Association between number of previous malaria episodes and treatment failure among children and adults with laboratory-confirmed Plasmodium infection treated with pyronaridine-artesunate in Gabon: a retrospective cohort study

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BACKGROUND: Malaria remains a public health challenge in Gabon. Pyronaridine-artesunate is an effective oral treatment for uncomplicated malaria. In real-world context, treatment failures, though still rare, are expected to be more frequent than in clinical trials. Prior malaria episodes have been suggested as risk factor for treatment failure. However, most evidence relies on self-reported history, which is prone to bias. METHODS: A secondary data analysis of the CANTAM study, a prospective multicenter single arm open-label phase IIIB/IV study assessing the safety and efficacy of pyronaridine-artesunate in real-world context, was conducted. Adults and children weighing ≥ 5 kg with uncomplicated malaria were included. Data from the Centre de Recherches Médicales de Lambaréné (CERMEL), Gabon, were used in this sub-group analyses to assess the impact of previous malaria episodes on the risk for treatment failure, measured both as recurrence and recrudescence. Multivariate logistic regression models were used to adjust for potential confounders. RESULTS: From June 2017 to March 2019, 2,082 patients were enrolled in Gabon; 1,969 were included in the intention-to-treat and 1,687 in the per-protocol analysis. Adults comprised 22.6% and males 53.7% of participants. In the per-protocol population, 129 (7.7%) participants experienced recurrence from which 22 (1.3%) were recrudescence. Repeated malaria episodes accounted for 294 (17.4%) of the malaria cases. Each one-year increase in age was associated with 11% decrease in the odds of recurrence (OR 0.89, 95%CI 0.86-0.92; p-value < 0.001) and recrudescence (OR 0.89, 95%CI 0.81-0.97; p-value 0.007). Previous malaria was associated with recurrence (OR 1.96; 95%CI 1.31-2.94; p-value 0.001) and recrudescence (OR 2.44; 95%CI 1.01-5.94; p-value 0.049) in the per-protocol multivariate analysis. The association between prior malaria and treatment failure was modified by age, indicating that treatment failure was less associated with previous exposure in older children. CONCLUSIONS: Previous malaria episodes may constitute a surrogate marker for increased risk of recurrence and recrudescence, particularly in younger children. This association may reflect increased vulnerability or transient alterations in host immunity, although other unmeasured factors may also contribute. This understanding could improve malaria management in high-transmission settings, highlighting the need for targeted follow-up of patients at highest risk of treatment failure.

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