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Background: Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin-piperaquine for the radical cure of P vivax malaria., Methods: In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin-piperaquine alone, dihydroartemisinin-piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin-piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin-piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed., Findings: Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4-22) in patients treated with dihydroartemisinin-piperaquine alone versus 21% (11-34) in patients treated with tafenoquine plus dihydroartemisinin-piperaquine (hazard ratio 0·44; 95% CI [0·29-0·69]) and 52% (37-65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin-piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin-piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin-piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively., Interpretation: Although tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria., Funding: ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK., Translation: For the Indonesian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests IS reports grants or contracts from Menzies School of Health Research, Darwin and the National Health and Medical Research Council, and funding from Medicines for Malaria Venture (MMV) and GSK. AS, KC, RN, DS, YWS, II, WB, CBP, and SL report that they or their institutions received funding from MMV to do the study and editorial support from GSK for this publication. LLE and AWS report institutional funding from Menzies School of Health Research, MMV, and GSK. CC-D reports institutional funding from MMV, GSK, and the Chan Zuckerberg Initiative. IE reports institutional funding from MMV, GSK, WHO, SPARK (University of Melbourne), and honoraria from the Indonesian Ministry of Health. SD is an employee of MMV; his institution received funding from ExxonMobil, the Bill & Melinda Gates Foundation (grant number INV-007155/19-BMGF-006), Newcrest Mining, and the UK Government to fund the INSPECTOR study. EC is a former independent contractor at GSK and holds shares in the company. EC developed the first draft of the manuscript and provided editorial services as an independent medical writer funded by GSK. KR, DF, AB, SJ, KF, HS, AM, MT, and LKT are employees of GSK and hold shares in the company. J-PK, NG, and JAG are former employees of GSK and hold shares in GSK. JKB reports institutional research funding from MMV, GSK, the Wellcome Trust, the Gates Foundation, FIND, Sanaria, UKAid, University of Oxford, US Centers for Disease Control and Prevention, and the Chinese Center for Disease Control; travel and speaking fees from the Belgian Society of Tropical Medicine, the International Conference of Tropical Medicine and Malariology, and Singapore Malaria Group Conference; and participation on the US National Health Institute Data Safety Monitoring Board., (Copyright © 2023 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.)

Drug resistant Plasmodium parasites are a major threat to malaria control and elimination. After reports of high levels of multidrug resistant P. falciparum and P. vivax in Indonesia, in 2005, the national first-line treatment policy for uncomplicated malaria was changed in March 2006, to dihydroartemisinin-piperaquine against all species. This study assessed the temporal trends in ex vivo drug susceptibility to chloroquine (CQ) and piperaquine (PIP) for both P. falciparum and P. vivax clinical isolates collected between 2004 and 2018, by using schizont maturation assays, and genotyped a subset of isolates for known and putative molecular markers of CQ and PIP resistance by using Sanger and next generation whole genome sequencing. The median CQ IC 50 values varied significantly between years in both Plasmodium species, but there was no significant trend over time. In contrast, there was a significant trend for increasing PIP IC 50 s in both Plasmodium species from 2010 onwards. Whereas the South American CQ resistant 7G8 pfcrt SVMNT isoform has been fixed since 2005 in the study area, the pfmdr1 86Y allele frequencies decreased and became fixed at the wild-type allele in 2015. In P. vivax isolates, putative markers of CQ resistance (no pvcrt-o AAG (K10) insertion and pvmdr1 Y967F and F1076L) were fixed at the mutant alleles since 2005. None of the putative PIP resistance markers were detected in P. falciparum. The ex vivo drug susceptibility and molecular analysis of CQ and PIP efficacy for P. falciparum and P. vivax after 12 years of intense drug pressure with DHP suggests that whilst the degree of CQ resistance appears to have been sustained, there has been a slight decline in PIP susceptibility, although this does not appear to have reached clinically significant levels. The observed decreasing trend in ex vivo PIP susceptibility highlights the importance of ongoing surveillance., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance., Competing Interests: The authors have declared that no competing interests exist.

Genetic epidemiology can provide important insights into parasite transmission that can inform public health interventions. The current study compared long-term changes in the genetic diversity and structure of co-endemic Plasmodium falciparum and P. vivax populations. The study was conducted in Papua Indonesia, where high-grade chloroquine resistance in P. falciparum and P. vivax led to a universal policy of Artemisinin-based Combination Therapy (ACT) in 2006. Microsatellite typing and population genetic analyses were undertaken on available isolates collected between 2004 and 2017 from patients with uncomplicated malaria (n = 666 P. falciparum and n = 615 P. vivax). The proportion of polyclonal P. falciparum infections fell from 28% (38/135) before policy change (2004-2006) to 18% (22/125) at the end of the study (2015-2017); p<0.001. Over the same period, polyclonal P. vivax infections fell from 67% (80/119) to 35% (33/93); p<0.001. P. falciparum strains persisted for up to 9 years compared to 3 months for P. vivax, reflecting higher rates of outbreeding in the latter. Sub-structure was observed in the P. falciparum population, but not in P. vivax, confirming different patterns of outbreeding. The P. falciparum population exhibited 4 subpopulations that changed in frequency over time. Notably, a sharp rise was observed in the frequency of a minor subpopulation (K2) in the late post-ACT period, accounting for 100% of infections in late 2016-2017. The results confirm epidemiological evidence of reduced P. falciparum and P. vivax transmission over time. The smaller change in P. vivax population structure is consistent with greater outbreeding associated with relapsing infections and highlights the need for radical cure to reduce recurrent infections. The study emphasizes the challenge in disrupting P. vivax transmission and demonstrates the potential of molecular data to inform on the impact of public health interventions., Competing Interests: The authors have declared that no competing interests exist.

