Key messages
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Pyronaridine-artesunate is effective in treating uncomplicated Plasmodium falciparum malaria (a less-serious form of malaria).
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Pyronaridine-artesunate is generally safe, but some people who receive it have blood tests showing liver irritation. This does not usually last long and does not make people feel ill.
What is malaria?
Malaria is a serious tropical disease that is spread to humans by mosquitoes that are infected with a parasite called Plasmodium falciparum. Uncomplicated Plasmodium falciparum malaria is a less serious form of malaria that can develop into serious malaria if not treated.
What is pyronaridine-artesunate for malaria treatment?
Pyronaridine-artesunate is a combination of medicines for treating uncomplicated malaria and is included in a group of medicines called artemisinin-based combination therapies. The World Health Organization (WHO) recommends treating people with malaria with artemisinin-based combination therapies to help prevent malaria from becoming more resistant to treatment (where the medicines are less or no longer effective against the parasites).
What did we want to find out?
We wanted to assess new and previously reviewed evidence to find out if pyronaridine-artesunate is effective and safe in treating uncomplicated Plasmodium falciparum malaria.
What did we do?
In this review update, we searched for studies comparing the benefits of pyronaridine-artesunate to other artemisinin-based combination therapies to evaluate its effectiveness against Plasmodium falciparum malaria, and searched for other studies comparing pyronaridine-artesunate and pyronaridine alone to other medicines to evaluate potential unwanted effects. We also sought information on whether patients accepted the medicine (acceptability), and whether it could be used easily and at low cost (feasibility).
What are the main results of the review?
We found 15 studies with 7295 people contributing towards our assessment of benefits, unwanted effects, acceptability, and feasibility. Five studies compared the benefits and unwanted effects of pyronaridine-artesunate to artemether-lumefantrine in adults and children of all ages in Africa and Asia. One of these studies also compared the benefits and unwanted effects of pyronaridine-artesunate to artesunate-amodiaquine in adults and older children in Africa, whilst one further study compared the benefits and unwanted effects of pyronaridine-artesunate to artesunate-mefloquine in adults and older children in Africa and Asia. Another eight studies reported the safety of the medicines, including one study of pregnant women. One study reported the acceptability and feasibility of pyronaridine-artesunate.
We found that pyronaridine-artesunate effectively treats uncomplicated Plasmodium falciparum malaria, and may be at least as good as or better than existing artemisinin-based combination therapies, although evidence is limited for comparisons against some artemisinin-based combination therapies (we are moderately confident in the results for artemether-lumefantrine, and have low-to-moderate confidence for artesunate-amodiaquine and artesunate-mefloquine). We are confident that pyronaridine-artesunate increases the risk of having abnormal blood test results suggesting an effect on the liver. We found no evidence that any such liver injury was severe or irreversible. We do not know how pyronaridine-artesunate might affect people who already have liver damage.
Limited evidence suggested that pyronaridine-artesunate was considered an acceptable treatment, and most people were able to follow treatment as recommended. We found no evidence on the cost-effectiveness of the medicine.
What are the limitations of the evidence?
A key limitation to the review findings was people's age, as the included studies mostly recruited older children and adults. Only 1054/7295 people were children under five years of age.
How up to date is this evidence?
We searched for studies that had been published up to 31 July 2024.
Pročitajte cijeli sažetak
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.
Ciljevi
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.
Metode pretraživanja
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.
Kriteriji odabira
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).
Prikupljanje podataka i obrada
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.
Glavni rezultati
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 unadjusted failures at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence). For PCR-adjusted failures at day 42, there may be little or no difference between groups (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-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); 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).
• Mefloquine plus artesunate. 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); 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 (RCTs)
For the RCT safety analysis, we identified eight RCTs, one of which was delineated by study site, comparing pyronaridine-artesunate to other antimalarials. 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, moderate-certainty evidence). No such effect was demonstrated 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. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns.
NRS safety review
A review on safety in NRS allowed us to increase the population within which safety was assessed. We included seven studies with 9546 participants: five single-arm observational studies, one cohort event monitoring study, and one dose-escalation study. All studies provided data on adverse event frequency, with a small number of participants experiencing serious adverse events and adverse effects related to pyronaridine: serious adverse events average 0.37%; drug-related 9.0%. In two studies reporting elevations in liver enzymes, small percentages of participants (2.4% and 14.1% respectively) experienced increases in either ALT, AST, or bilirubin on day 7; however, these were small increases that returned to normal by day 42.
Zaključak autora
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.
