Efficacy of Praziquantel for the Treatment of Human Schistosomiasis in Ethiopia: A Systematic Review and Meta-Analysis

Background Schistosomiasis is one of the neglected tropical diseases causing a serious human health problem in Ethiopia. Praziquantel is the only drug that has been used for the treatment of human schistosomiasis in the country. In line with this, the efficacy of praziquantel has been evaluated in a few interventional studies in the country, but there is a lack in systematically gathered and analyzed information for policymakers. The aim of this systematic review and meta-analysis was to provide a summary of the efficacy of praziquantel for the treatment of human schistosomiasis in Ethiopia. Methods We conducted a literature search from ScienceDirect, PubMed/Medlin, and Google Scholar databases. A total of 140 articles published in English from 1980 to June 2021 were accessed and 15 of them were eligible for this meta-analysis. The meta-analysis was conducted using Stata 14 software, “metan command.” The heterogeneities among studies were evaluated using I2 test. Results A total of 140 articles were reviewed, but only 15 of them fulfilled the inclusion criteria. The polled cure rate of 40 mg/kg praziquantel was 89.2% (95% CI: 85.4–93.1) and 93.6% (95% CI: 80.6–106) among Schistosoma mansoni and S. haematobium, respectively. Similarly, the mean egg reduction rates of 40 mg/kg praziquantel were 90.2% and 85% among S. mansoni and S. haematobium infected subjects, respectively. The common adverse events observed after receiving praziquantel include abdominal pain, vomiting, headache, diarrhea, and bloody stool. Conclusion This systematic review and meta-analysis has indicated that praziquantel is still an appropriate drug for the treatment of human schistosomiasis in Ethiopia.


Introduction
Schistosomiasis is one of the neglected tropical diseases (NTD) which affects more than 230 million people in tropical and subtropical regions [1]. More than 90% of the cases are concentrated in African countries [2,3]. Schistosomiasis is responsible for about 4.5 million disabilityadjusted life years (DALYs) in endemic countries [4]. Human schistosomiasis is caused by six Schistosoma species. Among these, Schistosoma mansoni, S. haematobium, and S. japonicum are responsible for 99% of human schistosomiasis [5], of which the first two are the predominant and widely distributed species [6,7], while S. japonicum is restricted in China, Indonesia, and parts of the Philippines [8].
In Ethiopia, estimates indicate that about 37.5 million people are living at risk of schistosomiasis, of which more than 5 million people are chronically infected [9]. Schistosomiasis is one of the major causes of outpatient morbidity in the country [10]. Schistosoma mansoni is the most common cause of human intestinal schistosomiasis followed by S. haematobium, which is a cause of urogenital schistosomiasis in the country. Although there is no nationwide survey, several epidemiological studies have indicated the existence of a moderate prevalence of schistosomiasis in the country. e prevalence of S. mansoni ranged from 10% to 92%, while S. haematobium ranged from 5% to 58% in the country [11]. High prevalence of schistosomiasis has been reported among school-aged children in the country [12,13].
Although intensive research has been carried out on the development of a vaccine against schistosomiasis, there is no licensed vaccine yet. us, the available option is the use of praziquantel for the treatment of infected cases in many endemic countries since the 1970s. Besides praziquantel for treatment and a future vaccine for prevention, there are at least three other mainstems for tackling schistosomiasis: snail control, sanitation, and health education. Praziquantel is a relatively safe, well-absorbed, and effective oral drug that is active against all schistosome species [14]. e recommended dose is 40 mg/kg body weight and it is taken orally as a single dose (40 mg/kg), or this dose is divided over a day (2 × 20 mg/kg doses every 4 hours) [15] for the treatment of human schistosomiasis. Similarly, 60 mg/kg dose of praziquantel is also recommended for the treatment of human schistosomiasis for children [16,17]. e drug usually acts within one hour of ingestion by paralyzing the worm and damaging the tegument. However, praziquantel has little or no effect on eggs and on immature worms [18]. In addition, repeated usage of praziquantel for the treatment of infected individuals and its mass drug administration among school children raise concerns about the efficacy of the drug in endemic countries. As a result, poor treatment outcomes of praziquantel were reported from several countries [19][20][21].
Praziquantel is widely used for the treatment of patients as well as mass drug administration (MDA) among schoolaged children in Ethiopia. Limited studies are available on the efficacy of praziquantel in the country. e standard approach to assess drug efficacy was by determining the cure rate (CR) after administration of the standard dose of praziquantel. WHO has recently recommended egg reduction rate (ERR) as another approach to assess the efficacy of anthelminthic drugs [22]. CR is defined as the proportion of schistosome infected individuals who become parasitologically negative after administration of the standard dose (e.g., a single dose, 40 mg/kg) of the drug. ERR is equal to 1-(arithmetic mean of egg count after treatment divided by arithmetic mean egg count before treatment) expressed in percentage. Although quite limited and fragmented interventional studies are available in the country, to the best of our knowledge, there has not been any summarized data up to this point in time on the efficacy of praziquantel at the national level. erefore, this systematic review and metaanalysis aimed to systematically summarize the existing fragmented efficacy studies in the country. e PICOS (patients, interventions, comparisons, outcomes, and study design) framework used in this review is described as follows: P, schistosome infected individuals; I, administration of single-dose 40 mg/kg praziquantel; C, no comparisons; O, schistosome infection cure-rate and egg reduction rate; and S, observational studies.

