BackgroundArtemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS3), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border.Methods and Findings3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS3. The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001 to 21.9% since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00–2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS3 efficacy has declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07–1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0–98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95% CI, 3.2–5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30% (12/40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend).ConclusionArtesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage.

BackgroundExtensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species.Methodology/Principal FindingsA systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment. Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo). Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa. Efficacy was assessed as cure rate (CR, n = 17,017) and egg reduction rate (ERR, n = 13,007); safety as adverse events (AE) incidence. The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2–98.0) for S. japonicum, 77.1% (68.4–85.1) for S. haematobium, 76.7% (95%CI 71.9–81.2) for S. mansoni, and 63.5% (95%CI 48.2–77.0) for mixed S. haematobium/S. mansoni infections. Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium. The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni. No significant relationship between dose and ERR was detected. Tolerability was assessed in 40 studies (12,435 subjects). On average, 56.9% (95%CI 47.4–67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE. The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain.Conclusions/SignificanceThe large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses. The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.

BackgroundChildren carry most of the schistosomiasis burden. While school-aged children are the principal target group of preventive chemotherapy with praziquantel, limited information on efficacy and safety exists for preschool-aged children.MethodsHere, we conducted a meta-analysis of clinical trials of praziquantel for treating children with any form of schistosomiasis. Efficacy was reported as cure rate (CR) and egg reduction rates (ERR); statistical corrections were applied based on methodological disparities across trials to derive the predicted geometrical mean ERR (pERRgm). Safety was reported as frequencies of adverse events.ResultsForty-seven comparative and non-comparative studies were identified, enrolling 15,549 children of whom 14,340 (92%) were assessed between 3 and 8 weeks post-treatment with praziquantel 40 mg/kg (the WHO-recommended treatment, n = 8,380, 56%) or comparators (n = 5,960, 44%). The median age was 10 years (range 1–19), 11% (n = 1,694) were preschool-aged. The CR and pERRgm with praziquantel 40 mg/kg were respectively: S. haematobium, 73.6% (95% CI: 63.5–81.40, 25 study arms) and 94.7% (95% CI: 92.7–96.4); S. mansoni, 76.4% (95% CI: 71.5–81.0, 34 arms) and 95.3% (95% CI: 94.2–96.2); S. mansoni/S. haematobium, 67.6% (95% CI: 54.1–80.7, 5 arms) and 93.4% (95% CI: 89.9–96.2); S. japonicum, 94.7% (95% CI: 92.2–98.0) and 98.7% (95% CI: 98.3–99.2).Mixed-effect multivariate analysis found no significant difference between preschool- and school-aged children for CR or pERRgm in S. haematobium (P = 0.309 and P = 0.490, respectively) or S. mansoni (P = 0.982 and P = 0.895) after controlling for time of assessment, formulation, intensity of infection and detection method. Praziquantel was reportedly safe at all ages, with only mild reported adverse events which cleared rapidly after treatment.ConclusionsPraziquantel 40 mg/kg was effective at reducing infection intensity in all Schistosoma species without differences between preschool- and school-aged children. However, conclusions should be tempered because of the limited number of preschool-aged children enrolled, disparities in study procedures and limited information made available in publications, as well as the current imperfect test-of-cure. Also, although reportedly well-tolerated, safety was inconsistently assessed. Studies in target groups, individual-data meta-analysis and standardised methodologies are needed for more robust evidence-base.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1958-7) contains supplementary material, which is available to authorized users.

BackgroundThe fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda.Methods and FindingsIn total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28–63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6–99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site).ConclusionsDP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.

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.