Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria

BACKGROUND: The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate. OBJECTIVES: To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria. 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; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials. SELECTION CRITERIA: Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria. For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrine In two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquine In one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effects Serious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence). AUTHORS' CONCLUSIONS: Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment. PLAIN LANGUAGE SUMMARY: ARTESUNATE PLUS PYRONARIDINE FOR TREATING UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA: What is uncomplicated malaria and how might artesunate-pyronaridine work Uncomplicated malaria is the milder form of malaria which usually causes fever, with or without headache, tiredness, muscle pains, abdominal pains, nausea, and vomiting. If left untreated, uncomplicated malaria can rapidly develop into severe malaria with kidney failure, fitting, unconsciousness, and eventually death. Plasmodium falciparum is the most common parasite causing malaria in sub-Saharan Africa and causes most of the severe malaria worldwide. The World Health Organization currently recommends countries use one of five different artemisinin-based combination therapies (ACTs) to treat malaria. These combinations contain an artemisinin component (artemether, dihydroartemisinin, or artesunate), which works quickly to clear the parasite from the person's blood, and a longer-acting drug which clears the remaining parasites from the blood and may prevent new Plasmodium infections for several weeks. Artesunate plus pyronaridine is a new combination and in this review we evaluate its effectiveness and safety compared to the other ACTs. After examining the research published up to 16 January 2014, we included six randomized controlled trials, enrolling 3718 children and adults. What the research says Based on studies of mostly older children and adults living in Africa and Southeast Asia, artesunate-pyronaridine is probably as effective as artemether-lumefantrine at treating uncomplicated malaria and preventing further malaria infections after treatment (moderate quality evidence). In a study primarily of older children and adults in Asia, artesunate-pyronaridine is probably as effective as artesunate plus mefloquine at treating P. falciparum malaria and preventing recurrent parasitaemias (moderate quality evidence). Serious adverse events were rare in people treated with either artesunate-pyronaridine or other ACTs. However, short-lasting liver toxicity was more frequent in people treated with artesunate-pyronaridine than with the other antimalarials (moderate quality evidence). Authors' conclusions Artesunate-pyronaridine performed well compared to the other two ACT with which it has been compared, but further studies in African and Asian children are required to help clarify whether this combination is an option for first-line treatment.