Drugs for treating urinary schistosomiasis
Abstract
Background
Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine. Chronic infection can cause substantial morbidity and long‐term complications as the eggs become trapped in human tissues causing inflammation and fibrosis. We summarised evidence of drugs active against the infection. This is new edition of a review first published in 1997.
Objectives
To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014.
Selection criteria
Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other.
Data collection and analysis
Two researchers independently screened the records, extracted the data and assessed risk of bias. The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline. We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs). Where appropriate we combined trials in meta analyses or tables. We assessed the quality of evidence using the GRADE approach.
Main results
We included 30 RCTs enrolling 8165 participants in this review. Twenty‐four trials were conducted in children in sub‐Saharan Africa, and 21 trials were over 20 years old. Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods.
Praziquantel
On average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence). The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials. At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).
Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94).
Metrifonate
A single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial). In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).
Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial. In one trial both drugs performed badly and in one trial both performed well.
Other drugs
Three trials have evaluated the antimalarial artesunate; with inconsistent results. Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods. Similarly, another anti‐malarial mefloquine has been evaluated in two small trials with inconsistent effects.
Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality.
Authors' conclusions
Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.
Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.
PICOs
Plain language summary
Drugs for treating urinary schistosomiasis
What is urinary schistosomiasis and how is it treated?
Urinary schistosomiasis is a disease caused by infection of people with the parasitic worm Schistosoma haematobium. These worms live in blood vessels around the infected person's bladder and the worm releases eggs which are released in the person's urine. If the urine is passed into ponds or lakes, the eggs can hatch and infect people that are washing or swimming there. Infection can cause blood in the urine and if left untreated can eventually lead to anaemia, malnutrition, kidney failure, or bladder cancer. Urinary schistosomiasis is diagnosed by looking for worm eggs in the urine.
The disease occurs mainly in school‐aged children and young adults in sub‐Saharan Africa. The drug currently recommended for treatment is praziquantel, which can be given as a single dose, but other drugs such as metrifonate, artesunate, and mefloquine have also been evaluated.
After examining the research published up to 23th May 2014, we included 30 randomized controlled trials, enrolling 8165 children and adults.
What does the research say?
On average, the standard dose of praziquantel cures around 60% of people at one to two months after treatment (high quality evidence), and reduces the number of schistosome eggs in the urine by over 95% (high quality evidence).
Metrifonate, an older drug no longer in use, had little effect when given as a single dose but an improved effect when given as multiple doses two weeks apart. Two trials compared three doses of metrifonate with the single dose of praziquantel and found similar effects.
Two more recent trials evaluated a combination of artesunate and praziquantel compared to praziquantel alone. In one trial artesunate improved cure and in one it made no difference.
Authors conclusions
Future treatments for schistosomiasis could include combining praziquantel with metrifonate, or with artesunate, but these need to be evaluated in high quality trials.
Authors' conclusions
Summary of findings
| Praziquantel 40 mg/kg versus placebo for treating urinary schistosomiasis | |||||
| Patient or population: People with urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Praziquantel 40 mg/kg | ||||
| Parasitological failure At 1 to 2 months | 91 per 100 | 38 per 100 | RR 0.42 | 864 | ⊕⊕⊕⊕ |
| Percentage egg reduction | Mean change in egg excretion in the control groups ranged from a 53.2% reduction to a 138% increase. | Mean egg excretion in the intervention groups was reduced by > 98% in all trials | Not pooled | 678 (6 trials) | ⊕⊕⊕⊕ |
| Microhaematuria At 8 weeks | 53 per 100 | 28 per 100 | RR 0.53 | 119 | ⊕⊕⊝⊝ |
| Haemoglobin At 6 to 8 months | The mean haemoglobin ranged across control groups from | The mean haemoglobin in the intervention groups was 0.08 G/dL lower | ― | 727 | ⊕⊕⊕⊝ |
| Adverse events | ― | ― | ― | 1591 | ⊕⊕⊝⊝ |
| The basis for the assumed risk is the mean risk in the control groups across trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: Several trials were at unclear or low risk of selection bias. However, a sensitivity analysis excluding these trials still found a strong effect. | |||||
| Praziquantel 40 mg/kg compared to praziquantel 30 mg/kg for treating urinary schistosomiasis | |||||
| Patient or population: people with urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Praziquantel 30 mg/kg single dose | Praziquantel 40 mg/kg single dose | ||||
| Parasitological failure | 32 per 100 | 24 per 100 | RR 0.76 | 401 | ⊕⊕⊝⊝ |
| Mean percent egg reduction | The mean reduction in control groups ranged from an 85% reduction to a 99% reduction. | The mean reduction in the intervention groups was > 95% in all trials | Not pooled | 362 (4 trials) | ⊕⊕⊝⊝ |
| Parasitological failure | 29 per 100 | 28 per 100 (22 to 36) | RR 0.97 (0.76 to 1.23) | 669 (6 trials) | ⊕⊕⊕⊝ moderate 1,3,7,8 |
| Mean percent egg reduction | The mean reduction in control groups ranged from an 97% reduction to a 99% reduction. | The mean reduction in the intervention groups ranged from a 46% reduction15 to a 99% reduction | Not pooled | 362 (4 trials) | ⊕⊕⊝⊝ |
| Haematuria | 26 per 100 | 23 per 1000 | RR 0.89 | 117 | ⊕⊝⊝⊝ |
| Proteinuria | 15 per 100 | 13 per 100 | RR 0.85 | 117 | ⊕⊝⊝⊝ |
| Adverse events | ― | ― | Not estimable | 992 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias: None of the trials described a method of allocations concealment or blinding outcome assessors. | |||||
| Praziquantel 40 mg/kg multiple doses compared to single dose for treating urinary schistosomiasis | ||||||
| Patient or population: patients with treating urinary schistosomiasis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Praziquantel 40 mg/kg single dose | Praziquantel 40 mg/kg multiple doses | |||||
| Parasitological failure At 2 years | 90 per 100 | 244 per 100 | RR 2.71 | 62 | ⊕⊝⊝⊝ | |
| Mean percent egg reduction At 2 years | This study reports a81% reduction after a single dose of praziquantel | This study reports a96% reduction after multiple doses of praziquantel | ― | 62 (1 trial) | ⊕⊝⊝⊝ | |
| Parasitological failure At 3 years | 63 per 100 | 56 per 100 | RR 0.92 | 43 | ⊕⊝⊝⊝ | |
| Haematuria At 3 years | 48 per 100 | 34 per 100 | RR 0.7 | 43 | ⊕⊝⊝⊝ | |
| Adverse events | ― | This study reports a96% reduction after multiple doses of praziquantel | ― | 43 (1 trial) | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded by 2 for serious risk of bias. The one trial reporting the outcome did not report adequately on sequence generation and blinding. Allocation was not concealed, and loss to follow up was very high. | ||||||
| Metrifonate compared to placebo for treating urinary schistosomiasis | |||||
| Patient or population: patients with treating urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Metrifonate 3 x 7.5 mg/kg given two weeks apart | ||||
| Parasitological failure At 2 to 2.5 months | 40 per 100 | 16 per 100 (12 to 22) | RR 0.41 (0.3 to 0.56) | 93 (1 trial) | ⊕⊕⊝⊝ low1,2,3,4 |
| Mean percent egg reduction At 2 to 2.5 months | Egg excretion increased by 131% in the placebo group in this study | Egg excretion was reduced by 100% in this trial | ‐ | 93 (1 trial) | ⊕⊕⊝⊝ low1,2,3,4 |
| Parasitological failure At 6 months | 96 per 100 | 29 per 100 (23 to 36) | RR 0.3 (0.24 to 0.37) | 400 | ⊕⊕⊕⊝ |
| Mean percent egg reduction At 6 months | 13% increase | 94% reduction | ― | 400 (1 trial) | ⊕⊕⊕⊝ moderate2,3,5,7 |
| Adverse events | ― | ― | ― | 493 (2 trials) | 8 |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias; the single trial reporting this outcome did not adequately describe sequence generation, allocation concealment and blinding of participants, clinicians or outcome assessors. 3 No serious indirectness. This single trial was conducted in children in rural sub‐Saharan Africa. 5 Downgraded by 1 for serious risk of bias. The trial did not report on sequence generation and allocation concealment. The study described blinding of participants, clinicians and outcome assessors. 6 No serious imprecision. CIs are narrow and both CI limits have clinically important effects. The trial is adequately powered for this outcome. 7 No serious imprecision. The difference in effect between metrifonate and placebo group is large. 8 None of the trials reported on adverse events. | |||||
| Artesunate compared to placebo for treating urinary schistosomiasis | |||||
| Patient or population: patients with treating urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Artesunate | ||||
| Parasitological failure At 8 weeks | 87 per 100 | 46 per 100 | RR 0.53 | 251 | ⊕⊕⊝⊝ |
| Mean percent egg reduction At 8 weeks | Mean change in egg excretion ranged from range from 47.1% reduction to 111.5% increase. | Reduction in egg excretion ranged from 52.1% to a 69.3% | ― | 276 (2 trials) | ⊕⊝⊝⊝ |
| Microhaematuria At 8 weeks | 53 per 100 | 65 per 100 | RR 1.22 | 119 | ⊕⊕⊝⊝ |
| Adverse events | ― | ― | ― | 276 (2 trials) | ⊕⊕⊝⊝ low11,12 |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias. One trial described sequence generation, allocation concealment and blinding adequately, whereas the second study did not. 2 Downgraded by 1 for serious inconsistency. One of the trials (at high risk of bias) reported a large effect, while the other trial (at low risk of bias) detected no effect. 3 No serious indirectness. The trials were conducted in Gabon and Nigeria in patients of a similar age range. 4 Downgraded by 1 for serious imprecision. The CI is very wide and reaches from no benefit to a significant benefit after treatment. 5 No for serious inconsistency. Percent egg reductions the studies reported were similar. 6 Downgraded by 1 for serious imprecision. The meta analysis is underpowered. 7 No serious risk of bias. The one trial reporting the outcome reported adequately on sequence generation, allocation concealment and blinding. 8 No serious inconsistency: only one trial. 9 No serious indirectness: This trial was conducted in school children in Gabon. 10 Downgraded by 2 for very serious imprecision: only one trial reporting 74 events in 119 participants evaluated this outcome. 11Downgraded by 1 for serious risk of bias: only one trial was blinded. Both trials reported on adverse events, but the methods are unclear. 12 Downgraded by 1 for imprecision. One study reported on clinically diagnosed outcomes per treatment group, but was underpowered to confidently detect a difference. | |||||
| Praziquantel plus artesunate compared to praziquantel alone for treating urinary schistosomiasis | |||||
| Patient or population: patients with urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Praziquantel 40 mg/kg single dose alone | Praziquantel 40 mg/kg single dose plus artesunate 4 mg/kg/d for 3 days | ||||
| Parasitological failure at 8 weeks | 27 per 100 | 17 per 100 (10 to 27) | RR 0.62 (0.38 to 0.99) | 265 | ⊕⊕⊝⊝ |
| Percent egg reduction | Egg reduction in the Praziquantel groups ranged from 52.1% reduction to a 97.11% reduction. | Egg reduction in the Praziquantel and ARS groups ranged from 93.5% to 98.8% | ― | 265 (2 trials) | ⊕⊝⊝⊝ |
| Microhaematuria | 28 per 100 | 19 per 100 (11 to 33) | RR 0.69 | 177 | ⊕⊕⊝⊝ |
| Adverse events | ― | ― | ― | 156 (1 trial) | ⊕⊝⊝⊝ very low9,10 |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias: only one out of two studies did report adequate random sequence generation, allocation concealment and blinding or participants and clinicians, while the other study did not provide enough information to allow a judgement. | |||||
Background
Urinary schistosomiasis, also called bilharzia or snail fever, is an intravascular infection caused by parasitic Schistosoma haematobium worms. It is endemic in sub‐Saharan Africa, the Arabian peninsula and the Middle East. According to the World Health Organization (WHO), at least 243 million people required treatment for schistosomiasis in 2011 (WHO 2013), and more than 700 million people live in endemic areas (WHO 2014).
The WHO currently recommends regular chemoprophylaxis with praziquantel for populations at risk to prevent the long term consequences of infection. These programmes usually target school children (Table 1), but may be extended to the whole community in high risk settings (King 2011).
|
Category | Prevalence among school‐aged children | Action to be taken | Comment |
| High‐risk community | 50% by parasitological methods (intestinal or urinary schistosomiasis; or 30% by questionnaire for visible haematuria (urinary schistosomiasis) | Treat all school‐age children (enrolled and not enrolled) once a year | Also treat adults considered to be at risk (from special groups to entire communities living in endemic areas)
|
| Moderate‐risk community | > 10 to < 50% by parasitological methods (intestinal and urinary schistosomiasis); or 30% by questionnaire for visible haematuria (urinary schistosomiasis) | Treat all school‐age children (enrolled or not enrolled) once every two years | Also treat adults considered to be at risk (special groups only) |
| Low–risk community | < 10% by parasitological methods (intestinal and urinary schistosomiasis) | Treat all school‐age children (enrolled and not enrolled) twice during their primary schooling age (for example, once on of suspected cases entry and once on exit) | Praziquantel should be available in dispensaries and clinics for treatment of suspected cases. |
Description of the condition
Human infection with S. haematobium is acquired through contact with water bodies containing cercariae, the larval form of the parasite. The cercariae are able to penetrate human skin and migrate via blood vessels to the liver, where they mature into male and female forms for reproduction. Typically, they then migrate further to the venous plexus of the urinary bladder, and begin to produce eggs which the infected person excretes in their urine (Gryseels 2006). If these eggs reach water, they hatch into miracidia, infect specific freshwater snails which act as intermediate hosts, before emerging as cercariae that can infect humans (Gray 2011; Ross 2002).
Any illness associated with acute infection is typically mild, but chronic schistosomiasis can cause considerable morbidity with chronic pain, anaemia, fatigue, under nutrition and reduced exercise tolerance (King 2005). A review of 124 observational studies and 11 randomized controlled trials (RCTs) in 2005 estimated that up to 15% of people infected with any form of schistosomiasis suffer disabling long‐term complications (King 2005). The main pathological process occurs when schistosome eggs become trapped in the tissue around the bladder and ureters causing chronic inflammation, which may obstruct the ureters, damage the kidneys, and lead to bladder cancer. Occasionally, eggs can become trapped in other tissues such as the brain and spinal cord (WHO 1985).
Two‐thirds of all infected persons are schoolchildren (aged five to 14 years), and the intensity of infection with S. haematobium is highest in children aged ten to 14 years (WHO 1985).
The standard test for urinary schistosomiasis is urine filtration and microscopic examination of the urine sample (WHO 1991). The urine sample is passed through a filter paper and the eggs retained on the filter are counted either with or without staining. Sedimentation and centrifugation is less commonly used for urine concentration (Cook 2003). High urine egg counts are related to high infection intensity.
Parasitologists define cure when eggs can no longer be detected in one or more urine samples using standard methods. Besides parasitological cure, researchers also record the relative reduction in egg output after treatment compared to pre‐treatment levels. This outcome, expressed as % egg reduction, is an indirect estimate of a reduction of the worm burden (Cook 2003).
Blood and protein excretion in the urine is usually elevated in urinary schistosomiasis and decreases when the infection resolves. The most commonly used test is a dipstick test. Ultrasound can demonstrate organ involvement of the urinary tract as well as its resolution.
Description of the intervention
Praziquantel is the current treatment for urinary schistosomiasis recommended by the WHO (WHO 2006). Historically, metrifonate was also used but this fell out of favour due to the need for multiple doses (Feldmeier 1999; WHO 1998). More recently, there has been interest in the antischistosomal properties of artemisinin derivates and mefloquine, more commonly used for treating malaria (Utzinger 2004).
Praziquantel is an pyrazinoisoquinoline derivative with activity against adult worms of all schistosome species (S. mansoni, S. intercalatum and S. japonicum), but not against maturing worms. Praziquantel has a rapid onset of action. It is well‐tolerated, can be given as a single dose (Utzinger 2004) and paediatric formulations are available (Stothard 2013).
