Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

Laman, Moses; Moore, Brioni R.; Benjamin, John; Yadi, Gumul; Bona, Cathy; Warrel, Jonathan; Kattenberg, Johanna Helena; Koleala, Tamarah; Manning, Laurens; Kasian, Bernadine; Robinson, Leanne J.; Sambale, Naomi; Lorry, Lina; Karl, Stephan; Davis, Wendy A.; Rosanas-Urgell, Anna; Müeller, Ivo; Siba, Peter; Betuela, Inoni; Davis, Timothy

doi:10.1371/journal.pmed.1001773

Cited by 33 publications

(65 citation statements)

References 39 publications

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“…These data reflect between-treatment differences in reappearance of sexual parasite forms during follow-up. They are also consistent with the results of the main trial, in which the appearance/reappearance of P. vivax asexual parasitemia in a larger number of children than in the present substudy was significantly more common in the artemether-lumefantrine group regardless of whether P. vivax or P. falciparum was present on the blood smear at presentation (29).…”

Section: Resultssupporting

confidence: 92%

“…The full protocol and initial results of the randomized clinical trial (Australian New Zealand Clinical Trials Registry ACTRN12610000913077) have been published previously (29). The study received ethical approval from the Medical Research Advisory Committee of the PNG Department of Health (MRAC 10.39).…”

Section: Methodsmentioning

confidence: 99%

“…Giemsa-stained thick blood smears for each child and at each time point were examined independently by two skilled microscopists, and the parasitemia was quantified. Discrepancies were adjudicated by a third senior expert microscopist (29). Blood samples for QMF were processed on the day of collection.…”

Section: Methodsmentioning

confidence: 99%

“…The aim of the present study was to use QMF to characterize in detail the clearance kinetics of P. falciparum and P. vivax gametocytes in young children from Papua New Guinea (PNG) who were participating in a randomized trial of two 3-day ACT regimens for uncomplicated malaria, specifically artemether-lumefantrine and artemisinin-naphthoquine (29). Although artemisinin-naphthoquine proved as effective as artemether-lumefantrine therapy (the recommended first-line antimalarial therapy in PNG) for P. falciparum malaria, there was increased posttreatment gametocyte carriage in artemisinin-naphthoquine-treated children as assessed by conventional light microscopy (LM) (29).…”

mentioning

confidence: 99%

“…Although artemisinin-naphthoquine proved as effective as artemether-lumefantrine therapy (the recommended first-line antimalarial therapy in PNG) for P. falciparum malaria, there was increased posttreatment gametocyte carriage in artemisinin-naphthoquine-treated children as assessed by conventional light microscopy (LM) (29). Artemisinin-naphthoquine was superior to artemether-lumefantrine for P. vivax malaria, including in the comparison of gametocyte carriage during follow-up.…”

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confidence: 99%

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Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Karl

Laman

Moore

et al. 2015

Antimicrob Agents Chemother

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gQuantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/l for artemether-lumefantrine and 61/l for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/l (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia. Intraerythrocytic development of Plasmodium spp. comprises asexual reproduction, which underlies host pathophysiology or sexual reproduction (gametocyte formation) that is essential for malaria transmission. Apart from distinctive morphology, gametocytes have many characteristics that set them apart from asexual stages. Plasmodium falciparum gametocytes have a much longer life span in the circulation and, through metabolic inactivity during the mature phase, reduced antimalarial drug sensitivity (1-3). Artemisinin drugs have greater gametocytocidal activity than conventional agents, such as chloroquine, sulfadoxine, and pyrimethamine, in P. falciparum infections (4-7). As their half-lives are relatively short, this greater potency arises largely from their ability to destroy a wider range of early-stage gametocytes, presumably at their sequestration sites (4, 8). However, the exact effect of antimalarial drugs on the viability of more mature P. falciparum gametocytes that continue to circulate after treatment is unc...

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Karl

Laman

Moore

et al. 2015

Antimicrob Agents Chemother

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Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria

Pryce

Hine

2019

Cochrane Database of Systematic Reviews

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BackgroundThe World Health Organization (WHO) recommends artemisinin‐based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum (P falciparum) malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine‐artesunate is a novel ACT.ObjectivesTo evaluate the efficacy of pyronaridine‐artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine‐artesunate and other pyronaridine treatments compared to alternative treatments.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform Search Portal, and the International Standard Randomized Controlled Trial Number (ISRCTN) registry for ongoing or recently completed trials. The date of the last search was 8 May 2018.Selection criteriaEfficacy analysis: randomized controlled trials (RCTs) of pyronaridine‐artesunate for treating uncomplicated P falciparum malaria.Safety analysis: RCTs of pyronaridine‐artesunate or pyronaridine for treating P falciparum or P vivax malaria.Data collection and analysisFor this update, two review authors independently re‐extracted all data and assessed certainty of evidence. We meta‐analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons.Main resultsWe included 10 relevant studies. Seven studies were co‐funded by Shin Poong Pharmaceuticals which manufactures the drug. Three studies were funded by government agencies.For efficacy analysis we identified five RCTs with 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. It included 541 children aged less than five years.For polymerase chain reaction (PCR)‐adjusted failures at day 28, pyronaridine‐artesunate may have fewer failures compared to artemether‐lumefantrine (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low‐certainty evidence), artesunate‐amodiaquine (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low‐certainty evidence), and mefloquine plus artesunate (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low‐certainty evidence).For unadjusted failures at day 28, pyronaridine‐artesunate may have fewer failures compared to artemether‐lumefantrine (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low‐certainty evidence), and probably has fewer failures compared to artesunate‐amodiaquine (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate‐certainty evidence) and mefloquine plus artesunate (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate‐certainty evidence).For PCR‐adjusted failures at day 42, pyronaridine‐artesunat...

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Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria

Pryce

Taylor

Fox

et al. 2022

Cochrane Database of Systematic Reviews

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Background The World Health Organization (WHO) recommends artemisinin‐based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine‐artesunate is a novel ACT. Objectives To evaluate the efficacy of pyronaridine‐artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine‐artesunate and other pyronaridine treatments compared to alternative treatments. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the ISRCTN registry for ongoing or recently completed trials. The date of the last search was 27 October 2021. Selection criteria For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine‐artesunate for treating uncomplicated P falciparum malaria. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. In addition to these analyses, we conducted a separate systematic review summarizing data on safety from non‐randomized studies (NRS) of any patient receiving pyronaridine (NRS safety review). Data collection and analysis Two review authors independently extracted all data and assessed the certainty of the evidence. We meta‐analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Main results We included 10 relevant RCTs. Seven RCTs were co‐funded by Shin Poong Pharmaceuticals, and three were funded by government agencies. Efficacy analysis (RCTs) For the efficacy analysis, we identified five RCTs comprising 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. The analysis included 541 children aged less than five years. Overall, pyronaridine‐artesunate had a polymerase chain reaction (PCR)‐adjusted treatment failure rate of less than 5%. We evaluated pyronaridine‐artesunate versus the following. • Artemether‐lumefantrine. Pyronaridine artesunate may perform better for PCR‐adjusted failures at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low‐certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low‐certainty evidence); and for unadjus...

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Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial

Abstract: In a randomized controlled trial Tim Davis and colleagues investigate Artemisinin-naphthoquine versus artemether-lumefantrine for the treatment of P. falciparum and P. vivax malaria. Please see later in the article for the Editors' Summary

Cited by 33 publications

References 39 publications

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria

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