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Background: A practical and simple regimen for all malaria species is needed towards malaria elimination in Indonesia. It is worth to compare the efficacy and safety of a single dose of artemisinin-naphthoquine (AN) with a three-day regimen of dihydroartemisinin-piperaquine (DHP), the existing programme drug, in adults with uncomplicated symptomatic malaria., Methods: This is a phase III, randomized, open label using sealed envelopes, multi-centre, comparative study between a single dose of AN and a three-day dose of DHP in Jayapura and Maumere. The modified WHO inclusion and exclusion criteria for efficacy study were used in this trial. A total of 401 eligible adult malaria subjects were hospitalized for three days and randomly treated with AN four tablets single dose on day 0 or DHP three to four tablets single daily dose for three days, and followed for 42 days for physical examination, thick and thin smears microscopy, and other necessary tests. The efficacy of drug was assessed by polymerase chain reaction (PCR) uncorrected and corrected., Results: There were 153 Plasmodium falciparum, 158 Plasmodium vivax and 90 P. falciparum/P. vivax malaria. Mean of fever clearance times were similar, 13.0 ± 10.3 hours in AN and 11.3 ± 7.3 hours in DHP groups. The mean of parasite clearance times were longer in AN compared with DHP (28.0 ± 11.7 hours vs 25.5 ± 12.2 hours, p = 0.04). There were only 12 PCR-corrected P. falciparum late treatment failures: seven in AN and five in DHP groups. The PCR uncorrected and corrected on day -42 of adequate clinical and parasitological responses for treatment of any malaria were 93.7% (95% Cl: 90.3-97.2) and 96.3% (95% Cl: 93.6-99.0) in AN, 96.3% (95% Cl: 93.5-99.0) and 97.3% (95% Cl: 95.0-99.6) in DHP groups. Few and mild adverse events were reported. All the abnormal haematology and blood chemistry values had no clinical abnormality., Conclusion: AN and DHP are confirmed very effective, safe and tolerate for treatment of any malaria. Both drugs are promising for multiple first-line therapy policies in Indonesia.

Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia, we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum, 83 with Plasmodium vivax, and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [CI]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivax. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 2.1%). The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years old and 22% (31/140) of adults (P = 0.04), even though the overall dose (mg per kg of body weight) in children was 9% higher than that in adults (P < 0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (hazard ratio [HR] = 6.6 [95% CI: 1.9 to 23]; P = 0.003) or P. vivax (HR = 9.0 [95% CI: 2.3 to 35]; P = 0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that dose revision may be warranted in this age group.

Background: The burden of Plasmodium vivax infections has been underappreciated, especially in southeast Asia where chloroquine resistant strains have emerged. Our aim was to compare the safety and efficacy of dihydroartemisinin-piperaquine with that of artemether-lumefantrine in patients with uncomplicated malaria caused by multidrug-resistant P falciparum and P vivax., Methods: 774 patients in southern Papua, Indonesia, with slide-confirmed malaria were randomly assigned to receive either artemether-lumefantrine or dihydroartemisinin-piperaquine and followed up for at least 42 days. The primary endpoint was the overall cumulative risk of parasitological failure at day 42 with a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, trial number 00157833., Findings: Of the 754 evaluable patients enrolled, 466 had infections with P falciparum, 175 with P vivax, and 113 with a mixture of both species. The overall risk of failure at day 42 was 43% (95% CI 38-48) for artemether-lumefantrine and 19% (14-23) for dihydroartemisinin-piperaquine (hazard ratio=3.0, 95% CI 2.2-4.1, p<0.0001). After correcting for reinfections, the risk of recrudescence of P falciparum was 4.4% (2.6-6.2) with no difference between regimens. Recurrence of vivax occurred in 38% (33-44) of patients given artemether-lumefantrine compared with 10% (6.9-14.0) given dihydroartemisinin-piperaquine (p<0.0001). At the end of the study, patients receiving dihydroartemisinin-piperaquine were 2.0 times (1.2-3.6) less likely to be anaemic and 6.6 times (2.8-16) less likely to carry vivax gametocytes than were those given artemether-lumefantrine., Interpretation: Both dihydroartemisinin-piperaquine and artemether-lumefantrine were safe and effective for the treatment of multidrug-resistant uncomplicated malaria. However, dihydroartemisinin-piperaquine provided greater post-treatment prophylaxis than did artemether-lumefantrine, reducing P falciparum reinfections and P vivax recurrences, the clinical public-health importance of which should not be ignored.