Metrifonate, an organophosphorous cholinesterase inhibitor, is active against S. haematobium but not against other schistosome species (Utzinger 2004).
Artemisinin, extensively used as potent antimalarial, has highest activity against immature schistosomes. Artemsinins are safe and well‐tolerated (Utzinger 2004).
How the intervention might work
After treatment with praziquantel, the worms appear to die quickly but egg excretion continues for several weeks. There are several possible reasons for this:
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Firstly, some worms might not have been mature at the time of praziquantel treatment and therefore not killed by praziquantel (Cioli 2003). Maturation of the worms after infection takes four to six weeks, and after two months eggs can be detected in the urine.
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Secondly, the patient might have been re‐infected (Cioli 2003).
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Thirdly, dead eggs still wander out of the tissue into the urine several weeks after clearing adult worms (Taylor 1988 ZWE). Therefore, a follow‐up four to six weeks after treatment is useful (Renganathan 1998). There is also considerable variation in daily urinary egg output (Cook 2003).
Although there is concern that S. haematobium might develop resistance against praziquantel (Fenwick 2006), there is no clinically relevant evidence for resistance up to now (Doenhoff 2008).
In endemic settings, reinfection with S. haematobium is likely, and cure (often defined as complete cessation of egg excretion) is not a sustainable long term goal. However, reduction of infection intensity results in clinical improvement, low morbidity and prevention of long term complications. Therefore, WHO promotes morbidity control rather than cure as an objective for schistosomiasis control programmes (WHO 2002).
Why it is important to do this review
At present, praziquantel as the only drug in use that is exposed to resistance development. It is therefore important to monitor its performance and to assess the effects of other drugs against urinary schistosomiasis.
Dosing regimens for subgroups such as highly infected patient groups, incremental benefits of drug combinations, double dosing and optimal interval between doses have to be determined to inform control programmes for urinary schistosomiasis.
Paediatric schistosomiasis has gained attention as a public health problem, and evaluation of existing treatment studies is indicated.
Objectives
To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials.
Types of participants
Patients diagnosed with urinary schistosomiasis by:
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detection of macro or microhaematuria;
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identification of schistosome eggs by urine microscopy;
-
detection of parasite antigens in blood or urine.
Types of interventions
Intervention
Drugs used to treat urinary schistosomiasis. Drugs considered as obsolete (such as ambilhar, oltipraz and niridazole) were not included. Metrifonate was included.
Control
Placebo, no intervention, an alternative regimen of the same drug, or an alternative drug used to treat urinary schistosomiasis.
Types of outcome measures
Primary outcomes
-
Parasitological failure at one month post‐treatment (as defined by the trial authors);
-
Percent egg reduction at one month.
Secondary outcomes
-
Parasitological failure at time‐points > one month;
-
Percent egg reduction from baseline at > one month;
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Clinical outcomes: resolutions of signs and symptoms (for example, haematuria and proteinuria);
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Anaemia (decrease of the number of red blood cells or the quantity of haemoglobin in the blood);
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Growth outcomes (gain in body weight, body length).
Adverse events
-
Serious adverse events;
-
Other adverse events
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language and publication status (published, unpublished, in press, under review and in progress).
Electronic searches
We searched the following databases using the search terms outlined in Appendix 1: The Cochrane Infectious Diseases Group Specialized Register (23 May 2014); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2014, Issue 4); MEDLINE (1966 to 23 May 2014); EMBASE (1974 to 23 May 2014); and LILACS (1982 to 23 May 2014). We also searched the metaRegister of Controlled Trials (mRCT) using 'Schistosoma haematobium' as the search term (23 May 2014).
Searching other resources
We checked the reference lists of all studies identified by the above methods for additional studies relevant to this review.
Data collection and analysis
Selection of studies
Vittoria Lutje, the Cochrane Infectious Diseases Group (CIDG) Information Retrieval Specialist, searched the literature and retrieved trial titles and abstracts.
VK and FZ independently screened the results of the search and retrieved full trial reports of all potentially relevant trials. Then, VK and FZ independently assessed each trial for inclusion using an eligibility form based on the inclusion criteria. We resolved any discrepancies by discussion with PG.
Data extraction and management
VK and FZ independently extracted data using pre‐tested standardized forms. We resolved any differences through discussion with PG. For each trial we extracted details of the trial methods, participants, interventions and outcomes.
VK and FZ extracted the number of participants randomized and number of participants followed up in each treatment arm. For dichotomous outcomes, we extracted the number of participants experiencing the event in each group. For continuous outcomes summarized as geometric means, we extracted means and their standard error, if reported. If the data were presented as arithmetic means, we extracted arithmetic means and their standard deviations (SD), if reported, for each treatment group. Where continuous data were summarized as medians and ranges, these were extracted and entered into tables.
VK and FZ double‐entered the data and cross‐checked to minimise errors. VK tried to contact trial authors for clarification or insufficient of missing data when necessary and summarised data reported in multiple publications as one single data set.
Assessment of risk of bias in included studies
VK and FZ independently assessed the risk of bias of each trial using an assessment form based on the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2008). DS verified the assessment results.
We assessed the risk of bias for six domains: sequence generation; allocation concealment; blinding (of participants, personnel, and outcome assessors); incomplete outcome data; selective outcome reporting; and other sources of bias. We categorized these judgments as low, high or unclear risk of bias.
For sequence generation, allocation concealment and blinding, we quoted the method as described in the trial in the Characteristics of included studies tables. For blinding, we stated the blinding method and who was blinded separately for different outcomes. For incomplete outcome data, we assigned a judgement for different outcomes (for example, loss to follow‐up at different time points).
We resolved disagreements by discussion or consultation. Where risk of bias was unclear, we attempted to contact the trial authors for clarification.
Measures of treatment effect
We presented dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean differences or geometric mean ratios. All results are shown with a 95% confidence interval (CI).
Unit of analysis issues
For trials including more than two comparison groups, we split and analysed as individual pair‐wise comparisons. When conducting meta‐analysis we ensured that participants and cases in the placebo group were not counted more than once, by dividing the placebo cases and participants evenly between the intervention groups.
Dealing with missing data
The primary analysis is a complete case analysis where the number of evaluable participants at each time point is used as the denominator.
Assessment of heterogeneity
We assessed heterogeneity by inspecting forest plots for overlapping CIs and outlying data. We applied the Chi2 test with a P value < 0.10 to indicate statistically significant heterogeneity, and the I2 statistic with a value of greater than 50% to indicate moderate heterogeneity.
Assessment of reporting biases
We planned to evaluate the possibility of publication bias by constructing funnel plots, but there were too few trials within each comparison to make this meaningful.
Data synthesis
We analysed the data in pair‐wise comparisons using Review Manager (RevMan). We stratified the primary analysis by drug dose and the time point after treatment. Data were combined in meta‐analyses using a fixed‐effect model. If we detected moderate heterogeneity but still considered combination of the trials to be appropriate we used a random‐effects model. We presented data which could not be presented in forest plots in tables (medians, means without measure of variance, ranges).
We assessed quality of evidence using the GRADE approach, and displayed the results in 'Summary of Findings' tables. The GRADE approach defines quality as a measure of 'our confidence in the effect estimates' and defines four levels of quality; high, moderate, low and very low. The evidence from RCTs is rated as 'high quality' but can be downgraded where there are major concerns about: 1) the risk of bias of the trials; 2) inconsistency between the trial results; 3) a mismatch between the question being asked and the trial setting, population, intervention or control; 4) the trial being underpowered; or 5) evidence of publication bias.
Subgroup analysis and investigation of heterogeneity
We planned to conduct the following subgroup analyses to explore the potential causes of heterogeneity. However, there were too few trials within each comparison to make this meaningful: patient age (children versus adults), intensity of infection, endemicity.
Sensitivity analysis
Data were insufficient to assess the robustness of results by sensitivity analyses to evaluate risk of bias components and the effects of missing data.
Results
Description of studies
Results of the search
Following database searches, we identified 116 individual citations, and a further 40 potential studies after we checked trial abstracts. Following abstract screening, we assessed 71 full text articles for inclusion. Figure 1 shows the flow diagram of these trials.
Study flow diagram
Included studies
We included 30 RCTs, enrolling 8965 participants, and reported in 39 publications. Twenty trials were over 20 years old, and only eight were published since the year 2000.
Settings
All but one trial were conducted in sub Saharan Africa; 13 trials from East Africa: Somalia (one) Sudan (three), Tanzania (two), Kenya (six), Malawi (one); 13 trials from West Africa: Cameroon (two), Gabon (three), Niger (two), Mali (one), Nigeria (two), Cote d' Ivoire (one), Ghana (one), Gambia (one); and three trials from southern Africa: Zimbabwe (two), and Zambia (one). Most trials were based in rural settings, but two were conducted in peri‐urban or semi‐rural settings, three were from urban settings, and in one trial the setting was not described. The remaining trial was conducted in an urban setting in Saudi Arabia.
Twenty trials were based in schools and one in a college, seven in villages, farms or settlements, one in antenatal clinics and two in referral hospitals.
Participants
Twenty‐four trials enrolled school‐age children and young adults, although the exact age‐range varied; age six to 20 years (16 trials), age five to 18 years (three trials), age two to 23 years (five trials). Two trials enrolled adults only, and four trials didn't clearly state the age range.
All trials diagnosed S. haematobium infection by detection of eggs or miracidia on urine microscopy. Sixteen trials reported egg counts as geometric mean egg counts, four trials as arithmetic mean egg counts, three trials reported both. One study reported geometric mean miracidial counts. Six trials used ranges or medians.
Interventions
Eight trials compared praziquantel with placebo, and 14 trials published between 1981 and 2009 compared different doses or regimens of praziquantel.
Five trials compared metrifonate with placebo, and seven trials published between 1983 and 1990 directly compared the efficacy of praziquantel and metrifonate.
More recently, three trials published between 2001 and 2009 evaluated artesunate as single agent or in combination with praziquantel, and two trials published in 2009 and 2011 evaluated mefloquine.
Excluded studies
We excluded 65 studies for the reasons given in the 'Characteristics of excluded studies' table.
Risk of bias in included studies
Many trials lacked adequate descriptions of methods to allow judgements on risk of bias, and so have been classified as unclear (see Figure 2).
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Allocation
Fourteen trials adequately described a random method of sequence generation, but only six described a method of allocation concealment and could be considered at low risk of selection bias (Abden Abdi 1989 SOM; Basra 2012 GAB; Borrmann 2001 GAB; Olds 1999 KEN; Pugh 1983 MWI; Sacko 2009 MLI).
Blinding
Ten trials reported adequate attempts to blind participants and trial staff to treatment allocation, six trials were unblinded and blinding was unclear in the remaining trials. Seven trials reported adequate blinding of outcome assessors.
Incomplete outcome data
Many trials had high levels of attrition, particularly at later time points. When trials presented cure or failure rates as percentages, we were unable to assess attrition. We considered the risk of attrition bias to be unclear in 13 trials and high in nine trials.
Selective reporting
We found evidence of reporting bias in one trial, as trial authors did not present pre‐specified outcomes. In three trials, selective reporting was at unclear risk of bias.
Other potential sources of bias
Trial authors reported baseline imbalances in two trials, which we identified as sources of other bias.
The trials were mostly funded by funds, trusts or international agencies (see Characteristics of included studies tables). Eight trials did not declare funding, four received drug donations and only two trials declared funding by pharmaceutical companies (both Dafra Pharma).
Effects of interventions
See: Summary of findings for the main comparison Praziquantel 40 mg/kg versus placebo for treating urinary schistosomiasis; Summary of findings 2 Praziquantel 40 mg/kg single dose versus 30 mg/kg single dose; Summary of findings 3 Praziquantel 40 mg/kg multiple doses versus single dose; Summary of findings 4 Metrifonate 3 x 7.5 mg/kg given two weeks apart versus placebo; Summary of findings 5 Artesunate versus placebo; Summary of findings 6 Praziquantel and artesunate versus praziquantel
Section A: Praziquantel
Praziquantel 40 mg/kg single dose versus placebo (comparison 1)
On average, a single 40 mg/kg dose of praziquantel reduces the proportion of people still excreting eggs at one to two months after treatment by around 60% compared to placebo, and reduces the mean number of eggs excreted by over 95%.
Eight trials compared a single 40 mg/kg dose of praziquantel with placebo or no treatment in schoolchildren in sub‐Saharan Africa. We have listed the definitions of parasitological failure in Table 2.
| Study ID | Definition cure | Reporting of egg counts/10 mL urine | Methods to calculate egg counts | Comment |
| Patients without schistosome eggs in their urine after treatment | Mean (SD), % ER | Not reported | No hatching test employed, cured might be underestimated because of dead eggs | |
| Clinical improvement Disappearance of ova from the urine on three successive examinations | Mean, range | Not reported | ― | |
| Three consecutive urine samples without presence of eggs | Median, interquartile range | Not reported | ― | |
| Cure not reported | GMEC | Not reported | Hb and weight as outcomes | |
| Two negative egg counts on two consecutive days | GMEC | Arithmetric mean of two egg counts per participant before and after treatment including 0 egg counts (cured patients). Geometric means of these arithmetic means. | We received the data file from the study author Day to day variation in egg counts explains 10% cure rate with placebo. | |
| Defined as three negative urine defined as the absence of hatched miracidia, although recently dead or black eggs might be present. | Geometric mean miracidial count | At follow‐up: If the first urine specimen contained hatched miracidia, then random 10 mL samples were taken from further bladder collections, the miracidial count was recorded, and the geometric mean of the counts was compared directly with the geometric mean of the pretreatment counts. | Quantitaive hatching test. if the first sedimented urine specimen was negative, then two further urine specimens taken on consecutive days were sedimented and examined. | |
| No definition of cure given, presumably absence of urinary egg excretion | Minimum and maximum value, median, 90%value | Not reported | Excretion of eggs following treatment | |
| No definition of cure given, cure rates and egg reduction rates as end points | Mean ± SD | "Treatment‐related changes | ― | |
| No definition of cure given | "median urine egg count" | Not reported | ― | |
| No definition of cure given, "negative" | GMEC | Not reported | "It would appear that the cure rate determined in any trial is dependent on the pretreatment egg count and on the ...urine examination techniques used." | |
| Absence of urinary egg excretion Cure rate (CR, defined as the percentage of children excreting no S. haematobium eggs 26 days after treatment among children with confirmed parasites at baseline) | GMEC | S. haematobium egg counts before and after treatment were averaged for every child (arithmetic mean) and the GM egg count for each treatment group was calculated. Because egg counts are over dispersed, they were logarithmically transformed log [count+1], and the GM was expressed as the antilogarithm of the mean. Egg reduction rate (ERR) defined as reduction of geometric mean (GM) egg count among S. haematobium positive children after treatment, compared with the respective GM pretreatment. The ERR was calculated as (1 ‐ [GM egg count after treatment/GM egg counts at enrolment] x 100 | (ERR; defined as reduction of geometric mean egg count | |
| No definition of cure given | AMEC GMEC | Not reported | Infection was identified and quantified by Nucleopore filtration | |
| No definition of cure given | AMEC GMEC | Not reported | Infection was identified and quantified by Nucleopore filtration | |
| Cure defined as egg‐negative | GMEC | Not reported | ― | |
| Probable cure rate: excretion of no or only non viable eggs in the urine | GMEC, 95%confidence limit of the mean | Not reported | ― | |
| People were considered cured when no eggs or non‐viable eggs were excreted in the urine | Screening: GMEC of miracidia/10 mL urine reduction in egg excretion | "In non cured cases the reduction of egg excretion was calculated." | ― | |
| Absence of S. haematobium eggs in two random 5 mL samples of urine from the same specimen | GMEC 5 mL urine samples reduction in GMEC | Not reported | ― | |
| No definition given | GMEC | "Egg counts are geometric means in subjects who remained | ― | |
| 100% reduction of egg excretion (absence of egg excretion in the urine) or 98% egg reduction and neg miracidial hatching test | GMEC | Not reported | Only children with GMEC > 60/10 mL (in three egg counts) included | |
| No definition of cure given | GMEC mean ± SD | Not reported | Only children with GMEC > 60/10 mL (in three egg counts) included | |
| No definition of cure given | AMEC % egg count reduction | Percentage reduction in egg output was determined by comparing the arithmetic and geometric means of pooled egg counts before and after treatment. The geometric mean was obtained by recording the logarithm of egg counts and using the n +1 transformation for a series of counts after treatment that included zeros. | We did not use a hatching test to determine the viability of excreted ova since percentage reduction in egg output rather than parasitological cure was our main criterion of efficacy. | |
| No definition of cure given | AMEC "nombre moyenne" average number | Not reported | If possible, a hatching test was that at the last control (6 months) | |
| No definition of cure given, "negativation" | AMEC moyenne des nombres d'oeufs/10 mL urine Number average | Not reported | ― | |
| The | GMEC | Individual egg counts were | ― | |
| no definition of cure given | AMEC | Not reported | ― | |
| ― | AMEC GMEC | Not reported | ― | |
| Cure defined as negative egg counts "infections as were cured by a negative GMEC at 1,3 and 6 months" | GMEC | Not reported | "in cases were only one egg was found in three (urine) examinations the egg count was always taken as positive." | |
| The parasitologic cure rates were calculated as the proportion | GMEC | Geometric mean (GM) values of all The intensity reduction rate was calculated as [1 − (GM egg counts per 10 | The parasitological cure rates were calculated as the proportion of children excreting eggs at the first survey before treatment and who were not excreting eggs in their urine after treatment. | |
| Negative for both eggs and circulating antigen failure: pos. for eggs or circulating antigen | GMEC interquartile range | Not reported | ― | |
| No definition of cure given | GMEC | When appropriate a log10 transformation was used in statistical analysis to make their skewed distribution approximate to normal. This was reversed for the presentation of results to give a geometric mean which included zero values. | ― |
Parasitological failure
Praziquantel 40 mg/kg as a single dose reduced parasitological treatment failure by around 60% at one to two months compared to placebo (RR 0.42, 95% CI 0.29 to 0.59; 864 participants, seven trials, Analysis 1.1). The absolute level of treatment failure with praziquantel ranged from 16.6% (McMahon 1979 TZA) to 77.5% (de Jonge 1990 SDN). Treatment failure with placebo was greater than 80% in all seven trials and over 90% in four trials.
