Multilingual abstracts

Please see Additional file 1 for translations of the abstract into six official working languages of the United Nations.

Background

Schistosoma infection is a worldwide public health problem, particularly in sub-Saharan Africa where approximately 90% of the infections are found [1]. Both Schistosoma haematobium and Schistosoma mansoni are responsible for the burden of the disease although S. haematobium is more prevalent in the sub-Saharan region. In 2012, at least 249 million people required preventive treatment and only 42.1 million were reported to have been treated [2]. To date, praziquantel administered at the standard single oral dose of 40 mg/kg body weight is the mainstay drug recommended by WHO for chemo-preventive therapy [2, 3]. This dosage has been largely used in mass drug administration (MDA) programmes in endemic countries to reduce the morbidity of the disease [4].

In sub-Saharan Africa, studies have shown that praziquantel drastically reduces morbidity and transmission of schistosomiasis. It has a high cure rate (CR) and satisfactory egg reduction rate (ERR) [5, 6]. However, failure/resistant cases have been reported after the use of a single standard dose of praziquantel at 40 mg/kg body weight. A repeated standard dose regimen has been shown to be more efficacious than the single dose [7]. Even when the repeated dose was used, few treated cases continued to release viable eggs. This prompted trials with a single dose of 60 mg/kg body weight to prevent failure/resistant cases. Researchers that conducted comparative studies of praziquantel with the standard dose of 40 mg/kg versus 60 mg/kg at a split dose [8, 9] reported divergent results. Belizario et al. reported similar efficacy on S. mansoni with both dose therapies [8] and significantly higher but mild and transient side effects with 60 mg/kg regimen [8]. In contrast, Coulibaly et al. showed that 60 mg/kg was more efficacious than 40 mg/kg [9].

Various factors such as species of parasite [7], parasite stage [10] and infection intensity have been attributed to influence the treatment outcomes with praziquantel with regard to the CR and ERR. Praziquantel is reported to be more efficacious on S. japonicum than it is on S. mansoni. S. haematobium has the lowest CR among mixed infections of S. haematobium and S. mansoni [7, 11]. It is also known that praziquantel is not effective on immature worms [12]. Moreover, schistosome resistance to praziquantel treatment following its repeated dose use has been reported in field studies [10].

Since there is no vaccine to prevent Schistosoma infection, regular monitoring of the efficacy of praziquantel is crucial. Studies on S. mansoni and S. japonicum focusing on the genetic diversity of the parasite as the determinant praziquantel efficacy have been conducted in Japan, China and the Philippines. Since praziquantel is not active on immature worms [12], a combination of praziquantel with antimalarial drugs (artemether, artesunate) which kill immature worms has been suggested as a comprehensive cure [12, 13]. Phase 3 schistosome vaccine clinical trials are in progress [14]. In sub-Saharan Africa, where S. mansoni and S. haematobium are endemic, particularly among children, studies on the efficacy of praziquantel are limited and the few studies that investigated the relationship between morbidity due to S. haematobium and the genetic variation have reported conflicting results [15, 16]. This highlights the need for further investigations on the efficacy/failure of different doses of praziquantel against S. haematobium and S. mansoni in endemic areas of sub-Saharan African. In this paper we reviewed the status of use of praziquantel and identified gaps in the treatment of schistosomiasis in the sub-Saharan region? Electronic searches focusing on the efficacy of different regimens of praziquantel in treating schistosomiasis among children in sub-Saharan Africa were done to extract literature on the subject.

Main text

Review methods

Search strategy

A systematic electronic search of literature on PubMed, MEDLINE and Google Scholar databases was carried out using following terms and Boolean operators: praziquantel AND efficacy AND resistance AND schistosomiasis AND Schistosoma haematobium OR Schistosoma mansoni AND sub-Saharan Africa. At the initial stage of identifying articles, titles and abstracts were used to screen relevant papers. Relevant abstracts were further assessed for inclusion in the list of full text articles. The full texts were further assessed for eligibility in the review. All records were managed in Endnote version X7 (Clarivate Analytics, Philadelphia, PA, USA). The review included research articles published within a 10 year period from 2008 to 2017 (August).

Inclusion and exclusion criteria

Publications in peer-reviewed journals that focused on field studies on the efficacy and resistance/failure of praziquantel on S. haematobium and S. mansoni treatment among children in sub-Saharan Africa were included in the review. Studies that reported on interventional studies conducted among children less than 18 years old were also included in the review. Studies in which praziquantel was administrated at 40 mg single standard dose and/or repeated standard dose or at escalating dose (20/40/60 mg/kg) were added to the list of eligible articles.

The following studies were excluded:

  • Reports on work that involving both children and adults;

  • Studies that reported on the efficacy of praziquantel combined with other anti-schistosomal drugs;

  • Studies that assessed the efficacy of praziquantel in the co-infection settings of schistosomiasis with other parasitic diseases like soil transmitted helminthic diseases;

  • Laboratory experimental studies on praziquantel efficacy;

  • Studies in which praziquantel efficacy was assessed after more than nine weeks post first administration.

