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Meta-Analysis
. 2014 Mar 4:(3):CD006404.
doi: 10.1002/14651858.CD006404.pub2.

Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria

Hasifa Bukirwa  1 , B Unnikrishnan, Christine V Kramer, David Sinclair, Suma Nair, Prathap Tharyan
Affiliations
Meta-Analysis

Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria

Hasifa Bukirwa et al. Cochrane Database Syst Rev. .

Update in

Abstract

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 We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials.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-lumefantrineIn 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 mefloquineIn 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 effectsSerious 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.

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Figures

figure 1
figure 1
Flow diagram.
figure 2
figure 2
Risk of bias summary table (Methodological quality summary): review authors' judgements about each methodological quality item for each included trial.
figure 3
figure 3
Forest plot of comparison: 1 Artesunate-pyronaridine versus artemether-lumefantrine, outcome: 1.1 Total failure (Day 28).
Analysis 1.1.
Analysis 1.1.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 1 Total failure (Day 28).
Analysis 1.2.
Analysis 1.2.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 2 Total failure (Day 42).
Analysis 1.3.
Analysis 1.3.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 3 Early treatment failure.
Analysis 1.4.
Analysis 1.4.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 4 Parasite clearance time (hours).
Analysis 1.5.
Analysis 1.5.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 5 Fever clearance time (hours).
Analysis 1.6.
Analysis 1.6.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 6 Gametocyte clearance time.
Analysis 1.7.
Analysis 1.7.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 7 Serious adverse events.
Analysis 1.8.
Analysis 1.8.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 8 Adverse events leading to withdrawal from treatment.
Analysis 1.9.
Analysis 1.9.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 9 Patient reported symptoms.
Analysis 1.10.
Analysis 1.10.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 10 Patient reported symptoms judged as drug-related.
Analysis 1.11.
Analysis 1.11.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 11 Abnormal LFTs; grade 3 and 4 toxicity.
Analysis 1.12.
Analysis 1.12.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 12 Change in haemoglobin.
Analysis 1.13.
Analysis 1.13.
Comparison 1 Artesunate-pyronaridine versus artemether-lumefantrine, Outcome 13 Anaemia as an adverse event.
Analysis 2.1.
Analysis 2.1.
Comparison 2 Artesunate-pyronaridine versus artemether-lumefantrine; subgroup analysis, Outcome 1 Total failure PCR-adjusted (Day 28); subgrouped by age.
Analysis 2.2.
Analysis 2.2.
Comparison 2 Artesunate-pyronaridine versus artemether-lumefantrine; subgroup analysis, Outcome 2 Total failure PCR-adjusted (Day 28); subgrouped by region.
Analysis 2.3.
Analysis 2.3.
Comparison 2 Artesunate-pyronaridine versus artemether-lumefantrine; subgroup analysis, Outcome 3 Total failure PCR-adjusted (Day 28); subgrouped by country.
Analysis 3.1.
Analysis 3.1.
Comparison 3 Artesunate-pyronaridine versus artemether-lumefantrine; sensitivity analysis, Outcome 1 Total failure PCR-unadjusted (Day 28); Sensitivity analysis.
Analysis 3.2.
Analysis 3.2.
Comparison 3 Artesunate-pyronaridine versus artemether-lumefantrine; sensitivity analysis, Outcome 2 Total failure PCR-adjusted (Day 28); Sensitivity analysis.
Analysis 4.1.
Analysis 4.1.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 1 Total failure (Day 28).
Analysis 4.2.
Analysis 4.2.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 2 Total failure (Day 42).
Analysis 4.3.
Analysis 4.3.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 3 Early treatment failures.
Analysis 4.4.
Analysis 4.4.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 4 Parasite clearance time (hours).
Analysis 4.5.
Analysis 4.5.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 5 Fever clearance time (hours).
Analysis 4.6.
Analysis 4.6.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 6 Gametocyte clearance time (hours).
Analysis 4.7.
Analysis 4.7.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 7 Serious adverse events.
Analysis 4.8.
Analysis 4.8.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 8 Adverse events leading to withdrawal from treatment.
Analysis 4.9.
Analysis 4.9.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 9 Patient reported symptoms.
Analysis 4.10.
Analysis 4.10.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 10 Abnormal LFTs; Grade 2 toxicity.
Analysis 4.11.
Analysis 4.11.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 11 Abnormal LFTs; Grade 3 or 4 toxicity.
Analysis 4.12.
Analysis 4.12.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 12 Haemoglobin (g/dL).
Analysis 4.13.
Analysis 4.13.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 13 Platelet counts (x 109/L).
Analysis 4.14.
Analysis 4.14.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 14 White blood counts (x 109/L).
Analysis 4.15.
Analysis 4.15.
Comparison 4 Artesunate-pyronaridine versus artesunate-mefloquine, Outcome 15 Abnormal ECG finding.
Analysis 5.1.
Analysis 5.1.
Comparison 5 Artesunate-pyronaridine versus artesunate-mefloquine; subgroup analysis, Outcome 1 Total failure PCR-adjusted (Day 28); subgrouped by region.
Analysis 5.2.
Analysis 5.2.
Comparison 5 Artesunate-pyronaridine versus artesunate-mefloquine; subgroup analysis, Outcome 2 Total failure PCR-adjusted (Day 28); subgrouped by country.
Analysis 6.1.
Analysis 6.1.
Comparison 6 Artesunate-pyronaridine versus artesunate-mefloquine; sensitivity analysis, Outcome 1 Total failure PCR-unadjusted (Day 28); Sensitivity analysis.
Analysis 6.2.
Analysis 6.2.
Comparison 6 Artesunate-pyronaridine versus artesunate-mefloquine; sensitivity analysis, Outcome 2 Total failure PCR-adjusted (Day 28); Sensitivity analysis.
Analysis 7.1.
Analysis 7.1.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 1 Abnormal LFTs; Grade 3 or 4 toxicity.
Analysis 7.2.
Analysis 7.2.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 2 Combined abnormal LFTs.
Analysis 7.3.
Analysis 7.3.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 3 Renal function tests.
Analysis 7.4.
Analysis 7.4.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 4 Haemoglobin.
Analysis 7.5.
Analysis 7.5.
Comparison 7 Pyronaridine alone or with artesunate versus another antimalarial: laboratory findings, Outcome 5 Abnormal ECG findings.
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References

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