Four trials reported follow‐up beyond two months (Analysis 1.1). Failure rate increased over time in two trials, as might be expected in areas of schistosomiasis transmission as people become re‐infected (McMahon 1979 TZA; Pugh 1983 MWI). However, treatment outcomes improved in Taylor 1988 ZWE over time, with moderate reductions in treatment failure at one month and three months and a 70% reduction at six months. The trial authors stated that this improvement might have been due to excretion of remaining eggs from the urinary tract over time.
The fourth trial, de Jonge 1990 SDN, found no difference in treatment failure between praziquantel and placebo at any time point. The trial authors used a more sensitive diagnostic method (three urine samples, filtration of the whole volume up to 350 mL when the 10 mL urine sample contained fewer than 10 eggs) and a strict definition of cure (no excretion of eggs, no viability testing of eggs). This may explain the high failure rates observed despite high percent egg reductions comparable to other trials.
Stephenson 1989 KEN reported treatment failure at eight months, its only time point. A single dose of praziquantel reduced treatment failure by 86% compared to placebo (RR 0.14, 95% CI 0.08 to 0.22; 209 participants, one trial, Analysis 1.1).
Six trials reported parasitological failure stratified by intensity of infection; the categorisation of strata varied between trials (642 participants, see Appendix 2). At the first follow‐up at four to six weeks, three out of four trials had a tendency to higher failure in participants with higher infection intensity. The pattern attenuated at later time points.
Percent egg reduction
Seven trials reported mean urine egg counts per 10 mL urine at baseline, and at one to two months after a single dose of praziquantel 40 mg/kg or placebo (867 participants, seven trials, see Table 3), although we were only able to reliably interpret this data for six trials (678 participants).
| Study ID | Subgroup | Timepoint | Measure | Praziquantel 40 mg/kg single dose | Placebo | P value difference between groups | ||||
| Egg count/10 mL (Range/95% CI) N | % egg reduction | Egg count/10 mL (Range/95% CI) N | % egg reduction | |||||||
| Baseline | Follow‐up | Baseline | Follow‐up | |||||||
| ― | 1 month | Median | 66 N = 48 | 1 N = 40 | 98.5 | 124 N = 21 | 58 N = 18 | 53.2 | P = 0.29 not significant | |
| ― | 1 month | Miracidial count (95% CI) | 288.4 (33.2 to 2508.9) N = 32 | 1.1 (0 to 8.3) N = 30 | 99.6 | 324.9 (22.1 to 4783.3) N = 37 | 187.5 (6.3 to 5601.3) N = 29 | 42.3 | Not reported | |
| ― | 1 month | GMEC AMEC | 385.5 780.9 N = 97 | 1.8/ 1.8 | 99.5 99.7 | 136.8 188.8 N = 52 | 119.9 437.2 | 12.35 (GMEC) ‐ 131.5 (AMEC) (increase) | Not reported | |
| light infections < 50/10 mL | 1 month | GMEC N = (both light and heavy) | 15.1 N = 77 (both groups) | 0.4 | 99.7 | 15.7 N = 90 (both groups) | 37.5 | ‐138 (increase) | Not reported | |
| heavy infections < 100/10 mL | 1 month | GMEC N = (both light and heavy) | 204.7 N = 77 (both groups) | 4.0 | 98.1 | 191.9 N = 90 (both groups) | 147.0 | 23.39 | Not reported | |
| ― | 45 days | GMEC | Not reported N = 95 | 1.4 | ― | N = 94 | 29.8 | ― | Not reported | |
| ― | 8 weeks | GMEC (range) | 38.51 (1 to 3313) N = 90 | 1.11 N = 89 | 97.11 | 21.57 (1 to 778) N = 30 | 11.41 N = 30 | 47.1 | Significant | |
| without placebo | 8 weeks | ― | 42.0 ± 1.7 N = 52 | 9.8 ± 0.5 N = 42 | 76.7 | 34.1 ± 0.8 N = 52 | 72.0 ± 2.3 N = 44 | ‐ 111.5 (increase) | P < 0.0012 | |
1P for therapeutic efficacy (not defined) Praziquantel versus placebo
2 Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.
The mean egg count was reduced by more than 95% at one to two months following praziquantel in five trials, and by 75% in one trial. In the placebo groups the change in mean egg count ranged from a 53% decrease to a 115% increase.
Percent egg reduction in the praziquantel group remained high (> 95%) in all three trials reporting at three months, and in all four trials at six months. Percent egg reduction was variable in the placebo group, ranging from 26% increase to 54% reduction at three months and from 5% to 64% reduction at six months (see Table 4). One additional trial, Stephenson 1989 KEN, reported percent egg reduction at eight months as its only time point (209 participants, see Table 4). Percent egg reduction after praziquantel was 99% compared to 5% with placebo.
| Study ID | Subgroup | Time point | Measure | Praziquantel 40 mg/kg single dose | Placebo | P value for difference between groups | ||||
| Egg count /10 mL urine | % egg reduction | Egg count/10 mL urine | % egg reduction | |||||||
| Baseline | Follow‐up | Baseline | Follow‐up | |||||||
| ― | 3 months | miracidial count (95% CI) | 288.4 (33.2 to 2508.9) N = 32 | 1.1 (0 to 16.3) | 99.6 | 324.9 (22.1 to 4783.3) N = 37 | 149.4 (6.3 to 3556.6) | 54 | Not reported | |
| ― | 3 months | GMEC AMEC | 385.5 780.9 N = 97 | 1.9 1.9 | 99.5 (GMEC) 99.75(AMEC) | 136.8 188.8 N = 52 | 85.9 270.3 | 37.2 (GMEC) 43.16 (AMEC) | Not reported | |
| light infections < 50/10 mL | 3 months | GMEC | 15.1 N = 77 (for both groups) | 0.4 | 97.35 | 15.7 N = 90 | 19.8 | ‐26.11 (increase) | Not reported | |
| heavy infections < 100/10 mL | GMEC | 204.7 N = 77 (for both groups) | 2.0 | 99.02 | 191.9 N = 90 | 94.7 | 50.65 | Not reported | ||
| ― | 5 months | median | 66 N = 48 | 0 | 100 | 124 N = 21 | 95 | 23.38 | P = 0.27 not significant | |
| ― | 6 months | miracidial count (95% CI) | 288.4 (33.2 to 2508.9) N = 32 | 1.1 (0‐20.3) | 99.6 | 324.9 (22.1 to 4783.3) N = 37 | 188.6 (13.9 to 2563.5) | 41.95 | Not reported | |
| ― | 6 months | GMEC AMEC | 385.5 780.9 N = 97 | 2.4 20.1 | 99.3 (GMEC) 97.4 (AMEC) | 136.8 188.8 N = 52 | 69.7 261.8 | 49.0 GMEC ‐38.7 (increase) AMEC | Not reported | |
| ― | 6 months | GMEC | 41/10 mL N = 238 | 2/10 mL | 95.1 | 39/10 mL N = 198 | 14/10 mL | 64.1 | ||
| light infections < 50/10 mL | 6 months | GMEC | 15.1 N = 77 (for both groups) | 0.2 | 98.67 | 15.7 N = 90 | 11.7 | 25.5 | Not reported | |
| heavy infections < 100/10 mL | 204.7 N = 77 (for both groups) | 0.6 | 99.7 | 191.9 N = 90 | 75.5 | 60 | Not reported | |||
| ― | 8 months | GMEC AMEC | 57/ 112 N = 105 | 0.2/ 1 | 99.64 (GMEC) 99.1 (AMEC) | 38/ 85 N = 104 | 36/ 102 | 5.26 (GMEC) ‐20 (increase) (AMEC) | Not reported1 | |
1Praziquantel 40 mg/kg single dose: significant egg reduction in praziquantel group (before, after treatment) P < 0.0002. no significant reduction in the placebo group (before, after treatment).
Five trials reported percent egg reduction stratified by intensity of infection (764 participants, Appendix 2). At four to six weeks, all trials reported percent egg reductions over 90% across the strata. Percent egg reduction as a relative measure was at least as high in heavy infections as in mild infections, but post‐treatment egg counts as an absolute measure tended to be higher in people with high intensity infections. This pattern persisted at later time points.
Clinical resolution
At eight weeks the proportion of patients with persistent haematuria (defined as > 5 erythrocytes/mL) was lower in those given praziquantel than placebo in one small trial which reported this (RR 0.53, 95% CI 0.33 to 0.84; 119 participants, one trial, Analysis 1.2). There were substantial reductions in the mean number of erythrocytes in the urine in three trials at one to two months, but we could not combine these data in a meta‐analysis (357 participants, three trials, see Appendix 3).
Proteinuria was reduced by 65% to 84% at one to two months after praziquantel compared to increases in the placebo groups (238 participants, two trials, see Appendix 3).
Two trials reported mean haemoglobin at baseline and at six to eight months after treatment with no difference between groups (mean difference ‐0.08, 95% CI ‐0.24 to 0.09; 727 participants, two trials, Analysis 1.3).
Three trials measured a variety of growth parameters (Befidi Mengue 1992 CMR; Olds 1999 KEN; Stephenson 1989 KEN). Two trials reported little or no effect on the outcomes measured (Befidi Mengue 1992 CMR; Olds 1999 KEN). The third trial (Stephenson 1989 KEN) reports 14 measures, some of which are reported as statistically significant, but all appear to be of no or only borderline clinical importance (see Appendix 4). Most notably, there is a reported increase in children's physical fitness as measured by the Harvard Step test. The difference in mean improvement between groups was 6.8% at five weeks (mean end scores 81.2% praziquantel versus 75.5% placebo). Scores between 68% and 82% are considered average. Children that took praziquantel also gained 1.2 kg more weight than those in the control group, however baseline differences between groups were of a similar magnitude to this effect.
Adverse events
Of nine trials, six (with 1286 participants) commented on adverse events. Only four described the methods used for data collection, but rarely reported them in detail (see Appendix 5). Adverse events were usually monitored in the first days after medication. Only two trials actually reported numbers of adverse events, and only abdominal pain was reported by both trials. The absolute number of adverse events was low and none were more common with praziquantel than placebo (see Analysis 1.4). The other trials summarized narratively with comments such as "both treatments were well tolerated" (see Appendix 5).
Praziquantel 40 mg/kg versus lower doses (comparison 2)
Praziquantel doses of 20 to 40 mg/kg result in similar reductions in mean egg excretion, but 40 mg/kg is marginally superior at achieving cure.
Ten trials compared praziquantel 40 mg/kg with lower doses: 30 mg/kg (seven trials), 20 mg/kg (three trials), and 10 mg/kg (three trials). All trials were conducted in sub‐Saharan Africa in schoolchildren, apart from one trial, which recruited college students and army recruits.
Treatment with praziquantel 40 mg/kg had fewer treatment failures than lower doses when measured at four to six weeks after treatment (versus 30 mg/kg; RR 0.76, 95% CI 0.59 to 0.99; 401 participants, four trials, Analysis 2.1, versus 20 mg/kg; RR 0.74, 95% CI 0.59 to 0.93; 338 participants, two trials, Analysis 2.1). However, there was no difference between 40 mg/kg and 30 mg/kg at two to three months (517 participants, five trials, Analysis 2.2), or six months after treatment (699 participants, six trials, Analysis 2.3).
In the five trials comparing praziquantel 40 mg/kg and 30 mg/kg, the mean number of eggs excreted was reduced by greater than 90% with both doses and without significant differences between groups (495 participants, five trials, see Table 5).
