Efficacy of Different Drugs in Treating Urinary Schistosomiasis: Systematic Review and Network Meta-analysis

Background Praziquantel is the current pillar for morbidity control of schistosomiasis. Artesunate and its derivatives, widely used for malaria treatment, also display antischistosomal activities. This review compares the efficacy of three drugs, namely praziquantel (PZQ), artesunate, and metrifonate in urinary schistosomiasis. Methods Databases were searched for articles comparing the effectiveness of any of the three drugs to other medications or controls in urinary schistosomiasis in children aged 18 or less. Stata software was opted to generate the network meta-analysis. Efficacy (Cure rate and egg reduction rate) was the main outcome measure. Pairwise and network meta-analysis were used to report Odds Ratios (ORs) with either 95% confidence interval (CI) for direct comparisons or 95% credible intervals (CrI) for indirect comparisons. Results The SUCRA plot for cure rate revealed that PZQ (SUCRA= 40.4%) was the fourth effective drug after albendazole 400mg (SUCRA= 71.5), metrifonate 5 mg (SUCRA= 62.2%), and metrifonate 10 mg (SUCRA= 59.7). PZQ was only superior to metrifonate 7.5 mg. ORs were PZQ 40 mg (OR 0.48; 95% CI -3.55 to 4.51; p-value 0.816), artesunate 6 mg (OR 0.06; 95% CI -5.67 to 5.79; p-value 0.983), metrifonate 5 mg (OR -1.65; 95% CI -7.52 to 4.21; p-value 0.581), metrifonate 10 mg (OR -1.76; 95% CI -8.86 to 5.34; p-value 0.628), and metrifonate 7.5 mg (OR -2.40; 95% CI -9.78 to 4.98; p-value 0.524). A similar plot for egg reduction rate showed an exclusive superiority of PZQ 40 mg (SUCRA= 94.4%), Conclusions Our network analysis revealed that PZQ mg was the most efficient drug in reducing egg count, whereas albendazole 400mg showed the highest cure rates.


Introduction
Urinary schistosomiasis is a chronic parasitic infection caused by trematodes of the genus Schistosoma known as Schistosoma haematobium (SH). SH, also known as "urinary blood fluke", inhabits and produces eggs in the small venules of the peri-vesical and portal systems. Urinary schistosomiasis is endemic in 53 countries in Africa and the Middle East, where more than 110 million people are infected (1,2). Noteworthy, the prevalence reaches its peak among school-age children to be as high as 46.5% (3,4). A myriad of medications was evaluated for their efficacy in treating SH infection (5)(6)(7)(8)(9). Praziquantel (PZQ) is the most commonly used drug worldwide and is the drug of choice for controlling schistosomiasis in endemic regions (10). The reasons for that is its efficacy in reducing egg count at a relatively high rate across different types of schistosomiasis (11). Moreover, PZQ is has shown good safety profiles making it the drug of choice for children and pregnant women (12,13). Additionally, PZQ has a low risk of noncompliance because it is administered as a single oral dose of 40 mg/kg body weight. Noteworthy, recent literature questioned this treatment regimen and suggested that PZQ in multiple dosages is more effective than a single dose (14).
In the same context, artesunate, originally an antimalarial treatment, has proved efficacy and tolerability as an antischistosomal therapy (5,15). Two doses of artesunate were more cost-effective compared to single-dose PZQ (16). Nonetheless, PZQ-artesunate combination was safer and more effective as opposed to using either drug (8,17). Metrifonate, a cholinesterase inhibitor, is another selective treatment for SH; it has good efficacy and safety profiles. Although it is economic and causes low recurrence rates, the complicated dose regimen may limit its use (18). The reason for such complexity is the time needed for cholinesterase to return to its normal level, which may take 8-15 days (19). Moreover, three doses of metrifonate are needed to produce the same effect as one dose of PZQ in terms of egg reduction rates (20). Another limitation in using metrifonate is that a prophylactic dose is needed within two years to guard against recurrence (21). Niridazole is also highly effective for treating schistosomiasis, and a single dose of niridazole 25mg/kg daily has a high cure rate (22). However, it has serious side effects in susceptible individuals including central nervous system toxicities and allergic reactions, which limit its use compared to other safe alternatives (23).
In this study, we aim to compare efficacy (cure rate and egg reduction rate) of three drugs, namely praziquantel, artesunate, and metrifonate in cases of SH.

