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Efficacy of praziquantel syrup versus crushed praziquantel tablets in the treatment of intestinal schistosomiasis in Ugandan preschool children, with observation on compliance and safety
Transactions of the Royal Society of Tropical Medicine and Hygiene 106 (2012) 400–407
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Efficacy of praziquantel syrup versus crushed praziquantel tablets in the treatment of intestinal schistosomiasis in Ugandan preschool children, with observation on compliance and safety A.M.D. Navaratnam a,∗ , J.C. Sousa-Figueiredo b,c , J.R. Stothard b , N.B. Kabatereine d , A. Fenwick a , M.J. Mutumba-Nakalembe a a b c d
Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK Disease Control Strategy Group, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK Vector Control Division, Ministry of Health, Kampala, Uganda
a r t i c l e
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Article history: Received 19 August 2011 Received in revised form 28 March 2012 Accepted 28 March 2012 Available online 30 May 2012 Keywords: Child health Schistosoma mansoni Control programmes Mass drug administration Neglected tropical diseases Preventive chemotherapy
a b s t r a c t Preschool children (aged ≤5 years) have so far been overlooked by mass treatment campaigns targeting schistosomiasis, even though praziquantel (PZQ) has been shown to be well tolerated and effective within this age group. The WHO provided the Ugandan Ministry of Health with a syrup formulation of PZQ with the aim of assessing its safety and efficacy in comparison with crushed PZQ tablets for the treatment of intestinal schistosomiasis in preschool children. This study included 1144 preschool children randomly assigned to two treatment arms (PZQ syrup or crushed PZQ tablet) regardless of infection status for direct comparison. Diagnosis of intestinal schistosomiasis was assessed using single stool sample, double Kato–Katz smear examinations. Parasitological cure was assessed 3 weeks after treatment. The observed cure rate was 80.9% for the PZQ syrup arm and 81.7% for the crushed PZQ tablet arm, with egg reduction rates of 86.1% and 89.0%, respectively. Pre-treatment infection intensity was observed to influence cure rates significantly, with cure rates of 88.6% for light infections, 74.5% for moderate infections and 67.4% for heavy infections. No significant difference was found in non-compliance between the PZQ syrup (11.1%) and crushed PZQ tablet (14.7%) arms. PZQ syrup and crushed PZQ tablets have very similar efficacies in the treatment of intestinal schistosomiasis in preschool children. © 2012 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction Schistosomiasis is an important neglected tropical disease, affecting over 200 million people worldwide, particularly those living in rural communities with poor access to adequate sanitation.1 In Uganda alone, an estimated 4 million people are infected with Schistosoma spp. (particularly S. mansoni), with a prevalence that exceeds
∗ Corresponding author. Tel.: +44 7852 770 281. E-mail address: [email protected] (A.M.D. Navaratnam).
60% in 35 of the former 56 districts.2–4 A major intervention against schistosomiasis is preventive chemotherapy using praziquantel (PZQ) because of its efficacy, low cost and excellent safety record.5 To this end, a national-scale schistosomiasis and soil-transmitted helminth control programme was launched in 2003 targeting school-aged children >5 years old in endemic areas, which follows the standard WHO guidelines.1,4,6 With this focus upon school-aged children, S. mansoni infections in preschool children (aged ≤5 years) have been somewhat overlooked in mass drug administration (MDA) campaigns for a number of reasons, creating potential
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health inequality.7 These reasons include the basis that infant infections are hard to investigate using standard parasitological methods, which have low sensitivities for detection of schistosome infection.8 Preschool children were also assumed to have little contact with schistosomeinfested water, putting them at reduced risk of infection and/or they only have light intensity infections.8 Furthermore, producers of anthelminthic drugs provide prescribing information that excludes children <4 years of age owing to lack of information on treatment of this age group in terms of toxicity, adverse effects and pharmacokinetics.9 Young children are also thought to be at risk of choking due to the size, shape and palatability of PZQ tablets. All of the abovementioned reasons have dissuaded MDA initiatives to include younger children even though off-label use of PZQ is possible.9 Nonetheless, previous studies have found the administration of PZQ to preschoolers not only to be safe, with only minor and transient side effects recorded, but also efficacious against both urogenital and intestinal schistosomiasis, with reported cure rates ranging from 93.3% to 100% in Uganda and Zimbabwe.10–12 PZQ tablets are usually supplied as oblong-shaped tablets containing 600 mg of active ingredient, with three grooves for ease of subdivision into segments containing 150 mg of active ingredient each.13 In Uganda, using crushed PZQ tablets suspended in fruit juice is currently the pragmatic method for treatment of infants and preschool children to overcome issues of choking and palatability, but this approach is costly and a time-consuming process in targeted chemotherapy.10 Subject to their availability, specialist suspensions of PZQ syrup-based formulations could be a better alternative delivery strategy in targeted chemotherapy, but there are concerns, especially with its practicality in the field.10 Little information exists, however, on the safety and efficacy of the syrup formulation of PZQ. To investigate the performance of syrup-based PZQ, stocks of Epiquantel manufactured in Egypt, containing 600 mg/5 ml of active ingredient, were provided to the Ugandan Ministry of Health by the WHO to be used during targeted chemotherapy.14 In this study, the performance of Epiquantel in terms of therapeutic efficiency, non-compliance and side effects was assessed under field conditions alongside the crushed tablet alternative.