| Study ID | Subgroup | Time point | Measure | Praziquantel 40 mg/kg (SD) | Praziquantel 30 mg/kg (SD) | P value difference between groups | ||||
| Egg count/10 mL urine | % reduction | Egg count/10 mL urine | % reduction | |||||||
| Baseline | Follow‐up | Baseline | Follow‐up | |||||||
| ― | 1 month | GMEC (95 Confidence limits of mean) N | 288.4 (33.2 to 2508.9) N = 33 | 1.1 (0‐8.3) N = 30 | 99.61 | 308.5 (31.2 to 3034.7) N = 32 | 1.2 (0 to 15.4) N = 31 | 99.6 | Not significant P value not reported | |
| ― | 1 month | AMEC N | 7.5 ± 1.7 N = 57 | 0.24 N = 54 | 96.8 | 7.5 ± 1.7 N = 46 | 0.74 N = 39 | 90.13 | Not significant | |
| heavy infection < 100/10 mL | 1 month | GMEC N | 204.7 N = 77 for both groups | 4.0 | 98.04 | 185.4 N = 72 for both groups | 3.1 | 98.32 | Not reported | |
| light infection > 50/10 mL | 1 month | GMEC | 15.1 | 0.4 | 97.35 | 15.9 | 0.6 | 96.23 | ||
| ― | 1 month | GMEC mean ± SE, N = | Stratum 1 87.4 ± 23.46 N = 15 Stratum 2 339.4 ± 32.61 N = 5 Stratum 3 518.00 ± 0.71 N = 2 N = 22 | N = 21 | 97.69 ± 0.98 | Stratum 1: 111.67 ± 47.14 N = 15 Stratum 2: 306.83 ± 54.29 (N = 6) Stratum 3: 1507.00 ± 1400.07 N = 2 N = 23 | N = 19 | 85.65 ± 13.08 | Not significant Not reported | |
| 2‐3 months | AMEC (± SD) GMEC N = | 377 255 N = 64 | 31 (± 21) 2 N = 54 | 91.7 (AMEC) 99.2 (GMEC) | 327 204 N = 69 | 22 ± 17 2 N = 60 | 93.27 (AMEC) 99 (GMEC) | Not significant Not reported | ||
| 3 months | GMEC (95 Confidence limits of mean) N | 288.4 (33.2 to 2508.9) N = 33 | 1.1 (0‐16.3) N = 29 | 99.61 | 308.5 (31.2 to 3034.7) N = 31 | 0.9 (0 to 13.4) N = 31 | 97.08 | Not significant Not reported | ||
| 3 months | AMEC N = | 7.5 ± 1.7 N = 57 | 0.42 N = 52 | 94.4 | 7.5 ± 1.7 N = 46 | 1.21 N = 42 | 83.86 | Not reported | ||
| heavy infections < 100/10 mL | 3 months | GMEC N = | 204.7 N = 77 for both groups | 2.0 | 99.02 | 185.4 N = 72 for both groups | 1.1 | 99.4 | Not reported | |
| light infections > 50/10 mL | 3 months | GMEC | 15.1 | 0.4 | 97.35 | 15.9 | 0.4 | 97.48 | ||
| ― | 3 months | GMEC mean ± SE, N = | Stratum 1 87.4 ± 23.46 N = 15 Stratum 2 339.4 ± 32.61 N = 5 Stratum 3 518.00 ± 0.71 N = 2 N = 22 | 97.55 ± 0.85 (N = 18) | Stratum 1 111.67 ± 47.14 N = 15 Stratum 2 306.83 ± 54.29 N = 6 Stratum 3 1507.00 ± 1400.07 N = 2 N = 23 | 99.01 ± 0.47 (N = 19) | Not significant Not reported | |||
| ― | 6 months | GMEC (95 Confidence limits of mean) | 288.4 (33.2 to 2508.9) N = 33 | 1.1 (0 to 20.3) N = 28 | 99.6 | 308.5 (31.2 to 3034.7) N = 32 | 1.4 (0 to 39.5) N = 28 | 99.46 | Not significant Not reported | |
| ― | 6 months | AMEC | 7.5 ± 1.7 N = 57 | 4 N = 34 | 46.6 | 7.5 ± 1.7 N = 462 | 0.18 N = 28 | 97.6 | Not reported | |
| heavy infections < 100/10 mL | 6 months | GMEC N = | 204.7 (N = 77) | 0.6 | 99.7 | 185.4 (N = 72) | 0.7 | 99.62 | Not significant Not reported | |
| light infections > 50/10 mL | 6 months | GMEC N = | 15.1 (N = 77) | 0.2 | 98.67 | 15.9 (N = 72) | 0.1 | 99.37 | ||
| ― | 6 months | GMEC mean ± SE, (N =) | Stratum 1 87.4 ± 23.46 (N = 15) Stratum 2 339.4 ± 32.61 (N = 5) Stratum 3 518.00 ± 0.71 (N = 2) (N = 22) | (N = 15) | 93.09 ± 0.12 | Stratum 1 111.67 ± 47.14 (N = 15) Stratum 2 306.83 ± 54.29 (N = 6) Stratum 3 1507.00 ± 1400.07 (N = 2) (N = 23) | (N = 17) | 98.72 ± 0.28 | Not significant Not reported | |
| ― | 9 months | (N = 6) | 92.4 ± 5.92 | (N = 8) | 96.49 ± 1.59 | |||||
| ― | 12 months | (N = 3) | 99.3 ± 0.26 | (N = 4) | 99.28 ± 0.46 | |||||
1Baseline data not reported separately per group.
2A reduction as low as 46% after praziquantel 40 mg/kg was not observed by any other study that reported this outcome. At six months, five other studies reported % egg reduction above 90% (see Table 4 and Table 5)
3Heavy and light infections together; N = 77 for Praziquantel 40 mg/kg and N = 72 for Praziquantel 30 mg/kg.
4 GMEC/10 mL urine, stratum 1: 60 to 250, stratum 2: 251 to 500, stratum 3 > 500.
In trials comparing 40 mg/kg and 20 mg/kg, again the mean number of eggs excreted was reduced by more than 95% for both doses and differences in percent egg reduction appeared small (636 participants, four trials, see Appendix 2). Treatment with praziquantel 40 mg/kg appeared to result in greater percent egg reductions than 10 mg/kg (357 participants, three trials, see Appendix 2).
One small trial from Kenya (King 1989 KEN) reported similar numbers of participants with persistent haematuria or proteinuria at three months with praziquantel 40 mg/kg, 30 mg/kg and 20 mg/kg, but 40 mg/kg was superior to 10 mg/kg (haematuria at three months: RR 0.35, 95% CI 0.21 to 0.58, 119 participants, one trial, Analysis 2.4; proteinuria at three months: RR 0.25, 95% CI 0.12 to 0.51; 119 participants, one trial, Analysis 2.5). A larger trial by the same authors comparing 40 mg/kg and 20 mg/kg (King 2002 KEN) detected fewer participants with haematuria at six weeks following praziquantel 40 mg/kg (RR 0.63, 95% CI 0.47 to 0.86; 245 participants, one trial, Analysis 2.6), and fewer participants with proteinuria (RR 0.66, 95% CI 0.46 to 0.96; 245 participants, one trial, Analysis 2.7). These differences were still observed at nine months (haematuria: RR 0.59, 95% CI 0.44 to 0.78; 215 participants, one trial, Analysis 2.8; proteinuria RR 0.67, 95% CI 0.5 to 0.9; 214 participants, one trial, Analysis 2.9). King 2002 KEN also reported ultrasound findings (bladder thickening, bladder irregularity and hydronephrosis) before and after treatment with praziquantel 40 mg/kg and 20 mg/kg respectively, but the results were inconclusive (264 participants, see Appendix 6).
Six of these trials did not comment on adverse events. Four trials described the methods of data collection, but often in insufficient detail; two out of four trials used active, prospective surveillance for adverse events (Appendix 5). Two trials stated for all treatment arms collectively that adverse events after praziquantel treatment were mild and transient. Two trials reported numbers of adverse events with no differences between groups (163 participants, Analysis 3.2).
Praziquantel 40 mg/kg single dose versus split dose (comparison 3)
Splitting the dose of praziquantel 40 mg/kg into two 20 mg/kg doses over 24 hours has not been shown to improve tolerability and may actually cause more vomiting and dizziness.
Three trials compared the single 40 mg/kg dose with a split dose regimen giving two doses of 20 mg/kg over 24 hours. There was no statistically significant difference in treatment failure at one month (RR 0.75, 95% CI 0.51 to 1.11; 374 participants, three trials), three months (RR 0.74, 95% CI 0.45 to 1.2; 361 participants, three trials), or six months (RR 0.83, 95% CI 0.51 to 1.35; 234 participants, three trials, Analysis 3.1). Similarly percent egg reduction was over 90% for both groups (332 participants, three trials, see Appendix 2).
These trials enrolled 191 participants for a single dose of praziquantel 40 mg/kg and 195 participants for a split dose of 2 x 20 mg/kg. All trials used active surveillance for adverse events (see Appendix 5). Adverse events were generally reported to be mild and transient. However one trial reports significantly more vomiting and dizziness with the split dose compared to the single dose (vomiting: RR 0.5, 95% CI 0.29 to 0.86; dizziness: RR 0.39, 95% CI 0.16 to 0.94; 373 participants, three trials, Analysis 3.2).
Praziquantel 40 mg/kg single dose versus multiple doses (comparison 4 and 5)
There are too few trials to determine the optimal frequency and timing of repeated praziquantel dosing.
Two trials compared the standard single dose of praziquantel (40 mg/kg) with two or three doses given at two or three week intervals, and found no statistically significant differences in parasitological failure (Analysis 4.1, Analysis 4.2), percentage egg reduction (Appendix 2), or clinical resolution (Appendix 3; Analysis 4.3).
One additional very small trial from a high transmission setting in Gabon (van den Biggelaar 02 GAB), compared praziquantel 40 mg/kg every three months for two years to a single dose of praziquantel 40 mg/kg given at the beginning of the trial. At two years, patients who received only one dose of praziquantel had almost three times the risk of treatment failure compared to multiple doses (RR 2.71, 95% CI 1.47 to 5.00; 62 participants, one trial, Analysis 5.1). Percent egg reduction was 96% after multiple doses and 80% after a single dose of praziquantel at two years (90 participants, see Table 6). These effects were no longer apparent one year after the last praziquantel dose.
| Study ID | Time point | Measure | Praziquantel 40 mg/kg single dose | % egg reduction | Praziquantel 40 mg/kg multiple doses | % egg reduction | Comments | ||
| Egg count/10 mL | Egg count/10 mL | ||||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 2 years | GMEC (IQR) | 47 N = 45 | 9 (2‐45) | 80.85 | 47 N = 45 | 2 (1‐3) | 95.74 | Significant P = 0.002 | |
1Baseline egg counts not reported separately per treatment group; no difference at baseline stated. Praziquantel 40 mg/kg given every 3 months over 2 years. Location: Gabon, endemic area.
These trials did not report on adverse events.
Section B: Metrifonate
Metrifonate single dose versus placebo (comparison 6)
A single dose of metrifonate 10 mg/kg probably reduces egg excretion but is only marginally better than placebo at achieving cure.
Two trials compared a single dose of metrifonate to placebo, although one trial only reported outcomes at a single time point eight months after treatment (Stephenson 1989 KEN).
In the first trial (Pugh 1983 MWI), 80% of those treated with metrifonate continued to excrete eggs one month after treatment which was only marginally better than placebo (RR 0.83, 95% CI 0.74 to 0.94; 142 participants, one trial, Analysis 6.1), and no difference was seen at six months (RR 0.94, 95% CI 0.87 to 1.02; 102 participants, one trial, Analysis 6.1).
In the second trial (Stephenson 1989 KEN), 61% of those treated with metrifonate continued to excrete eggs eight months after treatment compared with almost 100% who received placebo (RR 0.63, 95% CI 0.54 to 0.73, 210 participants, one trial, Analysis 6.1). Egg excretion was also reduced by more than 90% eight months after treatment compared to just 5% with placebo (210 participants, see Appendix 2).
The second trial also reported mean haemoglobin at baseline and eight months (with no difference between groups, Analysis 6.2), and various measures of nutrition and growth (see Appendix 4). However, this trial had three arms and the nutritional measures are reported for the metrifonate and praziquantel groups combined. Consequently, we were unable to evaluate the effect of metrifonate. Trial authors did not report adverse events.
Metrifonate multiple doses versus placebo (comparison 7)
Subsequently trials evaluated multiple doses of metrifonate given two weeks apart, which improved the proportion of patients being cured.
Two trials evaluated three doses of metrifonate 7.5 mg/kg given two weeks apart (Jewsbury 1976 ZWE; Stephenson 1985 KEN), and reported much reduced treatment failures compared to placebo at 11 weeks (RR 0.41, 95% CI 0.30 to 0.56; 93 participants, one trial, Analysis 7.1) and six months respectively (RR 0.30, 95% CI 0.24 to 0.37; 400 participants, one trial, Analysis 7.1).
A third small trial (de Jonge 1990 SDN) comparing two 10 mg/kg doses given two weeks apart with placebo found very low levels of cure and no difference compared to placebo at one month or five months (51 participants, one trial, Analysis 7.1). However, this is the same trial that found very high levels of treatment failure with praziquantel, which may be a result of the highly sensitive method used for detecting low level egg excretion and the strict definition of cure.
All three trials found substantial reductions in the number of eggs being excreted at their various time points (> 90% reductions in all three trials, see Table 7).
| Study ID | Time point | Measure | Metrifonate 21.5 mg, 20 mg/kg given as divided dose | Placebo or no treatment | P value difference between groups | ||||
| Egg count/10 mL urine | % egg reduction | Egg count/10 mL urine | % egg reduction | ||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 1 month | median N = (reports min, max, 90th percentile and median of egg counts/10 mL) | 95 N = 38 | 1 N = 32 | 98.94 | 124 N = 21 | 58 N = 18 | 53.22 | Not significant P = 0.29 | |
| 11 weeks | median N = | 101 N = 32 | 0 | 100 | 26 N = 38 | 60 | ‐130.77 (increase) | Not reported | |
| 11 weeks | median N = | 40 N = 23 | 0 | 100 | |||||
| 5 months | median N = (reports min, max, 90th percentile and median of egg counts/10 mL) | 124 N = 38 | 1 N = 32 | 99.19 | 124 N = 21 | 95 N = 19 | 23.38 | Not significant P = 0.27 | |
| 6 months | AMEC N = | 109 N = 202 | 7 | 94 | 110 N = 198 | 124 | ‐12.7 (increase) | Not reported | |
1Metrifonate 2 x 10 mg/kg, dose interval two weeks. Placebo: multivitamins.
2Reports two groups with metrifonate 7.5 mg x 3, dose interval two weeks. Control group: nil.
3 Metrifonate 3 x 7.5 mg/kg, dose interval one to two weeks.
Stephenson 1985 KEN also reported mean haemoglobin, with slightly higher values at six months after metrifonate compared to placebo (mean difference 0.3 G/dL, 95% CI 0.14 to 0.46; 400 participants, one trial, Analysis 7.2). The authors noted that hookworm endemicity was high, and metrifonate also has an effect on hookworm which could account for this finding.
None of the trials reported on adverse events.
Direct comparisons of different metrifonate regimens (comparisons 8 and 9)
In one trial, multiple doses of 10 mg/kg were superior to a single dose.
One three‐arm trial directly compared a single dose of 10 mg/kg with two or three doses given two weeks apart. Parasitological failure at one month was 53% with a single dose, 40% with two doses, and 19% with three doses. The difference was statistically significant for three doses versus one dose (RR 0.36, 95% CI 0.17 to 0.77; 93 participants, one trial, Analysis 8.1), but not two doses versus one dose (RR 0.75, 95% CI 0.5 to 1.13; 112 participants, one trial, Analysis 8.1). Results were similar at four months (Analysis 8.2).
The percent egg reduction was also improved from 37% after a single dose to 88% after three doses, although this was not maintained at the four months' follow‐up (see Appendix 2). This trial did not report on adverse events.
One additional trial (Abden Abdi 1989 SOM) compared three doses of 7.5 mg/kg given two weeks apart with three doses of 5 mg/kg given in one day. The trial detected no difference for parasitological failure at one month, three months or six months (201 participants, one trial, Analysis 9.1). Egg reduction at one month was above 90% after both metrifonate doses and was sustained (> 90%) at two, three and six months (201 participants, see Appendix 2). This trial recorded adverse events by active surveillance (Appendix 5). It did not detect a significant difference for any of the symptoms between treatment groups (201 participants, one trial, Analysis 9.2) The adverse events were mild and transient.Headache and abdominal pain were most common.
Section C: Praziquantel versus metrifonate
Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose (comparison 10)
Single dose praziquantel 40 mg/kg was more effective than single dose metrifonate 10 mg/kg in curing patients and reducing egg excretion.
Three trials compared the standard dose of praziquantel 40 mg/kg with a single dose of metrifonate 10 mg/kg, although one trial only reported outcomes at eight months after treatment (Stephenson 1989 KEN).
In the first trial (Pugh 1983 MWI), parasitological failure at one month was halved with praziquantel 40 mg/kg compared to metrifonate 10 mg/kg (RR 0.46, 95% CI 0.34 to 0.61; 183 participants, one trial, Analysis 10.1). Treatment failure increased in both groups over the following five months which the authors suspect was due to egg excretion by maturing worms, as transmission and re‐infection were low in the trial setting (Analysis 10.1). The second trial (Wilkins 1987 GMB), also found praziquantel to be superior to metrifonate at two to three months as its only time point (RR 0.45, 95% CI 0.27 to 0.75; 72 participants, one trial, Analysis 10.1).
The third trial (Stephenson 1989 KEN), found substantial reductions in both treatment failure (RR 0.21, 95% CI 0.13 to 0.36; 208 participants, one trial, Analysis 10.1) and egg excretion (see Appendix 2), with praziquantel compared to metrifonate. Haemoglobin levels measured in this trial were higher in the praziquantel treatment arm both at baseline and at follow‐up (208 participants, one trial, Analysis 10.2). The trial did not detect a difference in growth parameters between groups but does not report them separately (see Appendix 4).
None of the trials reported on adverse events.
Praziquantel 40 mg/kg single dose versus multiple doses of metrifonate 10 mg/kg
Two small trials found no difference in parasitological treatment failure or egg excretion between single dose praziquantel 40 mg/kg and two or three doses of metrifonate 10 mg/kg.