Search strategy and study selection
The study was conducted following the accepted methodology recommendations of the PRISMA checklist for systematic reviews. On December 18, 2019, we searched PubMed, Cochrane Central, Scopus, Web of Science, and Ovid databases for pertinent English articles using search terms ("Schistosoma haematobium" OR "schistosomiasis haematobia" OR "Bilharzia haematobium" OR "urinary schistosomiasis" OR "urogenital schistosomiasis" OR "vesical schistosomiasis" OR "Bilharziasis haematobium" OR "Bilharzia haematobium") AND (Metrifonate OR "Praziquantel"OR "Artesunate" OR anthelmin* OR treat* OR therapy*). This search strategy was developed and implemented in collaboration with a medical librarian experienced in systematic review and database searching. A manual search was done by searching for relevant publications in reference list of included articles and excluded systematic reviews; relevant papers in PubMed and Google Scholar; and primary studies that had cited the included papers. We also hand-searched using each keyword to avoid missing any relevant publications.

Study selection
Three independent reviewers scanned the titles and abstracts to select potentially-relevant articles.
We included all original studies reporting treatment of urinary schistosomiasis. There was no restriction on country, language or publication date. Studies were included if they i) were children (less than 18 years old) and diagnosed with urinary schistosomiasis, ii) were clinical trial or any comparative observational study (cross sectional, case control, and cohort studies), iii) investigating the effect of PZQ, artesunate, and metrifonate comparing with other drugs or controls with no restrictions on the dose, frequency, and duration. iv) reporting the efficacy of cure rates, and egg reduction rates, v) were reported in English. We excluded papers if they met the following exclusion criteria: i) in vitro or animal studies, ii) data duplication, overlapping or unreliably extracted or incomplete data, iii) abstract only articles, reviews, theses, books, conference papers or articles with inavailable full texts (editorials, author responses, letters, and comments), and iv) any previous systematic reviews, meta-analyses and literature reviews on our topic of interest. Three reviewers independently performed an initial eligibility assessment of the retrieved titles and abstracts. Full texts of eligible articles were then retrieved and reviewed for inclusion. In both screening steps, inclusion or exclusion of a study by all three reviewers was considered conclusive. Conflicts were resolved through discussion among the authors. When necessary, the authors sought the opinion of senior reviewers on disagreements and discrepancies. All the references in this study were managed using Endnote X9, a reference manager software program.

Data extraction
Based on a pilot scan and extraction, two authors prepared a data extraction sheet using Microsoft Excel, and three reviewers independently extracted data from included studies. For accuracy, two different authors revised the data, and a third reviewer rechecked them. Disagreements or discrepancies were resolved through discussion and reaching consensus. Papers by the same research group and those studying the same factors were checked for potential duplicate data based on recruitment year, recruitment place, and confirmation from study authors. The outcome of interest was the efficacy of the medications of concern (PZQ, artesunate, and metrifonate), and outcome measurements were opted premised on the most commonly reported data in the included papers, namely cure rates, and egg reduction rates. Not only were these two measures endorsed for being frequently reported but also because they were feasible to assess pre and post-therapy using diagnostic tests. Two independent reviewers extracted and recapitulated data entailing study ID, last name of the first author, publication year, country, total number of participants, percentage of males, age touted as mean (SD), and the administered medication/s (name, dose, number of participants assigned to each drug). Regarding tools of outcome measurement, the extracted data encompassed drug name, the quantitative mean of efficacy, the total number of patients, the dose, the length of the therapeutic course in days, and the diagnostic test used for assessment. Whenever any article reported multiple checkpoints, only the last point was analyzed.

Quality assessment
Two reviewers have independently assessed the risk of bias of the included studies using the National Institute of Health (NIH) Quality Assessment Tool for Observational Cohort and Cross-sectional Studies and Case-control Studies (24). If the ratings were different, then the reviewers discussed to reach consensus. If consensus was not obtained, the study was forwarded to a third reviewer to settle the conflict. The elements of the quality assessment were indexed either Yes (1), No (0), or others including CD (Cannot Determine), NA (Not Applicable), and NR (Not Reported). Eventually, papers were rated fair, good, or high based on the final score.
Having four randomized controlled trials included the Cochrane collaboration risk of bias tool was used for its assessment (25). Five types of risks were evaluated selection (the adequacy of randomization), performance (the adequacy of blinding participants and study personnel), detection (the adequacy of blinding outcome assessors), attrition (the influence of missing data on the study results), and reporting (the adequacy of full, open reporting of results). participants and personnel (detection bias), incomplete outcome. The risk of each type of bias was graded "low," "high," or" unclear".

