Abstract

Introduction

The World Health Organization (WHO) currently recognizes 20 neglected tropical diseases (NTDs) mainly occurring in the tropics and sub-tropics (WHO, 2010). Schistosomiasis, the second most prevalent NTD, causes a significant public health problem in many parts of the world, mainly affecting people in Africa, Asia, the Caribbean, and South America (Hotez et al., 2007; U Olveda, 2013; Vos et al., 2017). Schistosoma haematobium (Schistosoma haematobium) and S. mansoni (Schistosoma mansoni) are the two most common species affecting people living in Sub-Saharan Africa (SSA), where 90% of the global disease burden occurs (Hotez and Kamath, 2009; Mnkugwe et al., 2020b; Gebreyesus et al., 2020). Schistosomiasis mainly affects children, and its chronic infection can lead to various health complications, including anemia, malnutrition, impaired childhood development, poor cognitive function, fatigue, and exercise intolerance (King and Dangerfield-Cha, 2008; Ezeamama et al., 2018).

Large-scale preventive chemotherapy with periodic mass administration of single-dose PZQ to all at-risk populations in endemic settings (deworming) is the core strategy to control and eliminate schistosomiasis recommended by the WHO. Previously, WHO set a target to eliminate schistosomiasis as a public health problem by reducing the disease burden to less than 1% with heavy infection by 2025 (WHO, 2013b). In addition to preventive chemotherapy, the WHO recommends supplementary control measures such as the provision of safe and clean drinking water, basic sanitation and hygiene, vector (snail) control, and health education (WHO, 2013b, 2015a). The revised WHO roadmap for NTD targets the elimination of schistosomiasis as a public health problem and interrupts schistosome transmission in endemic countries by 2030 (WHO, 2022a), contributing towards achieving Sustainable Development Goal 3.

During the past 2 decades, millions of school-age children received periodic PZQ preventive chemotherapy annually in endemic areas with a prevalence rate of ≥50% infection. The recent WHO recommendation increased the target population for PZQ preventive chemotherapy to all at risk age groups from 2 years old with 75% treatment coverage in areas where the prevalence of schistosomiasis infection is ≥10%. This scale-up in target population for preventive chemotherapy may impose a potential risk for parasite resistance (WHO, 2022b). The potential emergence of anthelmintic resistance could endanger progress towards these ambitious goals due to repeated sub-optimal drug exposure. Therefore, continued vigilance of the efficacy and safety of PZQ is recommended to evaluate the impact of the intervention and detect any reduced performance which may occurred due to parasite resistance (WHO, 2013a; WHO, 2022b). The world relies on PZQ for the treatment and prevention of schistosomiasis since there are no alternative drugs approved for the treatment of schistosomiasis so far (WHO, 2013a). Therefore, monitoring the treatment effectiveness is crucial as previous studies reported suboptimal PZQ efficacy (egg reduction rate <90%) and decreased cure rate after treatment (Crellen et al., 2016; Vale et al., 2017).

Repeated use of PZQ, especially in high transmission areas, may result in reduced efficacy (Crellen et al., 2016). Despite the repeated use of PZQ, the prevalence of schistosomiasis remains high in some areas (Alebie et al., 2014; Alemayehu and Tomass, 2015). Studies from SSA reported a low cure rate after single-dose PZQ administration for the treatment of schistosomiasis (Raso et al., 2004; Garba et al., 2013; Nalugwa et al., 2015; Crellen et al., 2016). Due to the reported low cure rate and reduced efficacy of PZQ after repeated administration in some areas, the WHO recommends that the NTD programs implementing MDA of PZQ to incorporate regular efficacy assessment in their working standard to monitor and evaluate the efficacy of the drug (WHO, 2010, 2015a). To sustain the impact of preventive chemotherapy and avoid possible future parasite resistance, additional measures like availing adequate clean water, implementing hygiene and sanitation programs, educating the community, and exploring other treatment options are crucial (Mnkugwe et al., 2020a).