2. Methods 2.1. Cohort selection The field study was undertaken in June and July 2010 in Buliisa District (Lake Albert, western Uganda), a region that is economically poor and has a very high prevalence of S. mansoni infection, the latter being a reason for the selection of this area.15 The study took place in six villages along the shoreline of Lake Albert in this district, namely Booma (1◦ 48 49 N, 31◦ 20 58 E), Kawebanda (1◦ 48 18 N, 31◦ 19 27 E), Nyamukuta (1◦ 52 0 N, 31◦ 23 28 E), Piida A (1◦ 49 13 N, 31◦ 19 30 E), Sonsio (1◦ 52 49 N, 31◦ 23 44 E) and Tugombilli (1◦ 49 44 N, 31◦ 20 58 E). Baseline surveillance was conducted from 3–15 June 2010. Participants
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were recruited by the villages’ local health assistant and community medicine distributors, informing parents and guardians about the study’s objectives the day before it took place. In each village, the study site was situated in easily accessible locations, e.g. churches or health centres. Families with preschool children (aged 12 months to 5 years) that volunteered to participate in the study were then fully informed about the study in the local language and written (or fingerprinted) informed consent was obtained. Those who volunteered were included in the study. Infants who were patently unwell were excluded and were taken to the local health centre. All children recruited had never been treated with PZQ previously. Participants were randomly placed in one of two treatment arms regardless of infection status; crushed PZQ tablet or PZQ syrup. Every second child was assigned to the same treatment arm. This was not a double-blinded study. 2.2. Treatment with praziquantel All children were treated regardless of infection status under one of the two treatment arms: PZQ syrup, Epiquantel (Egyptian International Pharmaceutical Industries Co. A.R.E, Cairo, Egypt); or crushed PZQ tablet (Shin Poong, Seoul, South Korea) dissolved in orange juice. All children were provided with juice and mandazi (local bread) at the time of treatment to ensure that treatment was not taken on an empty stomach. Standard doses were calculated using weight (40 mg/kg).16 For PZQ syrup, weight thresholds of 7.5, 11.25, 15.0 and 18.5 kg were used corresponding to 2.5, 3.75, 5 and 7.5 ml. In addition, a chewable albendazole tablet (GlaxoSmithKline, Uxbridge, UK) was administered to each child to treat soil-transmitted helminths (1/2 tablet if <2 years of age). Lonart antimalarials (Bliss Gvs Pharma Ltd., Mumbai, India) were administered on site to children who tested positive for Plasmodium falciparum using a Paracheck-Pf rapid diagnostic test (Orchid Biomedical Systems, Goa, India) or children who exhibited symptoms of malaria (fever). For malaria testing, a capillary blood sample was collected by pricking the infant’s index finger with a safety lancet. Infants were also given paracetamol if they presented with fever. Experienced local nurses from the local dispensary treated all children. Non-compliance was assessed by direct observation and was recorded as rejection by either spill, spit and/or vomit. These treatments were co-administered with PZQ during this study to replicate fully MDA protocols implemented in Uganda. 2.3. Symptoms questionnaire Before and 24 h after treatment, a side effects questionnaire consisting of 16 questions was carried out asking about the following symptoms: abdominal pain; vomiting; haematemesis; nausea; diarrhoea; cough; bloody stool; fatigue; headache; dizziness; drowsiness; fever; rash; swelling on any body parts; haematuria; and any other complaints including malaria. Questions were directed at the mother or guardian of the child and were asked either by a nurse or a health worker from the village’s health
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centre who was fluent in the local languages. A side effect or incident of symptoms is defined as a symptom absent at baseline and experienced after treatment. Amelioration is defined as a symptom that was experienced before treatment and was no longer present afterwards. 2.4. Diagnosis of Schistosoma mansoni and follow-up A single stool was received from each child and then duplicate 41.7 mg Kato–Katz thick smears were performed to determine S. mansoni faecal egg intensity of infection and parasitological cure rate by microscopy.17 Three weeks after treatment (24 June to 6 July 2010), preschool children who were positive for S. mansoni infection at baseline were re-tested by Kato–Katz examination as described above. 2.5. Targeted chemotherapy As the WHO provided PZQ syrup to determine its applicability in future targeted chemotherapy programmes, a large drug administration exercise was carried out in the same district as the main study, except in three different villages: Bugoigo (1◦ 54 22 N, 31◦ 24 32 E); Walukuba (1◦ 50 33 N, 31◦ 23 28 E); and Piida B (1◦ 49 4 N, 31◦ 19 27 E). Participants were recruited by local health assistants within each village by informing parents and guardians of the study the day before it took place. This exercise was conducted between 24 June and 4 July 2010. The same inclusion and exclusion criteria and site location criteria were applied. All children were treated with a single oral dose of PZQ syrup only, using height thresholds of 60, 84, 99 and 111 cm corresponding to doses of 2.5, 3.75, 5 and 7.5 ml. Non-compliance and side effects were assessed by direct observation and health questionnaires as described earlier. This exercise was carried out separately to the main study and none of the children recruited for the targeted chemotherapy exercise were participants of the main study. 2.6. Data management and analysis Data were collected and entered into Microsoft Word and Excel spreadsheet software 2007 (Microsoft Corp., Redmond, WA, USA). Data were analysed using Stata V.10 (StataCorp LP, College Station, TX, USA) statistical package and statistical significance was assessed at a p-value of <0.05. A 5% margin of error and 95% CIs for the prevalence of S. mansoni infection were estimated using the exact method, and a two-tailed Student’s t-test was conducted to compare arithmetic mean intensity of infection.18 Fisher’s exact test was used to compare differences in cure rates and egg reduction rates (ERR) between PZQ tablet and PZQ syrup using statistical package R 2.11.1.19 This test was also used for comparison of non-compliance and side effects between genders, age groups, heights, weights and villages. The ERR is the percentage reduction in egg intensity measured by eggs per gram of faeces (epg) 21 days after treatment, and cure rate refers to the percentage of the infected population negative for infection 21 days after drug treatment, both calculated using data from microscopy.
3. Results 3.1. Cohort population A total of 1144 preschool children were recruited into the study; treatment was unrecorded for 20 children, therefore 1124 (50.4% boys) were included in either the PZQ syrup arm (n = 549) or the crushed PZQ tablet arm (n = 575) (Figure 1). The overall mean age was 3.31 years (range 1.5–5 years). There was no significant difference in age between the two groups (p = 0.36). There was also no significant difference between treatment arms in the number of children who received Lonart antimalarials (OR = 0.99, 95% CI 0.83–1.18; p = 0.89) and paracetamol (OR = 1.0, 95% CI 0.81–1.23; p = 1.00). In the PZQ syrup and PZQ tablet cohorts, 148/549 (prevalence = 27.0%, 95% CI 23.3–30.9%) and 149/575 (prevalence = 25.9%, 95% CI 22.4–29.7%), respectively, were positive for S. mansoni, with no significant difference between the two groups (p = 0.79). The arithmetic mean intensity of infection among positives was 317.6 epg for the crushed tablet treatment arm and 292.1 epg for the syrup treatment arm, with no significant difference between the two groups (p = 0.72). There was no significant difference in the number of individuals within each infection intensity category (Table 1). Tugombilli had the highest prevalence (50.6%, 95% CI 39.5–61.6%; n = 85), followed by Nyamukuta (41.0%, 95% CI 33.8–48.5%; n = 183), Sonsio (35.1%, 95% CI 27.6–43.2%; n = 154), Piida A (23.5%, 95% CI 17.8–30.0%; n = 200), Kawebanda (18.2%, 95% CI 14.6–22.2%; n = 418) and Booma (2.4%, 95% CI 0.3–8.3%; n = 84) (Figure 2). The most heavily infected case was also the youngest at 1 year of age, a girl with 2400 epg in Sonsio village.
3.2. Observed cure rates Three weeks after treatment with crushed PZQ tablet and syrup formulations, 81.7% (89/109) and 80.9% (76/94) children, respectively, were found to be negative for intestinal schistosomiasis. The difference in cure rates between the crushed PZQ tablet and PZQ syrup arms was not significant (OR = 0.99, 95% CI 0.64–1.53; p = 1.00). Cure rates between S. mansoni infection categories regardless of PZQ formulation (crushed PZQ tablet or PZQ syrup) indicated an overall cure rate of 81.3%, with the highest cure rate in light infections (88.6%), followed by moderate infections (74.5%), whilst heavily infected children had the lowest cure rate (67.4%). Cure rates between S. mansoni infection categories were significantly different (OR = 0.50, 95% CI 0.33–0.76). Administration of crushed PZQ tablet had a mean ERR of 89.0% and PZQ syrup had an ERR of 86.1%. In children initially excreting 1–99 epg, the egg load decreased to 1.93 epg. Children initially excreting 100–399 epg decreased their egg load to 20.24 epg, and children excreting ≥400 epg decreased to 167.71 epg (Table 2). The difference in mean ERR between the PZQ tablet and PZQ syrup arms was not significantly different (OR = 1.27, 95% CI 0.78–2.09; p = 0.34).
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403
Enrolled at recruitment (n=1144)
Treatment received was unrecorded (n=20)
Tablet (n=575)
Syrup (n=549) Not egg-patent at baseline (n=827)
Infected with S. mansoni (n=149)
Infected with S. mansoni (n=148) Not present at 21-day follow-up (n=84) or did not provide a stool sample (n=10)
Follow-up stool sample (n=109)
Follow-up stool sample (n=94)
Figure 1. Diagram outlining the number of preschool children in each praziquantel treatment arm and those that were excluded from the analysis at various parts of the main cohort study only.
