Diagnosis and Treatment of Schistosomiasis in Children in the Era of Intensified Control

Stefanie Knopp; Sören L Becker; Katrin J Ingram; Jennifer Keiser; Jürg Utzinger

Disclosures

Expert Rev Anti Infect Ther. 2013;11(11):1237-1258. 

In This Article

Treatment of Schistosomiasis

At present, treatment and morbidity control of schistosomiasis rest on a single drug, praziquantel.[57–59] Discovered in the mid-1970s, praziquantel is active against all human Schistosoma species.[60,61] The drug has several properties that explain its wide use; it is safe, orally active, absorbs promptly and has a rapid onset of action. Praziquantel is acting by disrupting the Ca++ homeostasis in schistosomes, leading to spastic paralysis caused by rapid Ca++ influx.[62] However, the precise mechanism of action has yet to be fully elucidated. In large-scale programs, praziquantel is usually administered at a single oral dose of 40 mg/kg bodyweight, and the recommended treatment frequency depends on the local prevalence.[60,61] A dose pole has been developed and widely validated that allows treatment of children based on their height rather than weight.[63,64]

A median egg reduction rate of 98.7% and cure rates ranging between 63 and 100% determined 1–3 months after treatment have been reported in randomized controlled trials for praziquantel against S. haematobium.[65] As summarized in Table 2, the cure rates against S. mansoni, determined 1 month post-treatment, vary from 52 to 92%.[66] A recent systematic literature review revealed an overall cure rate of 71.3% of praziquantel against S. haematobium and S. mansoni.[61] Most common adverse events such as nausea, headache and dizziness are usually mild and last <24 h.[65,66]

Until recently, children below the age of 4 years (or <94 cm in height) have been excluded from praziquantel treatment. However, evidence is growing that this young age group is at risk of schistosomiasis, which raises the question of whether PSAC should be included in preventive chemotherapy campaigns.[43,44] Recently, the dose pole has been optimized and its downward extension now allows single, 3/4 and 1/2 tablet divisions of the standard 600 mg praziquantel tablet to be administered with high fidelity to PSAC, according to a broad validation using biometric data from PSAC from 36 African countries.[64] Crushed or broken praziquantel tablets administered to young children are efficacious against S. mansoni and S. haematobium and, in the absence of appropriate paediatric formulations, recommended for administration to young children.[44,67]

Noteworthy, praziquantel has several shortcomings. Most importantly, the drug lacks activity against the young developing stages of the parasite.[68] With regard to the oral formulation of praziquantel, there are additional drawbacks. Due to the activity of only one enantiomer (R-praziquantel) of the racemate in use, tablets are large in size and they are very bitter in taste, which leads to decreased compliance, especially among young patients.[69,70] The safety and efficacy of praziquantel syrup (Epiquantel®) have recently been investigated in studies in PSAC in Niger and Uganda. In Niger, Epiquantel® was well tolerated and yielded moderate-to-high efficacy against S. haematobium, but a considerably lower efficacy against S. mansoni.[54] The syrup had a similar efficacy to crushed praziquantel tablets against S. mansoni in Uganda.[71] Furthermore, operational issues such as storage, transport and adequate dosing are a concern. In the frame of a public-private partnership (PPP), including Merck KGaA, Astellas Pharma, the Swiss Tropical and Public Health Institute and TI Pharma, efforts are underway to develop a pediatric formulation of praziquantel, either a racemate praziquantel or a R-praziquantel formulation. The project is currently in the preclinical phase, and a candidate oral dispersible tablet has been developed.

Two additional antischistosomal drugs – oxamniquine and metrifonate – had been recommended by WHO until the late 1990s, but both drugs are not available any longer.[58,59] Oxamniquine was mainly used in Brazil in the frame of the national schistosomiasis control program aimed at S. mansoni. The mechanism of action of oxamniquine is well understood: the nucleic acid metabolism is irreversibly inhibited by alkylation. Oxamniquine used at a dosage of 40 mg/kg shows high cure rates at 1 month post-treatment (82%) and achieves egg reduction rates of 68–100%. Should praziquantel resistance emerge, oxamniquine could be reintroduced as an alternative drug against S. mansoni.[66] Metrifonate is an organophorus cholinesterase inhibitor and its activity profile is restricted to S. haematobium. The recommended treatment is three oral doses at 14-day intervals (7.5–10 mg/kg each).[65] Egg reduction rates after administration of metrifonate are above 90% and observed cure rates range between 52 and 81%.[65]