Background: Malaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic. We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based antimalarial treatment strategy for all Plasmodium species., Methods and Findings: A prospective, district-wide malariometric surveillance system was established in April 2004 to record all cases of malaria at community clinics and the regional hospital and maintained until December 2013. In March 2006, antimalarial treatment policy was changed to artemisinin combination therapy for uncomplicated malaria and intravenous artesunate for severe malaria due to any Plasmodium species. Over the study period, a total of 418,238 patients presented to the surveillance facilities with malaria. The proportion of patients with malaria requiring admission to hospital fell from 26.9% (7,745/28,789) in the pre-policy change period (April 2004 to March 2006) to 14.0% (4,786/34,117) in the late transition period (April 2008 to December 2009), a difference of -12.9% (95% confidence interval [CI] -13.5% to -12.2%). There was a significant fall in the mortality of patients presenting to the hospital with P. falciparum malaria (0.53% [100/18,965] versus 0.32% [57/17,691]; difference = -0.21% [95% CI -0.34 to -0.07]) but not in patients with P. vivax malaria (0.28% [21/7,545] versus 0.23% [28/12,397]; difference = -0.05% [95% CI -0.20 to 0.09]). Between the same periods, the overall proportion of malaria due to P. vivax rose from 44.1% (30,444/69,098) to 53.3% (29,934/56,125) in the community clinics and from 32.4% (9,325/28,789) to 44.1% (15,035/34,117) at the hospital. After controlling for population growth and changes in treatment-seeking behaviour, the incidence of P. falciparum malaria fell from 511 to 249 per 1,000 person-years (py) (incidence rate ratio [IRR] = 0.49 [95% CI 0.48-0.49]), whereas the incidence of P. vivax malaria fell from 331 to 239 per 1,000 py (IRR = 0.72 [95% CI 0.71-0.73]). The main limitations of our study were possible confounding from changes in healthcare provision, a growing population, and significant shifts in treatment-seeking behaviour following implementation of a new antimalarial policy., Conclusions: In this area with high levels of antimalarial drug resistance, adoption of a universal policy of efficacious artemisinin-based therapy for malaria infections due to any Plasmodium species was associated with a significant reduction in total malaria-attributable morbidity and mortality. The burden of P. falciparum malaria was reduced to a greater extent than that of P. vivax malaria. In coendemic regions, the timely elimination of malaria will require that safe and effective radical cure of both the blood and liver stages of the parasite is widely available for all patients at risk of malaria., Competing Interests: The authors have declared that no competing interests exist.

Dihydroartemisinin-piperaquine (DHP) has been the first-line treatment of uncomplicated malaria due to both Plasmodium falciparum and Plasmodium vivax infections in Papua, Indonesia, since March 2006. The efficacy of DHP was reassessed to determine whether there had been any decline following almost a decade of its extensive use. An open-label drug efficacy study of DHP for uncomplicated P. falciparum and P. vivax malaria was carried out between March 2015 and April 2016 in Timika, Papua, Indonesia. Patients with uncomplicated malaria were administered supervised DHP tablets once daily for 3 days. Clinical and laboratory data were collected daily until parasite clearance and then weekly for 6 weeks. Molecular analysis was undertaken for all patients with recurrent parasitemia. A total of 129 study patients were enrolled in the study. At day 42, the polymerase chain reaction-adjusted efficacy was 97.7% (95% confidence intervals [CI]: 87.4-99.9) in the 61 patients with P. falciparum malaria, and 98.2% [95% CI: 90.3-100] in the 56 patients with P. vivax malaria. By day 2, 98% (56/57) of patients with P. falciparum and 96.9% (63/65) of those with P. vivax had cleared their peripheral parasitemia; none of the patients were still parasitaemic on day 3. Molecular analysis of P. falciparum parasites showed that none (0/61) had K13 mutations associated previously with artemisinin resistance or increased copy number of plasmepsin 2-3 (0/61). In the absence of artemisinin resistance, DHP has retained high efficacy for the treatment of uncomplicated malaria despite extensive drug pressure over a 9-year period.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.

Background: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide., Methods: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ., Results: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively., Conclusions: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack., Trial Registration: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.