Hepatic safety of repeated treatment with pyronaridine-artesunate (PA) versus artemether-lumefantrine (AL) in patients with uncomplicated malaria: A secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso

Abstract

BackgroundThe use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether-lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso.MethodsWe secondarily analyzed data from a clinical trial conducted from 2012 to 2015, in which patients with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression models.ResultsA total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin with 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy’s law condition was recorded in a first treated participant of the PA arm. Patients from the retreatment group were 76% and 84% less likely to have elevated ALT and AST respectively in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms.ConclusionPyronaridine-artesunate and artemether-lumefantrine showed similar hepatic safety when used repeatedly in patients with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line antimalarial drugs in use in endemic areas.Trial RegistrationPan African Clinical Trials Registry. PACTR201105000286876