Two small trials compared praziquantel 40 mg/kg single dose to two and three doses of metrifonate 10 mg/kg given two weeks apart. The trials detected no difference in parasitological treatment failure at different time points and with different metrifonate regimens. However, in one trial both drugs performed poorly (de Jonge 1990 SDN), and in one trial both performed well (Al Aska 1990 SAU) (see Analysis 10.3). The trial where both drugs performed poorly for parasitological failure has been discussed above and this is likely to be due to the very sensitive method for detecting eggs. In this trial, both drugs reduced mean egg excretion by over 98% at one month and five months (see Appendix 2), and a decrease in haematuria by over 90% at one month. Reduction in proteinuria was almost 80% in both groups (see Appendix 3).
Only Al Aska 1990 SAU reported adverse events; dizziness was more common after praziquantel (RR 2.9, 95% CI 1.59 to 5.3; 100 participants, one trial, Analysis 10.4). Dizziness (20% in the praziquantel group and 10% in the metrifonate group) and abdominal pain (12% both in the praziquantel and metrifonate group) were the most common side effects (Appendix 5).
Additional comparisons of praziquantel and metrifonate
One small trial compared a single dose of praziquantel 30 mg/kg to three doses of metrifonate 10 mg/kg given two weeks apart and found no difference in parasitological failure at two months, but a statistically significant difference in favour of praziquantel at four months (RR 0.24, 95% CI 0.07 to 0.8; 52 participants, one trial, Analysis 10.5). Egg reduction at four months was above 98% in both treatment groups (Appendix 2). In this trial, abdominal pain was more common in the metrifonate group (RR 0.33, 95% CI 0.12 to 0.92; 60 participants, one trial, Analysis 10.6), while no difference was detected for the eight other clinically diagnosed symptoms reported.
One large population‐based trial from Kenya compared praziquantel 40 mg/kg given once a year to metrifonate 10 mg/kg given three times a year. After one year, this trial detected no difference in treatment failure, haematuria or proteinuria (1400 participants, one trial, Analysis 10.7), but mean egg excretion was reduced by over 80% in both groups at one year (Appendix 2). There continued to be no difference in parasitological failure at two years, but praziquantel was superior in the third year (RR 0.62, 95% CI 0.42 to 0.93; 827 participants one trial, Analysis 10.8). Ultrasound findings, recorded in a sub‐sample of children, were inconclusive (373 participants, Appendix 6).
One further small trial compared a single dose of praziquantel 40 mg/kg with a combination of praziquantel 10 mg/kg and metrifonate 10 mg/kg. At two to three months there was no difference in treatment failure (72 participants, one trial, Analysis 10.9). Percent egg reduction was 99.4% after praziquantel alone and 92.9% after the combination treatment (see Appendix 2).
Section D: Artesunate
Artesunate versus placebo (comparison 11)
The two placebo controlled trials of artesunate had inconsistent results, and the single trial at low risk of bias found only a modest effect on egg excretion compared to placebo.
Two trials compared artesunate 4 mg/kg once daily for three days with placebo. The two trials had inconsistent results on parasitological failure, with one trial finding no difference between artesunate and placebo, and one finding lower treatment failures with artesunate at eight weeks (251 participants, two trials, Analysis 11.1). The trial finding an effect was at unclear risk of both selection and detection bias due to an inadequate description of trial methods (Inyang Etoh 2009 NGA).
Both trials found that artesunate reduced egg excretion compared to placebo (Table 8), but the percent reduction was low compared to that seen in placebo controlled trials of praziquantel (percent egg reductions of between 52% and 69%).
| Study ID | Time point | Measure | Artesunate 4 mg/kg/d for 3 days | Placebo | P value difference between groups | ||||
| Egg count/10 mL urine | % egg reduction | Egg count/10 mL | % egg reduction | ||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 8 weeks | GMEC (range) 95% CI N = | 35.22 (1‐4360) N = 90 | 10.8 N = 89 | 69.34 | 21.56 (1‐778) N = 30 | 11.41 N = 30 | 47.1 | Not significant | |
| 8 weeks | Mean ova count ± SD N = | 39.8 ± 1.1 N = 52 | 19.1 ± 1.0 N = 44 | 52.1 | 34.1 ± 0.8 N = 52 | 72.0 ± 2.3 N = 44 | 111.5 (increase) | P for "therapeutic efficacy" < 0.001 | |
1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.
The trial at unclear risk of bias also reported improved reductions in haematuria and proteinuria compared to placebo, while the trial at low risk of bias (Borrmann 2001 GAB) found no effect on proteinuria (see Appendix 3). No differences in adverse events were reported (see Appendix 5, Analysis 11.3).
Praziquantel versus artesunate (comparison 12)
The results of the three trials are inconsistent, with the single trial at low risk of bias finding only a modest reduction in egg excretion with artesunate.
Three trials (Borrmann 2001 GAB; Inyang Etoh 2009 NGA; Keiser 2010 CIV) compared artesunate 4 mg/kg/d for three days with praziquantel 40 mg/kg single dose.
The three trials had mixed results. In two trials artesunate performed poorly, with parasitological treatment failures of over 70% at one month and two months respectively (Borrmann 2001 GAB; Keiser 2010 CIV). In these trials praziquantel was clearly superior (Analysis 12.1). In the third trial (Inyang Etoh 2009 NGA), at unclear risk of bias due to inadequate description of trial methods, artesunate performed similarly to praziquantel with 28% treatment failures at two months (Analysis 12.1).
The percent egg reduction with artesunate varied across the three trials from 52% to 85% (see Appendix 2). In the single trial where both praziquantel and artesunate performed well at reducing treatment failures, both drugs had fairly modest effects on egg excretion (Inyang Etoh 2009 NGA).
Only the trial at unclear risk of bias (Inyang Etoh 2009 NGA) reported substantial effects of artesunate on haematuria and proteinuria (see Appendix 3). In the trial at low risk of bias (Borrmann 2001 GAB) praziquantel was clearly superior at reducing microhematuria (RR 0.43, 95% CI 0.3 to 0.62; 178 participants, one trial, Analysis 12.2).
All trials reported on adverse events with no significant differences noted between groups (see Appendix 5, Analysis 12.3).
Praziquantel versus praziquantel plus artesunate (comparison 13)
The results of the two trials were inconsistent but the trial at low risk of bias found no benefit with adding artesunate to praziquantel.
Two of the trials comparing artesunate with praziquantel also had a treatment arm where patients received both drugs (Borrmann 2001 GAB; Inyang Etoh 2009 NGA). Again, in the trial at low risk of bias (Borrmann 2001 GAB) adding artesunate to praziquantel did not substantially reduce treatment failures or percent egg reduction at eight weeks compared to praziquantel alone, whereas in the trial at unclear risk of bias (Inyang Etoh 2009 NGA), adding artesunate improved outcomes (Analysis 13.1; Table 9; Appendix 2). No differences in adverse events were reported (see Appendix 5).
| Study ID | Time point | Measure | Praziquantel 40 mg/kg single dose and artesunate 4 mg/kg/d for 3 days | Praziquantel 40 mg/kg single dose | P value difference between groups | ||||
| Egg count/10 mL | % egg reduction | Egg count/10 mL | % egg reduction | ||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 8 weeks | GMEC (range), (95% CI) N = | 31.5 (1 to 3225) N = 90 | 0.36 N = 88 | 98.8 | 38.51 (1 to 3313) N = 90 | 1.11 (0.7 to 1.7) N = 89 | 97.11 | Not significant | |
| 8 weeks | mean ± SD N = | 62.2 ± 2.1 N = 52 | 4.0 (± 15.2) N = 44 | 93.6 | 39.8 (± 1.1) N = 52 | 19.1 (± 1.0) N = 44 | 52.1 | Not reported | |
1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.
Section E: Others
Mefloquine versus sulfadoxine‐pyrimethamine (comparison 14)
In a single trial comparing the use of mefloquine and sulfadoxine‐pyrimethamine as intermittent preventive treatment for malaria in pregnancy, a re‐analysis of the small number of mothers infected with S. haematobium found more women were cured at one month after mefloquine compared to sulfadoxine‐pyrimethamine (RR 0.57, 95% CI 0.4 to 0.83; 44 participants, one trial, Analysis 14.1), and an egg reduction of 80% four weeks after treatment and 98% ten weeks after treatment (see Appendix 2).
Praziquantel versus mefloquine alone or mefloquine in combination with artesunate (comparison 15 and 16)
A single small trial (Keiser 2010 CIV) reported lower treatment failures with praziquantel 40 mg/kg alone than with mefloquine 25 mg/kg (RR 0.15, 95% CI 0.05 to 0.43; 45 participants, one trial, Analysis 15.1) or with mefloquine in combination with artesunate 4 mg/kg/d for three days (RR 0.23, 95% CI 0.07 to 0.74; 44 participants, one trial, Analysis 16.1). At four weeks, this trial reports a percent egg reduction of 74% at four weeks with mefloquine alone (19 participants), 96% with mefloquine and artesunate combined, and 97% with praziquantel (Appendix 2).
Keiser 2010 CIV recorded adverse events by active, prospective surveillance. Adverse events were mild to moderate and common in all groups. There were no statistically significant differences in any individual adverse event (Appendix 5).
Praziquantel versus praziquantel and albendazole (comparison 17)
One trial (Olds 1999 KEN) compared a single dose of praziquantel 40 mg/kg with a combination of single dose praziquantel 40 mg/kg plus albendazole 400 mg at day 45 (RR 0.9, 95% CI 0.62 to 1.3; 193 participants, one trial, Analysis 17.1). The authors concluded that albendazole does not influence the effect of praziquantel.
Adverse events were monitored by active, prospective surveillance and described as mild and transient. Diarrhoea, headache and abdominal pain were observed most frequently, but adverse events were reported for participants treated for S. haematobium and S. mansoni together (Appendix 5).
Discussion
For a summary of the main results of the review and GRADE assessment of the quality of evidence see: summary of findings Table for the main comparison; Summary of findings table 2; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5; and summary of findings Table 6.
Summary of main results
On average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting S. haematobium eggs in their urine by around 60% compared to placebo at one to two months after treatment (high quality evidence), and reduced the mean number of schistosome eggs in the urine by over 95% in five out of six trials (high quality evidence). Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose.
Two small trials compared a single 40 mg/kg dose of praziquantel with two or three doses of 10 mg/kg metrifonate and found no differences in cure. In one trial both drugs performed badly and in one trial both performed well.
Three trials evaluated the antimalarial artesunate, and two trials evaluated mefloquine, with inconsistent results.
Overall completeness and applicability of evidence
The WHO currently recommend that schistosomiasis is treated with a single dose of praziquantel of at least 40 mg/kg (WHO 2006). In this review we found no trials evaluating doses higher than 40 mg in urinary schistosomiasis, but doses of 40 mg/kg or even 30 mg/kg are effective at reducing egg excretion and achieving cure.
Of all the drugs that have been evaluated for treating urinary schistosomiasis, praziquantel has by far the strongest evidence base. It has been evaluated across a wide range of endemic countries, and most trials were conducted in children who bear the highest burden of disease. However, few trials included children younger than five years of age, and Stothard 2013 suggested that higher doses of praziquantel might be required for this group. We would have liked to explore this possibility through an analysis stratified by age, but the data did not allow this and no firm conclusions can be made. In addition, most trials concentrated on parasitological efficacy, and few reported clinical outcomes such as improvement in haematuria or anaemia. Data on resolution of long‐term morbidity after treatment, as nutritional outcomes and sonographic findings are very rare, and follow‐up is limited to less than one year.
The absolute proportion of people cured by praziquantel varied between trials while percent egg reduction was relatively homogenous. This may be explained by low sensitivity and negative predictive value of the diagnostic test, compounded with the fact that egg yield varies during the day and with physical activity. This means that patients with few eggs in their urine may be variably declared as positive or negative in different settings. The proportional reduction in the mean egg counts from before to after treatment is less prone to this error. It also appears that some trials based post‐treatment egg reduction on the whole trial population (including cured patients with zero egg counts), while other trials based the post‐treatment calculations on those patients still excreting eggs. We were unable to combine egg reduction values in meta‐analysis, and assess statistical significance, due to the poor reporting of standard deviations and methods for calculating the mean (Table 2).
None of the included trials suggested drug resistance as a possible cause of high parasitological failure, or of recurrent schistosomiasis over prolonged follow‐up. In high transmission areas two mechanisms could explain rising parasitological failure over time: maturation of immature worms (which escape the action of praziquantel) to egg producing adults, and reinfection.
Previously the WHO also recommended metrifonate at 7.5 mg/kg for three doses (given two weeks apart), but this drug is now largely unavailable (Danso‐Appiah 2008). We found some evidence that repeated doses of metrifonate had reasonable antischistosomal effects but we found no trials directly comparing this dose with the standard dose of praziquantel. Combining praziquantel with metrifonate is one possible strategy for improving parasitological cure as they attack S. haematobium by different mechanisms (Utzinger 2004). However, we only found one small trial evaluating a combination approach and this used a low dose of praziquantel rather than the standard 40 mg/kg (Wilkins 1987 GMB).
Antimalarials (such as artesunate and mefloquine) given alone or in combination with praziquantel are another potential future treatment option, but the current evidence base is limited to a few trials with inconsistent results. As many locations in sub‐Saharan Africa are co‐endemic for schistosomiasis and malaria, there are also concerns about development of Plasmodium parasite resistance to artemisinins, especially as they would be used in a single dose and without a companion antimalarial drug (Utzinger 2004). Any change in policy would need to fully consider this potential public health harm.
Quality of the evidence
We used the GRADE approach to assess the quality for the evidence.
We consider the evidence for substantial benefits with praziquantel compared to placebo to be of high quality, meaning we have confidence in this result. Many of the included trials are old, but reassuringly the findings of the most recent trial conducted in 2005/2006 are consistent with the older studies.
However, we consider most of the evidence for other comparisons in this review to be of low or even very low quality. Most of the trials evaluating metrifonate are old and precede guidelines on transparent reporting of clinical trials. As such, many trials lacked adequate descriptions of methods to allow judgements on risk of bias, and so risk of bias has been classified as unclear. Trials were also generally small and underpowered to reliably detect or exclude effects.
Of the three trials reporting on the antischistosomal effects of artesunate, only one was at low risk of bias and this trial found little effect with artesunate compared to placebo (Borrmann 2001 GAB). Although the metanalysis suggests artesunate may improve cure when added to praziquantel, this evidence was of low quality due to inconsistency between trials, and the single trial showing a large effect being at unclear risk of bias for all domains.
Potential biases in the review process
Our information specialist followed a detailed, reproducible search strategy, and we searched reference lists of included trials. However, some trials might not be available online, and therefore an electronic search will not identify them.
In many cases, clarification of information with authors was not possible as no contact e‐mail addresses were available as the trials were very old.
Agreements and disagreements with other studies or reviews
Two recent systematic reviews evaluated the use of artemisinins in treating urinary schistosomiasis (Liu 2011; Pérez del Villar 2012), and both concluded that the combination of artesunate plus praziquantel is superior to praziquantel alone, While we find some evidence to support this we conclude that this evidence is only of low quality and encourage further high quality and adequately powered trials before any change in treatment policy. Of note, the trial at lowest risk of bias (Borrmann 2001 GAB), found no significant difference in cure between artesunate alone and placebo, or between praziquantel plus artesunate and praziquantel alone.
One further systematic review evaluated single or repeated doses of praziquantel, and found no evidence of benefit with repeated dosing compared to a single dose in people with S. haematobium infection (King 2011). We would agree that repeating doses two or three weeks apart does not seem to provide benefit over a single dose based on two trials with 686 participants. However, repeating doses at three monthly intervals over two years did seem to provide some additional benefits in a single small trial and further trials could evaluate this.
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 1 Parasitological failure.
Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 2 Haematuria at eight weeks.
Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 3 Haemoglobin.
Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 4 Adverse events.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 1 Parasitological failure at four to six weeks.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 2 Parasitological failure at two to three months.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 3 Parasitological failure at six to seven months.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 4 Haematuria at three months.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 5 Proteinuria at three months.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 6 Haematuria at six weeks.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 7 Proteinuria at six weeks.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 8 Haematuria at nine months.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 9 Proteinuria at nine months.
Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 10 Adverse events.
Comparison 3 Praziquantel 40 mg/kg single dose versus 2 x 20 mg/kg split dose, Outcome 1 Parasitological failure.
Comparison 3 Praziquantel 40 mg/kg single dose versus 2 x 20 mg/kg split dose, Outcome 2 Adverse events.
Comparison 4 Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg, Outcome 1 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: parasitological failure.
Comparison 4 Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg, Outcome 2 Praziquantel 40 mg/kg single dose versus praziquantel 3 x 40 mg/kg: parasitological failure.
Comparison 4 Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg, Outcome 3 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: microhaematuria at six months.
Comparison 5 Praziquantel 40 mg/kg single dose versus multiple doses, Outcome 1 Parasitological failure.
Comparison 5 Praziquantel 40 mg/kg single dose versus multiple doses, Outcome 2 Haematuria.
Comparison 6 Metrifonate single dose (10 mg/kg) versus placebo, Outcome 1 Parasitological failure.
Comparison 6 Metrifonate single dose (10 mg/kg) versus placebo, Outcome 2 Haemoglobin.
Comparison 7 Metrifonate multiple doses versus placebo, Outcome 1 Parasitological failure.
Comparison 7 Metrifonate multiple doses versus placebo, Outcome 2 Haemoglobin.
Comparison 8 Metrifonate multiple doses versus single dose, Outcome 1 Parasitological failure at one month.
Comparison 8 Metrifonate multiple doses versus single dose, Outcome 2 Parasitological failure at four months.
Comparison 9 Metrifonate 3 doses 2 weeks apart: 7.5 mg/kg versus 5 mg/kg, Outcome 1 Parasitological failure.
Comparison 9 Metrifonate 3 doses 2 weeks apart: 7.5 mg/kg versus 5 mg/kg, Outcome 2 Adverse events.
Comparison 10 Praziquantel versus metrifonate, Outcome 1 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: parasitological failure.
Comparison 10 Praziquantel versus metrifonate, Outcome 2 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: haemoglobin.
Comparison 10 Praziquantel versus metrifonate, Outcome 3 Praziquantel 40 mg/kg single dose versus metrifonate 20 and 30 mg/kg given as split doses: parasitological failure.
Comparison 10 Praziquantel versus metrifonate, Outcome 4 Praziquantel 40 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events.
Comparison 10 Praziquantel versus metrifonate, Outcome 5 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: parasitological failure.
Comparison 10 Praziquantel versus metrifonate, Outcome 6 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events.
Comparison 10 Praziquantel versus metrifonate, Outcome 7 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months.
Comparison 10 Praziquantel versus metrifonate, Outcome 8 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months: parasitological failure.
Comparison 10 Praziquantel versus metrifonate, Outcome 9 Praziquantel 40 mg/kg versus praziquantel 10 mg/kg and metrifonate 10 mg/kg.
Comparison 11 Artesunate versus placebo, Outcome 1 Parasitological failure at eight weeks.
Comparison 11 Artesunate versus placebo, Outcome 2 Haematuria.
Comparison 11 Artesunate versus placebo, Outcome 3 Adverse events.
Comparison 12 Praziquantel versus artesunate, Outcome 1 Parasitological failure.
Comparison 12 Praziquantel versus artesunate, Outcome 2 Haematuria.
Comparison 12 Praziquantel versus artesunate, Outcome 3 Adverse events.
Comparison 13 Praziquantel and artesunate versus praziquantel, Outcome 1 Parasitological failure at eight weeks.
Comparison 13 Praziquantel and artesunate versus praziquantel, Outcome 2 Haematuria at eight weeks.
Comparison 13 Praziquantel and artesunate versus praziquantel, Outcome 3 Adverse events.
Comparison 14 Mefloquine versus placebo, Outcome 1 Parasitological failure at six weeks.
Comparison 15 Praziquantel versus mefloquine, Outcome 1 Parasitological failure at one month.
Comparison 16 Praziquantel versus artesunate and mefloquine, Outcome 1 Parasitological failure at one month.
Comparison 17 Praziquantel versus praziquantel and albendazole, Outcome 1 Parasitological failure.
Comparison 18 Praziquantel versus praziquantel and artesunate, Outcome 1 Parasitological failure at eight weeks.
Comparison 18 Praziquantel versus praziquantel and artesunate, Outcome 2 Haematuria at eight weeks.
Comparison 18 Praziquantel versus praziquantel and artesunate, Outcome 3 Adverse events.
| Praziquantel 40 mg/kg versus placebo for treating urinary schistosomiasis | |||||
| Patient or population: People with urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Praziquantel 40 mg/kg | ||||
| Parasitological failure At 1 to 2 months | 91 per 100 | 38 per 100 | RR 0.42 | 864 | ⊕⊕⊕⊕ |
| Percentage egg reduction | Mean change in egg excretion in the control groups ranged from a 53.2% reduction to a 138% increase. | Mean egg excretion in the intervention groups was reduced by > 98% in all trials | Not pooled | 678 (6 trials) | ⊕⊕⊕⊕ |
| Microhaematuria At 8 weeks | 53 per 100 | 28 per 100 | RR 0.53 | 119 | ⊕⊕⊝⊝ |
| Haemoglobin At 6 to 8 months | The mean haemoglobin ranged across control groups from | The mean haemoglobin in the intervention groups was 0.08 G/dL lower | ― | 727 | ⊕⊕⊕⊝ |
| Adverse events | ― | ― | ― | 1591 | ⊕⊕⊝⊝ |
| The basis for the assumed risk is the mean risk in the control groups across trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 No serious risk of bias: Several trials were at unclear or low risk of selection bias. However, a sensitivity analysis excluding these trials still found a strong effect. | |||||
| Praziquantel 40 mg/kg compared to praziquantel 30 mg/kg for treating urinary schistosomiasis | |||||
| Patient or population: people with urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Praziquantel 30 mg/kg single dose | Praziquantel 40 mg/kg single dose | ||||
| Parasitological failure | 32 per 100 | 24 per 100 | RR 0.76 | 401 | ⊕⊕⊝⊝ |
| Mean percent egg reduction | The mean reduction in control groups ranged from an 85% reduction to a 99% reduction. | The mean reduction in the intervention groups was > 95% in all trials | Not pooled | 362 (4 trials) | ⊕⊕⊝⊝ |
| Parasitological failure | 29 per 100 | 28 per 100 (22 to 36) | RR 0.97 (0.76 to 1.23) | 669 (6 trials) | ⊕⊕⊕⊝ moderate 1,3,7,8 |
| Mean percent egg reduction | The mean reduction in control groups ranged from an 97% reduction to a 99% reduction. | The mean reduction in the intervention groups ranged from a 46% reduction15 to a 99% reduction | Not pooled | 362 (4 trials) | ⊕⊕⊝⊝ |
| Haematuria | 26 per 100 | 23 per 1000 | RR 0.89 | 117 | ⊕⊝⊝⊝ |
| Proteinuria | 15 per 100 | 13 per 100 | RR 0.85 | 117 | ⊕⊝⊝⊝ |
| Adverse events | ― | ― | Not estimable | 992 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias: None of the trials described a method of allocations concealment or blinding outcome assessors. | |||||
| Praziquantel 40 mg/kg multiple doses compared to single dose for treating urinary schistosomiasis | ||||||
| Patient or population: patients with treating urinary schistosomiasis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Praziquantel 40 mg/kg single dose | Praziquantel 40 mg/kg multiple doses | |||||
| Parasitological failure At 2 years | 90 per 100 | 244 per 100 | RR 2.71 | 62 | ⊕⊝⊝⊝ | |
| Mean percent egg reduction At 2 years | This study reports a81% reduction after a single dose of praziquantel | This study reports a96% reduction after multiple doses of praziquantel | ― | 62 (1 trial) | ⊕⊝⊝⊝ | |
| Parasitological failure At 3 years | 63 per 100 | 56 per 100 | RR 0.92 | 43 | ⊕⊝⊝⊝ | |
| Haematuria At 3 years | 48 per 100 | 34 per 100 | RR 0.7 | 43 | ⊕⊝⊝⊝ | |
| Adverse events | ― | This study reports a96% reduction after multiple doses of praziquantel | ― | 43 (1 trial) | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded by 2 for serious risk of bias. The one trial reporting the outcome did not report adequately on sequence generation and blinding. Allocation was not concealed, and loss to follow up was very high. | ||||||
| Metrifonate compared to placebo for treating urinary schistosomiasis | |||||
| Patient or population: patients with treating urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Metrifonate 3 x 7.5 mg/kg given two weeks apart | ||||
| Parasitological failure At 2 to 2.5 months | 40 per 100 | 16 per 100 (12 to 22) | RR 0.41 (0.3 to 0.56) | 93 (1 trial) | ⊕⊕⊝⊝ low1,2,3,4 |
| Mean percent egg reduction At 2 to 2.5 months | Egg excretion increased by 131% in the placebo group in this study | Egg excretion was reduced by 100% in this trial | ‐ | 93 (1 trial) | ⊕⊕⊝⊝ low1,2,3,4 |
| Parasitological failure At 6 months | 96 per 100 | 29 per 100 (23 to 36) | RR 0.3 (0.24 to 0.37) | 400 | ⊕⊕⊕⊝ |
| Mean percent egg reduction At 6 months | 13% increase | 94% reduction | ― | 400 (1 trial) | ⊕⊕⊕⊝ moderate2,3,5,7 |
| Adverse events | ― | ― | ― | 493 (2 trials) | 8 |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias; the single trial reporting this outcome did not adequately describe sequence generation, allocation concealment and blinding of participants, clinicians or outcome assessors. 3 No serious indirectness. This single trial was conducted in children in rural sub‐Saharan Africa. 5 Downgraded by 1 for serious risk of bias. The trial did not report on sequence generation and allocation concealment. The study described blinding of participants, clinicians and outcome assessors. 6 No serious imprecision. CIs are narrow and both CI limits have clinically important effects. The trial is adequately powered for this outcome. 7 No serious imprecision. The difference in effect between metrifonate and placebo group is large. 8 None of the trials reported on adverse events. | |||||
| Artesunate compared to placebo for treating urinary schistosomiasis | |||||
| Patient or population: patients with treating urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Artesunate | ||||
| Parasitological failure At 8 weeks | 87 per 100 | 46 per 100 | RR 0.53 | 251 | ⊕⊕⊝⊝ |
| Mean percent egg reduction At 8 weeks | Mean change in egg excretion ranged from range from 47.1% reduction to 111.5% increase. | Reduction in egg excretion ranged from 52.1% to a 69.3% | ― | 276 (2 trials) | ⊕⊝⊝⊝ |
| Microhaematuria At 8 weeks | 53 per 100 | 65 per 100 | RR 1.22 | 119 | ⊕⊕⊝⊝ |
| Adverse events | ― | ― | ― | 276 (2 trials) | ⊕⊕⊝⊝ low11,12 |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias. One trial described sequence generation, allocation concealment and blinding adequately, whereas the second study did not. 2 Downgraded by 1 for serious inconsistency. One of the trials (at high risk of bias) reported a large effect, while the other trial (at low risk of bias) detected no effect. 3 No serious indirectness. The trials were conducted in Gabon and Nigeria in patients of a similar age range. 4 Downgraded by 1 for serious imprecision. The CI is very wide and reaches from no benefit to a significant benefit after treatment. 5 No for serious inconsistency. Percent egg reductions the studies reported were similar. 6 Downgraded by 1 for serious imprecision. The meta analysis is underpowered. 7 No serious risk of bias. The one trial reporting the outcome reported adequately on sequence generation, allocation concealment and blinding. 8 No serious inconsistency: only one trial. 9 No serious indirectness: This trial was conducted in school children in Gabon. 10 Downgraded by 2 for very serious imprecision: only one trial reporting 74 events in 119 participants evaluated this outcome. 11Downgraded by 1 for serious risk of bias: only one trial was blinded. Both trials reported on adverse events, but the methods are unclear. 12 Downgraded by 1 for imprecision. One study reported on clinically diagnosed outcomes per treatment group, but was underpowered to confidently detect a difference. | |||||
| Praziquantel plus artesunate compared to praziquantel alone for treating urinary schistosomiasis | |||||
| Patient or population: patients with urinary schistosomiasis | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Praziquantel 40 mg/kg single dose alone | Praziquantel 40 mg/kg single dose plus artesunate 4 mg/kg/d for 3 days | ||||
| Parasitological failure at 8 weeks | 27 per 100 | 17 per 100 (10 to 27) | RR 0.62 (0.38 to 0.99) | 265 | ⊕⊕⊝⊝ |
| Percent egg reduction | Egg reduction in the Praziquantel groups ranged from 52.1% reduction to a 97.11% reduction. | Egg reduction in the Praziquantel and ARS groups ranged from 93.5% to 98.8% | ― | 265 (2 trials) | ⊕⊝⊝⊝ |
| Microhaematuria | 28 per 100 | 19 per 100 (11 to 33) | RR 0.69 | 177 | ⊕⊕⊝⊝ |
| Adverse events | ― | ― | ― | 156 (1 trial) | ⊕⊝⊝⊝ very low9,10 |
| *The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 for serious risk of bias: only one out of two studies did report adequate random sequence generation, allocation concealment and blinding or participants and clinicians, while the other study did not provide enough information to allow a judgement. | |||||
|
Category | Prevalence among school‐aged children | Action to be taken | Comment |
| High‐risk community | 50% by parasitological methods (intestinal or urinary schistosomiasis; or 30% by questionnaire for visible haematuria (urinary schistosomiasis) | Treat all school‐age children (enrolled and not enrolled) once a year | Also treat adults considered to be at risk (from special groups to entire communities living in endemic areas)
|
| Moderate‐risk community | > 10 to < 50% by parasitological methods (intestinal and urinary schistosomiasis); or 30% by questionnaire for visible haematuria (urinary schistosomiasis) | Treat all school‐age children (enrolled or not enrolled) once every two years | Also treat adults considered to be at risk (special groups only) |
| Low–risk community | < 10% by parasitological methods (intestinal and urinary schistosomiasis) | Treat all school‐age children (enrolled and not enrolled) twice during their primary schooling age (for example, once on of suspected cases entry and once on exit) | Praziquantel should be available in dispensaries and clinics for treatment of suspected cases. |
| Study ID | Definition cure | Reporting of egg counts/10 mL urine | Methods to calculate egg counts | Comment |
| Patients without schistosome eggs in their urine after treatment | Mean (SD), % ER | Not reported | No hatching test employed, cured might be underestimated because of dead eggs | |
| Clinical improvement Disappearance of ova from the urine on three successive examinations | Mean, range | Not reported | ― | |
| Three consecutive urine samples without presence of eggs | Median, interquartile range | Not reported | ― | |
| Cure not reported | GMEC | Not reported | Hb and weight as outcomes | |
| Two negative egg counts on two consecutive days | GMEC | Arithmetric mean of two egg counts per participant before and after treatment including 0 egg counts (cured patients). Geometric means of these arithmetic means. | We received the data file from the study author Day to day variation in egg counts explains 10% cure rate with placebo. | |
| Defined as three negative urine defined as the absence of hatched miracidia, although recently dead or black eggs might be present. | Geometric mean miracidial count | At follow‐up: If the first urine specimen contained hatched miracidia, then random 10 mL samples were taken from further bladder collections, the miracidial count was recorded, and the geometric mean of the counts was compared directly with the geometric mean of the pretreatment counts. | Quantitaive hatching test. if the first sedimented urine specimen was negative, then two further urine specimens taken on consecutive days were sedimented and examined. | |
| No definition of cure given, presumably absence of urinary egg excretion | Minimum and maximum value, median, 90%value | Not reported | Excretion of eggs following treatment | |
| No definition of cure given, cure rates and egg reduction rates as end points | Mean ± SD | "Treatment‐related changes | ― | |
| No definition of cure given | "median urine egg count" | Not reported | ― | |
| No definition of cure given, "negative" | GMEC | Not reported | "It would appear that the cure rate determined in any trial is dependent on the pretreatment egg count and on the ...urine examination techniques used." | |