Table 1 Number of participants affected by various confounding factors in each praziquantel treatment arm Confounding factor
Tablet (n = 575)
262 No. of boys Mean age (years) 3.34 476 No. receiving Lonart antimalarials No. receiving paracetamol 281 No. infected with Schistosoma mansoni 149 No. in each S. mansoni infection intensity category 31 Heavy (≥400 epg) Medium (100–399 epg) 42 Light (≤99 epg) 76 317.56 Arithmetic mean intensity (epg)
Syrup (n = 549)
OR
95% CI
p-value
305 3.27 461 267 148
0.90 – 0.99 1.0 1.04
0.73–1.11 – 0.83–1.18 0.81–1.23 0.80–1.35
0.32 0.36 0.89 1.00 0.79
26 27 95 292.05
0.84 0.64 1.26 –
0.46–1.55 0.36–1.14 0.85–1.87 –
0.57 0.14 0.25 0.72
epg: eggs per gram of faeces.
Table 2 Arithmetic mean eggs per gram of faeces (epg) at baseline and after treatment at follow-up, overall and in each praziquantel treatment arm, by baseline infection intensity
Overall Baseline Follow-up Tablet Baseline Follow-up Syrup Baseline Follow-up
Heavy intensity (≥400 epg)
Medium intensity (100–399 epg)
Light intensity (≤99 epg)
1209.66 167.71
238.59 20.24
37.07 1.93
1117.04 149.22
227.65 9.88
37.83 1.83
1328.00 191.33
260.47 40.94
37.07 2.04
3.3. Compliance and side effects Of the 549 children treated with PZQ syrup formulation, 488 complied, and of the 575 children treated with crushed PZQ tablet, 490 complied. Non-compliance of PZQ syrup was 11.1% (95% CI 8.6–14.0%) and that of PZQ tablet was
14.7% (95% CI 12.0–18.0%), with no significant difference found between the two formulations (OR = 1.33, 95% CI 0.93–1.92; p = 0.11). Of the 508 children (249 in the syrup arm, 254 in the crushed tablet arm and 5 unrecorded) whose parents or guardians answered a health questionnaire, no significant
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Figure 2. Map illustrating where the field study took place along the shoreline of Lake Albert (western Uganda) and the prevalence of intestinal schistosomiasis found at baseline.
difference in the incidence of side effects between PZQ tablet and PZQ syrup was identified. The most common side effects in both treatment arms were dizziness, drowsiness and fatigue (Table 3). Amelioration of vomiting (OR = 1.65; p = 0.006) and per rectal bleeding (OR = 1.40; p = 0.007) was significantly higher when treated with crushed PZQ tablet. No significant difference was found in the amelioration of all other symptoms reported before and after treatment.
3.4. Targeted chemotherapy exercise In this exercise, 1095 children were enrolled (564 girls, 506 boys and 25 unrecorded) with a mean age of 2.87 years and a median age of 3 years. Of these 1095 children treated with PZQ syrup, a total of 100 (9.1%) reacted negatively to the syrup; 33 spilt, 59 spat and 8 vomited the medication. Of these 100 children who resisted treatment, 46 were 12 months old. Infants 12 months of age were 20.3 times
Table 3 Percentage of children who experienced amelioration of symptoms and side effects in each praziquantel treatment arm Tablet (n = 254)
Syrup (n = 249)
Amelioration
Abdominal pain Vomiting Haematemesis Nausea Diarrhoea Cough Bloody stool Fatigue Headache Dizziness Drowsiness Fever Rash Swelling Blood in urine a b
Side effect
Amelioration
Side effect
%
n/Na
%
n/Nb
%
n/Na
%
n/Nb
34.7 68.0 100.0 65.7 46.3 57.5 90.9 69.4 35.5 60.0 57.1 31.1 58.3 48.4 66.7
75/216 121/178 3/3 69/105 99/214 131/228 100/110 34/49 78/220 15/25 4/7 70/225 98/168 31/64 2/3
60.5 30.3 6.0 21.5 40.0 38.5 1.4 25.9 50.0 37.6 28.7 65.5 26.7 25.3 0.0
23/38 23/76 15/251 32/149 16/40 10/26 2/144 53/205 17/34 86/229 71/247 19/29 23/86 48/190 0/251
34.5 61.8 100.0 69.4 49.8 58.4 88.8 68.6 41.1 52.0 71.4 33.2 66.5 55.6 100.0
70/203 89/144 2/2 77/111 107/215 125/214 79/89 35/51 85/207 13/25 5/7 73/220 109/164 30/54 3/3
52.2 22.9 6.1 15.9 29.4 22.9 3.8 23.2 35.7 36.6 31.0 55.2 23.5 23.1 0.4
24/46 24/105 15/247 22/138 10/34 8/35 6/160 46/198 15/42 82/224 75/242 16/29 20/85 45/195 1/246
Number of children experiencing amelioration of symptom/total number of children with that symptom before treatment. Number of children experiencing side effect/total number of children without that symptom before treatment.
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more likely (p < 0.0001) to react negatively to the syrup formulation than 5 year olds. Non-compliance between villages varied, with the highest rate being in Kigungu, part of Bugoigo village (15.6%), and the lowest in Walukuba (3.4%). Although there was a higher non-compliance among girls than boys, no significant difference was found between genders. The most common post-treatment symptoms reported were abdominal pain (14.5%), diarrhoea (14.9%) and dizziness (7.5%). The only significant difference in symptom profile between genders was in the amelioration of vomiting (OR = 0.36; p < 0.01), with a higher prevalence among boys. With regard to the amelioration of ‘other’ symptoms, this was the flu in 121 of 133 girls and 87 of 121 boys. The only side effects categorised under ‘other’ symptoms were loss of appetite in boys, and the flu in all three cases among girls. There was no incidence of haematuria in either gender, which was expected since S. haematobium is absent from the study areas.