Search Strategies.
We conducted a literature search from online public databases, mainly from PubMed/Medline, Google Scholar, and ScienceDirect in June 2021. e selection was done using the following terms and Boolean operators: "Schistosomiasis" OR "praziquantel efficacy" OR "S. mansoni" OR "S. haematobium" AND "Ethiopia." All articles published between 1980 and June 2021 in English were included in this meta-analysis. e systematic review and selection of relevant literature were conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [23] (Table S1).

Inclusion and Exclusion Criteria.
Literatures published in the English language were extracted from online public databases. Only original articles published in peer review journals report the efficacy of praziquantel among Ethiopian populations. All articles that were interventional studies (observational studies) that administered single-dose praziquantel at 40 mg/kg body weight were included in the list of eligible articles. Articles that lacked information about cure rates or detailed information about study subjects and review papers and studies conducted on nonhuman subjects were excluded from this meta-analysis.

Data Extraction Protocol.
e data extraction protocol was developed by TH and reviewed by EN and AM. e data extraction protocol consisted of the name of authors, year of publication, study region, sample size (population), population type (community or outpatient or school or preschool), age range, diagnostic methods, Schistosoma species targeted, cure rate praziquantel (number of cured/number of positive subjects), egg reduction rate, follow-up time, side effects of the praziquantel, and purpose of intervention (treatment or prevention).

Quality of Individual Study.
e quality of individual studies was assessed using Quality Assessment Tools for interventional studies [24]. Individual studies were assigned a score of either No (0) or Yes (1) for the ten parameters that were formulated based on the objective of the review. e quality was determined by counting the number of Yes (1) scores in each of the ten parameters. e overall quality of the individual study was classified as low quality (scores of 1-4), moderate quality (scores of 5-7), and high quality (scores of 8-10).

Risk of Publication Bias.
e risks of publication bias across studies were assessed using funnel plot symmetry (qualitative estimation) and Egger's regression test and Begg's rank correlation test (quantitative estimation).

Intervention and Outcomes. Schistosomiasis caused by
S. mansoni and S. haematobium was included in this metaanalysis. e participants involved in the interventional studies were outpatients, school children, preschool children, and community-based studies of any age. e participants of all the interventional studies received the WHO recommended 40 mg/kg body weight single-dose praziquantel for the treatment of schistosomiasis. e outcome of the evaluation was a parasitological cure, which was defined as eggs-positive or eggs-negative or absence of symptoms associated with schistosomiasis.