| Absence of urinary egg excretion Cure rate (CR, defined as the percentage of children excreting no S. haematobium eggs 26 days after treatment among children with confirmed parasites at baseline) | GMEC | S. haematobium egg counts before and after treatment were averaged for every child (arithmetic mean) and the GM egg count for each treatment group was calculated. Because egg counts are over dispersed, they were logarithmically transformed log [count+1], and the GM was expressed as the antilogarithm of the mean. Egg reduction rate (ERR) defined as reduction of geometric mean (GM) egg count among S. haematobium positive children after treatment, compared with the respective GM pretreatment. The ERR was calculated as (1 ‐ [GM egg count after treatment/GM egg counts at enrolment] x 100 | (ERR; defined as reduction of geometric mean egg count | |
| No definition of cure given | AMEC GMEC | Not reported | Infection was identified and quantified by Nucleopore filtration | |
| No definition of cure given | AMEC GMEC | Not reported | Infection was identified and quantified by Nucleopore filtration | |
| Cure defined as egg‐negative | GMEC | Not reported | ― | |
| Probable cure rate: excretion of no or only non viable eggs in the urine | GMEC, 95%confidence limit of the mean | Not reported | ― | |
| People were considered cured when no eggs or non‐viable eggs were excreted in the urine | Screening: GMEC of miracidia/10 mL urine reduction in egg excretion | "In non cured cases the reduction of egg excretion was calculated." | ― | |
| Absence of S. haematobium eggs in two random 5 mL samples of urine from the same specimen | GMEC 5 mL urine samples reduction in GMEC | Not reported | ― | |
| No definition given | GMEC | "Egg counts are geometric means in subjects who remained | ― | |
| 100% reduction of egg excretion (absence of egg excretion in the urine) or 98% egg reduction and neg miracidial hatching test | GMEC | Not reported | Only children with GMEC > 60/10 mL (in three egg counts) included | |
| No definition of cure given | GMEC mean ± SD | Not reported | Only children with GMEC > 60/10 mL (in three egg counts) included | |
| No definition of cure given | AMEC % egg count reduction | Percentage reduction in egg output was determined by comparing the arithmetic and geometric means of pooled egg counts before and after treatment. The geometric mean was obtained by recording the logarithm of egg counts and using the n +1 transformation for a series of counts after treatment that included zeros. | We did not use a hatching test to determine the viability of excreted ova since percentage reduction in egg output rather than parasitological cure was our main criterion of efficacy. | |
| No definition of cure given | AMEC "nombre moyenne" average number | Not reported | If possible, a hatching test was that at the last control (6 months) | |
| No definition of cure given, "negativation" | AMEC moyenne des nombres d'oeufs/10 mL urine Number average | Not reported | ― | |
| The | GMEC | Individual egg counts were | ― | |
| no definition of cure given | AMEC | Not reported | ― | |
| ― | AMEC GMEC | Not reported | ― | |
| Cure defined as negative egg counts "infections as were cured by a negative GMEC at 1,3 and 6 months" | GMEC | Not reported | "in cases were only one egg was found in three (urine) examinations the egg count was always taken as positive." | |
| The parasitologic cure rates were calculated as the proportion | GMEC | Geometric mean (GM) values of all The intensity reduction rate was calculated as [1 − (GM egg counts per 10 | The parasitological cure rates were calculated as the proportion of children excreting eggs at the first survey before treatment and who were not excreting eggs in their urine after treatment. | |
| Negative for both eggs and circulating antigen failure: pos. for eggs or circulating antigen | GMEC interquartile range | Not reported | ― | |
| No definition of cure given | GMEC | When appropriate a log10 transformation was used in statistical analysis to make their skewed distribution approximate to normal. This was reversed for the presentation of results to give a geometric mean which included zero values. | ― |
| Study ID | Subgroup | Timepoint | Measure | Praziquantel 40 mg/kg single dose | Placebo | P value difference between groups | ||||
| Egg count/10 mL (Range/95% CI) N | % egg reduction | Egg count/10 mL (Range/95% CI) N | % egg reduction | |||||||
| Baseline | Follow‐up | Baseline | Follow‐up | |||||||
| ― | 1 month | Median | 66 N = 48 | 1 N = 40 | 98.5 | 124 N = 21 | 58 N = 18 | 53.2 | P = 0.29 not significant | |
| ― | 1 month | Miracidial count (95% CI) | 288.4 (33.2 to 2508.9) N = 32 | 1.1 (0 to 8.3) N = 30 | 99.6 | 324.9 (22.1 to 4783.3) N = 37 | 187.5 (6.3 to 5601.3) N = 29 | 42.3 | Not reported | |
| ― | 1 month | GMEC AMEC | 385.5 780.9 N = 97 | 1.8/ 1.8 | 99.5 99.7 | 136.8 188.8 N = 52 | 119.9 437.2 | 12.35 (GMEC) ‐ 131.5 (AMEC) (increase) | Not reported | |
| light infections < 50/10 mL | 1 month | GMEC N = (both light and heavy) | 15.1 N = 77 (both groups) | 0.4 | 99.7 | 15.7 N = 90 (both groups) | 37.5 | ‐138 (increase) | Not reported | |
| heavy infections < 100/10 mL | 1 month | GMEC N = (both light and heavy) | 204.7 N = 77 (both groups) | 4.0 | 98.1 | 191.9 N = 90 (both groups) | 147.0 | 23.39 | Not reported | |
| ― | 45 days | GMEC | Not reported N = 95 | 1.4 | ― | N = 94 | 29.8 | ― | Not reported | |
| ― | 8 weeks | GMEC (range) | 38.51 (1 to 3313) N = 90 | 1.11 N = 89 | 97.11 | 21.57 (1 to 778) N = 30 | 11.41 N = 30 | 47.1 | Significant | |
| without placebo | 8 weeks | ― | 42.0 ± 1.7 N = 52 | 9.8 ± 0.5 N = 42 | 76.7 | 34.1 ± 0.8 N = 52 | 72.0 ± 2.3 N = 44 | ‐ 111.5 (increase) | P < 0.0012 | |
| 1P for therapeutic efficacy (not defined) Praziquantel versus placebo 2 Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown. | ||||||||||
| Study ID | Subgroup | Time point | Measure | Praziquantel 40 mg/kg single dose | Placebo | P value for difference between groups | ||||
| Egg count /10 mL urine | % egg reduction | Egg count/10 mL urine | % egg reduction | |||||||
| Baseline | Follow‐up | Baseline | Follow‐up | |||||||
| ― | 3 months | miracidial count (95% CI) | 288.4 (33.2 to 2508.9) N = 32 | 1.1 (0 to 16.3) | 99.6 | 324.9 (22.1 to 4783.3) N = 37 | 149.4 (6.3 to 3556.6) | 54 | Not reported | |
| ― | 3 months | GMEC AMEC | 385.5 780.9 N = 97 | 1.9 1.9 | 99.5 (GMEC) 99.75(AMEC) | 136.8 188.8 N = 52 | 85.9 270.3 | 37.2 (GMEC) 43.16 (AMEC) | Not reported | |
| light infections < 50/10 mL | 3 months | GMEC | 15.1 N = 77 (for both groups) | 0.4 | 97.35 | 15.7 N = 90 | 19.8 | ‐26.11 (increase) | Not reported | |
| heavy infections < 100/10 mL | GMEC | 204.7 N = 77 (for both groups) | 2.0 | 99.02 | 191.9 N = 90 | 94.7 | 50.65 | Not reported | ||
| ― | 5 months | median | 66 N = 48 | 0 | 100 | 124 N = 21 | 95 | 23.38 | P = 0.27 not significant | |
| ― | 6 months | miracidial count (95% CI) | 288.4 (33.2 to 2508.9) N = 32 | 1.1 (0‐20.3) | 99.6 | 324.9 (22.1 to 4783.3) N = 37 | 188.6 (13.9 to 2563.5) | 41.95 | Not reported | |
| ― | 6 months | GMEC AMEC | 385.5 780.9 N = 97 | 2.4 20.1 | 99.3 (GMEC) 97.4 (AMEC) | 136.8 188.8 N = 52 | 69.7 261.8 | 49.0 GMEC ‐38.7 (increase) AMEC | Not reported | |
| ― | 6 months | GMEC | 41/10 mL N = 238 | 2/10 mL | 95.1 | 39/10 mL N = 198 | 14/10 mL | 64.1 | ||
| light infections < 50/10 mL | 6 months | GMEC | 15.1 N = 77 (for both groups) | 0.2 | 98.67 | 15.7 N = 90 | 11.7 | 25.5 | Not reported | |
| heavy infections < 100/10 mL | 204.7 N = 77 (for both groups) | 0.6 | 99.7 | 191.9 N = 90 | 75.5 | 60 | Not reported | |||
| ― | 8 months | GMEC AMEC | 57/ 112 N = 105 | 0.2/ 1 | 99.64 (GMEC) 99.1 (AMEC) | 38/ 85 N = 104 | 36/ 102 | 5.26 (GMEC) ‐20 (increase) (AMEC) | Not reported1 | |
| 1Praziquantel 40 mg/kg single dose: significant egg reduction in praziquantel group (before, after treatment) P < 0.0002. no significant reduction in the placebo group (before, after treatment). | ||||||||||
| Study ID | Subgroup | Time point | Measure | Praziquantel 40 mg/kg (SD) | Praziquantel 30 mg/kg (SD) | P value difference between groups | ||||
| Egg count/10 mL urine | % reduction | Egg count/10 mL urine | % reduction | |||||||
| Baseline | Follow‐up | Baseline | Follow‐up | |||||||
| ― | 1 month | GMEC (95 Confidence limits of mean) N | 288.4 (33.2 to 2508.9) N = 33 | 1.1 (0‐8.3) N = 30 | 99.61 | 308.5 (31.2 to 3034.7) N = 32 | 1.2 (0 to 15.4) N = 31 | 99.6 | Not significant P value not reported | |
| ― | 1 month | AMEC N | 7.5 ± 1.7 N = 57 | 0.24 N = 54 | 96.8 | 7.5 ± 1.7 N = 46 | 0.74 N = 39 | 90.13 | Not significant | |
| heavy infection < 100/10 mL | 1 month | GMEC N | 204.7 N = 77 for both groups | 4.0 | 98.04 | 185.4 N = 72 for both groups | 3.1 | 98.32 | Not reported | |
| light infection > 50/10 mL | 1 month | GMEC | 15.1 | 0.4 | 97.35 | 15.9 | 0.6 | 96.23 | ||
| ― | 1 month | GMEC mean ± SE, N = | Stratum 1 87.4 ± 23.46 N = 15 Stratum 2 339.4 ± 32.61 N = 5 Stratum 3 518.00 ± 0.71 N = 2 N = 22 | N = 21 | 97.69 ± 0.98 | Stratum 1: 111.67 ± 47.14 N = 15 Stratum 2: 306.83 ± 54.29 (N = 6) Stratum 3: 1507.00 ± 1400.07 N = 2 N = 23 | N = 19 | 85.65 ± 13.08 | Not significant Not reported | |
| 2‐3 months | AMEC (± SD) GMEC N = | 377 255 N = 64 | 31 (± 21) 2 N = 54 | 91.7 (AMEC) 99.2 (GMEC) | 327 204 N = 69 | 22 ± 17 2 N = 60 | 93.27 (AMEC) 99 (GMEC) | Not significant Not reported | ||
| 3 months | GMEC (95 Confidence limits of mean) N | 288.4 (33.2 to 2508.9) N = 33 | 1.1 (0‐16.3) N = 29 | 99.61 | 308.5 (31.2 to 3034.7) N = 31 | 0.9 (0 to 13.4) N = 31 | 97.08 | Not significant Not reported | ||
| 3 months | AMEC N = | 7.5 ± 1.7 N = 57 | 0.42 N = 52 | 94.4 | 7.5 ± 1.7 N = 46 | 1.21 N = 42 | 83.86 | Not reported | ||
| heavy infections < 100/10 mL | 3 months | GMEC N = | 204.7 N = 77 for both groups | 2.0 | 99.02 | 185.4 N = 72 for both groups | 1.1 | 99.4 | Not reported | |
| light infections > 50/10 mL | 3 months | GMEC | 15.1 | 0.4 | 97.35 | 15.9 | 0.4 | 97.48 | ||
| ― | 3 months | GMEC mean ± SE, N = | Stratum 1 87.4 ± 23.46 N = 15 Stratum 2 339.4 ± 32.61 N = 5 Stratum 3 518.00 ± 0.71 N = 2 N = 22 | 97.55 ± 0.85 (N = 18) | Stratum 1 111.67 ± 47.14 N = 15 Stratum 2 306.83 ± 54.29 N = 6 Stratum 3 1507.00 ± 1400.07 N = 2 N = 23 | 99.01 ± 0.47 (N = 19) | Not significant Not reported | |||
| ― | 6 months | GMEC (95 Confidence limits of mean) | 288.4 (33.2 to 2508.9) N = 33 | 1.1 (0 to 20.3) N = 28 | 99.6 | 308.5 (31.2 to 3034.7) N = 32 | 1.4 (0 to 39.5) N = 28 | 99.46 | Not significant Not reported | |
| ― | 6 months | AMEC | 7.5 ± 1.7 N = 57 | 4 N = 34 | 46.6 | 7.5 ± 1.7 N = 462 | 0.18 N = 28 | 97.6 | Not reported | |
| heavy infections < 100/10 mL | 6 months | GMEC N = | 204.7 (N = 77) | 0.6 | 99.7 | 185.4 (N = 72) | 0.7 | 99.62 | Not significant Not reported | |
| light infections > 50/10 mL | 6 months | GMEC N = | 15.1 (N = 77) | 0.2 | 98.67 | 15.9 (N = 72) | 0.1 | 99.37 | ||
| ― | 6 months | GMEC mean ± SE, (N =) | Stratum 1 87.4 ± 23.46 (N = 15) Stratum 2 339.4 ± 32.61 (N = 5) Stratum 3 518.00 ± 0.71 (N = 2) (N = 22) | (N = 15) | 93.09 ± 0.12 | Stratum 1 111.67 ± 47.14 (N = 15) Stratum 2 306.83 ± 54.29 (N = 6) Stratum 3 1507.00 ± 1400.07 (N = 2) (N = 23) | (N = 17) | 98.72 ± 0.28 | Not significant Not reported | |
| ― | 9 months | (N = 6) | 92.4 ± 5.92 | (N = 8) | 96.49 ± 1.59 | |||||
| ― | 12 months | (N = 3) | 99.3 ± 0.26 | (N = 4) | 99.28 ± 0.46 | |||||
| 1Baseline data not reported separately per group. 2A reduction as low as 46% after praziquantel 40 mg/kg was not observed by any other study that reported this outcome. At six months, five other studies reported % egg reduction above 90% (see Table 4 and Table 5) 3Heavy and light infections together; N = 77 for Praziquantel 40 mg/kg and N = 72 for Praziquantel 30 mg/kg. 4 GMEC/10 mL urine, stratum 1: 60 to 250, stratum 2: 251 to 500, stratum 3 > 500. | ||||||||||
| Study ID | Time point | Measure | Praziquantel 40 mg/kg single dose | % egg reduction | Praziquantel 40 mg/kg multiple doses | % egg reduction | Comments | ||
| Egg count/10 mL | Egg count/10 mL | ||||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 2 years | GMEC (IQR) | 47 N = 45 | 9 (2‐45) | 80.85 | 47 N = 45 | 2 (1‐3) | 95.74 | Significant P = 0.002 | |
| 1Baseline egg counts not reported separately per treatment group; no difference at baseline stated. Praziquantel 40 mg/kg given every 3 months over 2 years. Location: Gabon, endemic area. | |||||||||
| Study ID | Time point | Measure | Metrifonate 21.5 mg, 20 mg/kg given as divided dose | Placebo or no treatment | P value difference between groups | ||||
| Egg count/10 mL urine | % egg reduction | Egg count/10 mL urine | % egg reduction | ||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 1 month | median N = (reports min, max, 90th percentile and median of egg counts/10 mL) | 95 N = 38 | 1 N = 32 | 98.94 | 124 N = 21 | 58 N = 18 | 53.22 | Not significant P = 0.29 | |
| 11 weeks | median N = | 101 N = 32 | 0 | 100 | 26 N = 38 | 60 | ‐130.77 (increase) | Not reported | |
| 11 weeks | median N = | 40 N = 23 | 0 | 100 | |||||
| 5 months | median N = (reports min, max, 90th percentile and median of egg counts/10 mL) | 124 N = 38 | 1 N = 32 | 99.19 | 124 N = 21 | 95 N = 19 | 23.38 | Not significant P = 0.27 | |
| 6 months | AMEC N = | 109 N = 202 | 7 | 94 | 110 N = 198 | 124 | ‐12.7 (increase) | Not reported | |
| 1Metrifonate 2 x 10 mg/kg, dose interval two weeks. Placebo: multivitamins. 2Reports two groups with metrifonate 7.5 mg x 3, dose interval two weeks. Control group: nil. 3 Metrifonate 3 x 7.5 mg/kg, dose interval one to two weeks. | |||||||||
| Study ID | Time point | Measure | Artesunate 4 mg/kg/d for 3 days | Placebo | P value difference between groups | ||||
| Egg count/10 mL urine | % egg reduction | Egg count/10 mL | % egg reduction | ||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 8 weeks | GMEC (range) 95% CI N = | 35.22 (1‐4360) N = 90 | 10.8 N = 89 | 69.34 | 21.56 (1‐778) N = 30 | 11.41 N = 30 | 47.1 | Not significant | |
| 8 weeks | Mean ova count ± SD N = | 39.8 ± 1.1 N = 52 | 19.1 ± 1.0 N = 44 | 52.1 | 34.1 ± 0.8 N = 52 | 72.0 ± 2.3 N = 44 | 111.5 (increase) | P for "therapeutic efficacy" < 0.001 | |
| 1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown. | |||||||||
| Study ID | Time point | Measure | Praziquantel 40 mg/kg single dose and artesunate 4 mg/kg/d for 3 days | Praziquantel 40 mg/kg single dose | P value difference between groups | ||||
| Egg count/10 mL | % egg reduction | Egg count/10 mL | % egg reduction | ||||||
| Baseline | Follow‐up | Baseline | Follow‐up | ||||||
| 8 weeks | GMEC (range), (95% CI) N = | 31.5 (1 to 3225) N = 90 | 0.36 N = 88 | 98.8 | 38.51 (1 to 3313) N = 90 | 1.11 (0.7 to 1.7) N = 89 | 97.11 | Not significant | |
| 8 weeks | mean ± SD N = | 62.2 ± 2.1 N = 52 | 4.0 (± 15.2) N = 44 | 93.6 | 39.8 (± 1.1) N = 52 | 19.1 (± 1.0) N = 44 | 52.1 | Not reported | |
| 1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown. | |||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 8 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 at one month to two months | 7 | 864 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.29, 0.59] |
| 1.2 at three months | 3 | 354 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.34, 0.77] |
| 1.3 at five months | 1 | 54 | Risk Ratio (M‐H, Random, 95% CI) | 0.73 [0.58, 0.91] |
| 1.4 at six months | 3 | 332 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.10, 1.84] |
| 1.5 at eight months | 1 | 209 | Risk Ratio (M‐H, Random, 95% CI) | 0.14 [0.08, 0.22] |
| 2 Haematuria at eight weeks Show forest plot | 1 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.33, 0.84] |
| 3 Haemoglobin Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 3.1 at baseline | 2 | 727 | Mean Difference (IV, Random, 95% CI) | ‐0.17 [‐0.35, 0.02] |
| 3.2 at six to eight months | 2 | 727 | Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.24, 0.09] |
| 4 Adverse events Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Diarrhoea | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 4.2 Vomiting | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.15, 2.87] |
| 4.3 Dizziness | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.11, 1.27] |
| 4.4 Anorexia | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.05, 0.85] |
| 4.5 Abdominal pain | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.22, 1.14] |
| 4.6 Tiredness | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.14, 1.71] |
| 4.7 Weakness | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.36, 2.57] |
| 4.8 Headache | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.02, 1.47] |
| 4.9 Fever | 2 | 226 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.07, 17.22] |
| 4.10 Pain in limbs | 1 | 70 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.59 [0.28, 112.34] |
| 4.11 Itching | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.19, 5.28] |
| 4.12 Cough | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.09, 10.78] |
| 4.13 Chills | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.16, 14.07] |
| 4.14 Nausea | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.09, 10.78] |
| 4.15 Constipation | 1 | 156 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.51 [0.06, 36.54] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at four to six weeks Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 versus 30 mg/kg | 4 | 401 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.59, 0.99] |
| 1.2 versus 20 mg/kg | 2 | 338 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.59, 0.93] |
| 1.3 versus 10 mg/kg | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.53, 0.84] |
| 2 Parasitological failure at two to three months Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 versus 30 mg/kg | 5 | 517 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.72, 1.24] |
| 2.2 versus 20 mg/kg | 3 | 330 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.56, 0.92] |