Schistosoma mansoni, which causes the intestinal form of schistosomiasis, is endemic throughout Ethiopia (WHO_Africa, 2016). More than one-third of the Ethiopian population (39 million) is currently living in schistosomiasis endemic area (Leta et al., 2020), and the disease remains among the leading causes of morbidity in the country (Jember, 2014). Since 2014, the national NTD program of Ethiopia has been implementing targeted school-based mass drug administration (MDA) with PZQ and ALB annually in regions with a moderate-to-high prevalence of schistosomiasis and STHs infections (WHO_Africa, 2016). Although MDA is currently expanded to all endemic areas, surveillance data on treatment outcomes is limited. The efficacy and safety surveillance during PZQ mass drug administration (MDA), especially in high transmission areas, is essential to inform policymakers and NTD control programs on the effectiveness of the intervention in curing the diseases and reducing transmission. This study evaluated the efficacy of single-dose PZQ in treating S. mansoni infection and the safety of PZQ plus ALB preventive chemotherapy in S. mansoni infected school children in Ethiopia.

Methodology

Result

A total of 512 S. mansoni-infected children were enrolled in this study and received single-dose PZQ and ALB as preventive chemotherapy. Safety data were collected from all study participants during the 7-follow-up period. PZQ efficacy data were obtained from 507 to 345 children at weeks four and eight follow-up visits, respectively. The socio-demographic characteristics of the study participants are presented in Table 1. The frequency distributions of male and female participants were almost similar. At baseline, most participants had light infection intensity (71%) followed by moderate (24.1%). About 59.4% of the study participants were co-infected with STH. The proportions of wasted and stunted children were 8.7% and 16.4%, respectively.

Parasitological cure rates and associated factors

Study enrollment and flow chart with cure rate stratified by follow-up visits for the efficacy study (week four and week eight post-MDA) is presented in Figure 1. Cure rates (CR) and egg reduction rates (ERR) data were collected from 507 to 345 children at week four and week 8, respectively. The overall cure rates at week four and week eight of post-MDA were 89.1% (452/507, 95%CI = 86.1–91.7) and 87.5% (302/345, 95%CI = 83.6–90.8), respectively. The cure rates at week four significantly varied among the baseline infection intensity categories. Children with moderate to heavy infection intensity at baseline had significantly lower cure rates than those with light infection at both study follow-up weeks [week 4; 84.4% versus 91.1%, p = 0.026, Odds ratio (OR) = 1.90 (95% CI of OR = 1.05–3.33), at week 8 (78.6% versus 91.9%, p = 0.001, OR = 2.80 (95% CI of OR = 1.49–5.25)] (Figure 1; Table 2). Similarly, the cure rate was significantly higher (p = 0.01) among the older age groups (90.1%) compared to the lower age groups (79.5%) at week 8. Older age groups were more cured (90.1%) compared to the younger age groups (85.7%) at week 4 (p = 0.18). The cure rate was significantly associated with age group (p = 0.01) and baseline infection intensity (p = 0.001) at week eight follow-up. The cure rate was higher among male participants (90.1%) compared to females (88.2%) (Table 2).

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FIGURE 1

Study flow chart and observed cure rates stratified by treatment follow-up visits (in weeks).

TABLE 2

Cure rate and associated factors at week four and week eight of post-treatment.

