Pyronaridine-artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study

Background In Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine–artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa. Methods and findings This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine–artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine–artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine–artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated. Conclusions Pyronaridine–artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine–artesunate as an operationally useful addition to the management of acute uncomplicated malaria. Trial registration ClinicalTrials.gov NCT03201770.
Gaston Tona Lutete and co-workers report on safety and effectiveness of the antimalarial drug pyronaridine-artesunate in African countries.
Author summary Why was this study done? Pyronaridine–artesunate has shown high efficacy and an acceptable safety profile in randomized controlled clinical trials for the treatment of acute uncomplicated Plasmodium falciparum malaria. Transient, asymptomatic, mostly mild-to-moderate increases in liver aminotransferases have been observed with pyronaridine–artesunate in some patients. We assessed pyronaridine–artesunate hepatic safety, tolerability, and effectiveness in adults and children for the treatment of acute uncomplicated malaria under real-world conditions in Africa, including patients with elevated baseline liver aminotransferases. What did the researchers do and find? In a single-arm, open-label, cohort event monitoring study conducted across 5 African countries, patients of any age, weighing >5 kg with acute uncomplicated malaria received fixed-dose pyronaridine–artesunate once daily for 3 days. Patient exclusion and inclusion criteria were consistent with the approved prescribing information, and patients with elevated baseline liver enzymes could be treated under the protocol. The study included 8,560 malaria episodes, 158 of which occurred in patients with baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) abnormalities. There were no hepatic events following pyronaridine–artesunate treatment. Tolerability was as reported in previous studies, and treatment effectiveness at day 28 was 98.6% in patients with acute uncomplicated P. falciparum malaria. What do these findings mean? Pyronaridine–artesunate was an operationally effective and well-tolerated antimalarial therapy in this unselected population of patients from 5 African countries.