Quality assessment of the studies was performed using the Study Quality Assessment Tool for Quality Assessment of Controlled Intervention Studies. Individual studies were assigned a score that was computed using different parameters in line with the review objectives. The responses were scored 0 for “No” and 1 for “Yes”. Total scores ranged between 0 and 10; 1–4 = (Low); 5–7 = (Moderate) and 8–10 = (High). The overall score was moderate.

Results

The literature search from Google Scholar provided one thousand two hundred and thirty (1230) records of which only 1010 were accessible. The search setting for ten results per page could not allow to go further than the 100th webpage. We obtained 463 records from the PubMed database and sixty eight (68) from MEDLINE. Overall, the electronic search provided a total of n = 1541 hits (Fig. 1). Hundred and ninety duplicate articles were removed from the records. During the screening of titles 1315 were deemed ineligible based on their relevance and the language in which they were published. Therefore, they were excluded from the screening process for abstracts. Out of the remaining 36 abstracts that were deemed relevant, 13 were excluded as they did not focus specifically on the efficacy of praziquantel against S. haematobium and/or S. mansoni in sub-Saharan Africa in a field setting. This gave a total of 23 studies eligible for full text screening. The review included interventional studies (cohort and randomised control). Excluded studies were those that reported either on the efficacy of praziquantel in combination with other medications or experimental laboratory studies or reviews. Studies in which the study population comprised children and adults were also excluded. Out of the twenty three studies whose full texts were reviewed, three were removed as the time line of assessing for praziquantel efficacy did not meet the inclusion criteria (3–9 weeks). An additional study was removed as it was published in 2008 but was carried out in 2004. Therefore, nineteen (19) publications were deemed relevant for final inclusion and were reviewed (Fig. 1).

Fig. 1
figure 1

PRISMA diagram showing the process of studies search. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Full size image

Efficacy of praziquantel by age group

The reviewed studies were conducted among children. School-going children were the most represented (eight studies) followed by pre-school children (seven studies). Four studies involved both age groups. The highest number of the studies (nine) were conducted between 2012 and 2013.

The cure rate had been largely used in assessing praziquantel efficacy in the past. The use of the egg reduction rate was recently recommended [17]. In most studies that were carried out among school going children, the efficacy of praziquantel improved significantly after the repeated standard dose of 40 mg/kg body weight [18,19,20,21,22,23]. Higher cure rates were observed among people infected with S. mansoni those infected with S. haematobium infection [24]. Pre-school children were included among the target group for schistosmiasis treatment after realizing that they were a high risk group as well. [25]. Praziquantel administered at 40 mg/kg single dose demonstrated satisfactory efficacy among children [26,27,28]. Efficacy was lower in children that received multiple rounds of praziquantel treatment than in those that did not receive any treatment before [29]. In response to the pressing need of standardizing treatment in pre-school children, alternative paediatric forms of praziquantel have been on trial. Crushed praziquantel has been reported to have satisfactory efficacy for all species [30] while praziquantel syrup (Epiquantel®) showed diminished efficacy [31] for reasons not known.

Distribution of studies by country and species

Of the 19 studies reviewed, the majority of them (7/19 = 37%) were carried out in Uganda where S. mansoni was the predominant species (Additional file 2: Table S1). Another study on S. mansoni infection carried out in Ethiopia [19] indicated an East Africa dominance in distribution of S. mansoni. Elsewhere in other countreis of sub-Saharan Africa S. haematobium and mixed infections were found (Additional file 3: Table S2 and Additional file 4: Table S3). As shown in Additional file 4: Table S3, of the 6 mixed infections that were reported, 2 were from Niger [31, 32] and one from Cameroun, Ivory Coast, Senegal and Zimbabwe [23, 24, 28, 30]. The rest of the infections were due to S. haematobium (Additional file 3: Table S2).

Efficacy of praziquantel on S. haematobium and S. mansoni

S. haematobium and S. mansoni both exist separately or in co-infection in sub-Saharan countries. Praziquantel is efficacious on all species, therefore, it is the only recommended drug for preventing and treating schistosomiasis [2] despite some observed low cure rates and possible resistance recently reported. This review shows that for most of the studies praziquantel had high efficacy on both species [19, 22, 27, 28, 29, 34]. However, higher efficacy was reported against S. haematobium [30,31,32] than it was with S. mansoni [24] in co-infection settings as shown in Additional file 4: Table S3.

Efficacy of different dose regimens of praziquantel

Praziquantel administered at 40 mg/kg body weight is the standard dose recommended by WHO for chemotherapy in treating schistosomiasis. Articles reviewed mainly reported on the efficacy of different dosages of praziquantel used against both S. haeamtobium and/or S. mansoni in sub-Saharan Africa. Most studies used single dose (9/19, 47%) followed by studies that used single dose versus repeated standard dose (6/19, 32%). Repeated standard dose was administered in three studies while one study used the escalating dose (20/40/60 mg/kg). The efficacy of praziquantel varied significantly depending on whether it was single or repeated dose. Overall, the repeated dose was more efficacious compared to the single dose. Cure rates and egg reduction rates were low or moderate after the single dose and improved after the administration of the second dose [23, 27, 31,32,33]. In some studies, praziquantel given at single dose revealed high cure rates and egg reduction rates [19, 28, 34, 35] while they were low in others [31, 36]. Escalating dose of praziquantel was more efficacious at high dose than at low dose [9].