4. Discussion Baseline data from this study clearly demonstrate that intestinal schistosomiasis affects preschool children and therefore investigation is required into ways for their inclusion in targeted chemotherapy. Of the children screened, 26.0% (n = 297) were egg patent, categorising this prevalence as moderate and therefore in need of targeted chemotherapy. The PZQ syrup formulation was procured and donated to Uganda with the intention of improving safety and compliance and assessing its clinical efficacy against crushed tablets in targeted chemotherapy. From reviewing the published literature, this study appears to be the only study directly comparing the two formulations. The PZQ syrup formulation was demonstrated to have a cure rate of 80.9%, which was statistically equal to that obtained using the crushed PZQ tablet (cure rate 81.7%). As artemisinin-based therapies have been demonstrated to have antischistosomal activity, it is important to note that there was no significant difference in the number of children who were given Lonart antimalarials between treatment arms.20 There was a clear association between cure rates and infection intensities, however, with the highest cure rate being in low infection intensity categories (88.6%), followed by moderate (74.5%) and finally heavy infection intensity (67.4%). This has also been evident in previous studies, demonstrating a constantly higher cure rate in children with light intensity infections, and therefore direct comparison of cure rates alone is not a valid assessment of drug efficacy.21–24 Both PZQ syrup and PZQ tablet formulations proved to provide a high ERR in participants (86.1% and 89.0%, respectively), and neither proved to be significantly more efficacious than the other. This was more apparent in children with high intensity infections at baseline, an observation that is consistent with previous studies.21 Reduction in worm burden is beneficial, despite individuals not being completely cured, as the severity of pathology and morbidity in these endemic areas is determined by infection intensity of the individuals.5
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As procurement of the PZQ syrup formulation was driven by the intention to improve compliance and safety in the targeted chemotherapy of preschool children, it was interesting to find no significant difference between the syrup and the crushed tablet formulations in terms of compliance (p = 0.11). To mask the bitter taste of PZQ, aniseed flavouring was added to the syrup formulation, a flavour that is popular among children in North Africa where the syrup was developed (Egypt). This is not the case for East Africa, however, explaining why non-compliance was not significantly lower than crushed tablet. Other flavours should be explored before dismissing this formulation of the medication as a way to improve compliance. Non-compliance was much higher in the 1–2 year olds than in the 3–5 year olds (OR = 5.48, 95% CI 3.11–10.23; p < 0.001), possibly explained by the natural suspicion young children feel when faced with ‘medical staff’. Furthermore, an anecdotal observation from both studies reported here was that 1–2 year olds were more prone to cry or to be disturbed by the crying of others, therefore contributing to overall non-compliance. No significant difference was found between symptoms experienced 24 h after treatment with either formulation, indicating that they have a similar safety profile. This profile is similar to what has been previously reported about adverse reactions to PZQ, with 31.2% of school children also reporting dizziness in North East Ethiopia, providing more information to include preschool children in the prescriptive directions for drug administration.21,25,26 Children given crushed PZQ tablet did, however, have a significantly higher chance of amelioration of vomiting (OR = 1.65; p < 0.006) and rectal bleeding (OR = 1.40; p = 0.007). As there was no significant difference in non-compliance, efficacy and co-administration of other substances (i.e. artemisinins, albendazole and food substances) between treatment arms and little is known about the mechanism of action of PZQ and its syrup formulation, it is only possible to hypothesise what caused this significant difference.27 This approach of using a health questionnaire 24 h after treatment to gather safety data does not allow distinguishing between disease-related and drug-related events, therefore the frequency of events is independent of causality.28 The financial and practical implications of using PZQ syrup in this study must also be explored to assess fully its use in targeted chemotherapy. PZQ syrup was stored in small glass bottles containing 600 mg, the equivalent of three doses. To treat 1000 preschool children, 13 boxes (25 glass bottles of syrup per box) were transported to the field site, whereas with tablets only one plastic container is needed for the same number of children. The crushed tablet system has the disadvantage of needing juice; however, in Uganda, one does not need to transport juice because it can be sourced locally. Something else to consider is the fact that several PZQ syrup glass bottles were accidently broken or cracked after storage or transport during this exercise, and therefore were not safe to use, creating problems in the logistics of the fieldwork. Furthermore, bottles were prone to leak after first use and so created difficulty removing the lids, which was overcome by using a knife. Both the broken glass and requiring a knife to open the glass bottles not only affects
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the efficiency of the targeted chemotherapy operation but also creates potential severe safety hazards. Perhaps this logistical and safety issue could be overcome by using plastic containers for storage of the syrup formulation.
were enrolled in the study. All information was kept confidential by personal information being removed from the data set before analyses were undertaken. References
5. Conclusion The results of this study have further revealed that children under-5 are at risk of intestinal schistosomiasis and that this important public health issue can be resolved. The study has also demonstrated high efficacy of crushed PZQ tablet and PZQ syrup at the recommended dose of 40 mg/kg, with no significant difference between the two formulations in terms of parasitological performance. On the whole, there was no difference in safety and non-compliance between the two formulations, with the few recorded side effects in both groups being mild and transient in nature. Both PZQ formulations proved to be effective for targeted chemotherapy campaigns in preschool children. However, further syrup flavours and packaging solutions should be explored if the syrup is to be extensively used in future for the treatment of preschoolers. Authors’ contributions: MJM-N, AMDN and NBK coordinated and conducted the fieldwork with the Vector Control Division field team, analysed and interpreted the data, and drafted the manuscript; AF and NBK conceived the study and assisted in the drafting of the manuscript, with NBK being the local contact and supervisor of the fieldwork; JRS provided guidance in the field and assisted in drafting the manuscript; JCS-F assisted in analysis and interpretation of the data. All authors revised and read and approved the final manuscript. NBK is guarantor of the paper. Acknowledgements: The authors would like to thank the children, mothers, nurses and healthcare workers who took part in this study. The authors are also grateful to the Vector Control Division and the field team members who assisted in the surveys and drug administration. Further thanks go to the WHO, and Lester Chitsulo in particular, for providing the study with the praziquantel syrup formulation. Funding: This project was financially supported by the Bill & Melinda Gates Foundation, the Schistosomiasis Control Initiative and Imperial College London. Competing interests: None declared. Ethical approval: Ethical approval for this study was granted by the Ugandan National Council of Science and Technology and the London School of Hygiene & Tropical Medicine (application nos. LSHTM 06 45 and LSHTM 5538.09). The project was supported by Imperial College London, the National History Museum and the London School of Hygiene & Tropical Medicine. Before the study was carried out, local health workers and community leaders informed villagers about the purpose of this study. Only children with oral consent from their parent or guardian
