Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria

RATIONALE: 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 (PY-AS) is a novel ACT first recommended by the WHO in 2022. OBJECTIVES: To evaluate the benefits of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the harms of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments. 

SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), 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 31 July 2024. 

ELIGIBILITY CRITERIA: For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine-artesunate for treating adults and children with uncomplicated P falciparum malaria compared to any other WHO-recommended ACT. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. 

OUTCOMES: Our primary outcomes were treatment failure at days 28 and 42 (PCR-adjusted and -unadjusted), serious adverse events, adverse events leading to withdrawal from treatment, and elevated liver function tests. Secondary outcomes included early treatment failure, other adverse events, cost-effectiveness, feasibility, and acceptability. 

RISK OF BIAS: We used the Cochrane RoB 1 tool to assess bias in the RCTs. SYNTHESIS METHODS: Two review authors independently extracted all data and assessed the certainty of the evidence. We meta-analyzed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons. 

INCLUDED STUDIES: We included 15 studies (14 RCTs reporting safety and efficacy, 1 quasi-experimental study reporting acceptability and feasibility) with 7295 participants. For a separate safety analysis, we included 10 non-randomized studies (NRS) with 11,783 participants. 

SYNTHESIS OF RESULTS: Efficacy analysis (RCTs) We evaluated pyronaridine-artesunate versus the following. - Artemether-lumefantrine. Pyronaridine-artesunate probably performs better for PCR-adjusted failures at day 28 (RR 0.40, 95% confidence interval (CI) 0.19 to 0.85; 5 RCTs, 3213 participants; moderate-certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.14 to 0.52; 5 RCTs, 3314 participants; moderate-certainty evidence); and for unadjusted failures at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants; moderate-certainty evidence). For PCR-adjusted failures at day 42, there is probably little or no difference between groups (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants; moderate-certainty evidence). - Artesunate-amodiaquine. Pyronaridine-artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants; low-certainty evidence, CI crosses line of no effect); probably performs better for unadjusted failures at day 28 (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants; moderate-certainty evidence); may make little or no difference for PCR-adjusted failures at day 42 (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants; low-certainty evidence); and probably makes little or no difference for unadjusted failures at day 42 (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants; moderate-certainty evidence). - Artesunate-mefloquine. Pyronaridine-artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants; low-certainty evidence, CI crosses line of no effect); probably performs better for unadjusted failures at day 28 (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants; moderate-certainty evidence); may make little or no difference for unadjusted failures at day 42 (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants; low-certainty evidence); but may lead to higher PCR-adjusted failures at day 42 (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants; low-certainty evidence). Safety analysis in adults and children (RCTs) Pyronaridine-artesunate was associated with raised liver enzymes compared to other antimalarials: alanine aminotransferase (ALT) (RR 3.59, 95% CI 1.76 to 7.33; 8 RCTs, 6669 participants; high-certainty evidence) and aspartate transaminase (AST) (RR 2.22, 95% CI 1.12 to 4.41; 8 RCTs, 6669 participants; high-certainty evidence). There was no such effect with bilirubin (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants; moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin. No study reported severe drug-induced liver injury. Safety analysis in pregnant women (RCTs) We do not know if malaria testing and treatment with pyronaridine-artesunate for positive cases resulted in any difference in serious adverse effects for pregnant women compared to intermittent preventive treatment with sulfadoxine-pyrimethamine (RR 0.57, 95% CI 0.28 to 1.15; 1 RCT, 250 participants; very-low certainty evidence). Acceptability and feasibility One study determined that the adherence rate to a three-day treatment with pyronaridine-artesunate in children aged under five years was 85.3%. Limited qualitative data suggests pyronaridine-artesunate is acceptable to patients and their carers. Certainty of the evidence and limitations The studies included in this review ranged between very low-certainty and high-certainty evidence, largely due to imprecision of the effect estimate with wide CIs, and indirectness, given that children under five years were under-represented (especially in Asia). We did not identify any evidence of cost-effectiveness. 

AUTHORS' CONCLUSIONS: Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria; achieved a PCR-adjusted treatment failure rate of less than 8% at days 28 and 42; and may be at least as good as artesunate-amodiaquine and artesunate-mefloquine (based on 1 RCT per drug) and may be at least as good as, or better than, artemether-lumefantrine. Pyronaridine-artesunate increases the risk of episodes of abnormally raised ALT and AST compared to other studied therapeutics. 

FUNDING: Tilly Fox and the Cochrane Infectious Diseases Group editorial base were funded by UK aid from the UK Government for the benefit of low- and middle-income countries (project number 300342-104, ended 31 December 2024). The views expressed do not necessarily reflect the UK Government's official policies. REGISTRATION: Protocol and previous versions available via doi.org/10.1002/14651858.CD006404, doi.org/10.1002/14651858.CD006404.pub2, doi.org/10.1002/14651858.CD006404.pub3, doi.org/10.1002/14651858.CD006404.pub4.