Discussion

The study reviewed the efficacy of different doses of praziquantel against S. mansoni and S. haematobium infection in endemic settings in sub-Saharan Africa. Our discussion is based on the used dose, the targeted species and the time of assessment post-treatment. An emphasis was also given to studies conducted in high endemic zones where several rounds of mass drug administration were done.

Praziquantel administered at a standard dose of 40 mg/kg was shown to be effective against Schistosoma infection. However, a low cure rate that may require a second or high dose to clear the infection was reported [36]. This may be because praziquantel kills mature schistosomes while immature worms are not affected but later become mature and release eggs at a later stage. Infection may also persist after praziquantel treatment due to the reduced susceptibility of juvenile parasites to the drug [37]. Such persistent infections may then contain a significant amount of juvenile schistosomes that are refractory to praziquantel at the standard dose leading to lower cure rate and egg reduction rate. In high endemic areas where school-going children had been subjected to several rounds of mass drug administration (MDA), it was evident that praziquantel at the standard dose was less efficacious among those that received higher rounds of praziquantel (8 to 9) compared to those that received lesser rounds of treatment (1 and 5) [38]. Thus, the use of praziquantel in MDA campaigns has raised concerns on the possibility of development of drug resistance. It is however important to realize that the parasite may acquire tolerance to praziquantel that needs to be distinguished from resistance. Repeated doses of praziquantel have been reported to improve the outcomes of infection, post treatment [7]. Follow-ups after large scale intervention such as MDA are needed since praziquantel is the only recommended drug for schistosomiasis at 40 mg/kg body weight and in most cases does not completely clear the parasite.

Studies that used repeated standard dose of praziquantel [20, 33] showed satisfactory efficacy after the second dose. These findings corroborate with those found in another study [7]. Administration of the second dose was intended to target immature worms missed by first treatment and that was done 3–4 weeks following the initial treatment. Moreover, the outcomes of praziquantel efficacy varied depending on whether it was a single infection or mixed infection. Studies that focused on one species reported satisfactory efficacy [20, 33, 39] while those focused on co-infection (S. haematobium and S. mansoni) had inconsistent results [24, 32]. The period of assessment between the first dose and follow up might have not been sufficient to allow complete release of dead eggs from the human host. However, the underlying cause of this reduced efficacy among mixed infection needs to be elucidated. Despite the use of the second dose, few refractory cases were still observed. Schistosome infections may persist after the treatment due to the reduced susceptibility of immature parasites to the drug [37] and may develop tolerance or resistance over time. This may be the same mechanism that schistosomes acquire tolerance/resistance in endemic areas after several rounds of MDAs.

In a study that used an escalating dose, the outcomes of praziquantel efficacy gradually improved with increasing dosage [9]. The initial dose of 20 mg/kg body weight was lower than the recommended dose of 40 mg/kg to kill schistosomes and showed low efficacy. Consistent with the above, results from a laboratory experiment showed that the use of praziquantel, especially at a lower dose than the recommended curative dose may lead to development of resistance to the drug in future generations [40]. Another study that compared praziquantel given at 40 mg/kg and 60 mg/kg single doses reported satisfactory efficacy with both regimens. However, there was no significant difference between the doses but more minor and transient side effects were observed at 60 mg/kg regimen [8].

This review showed that praziquantel was efficacious on both S. haematobium and S. mansoni with the former being more sensitive to praziquantel. In another comparative study, the efficacy of praziquantel was shown to be higher against S. japonicum than other species [11]. Factors responsible for this difference are not clear and need further investigation in co-infection settings.

Conclusions

This review revealed that praziquantel administrated at a repeated standard dose of 40 mg/kg was more efficacious than the standard single dose of 40 mg/kg. The outcomes of praziquantel efficacy depended on whether it was mixed infection of S. haematobium and S. mansoni or a single focus of infection. The efficacy of praziquantel in mixed infection foci required at least two rounds of standard dose at three weeks interval. Praziquantel given at 60 mg/kg single dose was shown to be slightly more efficacious than other regimens. S. haematobium was shown to be more sensitive to praziquantel than S. mansoni. Praziquantel showed moderate efficacy in areas that had received multiple MDA. The review suggests that follow ups should be done in endemic area after mass drug administration as recently initiated in Zimbabwe by Mutapi and Mduluza (personal communication). The use of repeated doses of 40 mg/kg and the high dose (60 mg/kg) need further investigations before being recommended for use in control programmes in endemic areas of sub-Saharan Africa to prevent possible resistance to praziquantel.