Repeated praziquantel treatments remodel the genetic and spatial landscape of schistosomiasis risk and transmission.
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ABSTRACT:
SUBMITTER: Barbosa LM
PROVIDER: S-EPMC4844855 | biostudies-literature | 2016 May
REPOSITORIES: biostudies-literature
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Project description:BackgroundLarge scale administration of the anthelminthic drug praziquantel (PZQ) to at-risk populations is the cornerstone of schistosomiasis control, although persisting high prevalence of infections in some areas and growing concerns of PZQ resistance have revealed the limitations of this strategy. Most studies assessing PZQ efficacy have used relatively insensitive parasitological diagnostics, such as the Kato-Katz (KK) and urine-filtration methods, thereby overestimating cure rates (CRs). This study aims to determine the efficacy of repeated PZQ treatments against Schistosoma mansoni infection in school-aged children in Côte d'Ivoire using the traditional KK technique, as well as more sensitive antigen- and DNA-detection methods.MethodsAn open-label, randomised controlled trial will be conducted in school-aged children (5 to 18 years) from the region of Taabo, Côte d'Ivoire, an area endemic for S. mansoni. This 8-week trial includes four two-weekly standard doses of PZQ in the "intense treatment" intervention group and one standard dose of PZQ in the "standard treatment" control group. The efficacy of PZQ will be evaluated in stool samples using the KK technique and real-time PCR as well as in urine using the point-of-care circulating cathodic antigen test and the up-converting phosphor, lateral flow, circulating anodic antigen assay. The primary outcome of the study will be the difference in CR of intense versus standard treatment with PZQ on individuals with a confirmed S. mansoni infection measured by KK. Secondary outcomes include the difference in CR and intensity reduction rate between the intense and standard treatment groups as measured by the other diagnostic tests, as well as the accuracy of the different diagnostic tests, and the safety of PZQ.DiscussionThis study will provide data on the efficacy of repeated PZQ treatment on the clearance of S. mansoni as measured by several diagnostic techniques. These findings will inform future mass drug administration policy and shed light on position of novel diagnostic tools to evaluate schistosomiasis control strategies.Trial registrationThe study is registered at EudraCT (2016-003017-10, date of registration: 22 July 2016) and ( NCT02868385 , date of registration: 16 August 2016).
| S-EPMC6295059 | biostudies-literature
Project description:BackgroundControversy persists about the optimal approach to drug-based control of schistosomiasis in high-risk communities. In a systematic review of published studies, we examined evidence for incremental benefits from repeated praziquantel dosing, given 2 to 8 weeks after an initial dose, in Schistosoma-endemic areas of Africa.Methodology/principal findingsWe performed systematic searches of electronic databases PubMed and EMBASE for relevant data using search terms 'schistosomiasis', 'dosing' and 'praziquantel' and hand searches of personal collections and bibliographies of recovered articles. In 10 reports meeting study criteria, improvements in parasitological treatment outcomes after two doses of praziquantel were greater for S. mansoni infection than for S. haematobium infection. Observed cure rates (positive to negative conversion in egg detection assays) were, for S. mansoni, 69-91% cure after two doses vs. 42-79% after one dose and, for S. haematobium, 46-99% cure after two doses vs. 37-93% after a single dose. Treatment benefits in terms of reduction in intensity (mean egg count) were also different for the two species-for S. mansoni, the 2-dose regimen yielded an weighted average 89% reduction in standardized egg counts compared to a 83% reduction after one dose; for S. haematobium, two doses gave a 93% reduction compared to a 94% reduction with a single dose. Cost-effectiveness analysis was performed based on Markov life path modeling.Conclusions/significanceAlthough schedules for repeated treatment with praziquantel require greater inputs in terms of direct costs and community participation, there are incremental benefits to this approach at an estimated cost of $153 (S. mansoni)-$211 (S. haematobium) per additional lifetime QALY gained by double treatment in school-based programs. More rapid reduction of infection-related disease may improve program adherence, and if, as an externality of the program, transmission can be reduced through more effective coverage, significant additional benefits are expected to accrue in the targeted communities.
| S-EPMC3176745 | biostudies-literature
Project description:Abstract This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To compare the effects of praziquantel given twice a year, with annual or biennial regimens on the prevalence and intensity of schistosomiasis infection.