1. WHO. Schistosomiasis. Geneva: World Health Organization; http://www.who.int/schistosomiasis/en/ [accessed 2 November 2010]. 2. Kabatereine NB, Brooker S, Tukahebwa EM, Kazibwe F, Onapa AW. Epidemiology and geography of Schistosoma mansoni in Uganda: implications for planning control. Trop Med Int Health 2004;9:372–80. 3. Kabatereine NB, Tukahebwa E, Kazibwe F, et al. Progress towards countrywide control of schistosomiasis and soil-transmitted helminthiasis in Uganda. Trans R Soc Trop Med Hyg 2006;100:208–15. 4. Kabatereine NB, Fleming FM, Nyandindi U, Mwanza JCL, Blair L. The control of schistosomiasis and soil-transmitted helminths in East Africa. Trends Parasitol 2006;22:332–9. 5. Mott KE. ‘Control of schistosomiasis’: morbidity-reduction and chemotherapy. Acta Leiden 1982;49:101–11. 6. Fleming FM, Fenwick A, Tukahebwa EM, et al. Process evaluation of schistosomiasis control in Uganda, 2003 to 2006: perceptions, attitudes and constraints of a national programme. Parasitology 2009;136:1–11. 7. Johansen MV, Sacko M, Vennervald BJ, Kabatereine NB. Leave children untreated and sustain inequity! Trends Parasitol 2007;23:568–9, author reply 569-70. 8. Odogwu SE, Ramamurthy NK, Kabatereine NB, et al. Schistosoma mansoni in infants (aged <3 years) along the Ugandan shoreline of Lake Victoria. Ann Trop Med Parasitol 2006;100:315–26. 9. Montresor A, Stoltzfus RJ, Albonico M, et al. Is the exclusion of children under 24 months from anthelmintic treatment justifiable? Trans R Soc Trop Med Hyg 2002;96:197–9. 10. Sousa-Figueiredo JC, Pleasant J, Day M, et al. Treatment of intestinal schistosomiasis in Ugandan preschool children: best diagnosis, treatment efficacy and side-effects, and an extended praziquantel dosing pole. Int Health 2010;2:103–13. 11. Mutapi F, Rujeni N, Bourke C, et al. Schistosoma haematobium treatment in 1–5 year old children: safety and efficacy of the antihelminthic drug praziquantel. PLoS Negl Trop Dis 2011;5:e1143. 12. Sousa-Figueiredo JC, Day M, Betson M, et al. Field survey for strongyloidiasis in eastern Uganda with observations on efficacy of preventive chemotherapy and co-occurrence of soil-transmitted helminthiasis/intestinal schistosomiasis. J Helminthol 2011;85:325–33. 13. Cioli D, Pica-Mattoccia L. Praziquantel. Parasitol Res 2003;90(Suppl 1): S3–9. 14. Doenhoff MJ, Hagan P, Cioli D, et al. Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs. Parasitology 2009;136:1825–35. 15. Kazibwe F, Makanga B, Rubaire-Akiiki C, et al. Transmission studies of intestinal schistosomiasis in Lake Albert, Uganda and experimental compatibility of local Biomphalaria spp. Parasitol Int 2010;59:49–53. 16. Hall A, Nokes C, Wen ST, et al. Alternatives to bodyweight for estimating the dose of praziquantel needed to treat schistosomiasis. Trans R Soc Trop Med Hyg 1999;93:653–8. 17. Katz N, Chaves A, Pellegrino J. A simple device for quantitative stool thick-smear technique in schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo 1972;14:397–400. 18. Armitage P, Berry G. Statistical methods in medical research. Oxford, UK: Blackwell Scientific Publications; 1994. 19. Fisher RA. On the interpretation of chi-square from contingency tables and the calculation of P. J R Stat Soc 1922;85:87–94. 20. Obonyo CO, Muok EM, Mwinzi PN. Efficacy of artesunate with sulfalene plus pyrimethamine versus praziquantel for treatment of Schistosoma mansoni in Kenyan children: an open-label randomised controlled trial. Lancet Infect Dis 2010;10:603–11. 21. Kabatereine NB, Kemijumbi J, Ouma JH, et al. Efficacy and side effects of praziquantel treatment in a highly endemic Schistosoma mansoni focus at Lake Albert, Uganda. Trans R Soc Trop Med Hyg 2003;97:599–603. 22. Xiao SH, Catto BA, Webster Jr LT. Effects of praziquantel on different developmental stages of Schistosoma mansoni in vitro and in vivo. J Infect Dis 1985;151:1130–7. 23. Berhe N, Medhin G, Erko B, et al. Variations in helminth faecal egg counts in Kato–Katz thick smears and their implications in assessing infection status with Schistosoma mansoni. Acta Trop 2004;92:205–12. 24. Montresor A. Cure rate is not a valid indicator for assessing drug efficacy and impact of preventive chemotherapy interventions against
A.M.D. Navaratnam et al. / Transactions of the Royal Society of Tropical Medicine and Hygiene 106 (2012) 400–407 schistosomiasis and soil-transmitted helminthiasis. Trans R Soc Trop Med Hyg 2011;105:361–3. 25. Gryseels B, Nkulikyinka L, Coosemans MH. Field trials of praziquantel and oxamniquine for the treatment of schistosomiasis mansoni in Burundi. Trans R Soc Trop Med Hyg 1987;81:641–4. 26. Berhe N, Gundersen SG, Abebe F, Birrie H, Girmay M, Teferi G. Praziquantel side effects and efficacy related to Schistosoma mansoni egg loads and morbidity in primary school children in north-east Ethiopia. Acta Trop 1999;72:53–63.
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27. Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 2008;21:659–67. 28. Olliaro PL, Vaillant MT, Belizario VJ, et al. A multicentre randomized controlled trial of the efficacy and safety of single-dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil. PLoS Negl Trop Dis 2011;5:e1165.
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Efficacy of praziquantel syrup versus crushed praziquantel tablets in the treatment of intestinal schistosomiasis in Ugandan preschool children, with observation on compliance and safety A.M.D. Navaratnam a,∗ , J.C. Sousa-Figueiredo b,c , J.R. Stothard b , N.B. Kabatereine d , A. Fenwick a , M.J. Mutumba-Nakalembe a a b c d
Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK Disease Control Strategy Group, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK Vector Control Division, Ministry of Health, Kampala, Uganda
a r t i c l e
i n f o
Article history: Received 19 August 2011 Received in revised form 28 March 2012 Accepted 28 March 2012 Available online 30 May 2012 Keywords: Child health Schistosoma mansoni Control programmes Mass drug administration Neglected tropical diseases Preventive chemotherapy
a b s t r a c t Preschool children (aged ≤5 years) have so far been overlooked by mass treatment campaigns targeting schistosomiasis, even though praziquantel (PZQ) has been shown to be well tolerated and effective within this age group. The WHO provided the Ugandan Ministry of Health with a syrup formulation of PZQ with the aim of assessing its safety and efficacy in comparison with crushed PZQ tablets for the treatment of intestinal schistosomiasis in preschool children. This study included 1144 preschool children randomly assigned to two treatment arms (PZQ syrup or crushed PZQ tablet) regardless of infection status for direct comparison. Diagnosis of intestinal schistosomiasis was assessed using single stool sample, double Kato–Katz smear examinations. Parasitological cure was assessed 3 weeks after treatment. The observed cure rate was 80.9% for the PZQ syrup arm and 81.7% for the crushed PZQ tablet arm, with egg reduction rates of 86.1% and 89.0%, respectively. Pre-treatment infection intensity was observed to influence cure rates significantly, with cure rates of 88.6% for light infections, 74.5% for moderate infections and 67.4% for heavy infections. No significant difference was found in non-compliance between the PZQ syrup (11.1%) and crushed PZQ tablet (14.7%) arms. PZQ syrup and crushed PZQ tablets have very similar efficacies in the treatment of intestinal schistosomiasis in preschool children. © 2012 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
1. Introduction Schistosomiasis is an important neglected tropical disease, affecting over 200 million people worldwide, particularly those living in rural communities with poor access to adequate sanitation.1 In Uganda alone, an estimated 4 million people are infected with Schistosoma spp. (particularly S. mansoni), with a prevalence that exceeds
∗ Corresponding author. Tel.: +44 7852 770 281. E-mail address: [email protected] (A.M.D. Navaratnam).
60% in 35 of the former 56 districts.2–4 A major intervention against schistosomiasis is preventive chemotherapy using praziquantel (PZQ) because of its efficacy, low cost and excellent safety record.5 To this end, a national-scale schistosomiasis and soil-transmitted helminth control programme was launched in 2003 targeting school-aged children >5 years old in endemic areas, which follows the standard WHO guidelines.1,4,6 With this focus upon school-aged children, S. mansoni infections in preschool children (aged ≤5 years) have been somewhat overlooked in mass drug administration (MDA) campaigns for a number of reasons, creating potential
0035-9203/$ – see front matter © 2012 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.trstmh.2012.03.013
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health inequality.7 These reasons include the basis that infant infections are hard to investigate using standard parasitological methods, which have low sensitivities for detection of schistosome infection.8 Preschool children were also assumed to have little contact with schistosomeinfested water, putting them at reduced risk of infection and/or they only have light intensity infections.8 Furthermore, producers of anthelminthic drugs provide prescribing information that excludes children <4 years of age owing to lack of information on treatment of this age group in terms of toxicity, adverse effects and pharmacokinetics.9 Young children are also thought to be at risk of choking due to the size, shape and palatability of PZQ tablets. All of the abovementioned reasons have dissuaded MDA initiatives to include younger children even though off-label use of PZQ is possible.9 Nonetheless, previous studies have found the administration of PZQ to preschoolers not only to be safe, with only minor and transient side effects recorded, but also efficacious against both urogenital and intestinal schistosomiasis, with reported cure rates ranging from 93.3% to 100% in Uganda and Zimbabwe.10–12 PZQ tablets are usually supplied as oblong-shaped tablets containing 600 mg of active ingredient, with three grooves for ease of subdivision into segments containing 150 mg of active ingredient each.13 In Uganda, using crushed PZQ tablets suspended in fruit juice is currently the pragmatic method for treatment of infants and preschool children to overcome issues of choking and palatability, but this approach is costly and a time-consuming process in targeted chemotherapy.10 Subject to their availability, specialist suspensions of PZQ syrup-based formulations could be a better alternative delivery strategy in targeted chemotherapy, but there are concerns, especially with its practicality in the field.10 Little information exists, however, on the safety and efficacy of the syrup formulation of PZQ. To investigate the performance of syrup-based PZQ, stocks of Epiquantel manufactured in Egypt, containing 600 mg/5 ml of active ingredient, were provided to the Ugandan Ministry of Health by the WHO to be used during targeted chemotherapy.14 In this study, the performance of Epiquantel in terms of therapeutic efficiency, non-compliance and side effects was assessed under field conditions alongside the crushed tablet alternative.
