Abstract

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate–mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6–14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg⁻¹ single dose; n = 364) or to artesunate–mefloquine (antimalarial dosage: artesunate 4 mg kg⁻¹ and mefloquine 8 mg kg⁻¹ daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate–mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings.

Discussion

In this proof-of-concept, pragmatic, open-label, randomized, noninferiority trial, we demonstrated that a 3-day course of artesunate–mefloquine at antimalarial dosage was noninferior to a standard single-dose of praziquantel, for the treatment of schistosomiasis in African schoolchildren. This observation was mainly driven by the effect on S. haematobium infection. The mean arithmetic egg reduction rates were, however, above the recommended threshold of 90% (ref. ⁹) for both S. hematobium and S. mansoni species. Drug-related AEs were more frequent in the artesunate–mefloquine arm compared with the praziquantel arm, but they were all mild or moderate. An additional second and third courses of artesunate–mefloquine substantially increased the cure rate compared with a single course, with only a marginal increment of AEs. The frequency of schistosomiasis symptoms and abnormal morbidity markers 24 weeks after initial treatment decreased in similar proportions in both study arms.

This is an adequately powered trial that evaluated the parasitological and clinical efficacy of the antimalarial combination artesunate–mefloquine as an alternative to praziquantel for the treatment of schistosomiasis. This study also explored the incremental benefit, as well as cumulative toxicity, of repeated courses of artesunate–mefloquine. Apart from its large sample size, other strengths of this trial included its pragmatic school-based design, which is similar to the MDA reality, the rigorous parasitological evaluation by experienced microscopists blinded to treatment, the careful follow-up of potential mefloquine toxicity up to 1 month after each drug administration, and the molecular monitoring of malaria infection on dried blood spots in both study arms. There were also some limitations. For the efficacy outcome, cure rates were assessed by conventional microscopy, which is still the WHO established standard for diagnosis of schistosomiasis and assessment of treatment response⁹. However, microscopy is considered an insensitive method that tends to overestimate treatment efficacy. Concurrently with microscopic examinations, we therefore evaluated a set of highly sensitive antigen-based (that is, circulating cathodic and anodic antigens) and DNA-based detection assays as alternative tests of cure²²; due to space limitations, comparative results on the performance of those diagnostics will be published elsewhere. The use of the egg reduction rate as measure for the efficacy outcome would have substantially inflated the required sample size, beyond the scope of a proof-of-concept trial. In addition, the study design did not allow to investigate the parasitic efficacy of a single course of artesunate–mefloquine beyond the week 4 assessment, although activity of mefloquine on juvenile worms may provide longer protection than praziquantel. For the safety analysis, the absence of praziquantel placebo comparison at weeks 6 and 12 might have overestimated the difference in occurrence of AEs between the two treatment arms. Also, this proof-of-concept trial, deliberately conducted in an area with low malaria endemicity to focus on schistosomiasis endpoints, did not provide insights on the potential benefits and risks of single and repeated artesunate–mefloquine administrations on malaria infection or on the potential emergence of resistance. Finally, the ultrasound assessments scheduled at the interim (week 24) and final (week 48) assessments could not take place because of the COVID-19 pandemic, during which schools were closed and large gatherings forbidden. The frequency of ultrasound abnormalities was, however, rather low at the initial assessment. The sampling of urine, stool and blood was able to be kept on schedule through door-to-door visits throughout the study period.

The clinical efficacy of artemisinin derivatives on schistosomiasis has been found inferior to that of praziquantel^18,27, as their activity is mainly restricted to the juvenile worms. In addition, the use of artemisinin derivatives in monotherapy as antischistosomal agents cannot be envisaged in the large areas of sub-Saharan Africa where P. falciparum is co-endemic, given the risk of malaria resistance to this key compound. Mefloquine is an antimalarial drug with activity against both juvenile and adult Schistosoma worms, but the clinical evidence of efficacy is very limited^16,19,20. The evaluation of the artesunate–mefloquine combination has provided equivocal results in two small exploratory trials, so far^16,20. The current trial demonstrates substantial antiparasitic activity of artesunate–mefloquine, with clinical benefit on schistosomiasis-related symptoms and morbidity, and the incremental effect of successive treatment courses. Additionally, its safety profile is confirmed, even in repeated administration, at least in the pediatric population^21,28,29. Therefore, the important potential of artesunate–mefloquine as repurposed antischistosomal drug is highlighted, with the key advantage that it is a cheap and immediately available treatment. The slightly lower tolerance and need of 3-day administration would, however, position it as second-line treatment, in case of intolerance or decreased susceptibility to praziquantel, pending future feasibility and acceptability studies. Acute schistosomiasis in nonimmune travelers could be another clinical scenario where the artesunate–mefloquine combination, with its activity on juvenile worms, would be worth being evaluated against praziquantel.

Moreover, the concomitant antimalarial and antischistosomal activity of artesunate–mefloquine opens exciting research perspectives in coinfected patients and in co-endemic areas³⁰. The dual benefit for coinfected patients appears quite obvious, but the simultaneous diagnosis of both infections is probably infrequent in first-line health facilities. However, artesunate–mefloquine could be studied as the preferred ACT in any child presenting with clinical malaria in regions moderately or highly prevalent for schistosomiasis. In a larger perspective, as transmission of both malaria and schistosomiasis peaks during the rainy season in Africa, it would also be interesting to explore the dual protective effect of seasonal administration of artesunate–mefloquine at the community level, by analogy with the seasonal preventive chemotherapies recommended by the WHO for malaria control^31,32,33,34. Since repeated courses are acceptably safe and provide cumulative efficacy on schistosomiasis, it would be worth evaluating different schedules and timing of artesunate–mefloquine as seasonal chemoprevention against both malaria³¹ and schistosomiasis in school-aged children. In a next step, research into artesunate–mefloquine as an alternative seasonal (malaria) chemoprevention in children <5 years could also be considered, as this age group is also particularly affected by both conditions.

Perennial or seasonal intermittent preventive treatment in school-aged children is conditionally recommended by the WHO in malaria-endemic settings with moderate to high transmission, preferably with regimens not used locally as first or second-line malaria treatment³¹. Artesunate–mefloquine could be a good investigational candidate for seasonal intermittent preventive treatment in children of different age groups, in settings where prevalence of both malaria and schistosomiasis is moderate or high. However, the emergence of artemisinin resistance in the past few years in East Africa³⁵ has increased legitimate concerns about the use of ACT-based preventive chemotherapies. Although there is no evidence that such interventions promote clinical resistance³⁶, adequate molecular monitoring should be integrated into each new trial and routinely established wherever implementation of such strategy is being considered. Next-generation sequencing tools such as deep amplicon sequencing, capable of targeting multiple markers in a single assay, are gradually being deployed to support the surveillance activities of malaria control programs³⁷.

In conclusion, the combination artesunate–mefloquine at antimalarial dosage is safe and its efficacy against schistosomiasis is noninferior to that of standard-care praziquantel, at least for S. haematobium infection. If similar results are reproduced in other epidemiological settings, especially where S. mansoni is more prevalent, or in other demographics, such as malaria-coinfected patients, more advanced schistosomiasis cases or pre-school-aged children, it could become one of the much-needed alternative drugs for individualized treatments.