| S-EPMC6713790 | biostudies-literature
Project description:In Sub-Saharan Africa, urogenital schistosomiasis remains a significant public health problem, causing 150.000 deaths/year with approximately 112 million cases diagnosed. The Niakhar district is a disease hotspot in central Senegal where transmission occurs seasonally with high prevalences. The aim of this study was to determine the effect of annual treatment over 3 years on the seasonal transmission dynamics of S. haematobium in 9 villages in the Niakhar district. Adults and children aged between 5 and 60 years were surveyed from 2011 to 2014. Urine samples were collected door-to-door and examined for S. haematobium eggs at baseline in June 2011, and all participants were treated in August 2011 with PZQ (40 mg/kg). After this initial examination, evaluations were conducted at 3 successive time points from September 2011 to March 2014, to measure the efficacy of the annual treatments and the rates of reinfection. Each year, during the transmission period, from July to November-December, malacological surveys were also carried out in the fresh water bodies of each village to evaluate the infestation of the snail intermediate hosts. At baseline, the overall prevalence of S. haematobium infection was 57.7%, and the proportion of heavy infection was 45.3%, but one month after the first treatment high cure rates (92.9%) were obtained. The overall infection prevalence and proportion of heavy infection intensities were drastically reduced to 4.2% and 2.3%, respectively. The level of the first reinfection in February-March 2012 was 9.5%. At follow-up time points, prevalence levels varied slightly between reinfection and treatment from 9.5% in June 2012 to 0.3% in March 2013, 11.2 in June 2013, and 10.1% April 2014. At the end of the study, overall prevalence was significantly reduced from 57.7% to 10.1%. The overall rate of infested Bulinid snails was reduced after repeated treatment from 0.8% in 2012 to 0.5% in 2013. Repeated annual treatments are suggested to have a considerable impact on the transmission dynamics of S. haematobium in Niakhar, due to the nature of the epidemiological system with seasonal transmission. Thus, to maintain this benefit and continue to reduce the morbidity of urogenital schistosomiasis, other approaches should be integrated into the strategy plans of the National program to achieve the goal of urogenital schistosomiasis elimination in seasonal foci in Senegal.
| S-EPMC4807842 | biostudies-other
Project description:Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 μM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 μM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.
| S-EPMC10359000 | biostudies-literature
Project description:Splenomegaly is a common feature of many infectious diseases, including schistosomiasis japonica. However, the immunopathogenesis and the treatment of splenomegaly due to schistosomiasis have been largely neglected. Praziquantel (PZQ), a classical schistosomicide, has been demonstrated by us and others to have antifibrotic and anti-inflammatory activities against schistosomiasis. In this study, we investigated the effect of PZQ on alleviating the splenomegaly caused by Schistosoma japonicum infection in mice. The results showed that the number of macrophages, especially the number of M1 macrophages, was significantly increased in the enlarged spleens of infected mice (P < 0.001). After PZQ treatment for 4 weeks, the number of splenic macrophages, especially the number of M1 macrophages, was significantly reduced (P < 0.001) by the way of apoptosis, and another schistosomicide, mefloquine, had no effect either on the splenomegaly or on reducing the number of macrophages. Furthermore, by using the murine macrophage line RAW 264.7, we found that PZQ could inhibit the formation of the NLRP3 inflammasome and attenuate phagocytic activity in M1 macrophages. Thus, our studies suggest that PZQ plays a powerful role in ameliorating the splenomegaly caused by S. japonicum infection, which presents a new strategy for the therapy of splenomegaly resulting from other pathological conditions.
| S-EPMC5740360 | biostudies-literature
Project description:Praziquantel (PZQ) has been extensively used as the drug of choice for the treatment of schistosomiasis on account of its safety and effectiveness against all major forms of schistosomiasis. However, low cure rate, reduced susceptibility of Schistosoma mansoni to PZQ and treatment failures in S. haematobium infections have been reported, raising concerns about its efficacy. Using the search terms, 'praziquantel efficacy, schistosomiasis, school children, reinfection' as well as defined inclusion criteria, and guided by the PRISMA guidelines, articles from 2001 to 2022 were selected from the PubMed and Google Scholar databases and reviewed to assess their importance to the research question. This review assessed the efficacy of PZQ against schistosomiasis and reinfection rates following treatment of Schistosoma infections in children. Majority of both intestinal and urinary schistosomiasis studies reported comparable egg reduction rates (ERRs) of 94.2% to 99.9% and 91.9% to 98%, respectively. However, ERRs suggestive of sub-optimal PZQ efficacy as well as generally high and comparable cure rates for intestinal (81.2%-99.1%) and urinary (79%-93.7%) schistosomiasis studies were reported. Schistosomiasis reinfection rates varied widely for urinary (8.1%-39.6%) and intestinal (13.9%-63.4%) studies within eight to 28 weeks following PZQ treatment. Praziquantel treatment of urinary and intestinal schistosomiasis should be accompanied by the provision of potable water, toilet, and recreational facilities to reduce reinfection and egg reduction rates and increase cure rate to expedite schistosomiasis elimination.
| S-EPMC10498796 | biostudies-literature
Project description:Schistosomiasis control programs rely heavily on mass drug administration (MDA) campaigns with praziquantel for preventative chemotherapy. Areas where the prevalence and/or intensity of schistosomiasis infection remains high even after several rounds of treatment, termed "persistent hotspots" (PHSs), have been identified in trials of MDA effectiveness conducted by the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) in Kenya, Mozambique, Tanzania, and Côte d'Ivoire. In this analysis, we apply a previously developed set of criteria to classify the PHS status of 531 study villages from five SCORE trials. We then fit logistic regression models to data from SCORE and publically available georeferenced datasets to evaluate the influence of local environmental and population features, pre-intervention infection burden, and treatment scheduling on PHS status in each trial. The frequency of PHS in individual trials ranged from 35.3% to 71.6% in study villages. Significant relationships between PHS status and MDA frequency, distance to freshwater, rainfall, baseline schistosomiasis burden, elevation, land cover type, and village remoteness were each observed in at least one trial, although the strength and direction of these relationships was not always consistent among study sites. These findings suggest that PHSs are driven in part by environmental conditions that modify the risk and frequency of reinfection.