Data
Analysis. Cure rate was determined by dividing the number of cured individuals by the total positive subjects before treatment as indicated in each article. e confidence intervals for the cure rate were set at 95%. e egg reduction rates were obtained from the articles and calculated as the arithmetic mean. All studies with a follow-up period of two to eight weeks were included in the meta-analysis. Subgroup analyses were conducted based on a region of study, nature of participants, Schistosoma species, and years of study. e random-effects model was used to combine the pooled cure rate due to the presence of heterogeneity among studies at 95% CI. Egger's regression test and Begg's rank correlation test (quantitative) and funnel plot (qualitative) were used to assess the presence of publication bias. Metaregression analyses were performed to assess the sources of heterogeneity.
e meta-analysis was performed using Stata software (version 14, STATA Corp, College Station, TX), where p < 0.05 was considered as statistically significant.

Selected Studies.
From the total of 140 articles available online in public databases, 48 articles were excluded due to duplicates. Of the remaining 92 screened articles, 60 were excluded after we reviewed their titles and abstracts. e remaining 32 full-text articles were accessed for eligibility based on the inclusion criteria and information indicated in the data extraction protocol. As a result, 17 articles were further excluded in the data extraction process primarily due to the outcome of interest, having no cure rate, and lack of clear figures on the total number of study participants and treated cases. Only 15 articles [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] fulfilled the eligibility criteria and were included in this systematic review and meta-analysis ( Figure 1).

Study Characteristics.
e studies included in this metaanalysis were obtained from six regional states of Ethiopia, namely, Amhara, Oromia, Somali, South Nations and Nationalities Peoples (SNNP), Tigray regions, and Addis Ababa city administration. All eligible articles that were nonrandomized interventional studies were used in this metaanalysis. All interventional studies that used 40 mg/kg single-dose praziquantel with a follow-up period ranging from 2 to 8 weeks were included in the analysis. Detailed information about the characteristics of the articles included in this meta-analysis is shown in Table 1.

Risk of Bias within Studies.
We assessed the quality of the individual study using Quality Assessment Tools for interventional studies. e quality score obtained from the individual study was moderate and high. e overall analysis showed that there was a low risk of publication bias within studies.

Pooled Efficacy of Praziquantel for the Treatment of Schistosomiasis.
e efficacy of praziquantel was assessed using the cure rate and egg reduction rate among schistosome infected subjects. e cure rate of 40 mg/kg single-dose praziquantel was ranged from 73.6% to 100% among schistosome infected individuals in Ethiopia (Table 1). e pooled cure rate of a single dose of 40 mg/kg praziquantel was 89.8% (95% CI: 86.2-93.5) for human schistosomiasis. e pooled cure rates of praziquantel were 89.2% (95% CI: 85.4-93.1) and 93.6% (95% CI: 80.6-106) among S. mansoni and S. haematobium infected individuals, respectively ( Figure 2). However, twelve of the total fourteen studies were carried out on S. mansoni, while only two studies were conducted on S. haematobium in the country.
Egg reduction rate was the second parameter used to assess the efficacy of praziquantel treatment.
e ERR among S. mansoni infected individuals ranged from 79.5% to 99.6%, while ERR was 85% among S. haematobium infected individuals. Unfortunately, 5 out of the 15 eligible articles (33.3%) did not report ERR among treated individuals.

Publication Bias Across Studies.
e funnel plot symmetry indicated that there was no publication bias across studies ( Figure 3). Similarly, Egger's test (p value � 0.069) and Begg's test (p value � 0.138) confirmed the absence of publication bias among studies included in this metaanalysis.
ere was no significant difference in the efficacy of praziquantel against human schistosomiasis among regions in Ethiopia. e pooled cure rate of praziquantel treatment was 88.4% (95% CI: 84.8-91.8) in the Amhara region and 92.1% (95% CI: 80.8-100) in the Oromia region. e results of the efficacy study from Addis Ababa, Afar, Tigray, and SNNP regional states (single efficacy study from each region) are presented in Figure 5. We assessed the possibility of efficacy variation with respect to years of study (1980 to 2000

Metaregression and Sensitivity Analysis.
e result of this meta-analysis showed the presence of heterogeneity among studies (I 2 > 90%). We performed a regression analysis to identify the sources of heterogeneity across studies included in this meta-analysis. e regression coefficient for several variables is as follows: region of study (1. e result of this analysis did not bring any significant change to the pooled CR.