Recently, WHO set the goal to scale up access to praziquantel, aiming for an annual treatment of 235 million people in 2018 (Figure 1).[72] This ambitious endeavor with only one available drug in hand will place additional selective pressure on schistosomes, which may accelerate the emergence of resistance.[73] Observed cure rates following standard single 40 mg/kg oral doses of praziquantel show considerable variation,[66,74] and low cure rates observed against S. mansoni in Senegal in the 1990s raised concern about tolerance or resistance.[75,76] Reduced susceptibility to praziquantel has indeed been detected for schistosomes isolated from Egyptian patients who failed to be cured after multiple treatments.[77] New drugs with novel mechanisms of action and activity against all Schistosoma stages and drugs that are eligible for combination chemotherapy are therefore urgently needed.[62,66,78]

Figure 1.

Reported number of countries (within bars) and people treated with praziquantel (above bars) against schistosomiasis since 1988 and projections for 2018.

An attractive starting option for drug development for neglected diseases where only limited resources are available is to work with existing drugs, the so-called repositioning or repurposing of drugs.[73,79,80] This strategy is at the root of detailed scientific inquiry with marketed antimalarials against Schistosoma.[81] Indeed, the antischistosomal activities of artemisinin derivatives (i.e., artemether and artesunate) were extensively studied in vitro, in vivo and in clinical trials. Key findings from these laboratory and clinical investigations have been summarized elsewhere.[58,81–84] It is worth highlighting that artemether and artesunate show highest activity against juvenile worms and are therefore interesting partner drugs for combination chemotherapy with praziquantel.[82,85–87] However, the superior efficacy of the combination over single praziquantel remains uncertain and has to be investigated in more detail as concluded in a recent systematic review and meta-analysis.[66]

Mefloquine is another antimalarial that has been widely studied for its antischistosomal properties since the discovery of its in vitro and in vivo activities against S. mansoni in 2009.[88] In combination with artesunate, cure rates of 61% were achieved in S. haematobium-infected children.[89] Similarly, when mefloquine was used as intermittent preventive treatment against malaria in pregnancy, it showed an ancillary benefit against S. haematobium: high egg reduction rates were observed in women co-infected with Plasmodium and S. haematobium.[90]

Discussion Point

Although some progress has been registered, the antischistosomal drug pipeline is still empty. Although antimalarials might have some impact against schistosomiasis in malaria co-endemic settings where artemisinin-based combination therapy and mefloquine are being used, these antimalarials will not replace praziquantel, given the superior clinical, economic and operational profile of praziquantel against schistosomiasis. The necessity of developing alternatives to praziquantel, now that this drug is still efficacious and in view of growing drug pressure, cannot be overemphasized.[62] Additionally, there is a pressing need to optimize existing drugs for the usage in PSAC.[91] It should be noted that using drugs in monotherapy enhances the risk of resistance development and that there is considerable concern that using antimalarials against schistosomiasis in malaria-endemic settings might select for resistance in malaria parasites.[59,92] Hence, despite there is evidence that artemisinin derivatives used in combination with praziquantel have the potential to increase the cure rates in schistosomiasis treatment,[84] at present, the application of this regimen should not be recommended in co-endemic settings.

The recent establishments of PPPs and new consortia illustrate an important and fruitful step toward a more productive and faster drug discovery and development as seen in malaria (e.g., Medicines for Malaria Venture[303]). These platforms bring together a diversity of expertise that is necessary to advocate the neglected field of drug development. Another issue of high priority is the appraisal of the impact of Schistosoma infection on the disposition kinetics of applied drugs. In addition, it will be important to study the drug disposition of antischistosomals in young children, as it is conceivable that preventive chemotherapy programs will further expand, perhaps also targeting PSAC. Recent studies have shown that cure rates in young children are lower than in their older counterparts, which might be explained by differences in pharmacokinetics.[93]

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