| S-EPMC7008331 | biostudies-literature
Project description:Antenatal corticosteroid (AC) treatment is given to pregnant women at risk for preterm birth to reduce infant morbidity and mortality by enhancing lung and brain maturation. However, there is no accepted regimen on how frequently AC treatments should be given and some studies found that repeated AC treatments can cause growth retardation and brain damage. Our goal was to assess the dose-dependent effects of repeated AC treatment and estimate the critical number of AC courses to cause harmful effects on the auditory brainstem response (ABR), a sensitive measure of brain development, neural transmission and hearing loss. We hypothesized that repeated AC treatment would have harmful effects on the offspring's ABRs and growth only if more than 3 AC treatment courses were given. To test this hypothesis, pregnant Wistar rats were given either a high regimen of AC (HAC), a moderate regimen (MAC), a low regimen (LAC), or saline (SAL). An untreated control (CON) group was also used. Simulating the clinical condition, the HAC dams received 0.2mg/kg Betamethasone (IM) twice daily for 6 days during gestation days (GD) 17-22. The MAC dams received 3 days of AC treatment followed by 3 days of saline treatment on GD 17-19 and GD 20-22, respectively. The LAC dams received 1 day of AC treatment followed by 5 days of saline treatment on GD 17 and GD 18-22, respectively. The SAL dams received 6 days of saline treatment from GD 17 to 22 (twice daily, isovolumetric to the HAC injections, IM). The offspring were ABR-tested on postnatal day 24. Results indicated that the ABR's P4 latencies (neural transmission time) were significantly prolonged (worse) in the HAC pups and that ABR's thresholds were significantly elevated (worse) in the HAC and MAC pups when compared to the CON pups. The HAC and MAC pups were also growth retarded and had higher postnatal mortality than the CON pups. The SAL and LAC pups showed little or no adverse effects. In conclusion, repeated AC treatment had harmful effects on the rat offspring's ABRs, postnatal growth and survival. The prolonged ABR latencies reflect slowed neural transmission times along the auditory nerve and brainstem auditory pathway. The elevated ABR thresholds reflect hearing deficits. We concluded that repeated AC treatment can have harmful neurological, sensory and developmental effects on the rat offspring. These effects should be considered when weighing the benefits and risks of repeated AC treatment and when monitoring and managing the prenatally exposed child for possible adverse effects.
| S-EPMC3268869 | biostudies-other
Project description:BackgroundThere is a general consensus that widespread use of praziquantel in populations where schistosomiasis is endemic prevents development of hepatic schistosomiasis and its complications. However, a few studies have reported discordant findings linking praziquantel to the occurrence of upper gastrointestinal bleeding (UGIB) in some patients with hepatic schistosomiasis and varices.ObjectiveWe explored if there was any causal association between recent praziquantel use (rPZQ) and upper gastrointestinal bleeding in hepatic schistosomiasis in rural Africa.Patients and methodsA quasi-experimental, retrospective case-controlled study was performed. It involved adult patients with past or acute UGIB, varices, periportal fibrosis, and/or cirrhosis. Cases had acute variceal bleeding while controls did not. The outcome was the frequency of lifetime episodes of UGIB and exposure was rPZQ (received praziquantel in the last 11 months from the date of enrollment). The data analysis included 2 × 2 tables, logistic regression, and propensity-score matching. Odds ratios (ORs), average treatment effects (ATEs), and their 95% confidence intervals (CIs) were used for inference.ResultsOver 6 weeks, we enrolled 19 cases with 92 lifetime episodes of UGIB, and 66 controls with 192 lifetime episodes of UGIB. Cases were more likely to experience UGIB than controls following rPZQ (92% vs. 62%; OR 7.6; 95% CI 3.4-17). Factors predictive of more lifetime episodes of UGIB at multivariable analysis included rPZQ (adjusted OR 13; 95% CI 2.9-53), relative leukocytosis (adjusted OR 26; 95% CI 7.6-89), large varices (adjusted OR 5.0; 95% CI 1.7-15), a family member with hepatosplenic schistosomiasis (adjusted OR 19; 95% CI 7.4-51), advanced periportal fibrosis (adjusted OR 8.0; 95% CI 2.6-22), ascites (adjusted OR 14; 95% CI 4.3-47), and jaundice (adjusted OR 32; 95% CI 7.8-128). While the ATE following rPZQ among the treated was 0.40 (95% CI 0.33-0.48).ConclusionsOur findings suggest the presence of a plausible causal association between recent praziquantel use and increased frequency of UGIB in our study population.
| S-EPMC8128957 | biostudies-literature