2. Methods 2.1. Cohort selection The field study was undertaken in June and July 2010 in Buliisa District (Lake Albert, western Uganda), a region that is economically poor and has a very high prevalence of S. mansoni infection, the latter being a reason for the selection of this area.15 The study took place in six villages along the shoreline of Lake Albert in this district, namely Booma (1◦ 48 49 N, 31◦ 20 58 E), Kawebanda (1◦ 48 18 N, 31◦ 19 27 E), Nyamukuta (1◦ 52 0 N, 31◦ 23 28 E), Piida A (1◦ 49 13 N, 31◦ 19 30 E), Sonsio (1◦ 52 49 N, 31◦ 23 44 E) and Tugombilli (1◦ 49 44 N, 31◦ 20 58 E). Baseline surveillance was conducted from 3–15 June 2010. Participants
401
were recruited by the villages’ local health assistant and community medicine distributors, informing parents and guardians about the study’s objectives the day before it took place. In each village, the study site was situated in easily accessible locations, e.g. churches or health centres. Families with preschool children (aged 12 months to 5 years) that volunteered to participate in the study were then fully informed about the study in the local language and written (or fingerprinted) informed consent was obtained. Those who volunteered were included in the study. Infants who were patently unwell were excluded and were taken to the local health centre. All children recruited had never been treated with PZQ previously. Participants were randomly placed in one of two treatment arms regardless of infection status; crushed PZQ tablet or PZQ syrup. Every second child was assigned to the same treatment arm. This was not a double-blinded study. 2.2. Treatment with praziquantel All children were treated regardless of infection status under one of the two treatment arms: PZQ syrup, Epiquantel (Egyptian International Pharmaceutical Industries Co. A.R.E, Cairo, Egypt); or crushed PZQ tablet (Shin Poong, Seoul, South Korea) dissolved in orange juice. All children were provided with juice and mandazi (local bread) at the time of treatment to ensure that treatment was not taken on an empty stomach. Standard doses were calculated using weight (40 mg/kg).16 For PZQ syrup, weight thresholds of 7.5, 11.25, 15.0 and 18.5 kg were used corresponding to 2.5, 3.75, 5 and 7.5 ml. In addition, a chewable albendazole tablet (GlaxoSmithKline, Uxbridge, UK) was administered to each child to treat soil-transmitted helminths (1/2 tablet if <2 years of age). Lonart antimalarials (Bliss Gvs Pharma Ltd., Mumbai, India) were administered on site to children who tested positive for Plasmodium falciparum using a Paracheck-Pf rapid diagnostic test (Orchid Biomedical Systems, Goa, India) or children who exhibited symptoms of malaria (fever). For malaria testing, a capillary blood sample was collected by pricking the infant’s index finger with a safety lancet. Infants were also given paracetamol if they presented with fever. Experienced local nurses from the local dispensary treated all children. Non-compliance was assessed by direct observation and was recorded as rejection by either spill, spit and/or vomit. These treatments were co-administered with PZQ during this study to replicate fully MDA protocols implemented in Uganda. 2.3. Symptoms questionnaire Before and 24 h after treatment, a side effects questionnaire consisting of 16 questions was carried out asking about the following symptoms: abdominal pain; vomiting; haematemesis; nausea; diarrhoea; cough; bloody stool; fatigue; headache; dizziness; drowsiness; fever; rash; swelling on any body parts; haematuria; and any other complaints including malaria. Questions were directed at the mother or guardian of the child and were asked either by a nurse or a health worker from the village’s health
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centre who was fluent in the local languages. A side effect or incident of symptoms is defined as a symptom absent at baseline and experienced after treatment. Amelioration is defined as a symptom that was experienced before treatment and was no longer present afterwards. 2.4. Diagnosis of Schistosoma mansoni and follow-up A single stool was received from each child and then duplicate 41.7 mg Kato–Katz thick smears were performed to determine S. mansoni faecal egg intensity of infection and parasitological cure rate by microscopy.17 Three weeks after treatment (24 June to 6 July 2010), preschool children who were positive for S. mansoni infection at baseline were re-tested by Kato–Katz examination as described above. 2.5. Targeted chemotherapy As the WHO provided PZQ syrup to determine its applicability in future targeted chemotherapy programmes, a large drug administration exercise was carried out in the same district as the main study, except in three different villages: Bugoigo (1◦ 54 22 N, 31◦ 24 32 E); Walukuba (1◦ 50 33 N, 31◦ 23 28 E); and Piida B (1◦ 49 4 N, 31◦ 19 27 E). Participants were recruited by local health assistants within each village by informing parents and guardians of the study the day before it took place. This exercise was conducted between 24 June and 4 July 2010. The same inclusion and exclusion criteria and site location criteria were applied. All children were treated with a single oral dose of PZQ syrup only, using height thresholds of 60, 84, 99 and 111 cm corresponding to doses of 2.5, 3.75, 5 and 7.5 ml. Non-compliance and side effects were assessed by direct observation and health questionnaires as described earlier. This exercise was carried out separately to the main study and none of the children recruited for the targeted chemotherapy exercise were participants of the main study. 2.6. Data management and analysis Data were collected and entered into Microsoft Word and Excel spreadsheet software 2007 (Microsoft Corp., Redmond, WA, USA). Data were analysed using Stata V.10 (StataCorp LP, College Station, TX, USA) statistical package and statistical significance was assessed at a p-value of <0.05. A 5% margin of error and 95% CIs for the prevalence of S. mansoni infection were estimated using the exact method, and a two-tailed Student’s t-test was conducted to compare arithmetic mean intensity of infection.18 Fisher’s exact test was used to compare differences in cure rates and egg reduction rates (ERR) between PZQ tablet and PZQ syrup using statistical package R 2.11.1.19 This test was also used for comparison of non-compliance and side effects between genders, age groups, heights, weights and villages. The ERR is the percentage reduction in egg intensity measured by eggs per gram of faeces (epg) 21 days after treatment, and cure rate refers to the percentage of the infected population negative for infection 21 days after drug treatment, both calculated using data from microscopy.
3. Results 3.1. Cohort population A total of 1144 preschool children were recruited into the study; treatment was unrecorded for 20 children, therefore 1124 (50.4% boys) were included in either the PZQ syrup arm (n = 549) or the crushed PZQ tablet arm (n = 575) (Figure 1). The overall mean age was 3.31 years (range 1.5–5 years). There was no significant difference in age between the two groups (p = 0.36). There was also no significant difference between treatment arms in the number of children who received Lonart antimalarials (OR = 0.99, 95% CI 0.83–1.18; p = 0.89) and paracetamol (OR = 1.0, 95% CI 0.81–1.23; p = 1.00). In the PZQ syrup and PZQ tablet cohorts, 148/549 (prevalence = 27.0%, 95% CI 23.3–30.9%) and 149/575 (prevalence = 25.9%, 95% CI 22.4–29.7%), respectively, were positive for S. mansoni, with no significant difference between the two groups (p = 0.79). The arithmetic mean intensity of infection among positives was 317.6 epg for the crushed tablet treatment arm and 292.1 epg for the syrup treatment arm, with no significant difference between the two groups (p = 0.72). There was no significant difference in the number of individuals within each infection intensity category (Table 1). Tugombilli had the highest prevalence (50.6%, 95% CI 39.5–61.6%; n = 85), followed by Nyamukuta (41.0%, 95% CI 33.8–48.5%; n = 183), Sonsio (35.1%, 95% CI 27.6–43.2%; n = 154), Piida A (23.5%, 95% CI 17.8–30.0%; n = 200), Kawebanda (18.2%, 95% CI 14.6–22.2%; n = 418) and Booma (2.4%, 95% CI 0.3–8.3%; n = 84) (Figure 2). The most heavily infected case was also the youngest at 1 year of age, a girl with 2400 epg in Sonsio village.