Variables		Week 4 (n = 507)				Week 8 (n = 345)
		Cured N (%)	Not cured N (%)	X2	p	Cured N (%)	Not cured N (%)	X2	p
Overall		452 (89.2)	55 (10.8)			302 (87.5)	43 (12.5)
Infection intensity	Light	328 (91.1)	32 (8.9)	4.9	0.026	225 (91.9)	22 (8.9)	10.1	0.001
	Moderate-to-heavy	124 (84.4)	23 (15.6)			77 (78.6)	21 (21.4)
Age group	5–9	96 (85.7)	16 (14.3)	1.76	0.18	66 (79.5)	17 (20.5)	6.44	0.01
	10–15	356 (90.1)	39 (9.9)			236 (90.1)	26 (9.9)
Sex	Male	228 (90.1)	25 (9.9)	0.49	0.48	152 (87.9)	21 (12.1)	0.03	0.86
	Female	224 (88.2)	30 (10.8)			150 (87.2)	22 (12.8)
Schools	Bushulo	117 (88.6)	15 (11.4)	3.61	0.31	84 (90.3)	9 (9.7)	3.63	0.30
	Finchawa	18 (100)	0 0)			9 (100)	0 0)
	Kiduspawulos	121 (86.4)	19 (13.6)			103 (83.7)	20 (16.3)
	Wosha	196 (90.3)	21 (9.7)			106 (88.3)	14 (11.7)
Stunting (HAZ)	Stunted	72 (86.8)	11 (13.2)	0.59	0.44	47 (88.7)	6 (11.3)	0.07	0.78
	Not stunted	380 (89.6)	44 (10.4)			255 (87.3)	37 (12.7)
Wasting (BAZ)	Wasted	41 (93.2)	3 (6.8)	0.81	0.37	28 (82.4)	6 (17.6)	0.92	0.33
	Not wasted	411 (88.8)	52 11.2)			274 (88.1)	37 (11.9)
STH co-infection	Yes	268 (89.0)	33 (11.0)	0.01	0.92	169 (87.1)	25 (12.9)	0.07	0.79
	No	184 (89.3)	22 (10.7)			133 (88.1)	18 (11.9)

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Significant values are indicated in bold.

On the follow-up visit, 7.8% (27/345) of the children who were cured (Schistosoma egg-free) at week four became egg positive at week 8 (Figure 1). Sixteen children (4.6%, 16/345) were persistently not cured during the study period (egg-positive both at week four and week 8). Among the 16 children who failed to cure, 44% (7/16) had moderate to heavy infection intensity before treatment.

To identify predictors of cure rate at week 4, and week 8, we conducted univariate followed by multivariate logistic regression analysis. In the multivariate regression, baseline infection intensity was the only significant predictor of cure rate, being lower in moderate-to-heavy infected participants than those with light infection at baseline (p = 0.026). At week 8, the lower age group and moderate-to-heavy infection intensity at baseline were significant independent predictors of lower cure rate (p = 0.002 and 0.012) (Table 3).

TABLE 3

Predictors of cure rate at weeks four and week eight of post single dose praziquantel administrations.

Variables		Cured N (%)	Week 4				Week 8
			Univariate		Multivariate		Univariate		Multivariate
			cOR (95% CI)	p	aOR (95% CI)	p	cOR (95% CI)	p	aOR (95% CI)	p
Intensity of infection	Light	328 (91.1)
	Moderate-to-Heavy	124 (84.4)	0.53 (0.3–0.9)	0.028	0.5 (0.3–0.9)	0.028	0.4 (0.2–0.7)	0.002	0.4 (0.2–0.7)	0.002
Age group	5–9	96 (85.7)	0.7 (0.4–1.2)	0.18	0.7 (0.3–1.2)	0.18	0.4 (0.2–0.8)	0.013	0.4 (0.2–0.8)	0.012
	10–15	356 (90.1)
Sex	Male	228 (90.1)	0.8 (0.5–1.4)	0.48			0.99 (0.5–1.9)	0.98
	Female	224 (88.2)
STH infection	Yes	268 (89.0)
	No	184 (89.3)	1 (0.6–1.8)	0.92			1.1 (0.6–2.1)	0.68
HAZ	Normal	411 (88.8)
	Stunted	41 (93.2)	1.3 (0.7–2.7)	0.44			1.3 (0.7–2.4)	0.442
BAZ	Normal	380 (89.6)
	Wasted	72 (86.8)	0.6 (0.2–1.9)	0.37			0.6 (0.2–1.9)	0.372

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COR, crude odd ratio; AOR, Adjusted odd ratio; CI, Confidence Interval; Significant values are indicated in bold.

