Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis

Abstract

Background: Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy.

Methods: An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints.

Results: A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6-77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2-94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery.

Conclusion: AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

Figure 1

Flow chart of comparative and non comparative studies by anti-malarial drug.

Figure 2

Crude (A) and PCR-adjusted (B) Day 28 efficacy with ASAQ by country stratified by site (mean and 95% CI). Note: The dotted horizontal line in panel B shows the WHO-recommended threshold of efficacy.

Figure 3

Prevalence rate of patients remaining with parasitaemic or febrile in the first 7 days of follow-up.

Figure 4

Overall risks of failure of artesunate-amodiaquine by comparator: (A) crude, (B) PCR-adjusted Day 28 outcome. Note: The forest plot represents the risk of failure of artesunate amodiaquine versus comparators in randomized comparative studies. Results were stratified by site. The size of boxes is proportional to the number of patients included. The square represents the adjusted hazard ratio and 95% CI.

Figure 5

Incidence rate of gametocyte appearance in AS&AQ groups by Day in patients without gametocyte on admission.

Figure 6

Gametocyte clearance time distribution in AS&AQ groups in patients with and without gametocyte on admission.

Figure 7

Overall risks of gametocyte appearance in artesunate-amodiaquine groups by drug comparator. Note: The forest plot represents the risk of failure of artesunate amodiaquine versus comparators in randomized comparative studies. Results were stratified by site. The size of boxes is proportional to the number of patients included. The square represents the adjusted hazard ratio and 95% CI.

Figure 8

Relative difference in gametocyte carriage rate (person-gametocyte-week, PGW) in artesunate amodiaquine groups and comparators in randomized comparative studies.