common in the DP4 group ( vs. the MAS3 group). P p .05 Conclusions. A once-daily, 3-dose regimen of DP is a highly efficacious treatment for multidrug-resistant falciparum malaria. This simple, safe, and relatively inexpensive fixed combination could become the treatment of choice for falciparum malaria.

Efficacy and safety of dihydroartemisinin-piperaquine

“…Five studies assessed efficacy using Kaplan-Meier survival analysis (Ashley et al, 2004(Ashley et al, , 2005Giao et al, 2004;Mayxay et al, 2006;Smithuis et al, 2006). There were differences between studies in the formulation of the drug given (Table 1), and the dosing schedule, with a four-dose regimen being used in nine studies and a three-dose regimen in five studies (Ashley et al, 2005 compared the three-dose and four-dose regimens). In addition four studies dosed by age rather than weight (Denis et al, 2002;Hien et al, 2004;Hung et al, 2004;.…”

“…In the study in Laos the proportion of patients with at least one adverse event was also higher in the MAS3 group (64/110; 58%) than in the DHA-PIP (48/110; 44%) group (P = 0.03) (Mayxay et al, 2006). The only potentially serious adverse effects of artemisinin derivatives reported to date are rare type 1 hypersensitivity reactions; two reports from Thailand reported urticaria occurring in four patients treated with DHA-PIP (Ashley et al, 2004(Ashley et al, , 2005.…”

“…In one study on the western border of Thailand, non-severe abdominal pain occurred more frequently in the DHA-PIP group than the MAS3 group; 12.3% (22/179) patients compared to 5% (8/176; P = 0.025) (Ashley et al, 2004). In other studies the median (range) proportion of patients reporting abdominal pain was 6.6% (4.7-11%) (Ashley et al, 2005;Denis et al, 2002;. Diarrhoea within the first 28 days of follow-up was reported by 12% of patients in the four-dose DHA-PIP regimen compared with 5% in the MAS3 group, and 8% in a three-dose DHA-PIP regimen (equivalent total dose DHA-PIP in the two regimens).…”

“…There was concern that the dose of DHA might not be optimal but efficacy was not improved by the addition of more DHA or artesunate in two Thai studies (Ashley et al, 2004). The P. falciparum recrudescences and new infections all occurred between days 28 and 35 in one Vietnamese study, whereas in the Thai studies the majority of patients' recrudescences appeared between days 43 and 63 with a median (range) time to recrudescence of 56 (28-63) days (Ashley et al, 2004(Ashley et al, , 2005Hien et al, 2004). The lowest efficacy of DHA-PIP reported was 88.6% (80.3-93.7) at 28 days, observed in Rukara, one of the Rwandan sites (Karema et al, 2006).…”

“…Current formulations contain only DHA 40 mg and PIP 320 mg per tablet. DHA-PIP has been evaluated in large clinical trials in Southeast Asia, China and Rwanda (Ashley et al, 2004(Ashley et al, , 2005Denis et al, 2002;Giao et al, 2004;Hien et al, 2004;Hung et al, 2004;Karema et al, 2006;Karunajeewa et al, 2004;Mayxay et al, 2006;Smithuis et al, 2006;Tangpukdee et al, 2005;Wilairatana et al, 2002;Ying et al, 2003). Further studies in Africa, Asia Oceania and South America have been conducted but not yet reported.…”