3.2. Observed cure rates Three weeks after treatment with crushed PZQ tablet and syrup formulations, 81.7% (89/109) and 80.9% (76/94) children, respectively, were found to be negative for intestinal schistosomiasis. The difference in cure rates between the crushed PZQ tablet and PZQ syrup arms was not significant (OR = 0.99, 95% CI 0.64–1.53; p = 1.00). Cure rates between S. mansoni infection categories regardless of PZQ formulation (crushed PZQ tablet or PZQ syrup) indicated an overall cure rate of 81.3%, with the highest cure rate in light infections (88.6%), followed by moderate infections (74.5%), whilst heavily infected children had the lowest cure rate (67.4%). Cure rates between S. mansoni infection categories were significantly different (OR = 0.50, 95% CI 0.33–0.76). Administration of crushed PZQ tablet had a mean ERR of 89.0% and PZQ syrup had an ERR of 86.1%. In children initially excreting 1–99 epg, the egg load decreased to 1.93 epg. Children initially excreting 100–399 epg decreased their egg load to 20.24 epg, and children excreting ≥400 epg decreased to 167.71 epg (Table 2). The difference in mean ERR between the PZQ tablet and PZQ syrup arms was not significantly different (OR = 1.27, 95% CI 0.78–2.09; p = 0.34).
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403
Enrolled at recruitment (n=1144)
Treatment received was unrecorded (n=20)
Tablet (n=575)
Syrup (n=549) Not egg-patent at baseline (n=827)
Infected with S. mansoni (n=149)
Infected with S. mansoni (n=148) Not present at 21-day follow-up (n=84) or did not provide a stool sample (n=10)
Follow-up stool sample (n=109)
Follow-up stool sample (n=94)
Figure 1. Diagram outlining the number of preschool children in each praziquantel treatment arm and those that were excluded from the analysis at various parts of the main cohort study only.
Table 1 Number of participants affected by various confounding factors in each praziquantel treatment arm Confounding factor
Tablet (n = 575)
262 No. of boys Mean age (years) 3.34 476 No. receiving Lonart antimalarials No. receiving paracetamol 281 No. infected with Schistosoma mansoni 149 No. in each S. mansoni infection intensity category 31 Heavy (≥400 epg) Medium (100–399 epg) 42 Light (≤99 epg) 76 317.56 Arithmetic mean intensity (epg)
Syrup (n = 549)
OR
95% CI
p-value
305 3.27 461 267 148
0.90 – 0.99 1.0 1.04
0.73–1.11 – 0.83–1.18 0.81–1.23 0.80–1.35
0.32 0.36 0.89 1.00 0.79
26 27 95 292.05
0.84 0.64 1.26 –
0.46–1.55 0.36–1.14 0.85–1.87 –
0.57 0.14 0.25 0.72
epg: eggs per gram of faeces.
Table 2 Arithmetic mean eggs per gram of faeces (epg) at baseline and after treatment at follow-up, overall and in each praziquantel treatment arm, by baseline infection intensity
Overall Baseline Follow-up Tablet Baseline Follow-up Syrup Baseline Follow-up
Heavy intensity (≥400 epg)
Medium intensity (100–399 epg)
Light intensity (≤99 epg)
1209.66 167.71
238.59 20.24
37.07 1.93
1117.04 149.22
227.65 9.88
37.83 1.83
1328.00 191.33
260.47 40.94
37.07 2.04
3.3. Compliance and side effects Of the 549 children treated with PZQ syrup formulation, 488 complied, and of the 575 children treated with crushed PZQ tablet, 490 complied. Non-compliance of PZQ syrup was 11.1% (95% CI 8.6–14.0%) and that of PZQ tablet was
14.7% (95% CI 12.0–18.0%), with no significant difference found between the two formulations (OR = 1.33, 95% CI 0.93–1.92; p = 0.11). Of the 508 children (249 in the syrup arm, 254 in the crushed tablet arm and 5 unrecorded) whose parents or guardians answered a health questionnaire, no significant
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Figure 2. Map illustrating where the field study took place along the shoreline of Lake Albert (western Uganda) and the prevalence of intestinal schistosomiasis found at baseline.
difference in the incidence of side effects between PZQ tablet and PZQ syrup was identified. The most common side effects in both treatment arms were dizziness, drowsiness and fatigue (Table 3). Amelioration of vomiting (OR = 1.65; p = 0.006) and per rectal bleeding (OR = 1.40; p = 0.007) was significantly higher when treated with crushed PZQ tablet. No significant difference was found in the amelioration of all other symptoms reported before and after treatment.
3.4. Targeted chemotherapy exercise In this exercise, 1095 children were enrolled (564 girls, 506 boys and 25 unrecorded) with a mean age of 2.87 years and a median age of 3 years. Of these 1095 children treated with PZQ syrup, a total of 100 (9.1%) reacted negatively to the syrup; 33 spilt, 59 spat and 8 vomited the medication. Of these 100 children who resisted treatment, 46 were 12 months old. Infants 12 months of age were 20.3 times
Table 3 Percentage of children who experienced amelioration of symptoms and side effects in each praziquantel treatment arm Tablet (n = 254)
Syrup (n = 249)
Amelioration
Abdominal pain Vomiting Haematemesis Nausea Diarrhoea Cough Bloody stool Fatigue Headache Dizziness Drowsiness Fever Rash Swelling Blood in urine a b
Side effect
Amelioration
Side effect
%
n/Na
%
n/Nb
%
n/Na
%
n/Nb
34.7 68.0 100.0 65.7 46.3 57.5 90.9 69.4 35.5 60.0 57.1 31.1 58.3 48.4 66.7
75/216 121/178 3/3 69/105 99/214 131/228 100/110 34/49 78/220 15/25 4/7 70/225 98/168 31/64 2/3
60.5 30.3 6.0 21.5 40.0 38.5 1.4 25.9 50.0 37.6 28.7 65.5 26.7 25.3 0.0
23/38 23/76 15/251 32/149 16/40 10/26 2/144 53/205 17/34 86/229 71/247 19/29 23/86 48/190 0/251
34.5 61.8 100.0 69.4 49.8 58.4 88.8 68.6 41.1 52.0 71.4 33.2 66.5 55.6 100.0
70/203 89/144 2/2 77/111 107/215 125/214 79/89 35/51 85/207 13/25 5/7 73/220 109/164 30/54 3/3
52.2 22.9 6.1 15.9 29.4 22.9 3.8 23.2 35.7 36.6 31.0 55.2 23.5 23.1 0.4
24/46 24/105 15/247 22/138 10/34 8/35 6/160 46/198 15/42 82/224 75/242 16/29 20/85 45/195 1/246
Number of children experiencing amelioration of symptom/total number of children with that symptom before treatment. Number of children experiencing side effect/total number of children without that symptom before treatment.
