Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria.

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.

Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and posttreatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria.

BACKGROUND: Antimalarial drug resistance is now well established in both Plasmodium falciparum and Plasmodium vivax. In southern Papua, Indonesia, where both strains of plasmodia coexist, we have been conducting a series of studies to optimize treatment strategies. METHODS: We conducted a randomized trial that compared the efficacy and safety of dihydroartemisinin-piperaquine (DHP) with artesunate-amodiaquine (AAQ). The primary end point was the overall cumulative parasitological failure rate at day 42. RESULTS: Of the 334 patients in the evaluable patient population, 185 were infected with P. falciparum, 80 were infected with P. vivax, and 69 were infected with both species. The overall parasitological failure rate at day 42 was 45% (95% confidence interval [CI], 36%-53%) for AAQ and 13% (95% CI, 7.2%-19%) for DHP (hazard ratio [HR], 4.3; 95% CI, 2.5-7.2; P<.001). Rates of both recrudescence of P. falciparum infection and recurrence of P. vivax infection were significantly higher after receipt of AAQ than after receipt of DHP (HR, 3.4 [95% CI, 1.2-9.4] and 4.3 [95% CI, 2.2-8.2], respectively; P<.001). By the end of the study, AAQ recipients were 2.95-fold (95% CI, 1.2- to 4.9-fold) more likely to be anemic and 14.5-fold (95% CI, 3.4- to 61-fold) more likely to have carried P. vivax gametocytes. CONCLUSIONS: DHP was more effective and better tolerated than AAQ against multidrug-resistant P. falciparum and P. vivax infections. The prolonged therapeutic effect of piperaquine delayed the time to P. falciparum reinfection, decreased the rate of recurrence of P. vivax infection, and reduced the risk of P. vivax gametocyte carriage and anemia.

Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison.

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.

Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia.

To determine the level of antimalarial drug resistance in southern Papua, Indonesia, we assessed the therapeutic efficacy of chloroquine plus sulfadoxine-pyrimethamine (CQ+SP) for Plasmodium falciparum infections as well as CQ monotherapy for P. vivax infections. Patients with P. falciparum failing therapy were re-treated with unsupervised quinine+/-doxycycline therapy and those with P. vivax with either unsupervised quinine+/-doxycycline or amodiaquine. In total, 143 patients were enrolled in the study (103 treated with CQ+SP and 40 with CQ). Early treatment failures occurred in four patients (4%) with P. falciparum and six patients (15%) with P. vivax. The failure rate by Day 28 for P. vivax was 65% (95% CI 49-81). After PCR correction for re-infections, the Day 42 recrudescence rate for P. falciparum infections was 48% (95% CI 31-65). Re-treatment with unsupervised quinine+/-doxycycline resulted in further recurrence of malaria in 48% (95% CI 31-65) of P. falciparum infections and 70% (95% CI 37-100) of P. vivax infections. Eleven patients with recurrent P. vivax were re-treated with amodiaquine; there were no early or late treatment failures. In southern Papua, a high prevalence of drug resistance of P. falciparum and P. vivax exists both to first- and second-line therapies. Preliminary data indicate that amodiaquine retains superior efficacy compared with CQ for CQ-resistant P. vivax.