Statistical analysis
Odds Ratios (ORs) with 95% confidence interval (CI) for direct comparisons or 95% credible intervals (CrI) for indirect comparisons were used. A network meta-analysis was performed using Stata software (version 14.2, StataCorp, College Station, TX) with random-effects models. To rank the treatments, the surface under the cumulative ranking probabilities (SUCRA) were opted to show which treatment was the best. Heterogeneity was considered significant with either I2>50 or P<0.05 with a subsequent adjustment of the model to small-study effects (incorporation of the heterogeneity) in this case. Inconsistency was also considered significant with either P<0.05, which was further investigated using node splitting methods (of direct and indirect comparisons) whenever indicated.

Search results and screening process
Our search retrieved 2303 studies with only 1434 left after removing duplicates. Title and abstract screening using the criteria aforementioned left only 89 studies eligible for further full-text screening.
Following the full-text screening, 20 studies were included in both quantitative and qualitative synthesis. The manual search retrieved no additional relevant studies. Figure 1 shows a summary of the search and screening process. Table 1 summarizes the patient characteristics and the designs of the included studies. The data extracted for these 20 articles allowed analysis to be conducted on ten treatment protocols: PZQ 40mg, Albendazole 400mg, metrifonate 10mg, niridazole 25mg plus metrifonate 10mg, niridazole 25mg, metrifonate 7.5mg, metrifonate 5mg, niridazole 25mg, PZQ 40mg plus artesunate 4mg, and artesunate 6mg. 17of the identified studies investigated PZQ 40mg, one Albendazole 400mg, three metrifonate 10mg, one niridazole 25mg plus metrifonate 10mg, one niridazole 25mg, one metrifonate 7.5mg, one metrifonate 5mg, one niridazole 25mg, one PZQ 40mg plus artesunate 4mg, one artesunate 4mg, and one artesunate 6mg. Of the included publications, 19 were conducted in Africa and only one in Asia. Four studies were randomized controlled trials, six were cross-sectional studies, eight were observational prospective cohort, one field trial, and one comparative study. Regarding randomized controlled trials included, most of them deemed of high quality (Figure 2). Regarding the rest of the included studies, apart from two studies of poor quality, most of them were either good or fair in quality (Supplementary file).

Cure rate
For cure rates, six different treatments/doses were compared, and the network plot is showcased in 2) ranked fourth. There was significant heterogeneity (t 2 = 2.78, I 2 = 71.55%) with no significant inconsistency (P= 0.06). Moreover, adjusting our model to small-study effects (incorporation of the heterogeneity) did not materially alter the relative effectiveness and the ranking of treatments ( Figure 3B). In the same context, pairwise comparisons of all drugs to albendazole 400mg revealed that albendazole was more effective than any other treatment/dose. However, this difference in cure rates was not statistically significant throughout all comparisons ( Table 2).  Table 3). There was a significant heterogeneity (t 2 = 1.21, I 2 = 65.73%) and significant inconsistency (P= 0.007). Moreover, adjusting our model to small-study effects (incorporation of the heterogeneity) did not materially alter the relative effectiveness and ranking of treatments ( Figure 4B). In the same context, pairwise comparisons of all drugs to Placebo revealed Praziquantel 40mg-Artesunate 4mg as a combination was the best, followed by Praziquantel 40mg and the Niridazole 25mg-Metrifonate 10mg combination.

Egg reduction rate
Interestingly, this difference in cure rate was statistically significant across all drugs when compared to placebo ( Table 3).

