Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda

Abstract

Background: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity.

Methods and findings: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003).

Conclusion: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).

Figure 1. Map of Uganda Based on Malaria Endemicity

Very low or no malaria: unstable malaria with varying parasite rates in children but generally below 5% (altitude above 1,700 m); low: parasite rates in children below 10% (altitude 1,500–1,700 m); medium to high: parasite rates in children above 10% and generally below 50%, except for seasonal peaks (altitude 1,300–1,500 m); very high: parasite rates in children above 50% (altitude below 1,300 m) (Malaria Control Program, Uganda Ministry of Health). EIR, entomological inoculation rate.

Figure 2. Trial Profile

Trial profile stratified by treatment group and site (Jinja, Arua, Tororo, Apac); screened: (693, 625, 718, 648); excluded during initial screening: (122, 74, 157, 61); randomized: CQ+SP (179, 184, 174, 196); AQ + SP (196, 185, 192, 197); AQ + AS (196, 182, 195, 194); excluded before enrollment: CQ + SP (4, 11, 8, 11); AQ + SP (5, 14, 11, 10); AQ + AS (8, 20, 1, 7); enrolled: CQ + SP (168, 180, 166, 185); AQ + SP (186, 180, 181, 183); AQ + AS (189, 174, 194, 174); excluded after enrollment: CQ + SP (8, 2, 4, 5); AQ + SP (13, 7, 9, 5); AQ + AS (8, 3, 13, 2); completed: CQ + SP (160, 178, 162, 180); AQ + SP (173, 173, 172, 178); AQ+AS (181, 171, 181, 172).

Figure 3. Comparison of AQ + SP versus AQ + AS

Risk differences and 95% CIs for recrudescence (adjusted by genotyping), new infections (adjusted by genotyping), and any recurrent infection (unadjusted, recrudescence or new infection) at day 28.