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Background: Dihydroartemisinin-piperaquine (DHA-PPQ) has been adopted as first-line therapy for uncomplicated falciparum malaria in Indonesia since 2010. The efficacy of DHA-PPQ was evaluated in 2 sentinel sites in Keerom District, Papua and Merangin District, Jambi, Sumatra from April 2017 to April 2018., Methods: Clinical and parasitological parameters were monitored over a 42-day period following the World Health Organization standard in vivo protocol and subjects meeting the inclusion criteria were treated with DHA-PPQ once daily for 3 days, administered orally., Results: In Papua, 6339 subjects were screened through active and passive cases detection. Of the 114 falciparum and 81 vivax cases enrolled, 102 falciparum and 80 vivax cases completed the 42 day follow up, and 12 falciparum and 1 vivax cases were either lost to follow up or withdrawn. Kaplan-Meier analysis of microscopy readings of 102 falciparum cases revealed 93.1% (95% CI 86.4-97.2) as Adequate Clinical and Parasitological Response (ACPR). No delay in parasite clearance nor severe adverse reaction was observed. Recurrent parasites of Plasmodium falciparum were detected in 7 cases and categorized as late treatment failures (LTF) at days 21, 35, and 42 and one of which was reinfected by Plasmodium vivax at day 42. Two cases were confirmed as recrudescent infection and 4 were re-infection. The PCR-corrected DHA-PPQ efficacy for P. falciparum was 97.9% (95% CI 92.7-99.7). Of the 80 cases of P. vivax that were followed up, 71 cases were completely cured and classified as ACPR (88.8%, 95% CI 79.7-94.7) and 9 cases showed recurrent infection at days 35 and 42, and classified as LTF. In Sumatra, of the 751 subjects screened, 35 vivax subjects enrolled, 34 completed the 42 day follow up. Thirty-three cases were completely cured and classified as ACPR (97.1%, 95% CI 84.7-99.9) and 1 recurrent infection was observed and classified as LTF. No delay in parasite clearance nor severe adverse reaction was observed. Analysis of the Pfk13 gene in P. falciparum cases from Papua revealed no mutations associated with artemisinin resistance in the 20 SNPs previously reported. Analysis of the Pfpm2 gene at day 0 and day of recurrence in recrudescent cases revealed the same single copy number, whereas 3 of the 4 re-infection cases carried 2-3 Pfpm2 gene copy numbers., Conclusion: Treatment of falciparum and vivax malaria cases with DHA-PPQ showed a high efficacy and safety., (© 2022. The Author(s).)

Background: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial., Methods and Findings: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high., Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RMF is employed currently by AstraZeneca but has no financial stake in the results of the current study. EAA and NJW are Academic Editors on PLOS Medicine's editorial board, and IM was previously an Academic Editor.

Background: Plasmodium falciparum and Plasmodium vivax infections are important causes of adverse pregnancy outcomes in the Asia-Pacific region. We hypothesised that monthly intermittent preventive treatment (IPT) or intermittent screening and treatment (IST) with dihydroartemisinin-piperaquine is more effective in reducing malaria in pregnancy than the existing single screening and treatment (SST) strategy, which is used to screen women for malaria infections at the first antenatal visit followed by passive case detection, with management of febrile cases., Methods: We did an open-label, three-arm, cluster-randomised, superiority trial in Sumba (low malaria transmission site) and Papua (moderate malaria transmission site), Indonesia. Eligible participants were 16-30 weeks pregnant. Clusters (antenatal clinics with at least ten new pregnancies per year matched by location, size, and malaria risk) were randomly assigned (1:1:1) via computer-generated lists to IPT, IST, or SST clusters. In IPT clusters, participants received the fixed-dose combination of dihydroartemisinin-piperaquine (4 and 18 mg/kg per day). In IST clusters, participants were screened with malaria rapid diagnostic tests once a month, whereas, in SST clusters, they were screened at enrolment only. In all groups, participants with fever were tested for malaria. Any participant who tested positive received dihydroartemisinin-piperaquine regardless of symptoms. The primary outcome was malaria infection in the mother at delivery. Laboratory staff were unaware of group allocation. Analyses included all randomly assigned participants contributing outcome data and were adjusted for clustering at the clinic level. This trial is complete and is registered with ISRCTN, number 34010937., Findings: Between May 16, 2013, and April 21, 2016, 78 clusters (57 in Sumba and 21 in Papua) were randomly assigned to SST, IPT, or IST clusters (26 clusters each). Of 3553 women screened for eligibility, 2279 were enrolled (744 in SST clusters, 681 in IPT clusters, and 854 in IST clusters). At enrolment, malaria prevalence was lower in IST (5·7%) than in SST (12·6%) and IPT (10·6%) clusters. At delivery, malaria prevalence was 20·2% (128 of 633) in SST clusters, compared with 11·6% (61 of 528) in IPT clusters (relative risk [RR] 0·59, 95% CI 0·42-0·83, p=0·0022) and 11·8% (84 of 713) in IST clusters (0·56, 0·40-0·77, p=0·0005). Conditions related to the pregnancy, the puerperium, and the perinatal period were the most common serious adverse events for the mothers, and infections and infestations for the infants. There were no differences between groups in serious adverse events in the mothers or in their infants., Interpretation: IST was associated with a lower prevalence of malaria than SST at delivery, but the prevalence of malaria in this group was also lower at enrolment, making interpretation of the effect of IST challenging. Further studies with highly sensitive malaria rapid diagnostic tests should be considered. Monthly IPT with dihydroartemisinin-piperaquine is a promising alternative to SST in areas in the Asia-Pacific region with moderate or high transmission of malaria., Funding: Joint Global Health Trials Scheme of the Medical Research Council, Department for International-Development, and the Wellcome Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)