| 2.3 versus 10 mg/kg | 3 | 339 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.48 [0.39, 0.60] |
| 3 Parasitological failure at six to seven months Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 versus 30 mg/kg | 6 | 669 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.76, 1.23] |
| 3.2 versus 20 mg/kg | 1 | 138 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.53, 1.44] |
| 3.3 versus 10 mg/kg | 1 | 150 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.29, 0.64] |
| 4 Haematuria at three months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 versus 30 mg/kg | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.47, 1.67] |
| 4.2 versus 20 mg/kg | 1 | 122 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.60, 2.33] |
| 4.3 versus 10 mg/kg | 1 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.35 [0.21, 0.58] |
| 5 Proteinuria at three months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 versus 30 mg/kg | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.34, 2.12] |
| 5.2 versus 20 mg/kg | 1 | 122 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.36, 2.30] |
| 5.3 versus 10 mg/kg | 1 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.12, 0.51] |
| 6 Haematuria at six weeks Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 versus 20 mg/kg | 1 | 245 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.47, 0.86] |
| 7 Proteinuria at six weeks Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 versus 20 mg/kg | 1 | 245 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.46, 0.96] |
| 8 Haematuria at nine months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 versus 20 mg/kg | 1 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.44, 0.78] |
| 9 Proteinuria at nine months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 versus 20 mg/kg | 1 | 214 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.50, 0.90] |
| 10 Adverse events Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 10.1 Vomiting | 2 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.05, 13.51] |
| 10.2 Dizziness | 2 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 0.73 [0.11, 4.62] |
| 10.3 Anorexia | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 4.85 [0.24, 97.31] |
| 10.4 Abdominal pain | 2 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 1.14 [0.23, 5.56] |
| 10.5 Tiredness | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.10, 1.09] |
| 10.6 Weakness | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.39, 3.44] |
| 10.7 Headache | 2 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.08, 2.85] |
| 10.8 Fever | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 68.95] |
| 10.9 Pain in limbs | 1 | 65 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.08, 1.86] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 at one month | 3 | 374 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.51, 1.11] |
| 1.2 at three months | 3 | 361 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.45, 1.20] |
| 1.3 at six to seven months | 3 | 234 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.51, 1.35] |
| 2 Adverse events Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Blood in stool | 1 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 Vomiting | 3 | 373 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.29, 0.86] |
| 2.3 Dizziness | 3 | 373 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.39 [0.16, 0.94] |
| 2.4 Anorexia | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.18 [0.21, 22.96] |
| 2.5 Abdominal pain | 3 | 373 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.83, 1.25] |
| 2.6 Tiredness | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.12, 1.41] |
| 2.7 Weakness | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.35, 2.50] |
| 2.8 Headache | 2 | 158 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.51 [0.20, 1.33] |
| 2.9 Fever | 2 | 284 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.23, 1.23] |
| 2.10 Pain in limbs | 1 | 69 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.09, 2.10] |
| 2.11 Diarrhoea | 1 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.67, 1.73] |
| 2.12 Skin reaction | 1 | 215 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [0.34, 9.83] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: parasitological failure Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 at six weeks | 1 | 269 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.50, 1.34] |
| 1.2 at nine weeks to three months | 2 | 686 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.91, 1.25] |
| 1.3 at six months | 1 | 556 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.95, 1.31] |
| 2 Praziquantel 40 mg/kg single dose versus praziquantel 3 x 40 mg/kg: parasitological failure Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 at nine weeks | 1 | 185 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.42, 2.12] |
| 3 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: microhaematuria at six months Show forest plot | 1 | 300 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.88, 1.56] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 at two years | 1 | 62 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.71 [1.47, 5.00] |
| 1.2 at three years | 1 | 43 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.59, 1.42] |
| 2 Haematuria Show forest plot | 1 | 43 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.42, 1.17] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 at one month | 1 | 142 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.74, 0.94] |
| 1.2 at two and a half to three months | 1 | 122 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.85, 0.99] |
| 1.3 at six months | 1 | 102 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.87, 1.02] |
| 1.4 at eight months | 1 | 210 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.54, 0.73] |
| 2 Haemoglobin Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 at baseline | 1 | 207 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐0.33, 0.33] |
| 2.2 at eight months | 1 | 207 | Mean Difference (IV, Fixed, 95% CI) | 0.30 [‐0.05, 0.65] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 at one month | 1 | 50 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.65, 1.09] |
| 1.2 at 11 weeks | 1 | 93 | Risk Ratio (M‐H, Random, 95% CI) | 0.41 [0.30, 0.56] |
| 1.3 at five months | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.76, 1.03] |
| 1.4 at six months | 1 | 400 | Risk Ratio (M‐H, Random, 95% CI) | 0.30 [0.24, 0.37] |
| 2 Haemoglobin Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.1 at baseline | 1 | 400 | Mean Difference (IV, Random, 95% CI) | ‐0.17 [‐0.45, 0.11] |
| 2.2 at six months | 1 | 391 | Mean Difference (IV, Random, 95% CI) | 0.30 [0.14, 0.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at one month Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 20 mg/kg versus 10 mg/kg | 1 | 112 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.50, 1.13] |
| 1.2 30 mg/kg versus 10 mg/kg | 1 | 93 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.17, 0.77] |
| 2 Parasitological failure at four months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 20 mg/kg versus 10 mg/kg | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.58, 1.06] |
| 2.2 30 mg/kg versus 10 mg/kg | 1 | 111 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.45, 0.99] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 at one month | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.69, 1.21] |
| 1.2 at two months | 1 | 165 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.72, 1.30] |
| 1.3 at three months | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.67, 1.26] |
| 1.4 at six months | 1 | 139 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.99, 2.05] |
| 2 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Nausea | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.51 [0.05, 5.48] |
| 2.2 Vomiting | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.06, 15.93] |
| 2.3 Dizziness | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.06, 15.93] |
| 2.4 Abdominal pain | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.03 [0.32, 28.64] |
| 2.5 Headache | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.04, 3.18] |
| 2.6 Heaviness of the tongue | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.02 [0.19, 21.92] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: parasitological failure Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 at one month | 1 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.34, 0.61] |
| 1.2 at two to three months | 2 | 243 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.57, 0.79] |
| 1.3 at six months | 1 | 149 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.79, 1.01] |
| 1.4 at eight months | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.13, 0.36] |
| 2 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: haemoglobin Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 at baseline | 1 | 208 | Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐0.52, ‐0.08] |
| 2.2 at eight months | 1 | 208 | Mean Difference (IV, Fixed, 95% CI) | ‐0.40 [‐0.66, ‐0.14] |
| 3 Praziquantel 40 mg/kg single dose versus metrifonate 20 and 30 mg/kg given as split doses: parasitological failure Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 2 x 10 mg/kg Metrifonate at one month | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.80, 1.34] |
| 3.2 2 x 10 mg/kg Metrifonate at five months | 1 | 67 | Risk Ratio (M‐H, Random, 95% CI) | 0.82 [0.64, 1.05] |
| 3.3 3 x 10 mg/kg Metrifonate at three months | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.07, 1.57] |
| 3.4 3 x 10 mg/kg Metrifonate at six months | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 0.2 [0.02, 1.65] |
| 4 Praziquantel 40 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.1 Dizziness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 Abdominal pain | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 Joint pain | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.4 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.5 Rash | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.6 Vomiting | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.7 Itching | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.8 Fatigue | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.9 Hair loss | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.10 Change in taste | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.11 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.12 Convulsion | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: parasitological failure Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 at two months | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.17, 1.68] |
| 5.2 at four months | 1 | 52 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.07, 0.80] |
| 6 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Nausea | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.13, 70.83] |
| 6.2 Vomiting | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.2 [0.01, 4.00] |
| 6.3 Abdominal pain | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.12, 0.92] |
| 6.4 Headache | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.87] |
| 6.5 Fever | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.87] |
| 6.6 Loose bowel motions | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.07, 15.26] |
| 6.7 Dizziness | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.07, 15.26] |
| 6.8 Itching | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.07, 15.26] |
| 6.9 Body pain | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.07, 15.26] |
| 7 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 Parasitological failure at one year | 1 | 1436 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [1.00, 1.11] |
| 7.2 Haematuria at one year | 1 | 1400 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.85, 1.36] |
| 7.3 Proteinuria at one year | 1 | 1400 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.79, 1.11] |
| 8 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months: parasitological failure Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 at one year | 1 | 1018 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.61, 1.00] |
| 8.2 at two years | 1 | 1025 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.53, 1.11] |
| 8.3 at three years | 1 | 827 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.42, 0.93] |
| 9 Praziquantel 40 mg/kg versus praziquantel 10 mg/kg and metrifonate 10 mg/kg Show forest plot | 1 | 72 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.34, 1.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at eight weeks Show forest plot | 2 | 251 | Risk Ratio (M‐H, Random, 95% CI) | 0.53 [0.16, 1.71] |
| 2 Haematuria Show forest plot | 1 | 119 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.85, 1.76] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1 Headache | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Vomiting | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Fever | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.4 Itching | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.5 Cough | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.6 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.7 Chills | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.8 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.9 Dizziness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.10 Abdominal pain | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.11 Constipation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 at day 28 | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 0.15 [0.05, 0.46] |
| 1.2 at day 56 | 2 | 352 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.23, 1.44] |
| 2 Haematuria Show forest plot | 1 | 178 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.30, 0.62] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Abdominal pain | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Dizziness | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.3 Headache | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.43, 2.30] |
| 3.4 Vomiting | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.26, 3.89] |
| 3.5 Fever | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.41, 3.35] |
| 3.6 Itching | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.26, 3.89] |
| 3.7 Cough | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.14, 6.97] |
| 3.8 Diarrhoea | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.9 Chills | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.26, 8.79] |
| 3.10 Nausea | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.0 [0.14, 6.97] |
| 3.11 Constipation | 1 | 208 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.12, 72.80] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at eight weeks Show forest plot | 2 | 265 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.38, 0.99] |
| 2 Haematuria at eight weeks Show forest plot | 1 | 177 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.69 [0.40, 1.18] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1 Abdominal pain | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Dizziness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Headache | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.4 Vomiting | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.5 Fever | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.6 Itching | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.7 Cough | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.8 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.9 Chills | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.10 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.11 Constipation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at six weeks Show forest plot | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.57 [0.40, 0.83] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at one month Show forest plot | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.05, 0.43] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at one month Show forest plot | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.23 [0.07, 0.74] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure Show forest plot | 1 | 193 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.62, 1.30] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Parasitological failure at eight weeks Show forest plot | 2 | 265 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [1.01, 2.60] |
| 2 Haematuria at eight weeks Show forest plot | 1 | 177 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.45 [0.85, 2.50] |
| 3 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1 Abdominal pain | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Dizziness | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Headache | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.4 Vomiting | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.5 Fever | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.6 Itching | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.7 Cough | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.8 Diarrhoea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.9 Chills | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.10 Nausea | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.11 Constipation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