Discussion
Praziquantel is the only drug available for the treatment of human schistosomiasis in many endemic countries. Praziquantel has been used for the treatment of human schistosomiasis for more than forty years. Several interventional studies on the efficacy of the praziquantel are available in Ethiopia. erefore, summarized data is needed to evaluate the overall efficacy of a single dose of 40 mg/kg praziquantel for the treatment of human schistosomiasis in the country.
is meta-analysis showed that a single dose of praziquantel has 89.8% cure rate for the treatment of human schistosomiasis in Ethiopia. In line with our findings, a higher cure rate of a single dose of 40 mg/kg praziquantel was reported in several countries [40][41][42][43]. In contrast, a lower cure rate of praziquantel was reported from a metaanalysis elsewhere [44,45]. e present study revealed that a single dose of 40 mg/kg praziquantel is effective against human schistosomiasis in Ethiopia. On the contrary, a repeated dose of 40 mg/kg praziquantel had a higher cure rate than a single dose of praziquantel [17,46]. Moreover, 60 mg/ kg praziquantel was more effective than the standard 40 mg/ kg single-dose praziquantel for the treatment of human schistosomiasis [47]. ese variations of the efficacy of praziquantel might be associated with baseline infection intensity, nature of study population, sample size, and brand of the drug used. e efficacy of praziquantel was slightly higher among S. haematobium infected patients than among S. mansoni infected cases. However, only two studies were conducted on the efficacy of praziquantel against S. haematobium from the total twelve studies included in this meta-analysis. Schistosoma haematobium is generally restricted in lowland (below 800 masl) areas [11,31,48,49] and only a few studies are available in the country. erefore, it is not wise to compare the efficacy of the drug against the two schistosome species based on the existing information. Similar to our finding, a higher cure rate of praziquantel was reported from preschool and schoolchildren infected with S. haematobium compared to those infected with S. mansoni [44,47,50]. In contrast, a higher cure rate of praziquantel was reported among individuals infected with S. mansoni than those infected with S. haematobium in Cameroon [51]. e difference in the  Journal of Tropical Medicine efficacy of praziquantel might be associated with the endemicity of the disease in the area, baseline infection intensity, age of study participants, and presence of immature stages in addition to the inherent biological difference of species.
e cure rate of a single dose of 40 mg/kg praziquantel was slightly lower in the Amhara region than in other regional states in Ethiopia. is might be associated with the high endemicity of the disease in the Amhara region. Several studies indicated high prevalence (>83%) of S. mansoni in    Journal of Tropical Medicine the region [12,13,38]. e high prevalence and intensity of infection may contribute to the slightly lower efficacy of praziquantel in the region. In line with the high infection intensity, there may be large number of immature worms, which is insensitive for the drug that contributes to lower efficacy in the region. Moreover, 8 (53.3%) of the interventional studies included in this meta-analysis were derived from the Amhara region. ere were only four studies reported from Tigray, SNNP, Somalia, and Addis Ababa city administrations (one study from each regional state). As the number of studies increased, there might be a variation in their methodology, follow-up time, level of endemicity, nature of the study population, and sample size. ese variations may lead to differences in the efficacy of praziquantel among interventional studies which might contribute to the slightly reduced cure rate in the region. e efficacies of praziquantel were almost similar in all types of study participants (patients, schoolchildren, preschool children, and the community). e efficacy of praziquantel was slightly higher among preschool children than among schoolchildren as reported elsewhere [44]. In this meta-analysis, only one study reported the efficacy of praziquantel from preschool children in Ethiopia. It might not be good to compare the efficacy of praziquantel between schoolchildren and preschool children. Similarly, we compared the cure rate of praziquantel from 1980 to 2000 and from 2001 to 2021 to assess the possibility of variation in response rate due to frequent exposure. e result showed that the cure rate is slightly lower in recent years than in studies reported before 2000. However, the difference is not statistically significant.
is shows the absence of drug failure and/or resistance against praziquantel, suggesting that the drug is still effective in the treatment of schistosomiasis in Ethiopia.
e study showed high heterogeneity (I 2 � 91.4%) across studies. We conducted a metaregression analysis to assess the source of heterogeneity by considering region of study, nature of study participants, year of study, and Schistosoma species. All these did not contribute to the observed heterogeneity. Other conditions such as sample size, infection intensity, and specific intervention time and area might contribute to the observed heterogeneity across studies.
Egg reduction rate was the second recommended option to assess the efficacy of anthelminthic drugs in endemic countries [22]. e egg reduction rate after praziquantel administration reported among studies included in this meta-analysis ranged from 68.2% to 99.6%. e pooled egg reduction rate was 89.6% among studies that reported ERR. Praziquantel contributes to more than 90% of ERR of schistosome infection as reported elsewhere [41,45,52]. Anthelminthic drugs that reduce the infection intensity at least by 90% are accepted and are recommended to continue   for the treatment of human schistosomiasis [22]. e studies included in this meta-analysis used the standard 40 mg/kg single-dose praziquantel. Studies showed that a double-dose arm of 40 mg/kg of praziquantel resulted in a higher ERR compared to the standard single-dose arm [17,46]. About 7/14 (50%) of the interventional studies reported the presence of adverse events of praziquantel within 4 hours after drug administration, but all adverse events were subsided within a short period of time. e most common adverse events including abdominal pain/discomfort/cramp, headache, and vomiting followed by diarrhea, nausea, itching, bloody stool, fever, fatigue, and dizziness were reported in at least four studies from the total seven studies that reported adverse events of praziquantel. Similar adverse events of praziquantel were reported in systematic review and meta-analysis from schistosomiasis endemic countries [44,45]. e adverse events might be associated with the host immune response to the parasite antigens released from the dead parasites. In addition, the intensity and location of the infection may also contribute to the adverse side effects.
About 89% of the treated individuals showed one or more adverse events of praziquantel observed in study subjects included in this review. Similar high adverse events of praziquantel were reported from Brazil [53] and Uganda [54]. In contrast to our findings, a lower adverse event of praziquantel was reported elsewhere [43,45,50]. ese differences might be associated with the difference in infection intensity, parasite, or host factors.

