Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial

Abstract

SummaryBackgroundArtemisinin-combination therapy (ACT) is recommended as first-line treatment of falciparum malaria throughout the world, and fixed-dose combinations are preferred by WHO; whether a single gametocytocidal dose of primaquine should be added is unknown. We aimed to compare effectiveness of four fixed-dose ACTs and a loose tablet combination of artesunate and mefloquine, and assess the addition of a single gametocytocidal dose of primaquine.MethodsIn an open-label randomised trial in clinics in Rakhine state, Kachin state, and Shan state in Myanmar (Burma) between Dec 30, 2008, and March 20, 2009, we compared the effectiveness of all four WHO-recommended fixed-dose ACTs (artesunate–mefloquine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, artemether–lumefantrine) and loose artesunate–mefloquine in Burmese adults and children. Eligible patients were those who presented to the clinics with acute uncomplicated Plasmodium falciparum malaria or mixed infection, who were older than 6 months, and who weighed more than 5 kg. Treatments were randomised in equal numbers within blocks of 50 and allocation was in sealed envelopes. All patients were also randomly assigned to receive either a single dose of primaquine 0·75 mg base/kg or not. Patients were followed up for 63 days. Treatment groups were compared by analysis of variance and multiple logistic regression. The primary outcome was the 63 day recrudescence rate. This study is registered with clinicaltrials.gov, number NCT00902811.Findings155 patients received artesunate–amodiaquine, 162 artemether–lumefantrine, 169 artesunate–mefloquine, 161 loose artesunate–mefloquine, and 161 dihydroartemisinin–piperaquine. By day 63 of follow-up, 14 patients (9·4%; 95% CI 5·7–15·3%) on artesunate–amodiaquine had recrudescent P falciparum infections, a rate significantly higher than for artemether–lumefantrine (two patients; 1·4%; 0·3–5·3; p=0·0013), fixed-dose artesunate–mefloquine (0 patients; 0–2·3; p<0·0001), loose artesunate–mefloquine (two patients; 1·3%; 0·3–5·3; p=0·0018), and dihydroartemisinin–piperaquine (two patients 1·3%; 0·3–5·2%; p=0·0012). Hazard ratios for re-infection (95% CI) after artesunate–amodiaquine were 3·2 (1·3–8·0) compared with the two artesunate–mefloquine groups (p=0·01), 2·6 (1·0–6–0) compared with artemether–lumefantrine (p=0·04), and 2·3 (0·9–6·0) compared with dihydroartemisinin–piperaquine (p=0·08). Mixed falciparum and vivax infections were common: 129 (16%) had a mixed infection at presentation and 330 (41%) patients had one or more episodes of Plasmodium vivax infection during follow-up. The addition of a single dose of primaquine (0·75 mg/kg) reduced P falciparum gametocyte carriage substantially: rate ratio 11·9 (95% CI 7·4–20·5). All regimens were well tolerated. Adverse events were reported by 599 patients, most commonly vomiting and dizziness. Other side-effects were less common and were not related to a specific treatment.InterpretationArtesunate–amodiaquine should not be used in Myanmar, because the other ACTs are s...

Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue

“…Studies with P. falciparum infections indicate that a single dose of primaquine supplemented to ACTs can substantially shorten the period of gametocyte carriage and importantly, clear submicroscopic gametocytes (46,47). In our assays, this 8-aminoquinoline drug displayed gametocytocidal activity against stage I-IV sexual forms, albeit at low micromolar concentrations compared with low to mid-nanomolar concentrations with DHA and MB.…”

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

“…Synergism among various artemisinins could be explained by the fact that they may affect the parasites by multiple mechanisms (see Discussion) that are effective at different concentrations. In view of these results and the availability of reference results of other ACTs (18,36,37,43), we conducted in vitro cytotoxicity experiments with THP1 cells and in vivo combination experiments to monitor artemiside combinations with mefloquine and piperaquine. Chloroquine also was examined due to its proven in vivo synergistic effect with artemisone, another 10-alkyl amino artemisinin (46).…”

Therapeutic Efficacies of Artemisinin-Based Combination Therapies in Nigerian Children with Uncomplicated Falciparum Malaria during Five Years of Adoption as First-Line Treatments

“…This trend is in sharp contradistinction to the situation in Myanmar, where parasitological efficiency of AA is declining. 38 The parasitemia half-life of 1 hour provides a baseline for which future changes in parasite population in vivo and in vitro susceptibility profiles from this endemic area may be measured or compared, and it may be relevant in the evolution of drug resistance to the adopted ACTs. With an overall parasitemia half-life of 1 hour, it would seem likely that genuine differences occur in the parasitemia kinetics after artemisinin or ACTs administration in children from this endemic area and in patients from Vietnam (8 hours) 39 or Thailand (3 hours), 35 where the half-lives of parasitemia are considerably longer than in the present study.…”