Discussion
This study is, to the best of our knowledge, the first network meta-analysis of its kind to assess the efficacy of all proposed treatments for urinary schistosomiasis in the literature through direct and indirect comparisons between the various treatment modalities. Our network analysis revealed that albendazole (400 mg) achieved higher percentages of cure rate than other treatment modalities.
Albendazole is used commonly for treating some human worm infections. Recently, it has been combined with praziquantel for the management of schistosomiasis and other soil-transmitted helminthiases (26,27).
Noteworthy, albendazole has never been investigated as monotherapy for SH, but one study reported the outcomes of a single dose of combined praziquantel and albendazole and concluded that albendazole impacts the effect of praziquantel (28). Olds et al. have reported a failure rate (defined as the continued detection of parasite eggs 45 days after treatment of SH (of 79.6% in patients treated with Albendazole alone (28). This percentage nosedived to 38.5% after adding praziquantel to the therapy (28). Furthermore, they reported a failure rate of 35.1% in praziquantel alone, which is still much better than albendazole alone. Olds et al. had a few limitations: First, they excluded female patients who were liable to pregnancy because albendazole is a known teratogenic. Accordingly, most of their patients were on praziquantel, which might have made their analysis standing in favor of praziquantel. Second, they did not provide any data on the characteristics of their study participants, the intensity of the infection, or the number of patients on each treatment modality. Another trial showed higher cure rates in praziquantel than cure rates of albendazole alone (78% vs 66%) but with statistically insignificant difference. Additionally, the mean post-treatment egg count was lower in patients on praziquantel compared to those on albendazole (2.0±1.2 and 2.7±1.3, respectively) (29).
Even though the reports aforementioned indicate that praziquantel is more efficient than albendazole in treating urinary schistosomiasis, albendazole is more readily available and cost-effective (29).
Our finding regarding the efficacy of PZQ is consistent with findings of a previous systematic review which reported PZQ was superior to artesunate in terms of cure rate (30). On the contrary, the World Health Organization recommends that schistosomiasis should be treated with single-dose PZQ of at least 40 mg/kg (31). Similarly, the recently updated review by Kramer et al (8). supports the current evidence of applying 40 mg/kg praziquantel to patients with urinary schistosomiasis. One major limitation to the study by Kramer et al., besides being mostly qualitative review with only minimal meta-analyses, is that all of their included trials were conducted in Sub-Saharan Africa, except for one conducted in Saudi Arabia. So, their conclusions cannot be generalized. On the other hand, our analysis revealed that PZQ held second record for cure rates after albendazole, metrifonate (5 mg/kg), and metrifonate (10 mg/kg). Herein, we propose multiple explanations for this finding. The low cure rates of PZQ could be a possibly increasing PZQ resistance in the assessed trials as observed by some authors (32)(33)(34)(35). Praziquantel is also kills the adult worms, not the immature stages; therefore, the majority of our patients on PZQ might have been harboring the immature stages at treatment time.
In our analysis, even though praziquantel was ranked fourth in cure rates, it was ranked first in egg reduction rates. There were no data available on egg count reduction in patients on albendazole; thus, it was not included in the analysis. Future studies should assess thoroughly the changes in egg count in patients on albendazole. On the other hand, a combination of niridazole and metrifonate was ranked second in our analysis, but one should keep in mind that both drugs are old, unavailable, and are no longer used in practice. Of note, egg count reduction is not a very sensitive parameter of clinical and parasitological cure, since negative urine examinations is not an indicator of cure. The literature reported that the absence of eggs in the urine is only an occasional finding and does not necessarily exclude infection (36); accordingly, repeated urine examination after treatment is more useful in diagnosing persistent excretion of eggs in the urine and controlling any the possible transmission of the infection. That being said, cystoscopy, in addition to biopsy and histopathological evaluation, is a pivotal indicator of parasitological cure (36). Therefore, extra caution should be given to the interpretation of the data on egg count as they do not necessarily reflect the efficacy of treatments.

Strengths and Limitations
The main strength of our study is being, to the best of our knowledge, the first network meta-analysis to assess the direct and indirect comparisons among different treatment modalities for urinary schistosomiasis in terms of cure and egg reduction rates. Also, unlike the recent Cochrane review of Kramer et al., we assessed the efficacy of albendazole in treating urinary schistosomiasis. However, we encountered several limitations, the biggest of which is the lack of data regarding the egg count reduction in patients on albendazole, and that restricted us from including the egg count networking.
Also, the definition of cure differed among the included trials, which impeded us from reaching a sheer conclusion on the best treatment for urinary schistosomiasis. Moreover, the intensity of infection was not reported in most trials; the thing that might have affected the results of egg count reduction to somewhat. Therefore, these issues should be addressed in future work.

Conclusions
Our network analysis revealed that albendazole is the most efficient drug with the highest cure rates in cases of urinary schistosomiasis, whereas PZQ took second place. As regards the percentage of egg count reduction, PZQ was superior to other medications.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests

Not applicable
Authors' contributions HF conceptualised the review. All authors screened the articles. XG, CT, AB and FC extracted the data.      Quality assessment of the include randomized controlled trials.  The figure showcases a network of eight drug categories as related to their efficacy (egg reduction rate). the thickness of lines reflects the number of articles comparing each pair treatment, and the size of each node is proportionate with the number of participants. Also, (B) is the Sucra plot for ranking the egg reduction potential of plotted drugs; the SUCRA score is 100%. The more the score, the higher the treatment is ranked in terms of its cure rate. PZQ, Praziquantel; Niri, Niridazole; Met, Metformin; Artes, Artesunate.

Supplementary Files
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