Limitation of the Study
is meta-analysis summarized the praziquantel efficacy studies carried out in the country and produced pooled cure rates and egg reduction rates. Nevertheless, it has some limitations. First, the studies included in this meta-analysis lack a control group or individuals taking a placebo during the intervention time. is makes it is impossible to calculate risk ratio (RR) or relative risk. erefore, we were forced to use the cure rate rather than the risk ratio. Second, the studies eligible for this meta-analysis used different parasitological methods (Kato-Katz, urine filtration, and formolether concentration). ese methods have different sensitivity and specificity that may affect the outcome of praziquantel efficacy. It is known that Kato-Katz and urine

Conclusion
is systematic review and meta-analysis revealed that praziquantel is still an effective drug for the treatment of human schistosomiasis in Ethiopia. A single dose of 40 mg/kg praziquantel administration resulted in >90% in both cure and egg reduction rates in Ethiopia. Mild and transit adverse effects including abdominal pain/discomfort, headache, vomiting, diarrhea, bloody stool, nausea, and itching were consistently observed among individuals after receiving the treatment but resolved within 24 hours. is meta-analysis supports the use of a single dose of 40 mg/kg praziquantel for the treatment of patients as well as for mass drug administration. Praziquantel treatment should be supported by environmental sanitation and proper health education for effective control and elimination of human schistosomiasis in Ethiopia.

AEs:
Adverse events CI: Confidence interval CR: Cure rate DALYs: Disability-adjusted life years ERR: Egg reduction rate FECT: Formalin-ether concentration technique I 2 : Inverse Variance Index MDA: Mass drug administration NTD: Neglected tropical diseases PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis RR: Risk ratio SNNP: South Nations and Nationalities Peoples WHO: World Health Organization.

Data Availability
All data are included within the manuscript.

Conflicts of Interest
e authors declare that there are no conflicts of interest.

Authors' Contributions
Tamirat Hailegebriel contributed to the design and conduct of the review, data analysis, interpretation of the findings, and drafting of the manuscript. Endalkachew Nibret and Abaineh Munshea contributed to drafting, reviewing, and editing the manuscript.