Clinical tolerability of artesunate-amodiaquine versus comparator treatments for uncomplicated falciparum malaria: an individual-patient analysis of eight randomized controlled trials in sub-Saharan Africa

Abstract

BackgroundThe widespread use of artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria makes it important to gather and analyse information on its tolerability.MethodsAn individual-patient tolerability analysis was conducted using data from eight randomized controlled clinical trials conducted at 17 sites in nine sub-Saharan countries comparing ASAQ to other anti-malarial treatments. All patients who received at least one dose of the study drug were included in the analysis. Differences in adverse event (AE) and treatment emergent adverse event (TEAE) were analysed by Day 28.ResultsOf the 6,179 patients enrolled (74% <5 years of age), 50% (n = 3,113) received ASAQ, 20% (n = 1,217) another ACT, and 30% (n = 1,849) a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments.ConclusionASAQ was comparatively well-tolerated. Safety information is important, and must be collected and analysed in a standardized way. TEAEs are a more objective measure of treatment-induced toxicity.

Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia

“…Post-marketing information on safety and tolerability thus relies on individual studies. The need of standardized guidelines for adverse event monitoring of ACTs was recently emphasized [33,34]. More information on the tolerability of ACT specifically for patients suffering from chronic (viral) hepatitis, and/or HIV infection would also be of use.…”

Anti-malarial drug safety information obtained through routine monitoring in a rural district of South-Western Senegal

“…The incidence of SAEs (including death) was five per thousand; though, for comparison, about one-third of the rate revealed from a meta-analysis of randomized controlled trials of ASAQ in research settings [11], this shows that the system was accurate enough to capture serious events.…”

An artesunate-containing antimalarial treatment regimen did not suppress cytomegalovirus viremia

“…8 The main limitation of the study is that only a 3-day antimalarial regimen of artesunate combined with amodiaquine was studied. Although CMV log 10 copies/mL in whole blood or plasma decrease with first-order kinetics during (val)ganciclovir treatment in transplant patients, viral load reductions after 3 days of therapy are typically small (<0.5 log 10 copies/mL) and relatively variable.…”

“…3-6 Artesunate is widely used in combination malaria therapies, is very well tolerated, is orally bioavailable, and can be produced relatively inexpensively. 7, 8 However, data on the clinical use of artesunate for CMV infection is limited to 8 patients, in whom efficacy varied widely. 9-11 To gain insight into potential effects of artesunate on CMV infection in a larger cohort, we utilized banked samples from two randomized malaria treatment trials in Uganda.…”