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more likely (p < 0.0001) to react negatively to the syrup formulation than 5 year olds. Non-compliance between villages varied, with the highest rate being in Kigungu, part of Bugoigo village (15.6%), and the lowest in Walukuba (3.4%). Although there was a higher non-compliance among girls than boys, no significant difference was found between genders. The most common post-treatment symptoms reported were abdominal pain (14.5%), diarrhoea (14.9%) and dizziness (7.5%). The only significant difference in symptom profile between genders was in the amelioration of vomiting (OR = 0.36; p < 0.01), with a higher prevalence among boys. With regard to the amelioration of ‘other’ symptoms, this was the flu in 121 of 133 girls and 87 of 121 boys. The only side effects categorised under ‘other’ symptoms were loss of appetite in boys, and the flu in all three cases among girls. There was no incidence of haematuria in either gender, which was expected since S. haematobium is absent from the study areas.
4. Discussion Baseline data from this study clearly demonstrate that intestinal schistosomiasis affects preschool children and therefore investigation is required into ways for their inclusion in targeted chemotherapy. Of the children screened, 26.0% (n = 297) were egg patent, categorising this prevalence as moderate and therefore in need of targeted chemotherapy. The PZQ syrup formulation was procured and donated to Uganda with the intention of improving safety and compliance and assessing its clinical efficacy against crushed tablets in targeted chemotherapy. From reviewing the published literature, this study appears to be the only study directly comparing the two formulations. The PZQ syrup formulation was demonstrated to have a cure rate of 80.9%, which was statistically equal to that obtained using the crushed PZQ tablet (cure rate 81.7%). As artemisinin-based therapies have been demonstrated to have antischistosomal activity, it is important to note that there was no significant difference in the number of children who were given Lonart antimalarials between treatment arms.20 There was a clear association between cure rates and infection intensities, however, with the highest cure rate being in low infection intensity categories (88.6%), followed by moderate (74.5%) and finally heavy infection intensity (67.4%). This has also been evident in previous studies, demonstrating a constantly higher cure rate in children with light intensity infections, and therefore direct comparison of cure rates alone is not a valid assessment of drug efficacy.21–24 Both PZQ syrup and PZQ tablet formulations proved to provide a high ERR in participants (86.1% and 89.0%, respectively), and neither proved to be significantly more efficacious than the other. This was more apparent in children with high intensity infections at baseline, an observation that is consistent with previous studies.21 Reduction in worm burden is beneficial, despite individuals not being completely cured, as the severity of pathology and morbidity in these endemic areas is determined by infection intensity of the individuals.5
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As procurement of the PZQ syrup formulation was driven by the intention to improve compliance and safety in the targeted chemotherapy of preschool children, it was interesting to find no significant difference between the syrup and the crushed tablet formulations in terms of compliance (p = 0.11). To mask the bitter taste of PZQ, aniseed flavouring was added to the syrup formulation, a flavour that is popular among children in North Africa where the syrup was developed (Egypt). This is not the case for East Africa, however, explaining why non-compliance was not significantly lower than crushed tablet. Other flavours should be explored before dismissing this formulation of the medication as a way to improve compliance. Non-compliance was much higher in the 1–2 year olds than in the 3–5 year olds (OR = 5.48, 95% CI 3.11–10.23; p < 0.001), possibly explained by the natural suspicion young children feel when faced with ‘medical staff’. Furthermore, an anecdotal observation from both studies reported here was that 1–2 year olds were more prone to cry or to be disturbed by the crying of others, therefore contributing to overall non-compliance. No significant difference was found between symptoms experienced 24 h after treatment with either formulation, indicating that they have a similar safety profile. This profile is similar to what has been previously reported about adverse reactions to PZQ, with 31.2% of school children also reporting dizziness in North East Ethiopia, providing more information to include preschool children in the prescriptive directions for drug administration.21,25,26 Children given crushed PZQ tablet did, however, have a significantly higher chance of amelioration of vomiting (OR = 1.65; p < 0.006) and rectal bleeding (OR = 1.40; p = 0.007). As there was no significant difference in non-compliance, efficacy and co-administration of other substances (i.e. artemisinins, albendazole and food substances) between treatment arms and little is known about the mechanism of action of PZQ and its syrup formulation, it is only possible to hypothesise what caused this significant difference.27 This approach of using a health questionnaire 24 h after treatment to gather safety data does not allow distinguishing between disease-related and drug-related events, therefore the frequency of events is independent of causality.28 The financial and practical implications of using PZQ syrup in this study must also be explored to assess fully its use in targeted chemotherapy. PZQ syrup was stored in small glass bottles containing 600 mg, the equivalent of three doses. To treat 1000 preschool children, 13 boxes (25 glass bottles of syrup per box) were transported to the field site, whereas with tablets only one plastic container is needed for the same number of children. The crushed tablet system has the disadvantage of needing juice; however, in Uganda, one does not need to transport juice because it can be sourced locally. Something else to consider is the fact that several PZQ syrup glass bottles were accidently broken or cracked after storage or transport during this exercise, and therefore were not safe to use, creating problems in the logistics of the fieldwork. Furthermore, bottles were prone to leak after first use and so created difficulty removing the lids, which was overcome by using a knife. Both the broken glass and requiring a knife to open the glass bottles not only affects
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the efficiency of the targeted chemotherapy operation but also creates potential severe safety hazards. Perhaps this logistical and safety issue could be overcome by using plastic containers for storage of the syrup formulation.
were enrolled in the study. All information was kept confidential by personal information being removed from the data set before analyses were undertaken. References
5. Conclusion The results of this study have further revealed that children under-5 are at risk of intestinal schistosomiasis and that this important public health issue can be resolved. The study has also demonstrated high efficacy of crushed PZQ tablet and PZQ syrup at the recommended dose of 40 mg/kg, with no significant difference between the two formulations in terms of parasitological performance. On the whole, there was no difference in safety and non-compliance between the two formulations, with the few recorded side effects in both groups being mild and transient in nature. Both PZQ formulations proved to be effective for targeted chemotherapy campaigns in preschool children. However, further syrup flavours and packaging solutions should be explored if the syrup is to be extensively used in future for the treatment of preschoolers. Authors’ contributions: MJM-N, AMDN and NBK coordinated and conducted the fieldwork with the Vector Control Division field team, analysed and interpreted the data, and drafted the manuscript; AF and NBK conceived the study and assisted in the drafting of the manuscript, with NBK being the local contact and supervisor of the fieldwork; JRS provided guidance in the field and assisted in drafting the manuscript; JCS-F assisted in analysis and interpretation of the data. All authors revised and read and approved the final manuscript. NBK is guarantor of the paper. Acknowledgements: The authors would like to thank the children, mothers, nurses and healthcare workers who took part in this study. The authors are also grateful to the Vector Control Division and the field team members who assisted in the surveys and drug administration. Further thanks go to the WHO, and Lester Chitsulo in particular, for providing the study with the praziquantel syrup formulation. Funding: This project was financially supported by the Bill & Melinda Gates Foundation, the Schistosomiasis Control Initiative and Imperial College London. Competing interests: None declared. Ethical approval: Ethical approval for this study was granted by the Ugandan National Council of Science and Technology and the London School of Hygiene & Tropical Medicine (application nos. LSHTM 06 45 and LSHTM 5538.09). The project was supported by Imperial College London, the National History Museum and the London School of Hygiene & Tropical Medicine. Before the study was carried out, local health workers and community leaders informed villagers about the purpose of this study. Only children with oral consent from their parent or guardian
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