Discussion

We investigated the effectiveness of single-dose PZQ for the treatment of S. mansoni infection and the safety of PZQ plus ALB preventive chemotherapy among infected schoolchildren in southern Ethiopia. PZQ efficacy was assessed using the cure rate and egg reduction rate at week four and week eight to rule out any possible re-infection after being cured. Our result showed an overall high cure rate of PZQ with 89.1% and 87.5% at week four and week 8, respectively. Pre-treatment infection intensity and age were significant predictors of the cure rate. The observed egg reduction rate of 93.7% and 91.3% at week-4 and week-8, respectively, is above the 90% efficacy threshold set by WHO (WHO, 2013a). Accordingly, single-dose PZQ resulted in a satisfactory egg reduction rate at week four and week eight follow-ups. However, a reduced cure rate was observed among moderate to heavily infected and lower age group infected children. The higher egg reduction rate in moderate-to-heavy infected individuals may indicate that PZQ is still effective in reducing disease morbidity. However, preventive chemotherapy alone may not be adequate for controlling and eliminating schistosomiasis because the reduced cure rate in young children and moderate-to-heavily infected individuals may impede the progress toward halting the transmission.

The overall cure rate observed in our study at week four and week eight follow-up visits was nearly equal to the upper margin of the documented standard cure rate (60%–90%) for single-dose PZQ treatment (WHO, Expert committee report, 2002). This indicates that single-dose PZQ treatment resulted in satisfactory cure rate among school children in our study. Although PZQ preventive chemotherapy successfully reduced morbidity, PZQ alone may not be sufficient for the control and elimination of schistosomiasis, partly due to its poor efficacy against juvenile schistosomes (Inobaya et al., 2014). Despite the observed high cure rates in this study, 7.8% of the participants who were cured at week four became egg positive at the week eight follow-up visit. This might be attributed to either re-infection (new infection) or reduced egg clearance due to the poor PZQ effectiveness against juvenile worms, which may attain reproductive maturity to start laying eggs after week 4 (Inobaya et al., 2014). This could show the inadequacy of single-dose PZQ preventive chemotherapy alone to prevent and control S. mansoni. WHO also recommends the integration of other interventions in addition to the MDA towards preventing re-infection (WHO, 2022a). Repeated doses of PZQ or combining it with other anthelmintics that kills the juvenile schistosome is recommended to improve the efficacy against schistosomiasis (Munisi et al., 2017; Bergquist and Elmorshedy, 2018). A recent randomized clinical trial reported superior efficacy of PZQ and Dihydroartemisinin-piperaquine combination therapy (targeting both the adult and juvenile worm, respectively) than PZQ alone for treating intestinal schistosomiasis (Mnkugwe et al., 2020a).

The cure rate significantly varied across the infection intensity groups at baseline. The cure rate among moderate-to heavily infected children was significantly lower than children who had light infection intensity. In addition, the cure rate was lower among the younger age groups. This could be explained by the fact that the older age groups received higher doses of PZQ since the drug was given based on height. Like the cure rate, the ERR in the younger children was much lower than in older children at week-8 follow-up (Tables 2 and ​and4).4). A similar result was reported in a recent systematic review (Fukushige et al., 2021). Therefore, younger age groups may be at increased risk of reduced efficacy due to low cure rate and ERR.

The overall egg reduction rates observed at week four and week eight were above the 90% ERR threshold recommended by WHO guideline for assessing the efficacy of anthelmintic drugs (WHO, 2013a) which indicates its satisfactory result. Contrary to the lower cure rate, the moderate-to-heavily infected individuals had the highest ERR at both follow-up periods. A previous study reported that PZQ has a larger impact on the parasite fecundity, which may result in low egg count post-treatment (Lamberton et al., 2017). This may explain the higher ERR in moderate-to-heavily infected individuals. Since the morbidity of schistosomiasis is related to the burden of egg intensity (Fukushige et al., 2021), higher ERR among the moderate-to-heavily infected individual may reduce the morbidity associated with the disease and hence halt the transmission. Preventive chemotherapy in the form of MDA in endemic areas is implemented with the primary objective of morbidity reduction by reducing the intensity of infection after treatment (Kabatereine et al., 2003). Likewise, this higher egg reduction rate observed shows that single-dose PZQ treatment reduces morbidities associated with high egg burden in infected children which eventually help in the prevention of transmission for meeting the elimination goal.

PZQ and ALB were generally tolerated in our study participants, though 17% of the participants experienced at least one MDA-associated AE. Previous studies on school children reported an even higher incidence of AEs than we observed (Erko et al., 2012; Zwang and Olliaro, 2017; Muthoni et al., 2018). The relatively lower incidence of AEs could be due to our rigorous definition set for MDA-associated AEs (i.e., pre-existing clinical symptoms were cross-checked to verify that the same type of event was not reported after MDA). Higher incidence of MDA-associated AEs among females than males was observed, which is in line with recent studies conducted in SSA countries which assessed the safety of MDA for lymphatic filariasis (Khaemba et al., 2021; Fimbo et al., 2022). Like previous reports, abdominal pain and nausea were the most common AEs in our study. Most of the reported AEs were mild to moderate and transient, which indicates that single-dose PZQ and ALB treatment is safe and tolerable. However, the observed severe AEs in some children highlight the need to integrate safety surveillance into the MDA campaigns. Although millions of children are receiving periodic MDA in Africa, safety data are scarce partly due to the region’s lack of fully functional pharmacovigilance systems (Barry et al., 2020; 2021).

To assess PZQ efficacy, we used the Kato-Katz techniques as recommended by the WHO guideline, which indicates the CR and ERR reference thresholds to conclude on drug effectiveness (WHO, 2013a). Kato-Katz method is reported to be less sensitive in low infection intensity compared to the urine-based point-of-care circulating cathodic antigen test (POC-CCA). The WHO does not recommend detecting CCA using the POC-CCA test for parasitological drug efficacy assessment (WHO, 2013a). The POC-CCA test is recommended for mapping schistosomiasis prevalence and post-treatment infection monitoring (WHO, 2013b; Straily, et al., 2021). The suitability of the POC-CCA test in monitoring drug efficacy requires further evaluation, including the precise time for CCA clearance following PZQ treatment in different age groups and epidemiological setting remains to be established (Mazigo et al., 2021; Yin et al., 2021). Although the Kato-Katz technique is highly specific and can accurately detect high-intensity infection, its decreased sensitivity for diagnosis may result in overestimating the efficacy observed in our study, hence our study limitation. The Kato-Katz method used in our study may have a minor impact on our findings since the study was conducted in a high-infection-intensity area (Gebreyesus et al., 2020). Nevertheless, this PZQ efficacy and the safety surveillance of mass PZQ and ALB co-administration conducted in high transmission areas of Ethiopia may provide data to policymakers and NTD control programs on the effectiveness of the intervention in curing the diseases and reducing transmission.

Conclusion

In summary, single-dose PZQ treatment is still effective for treating S. mansoni infection and in reducing morbidity among moderate-to-heavy infected children, as shown by significant ERR. However, the observed lower cure rate, failure to cure, and re-infection in moderate-to-heavily infected and younger children may indicate reduced efficacy of PZQ. Therefore, preventive chemotherapy with PZQ alone may not be adequate to halt transmission and ultimately eliminate schistosomiasis as a public health problem. Alternative treatment strategies such as repeated dosage or combination therapy targeting juvenile and adult worms and integrating other preventive measures are recommended. Overall preventive chemotherapy with PZQ and ALB is generally safe and tolerable, and one-in-five schistosomiasis-infected children experience mild to moderate and transient adverse events. Our study finding highlights the need to integrate periodic efficacy and safety surveillance in the MDA programs for early detection of parasite resistance and management of AEs.

Acknowledgments

Funding Statement

This study was supported by the European and Developing Countries Clinical Trials Partnership (EDCTP) two program supported by the European Union and the Swedish International Development Cooperation Agency (SIDA) as part of the Pharmacovigilance infrastructure and post-marketing surveillance system capacity building for regional medicine regulatory harmonization in East Africa (PROFORMA) project (Grant number CSA2016S-1618).

References