Preventive Chemotherapy Programs Research Articles

Praziquantel-related visual disorders among recipients in mass drug administration campaigns in schistosomiasis endemic settings: Systematic review and meta-analysis protocol.

Hundreds of millions of doses of Praziquantel (PZQ) have been administered to persons with and without schistosomiasis living in schistosomiasis endemic settings, through the mass drug administration (MDA) strategy which started in the early 2000s. A recent publication suggested high risk of PZQ-related visual disorders, raising public health concerns. We aim to systematically synthesize evidence on the magnitude of PZQ-related visual disorders. We will search PubMed, Google Scholar, CINAHL, SCOPUS, CENTRAL and LILACS from 1977 (when the first human clinical trials on PZQ started) to 31st May 2024, with no language restrictions. The key search terms will include "Praziquantel", "PZQ", "visual disorder", "adverse events", "side effects", "blurry vision" and "visual impairment" together with alternative terms and synonyms. All the countries endemic for schistosomiasis will be included as search terms. We will also search HINARI, Africa Journals Online, Thesis Databases and Preprint Repositories. Where necessary, we will contact expert researchers working in the field of schistosomiasis, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), pharmaceutical industries, country-specific Food and Drug Authorities (FDAs) and the European Medicines Agency databases. We will search Conference Proceedings and reference lists of relevant studies for additional studies. At least two authors will independently select studies, extract data and assess risk of bias in the included studies. Any disagreements or discrepancies will be resolved through discussion between the reviewers. Heterogeneity will be explored graphically, and statistically using the I2-statistic. We will conduct random-effects meta-analysis when heterogeneity is appreciable, and express dichotomous outcomes (visual adverse events including excessive lacrimation, blurry vision and visual impairments) as risk ratio (RR) or Odds Ratio (OR) with their 95% confidence interval (CI). We will perform subgroup analysis to assess the impact of heterogeneity, and sensitivity analyses to test the robustness of the effect estimates. The overall level of evidence will be assessed using GRADE. The present review expects to identify and categorize visual disorders occurring after administration of PZQ, alone or in combination with other drugs. By synthesizing the data from multiple studies, the review aims to present a quantitative assessment of the risk or odds of experiencing a visual disorder in different populations after ingesting PZQ. The review will also generate insights into whether PZQ in combination with other drugs are associated with increased odds of visual disorders and whether the occurrence of visual disorders correlates with dosage or treatment duration. Policymakers, public health experts and stakeholders could rely on the review findings to deliver context-sensitive preventive chemotherapy programs by adjusting drug combinations or dosing schedules to reduce risk of visual adverse effects in populations treated with PZQ. The review aims to identify gaps in the current evidence regarding visual disorders following PZQ administration in schistosomiasis endemic settings which can serve as the basis for future research on important but unanswered questions. The findings of this study will be disseminated through stakeholder forums, conferences, and peer-review publications. The review protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO)- CRD42023417963.

Knowledge, attitudes, practices and acceptability of a school preventive chemotherapy programme for schistosomiasis and soil-transmitted helminths control in Angola.

Schistosomiasis and soil-transmitted helminth (STH) control programs require target population engagement, assessed through knowledge, attitudes and practices (KAP) surveys. We report the results of a KAP survey of Angolan schoolchildren supported by a school preventive chemotherapy (PC) programme, without or with a school water, sanitation and hygiene (WASH) programme (PC+/WASH- and PC+/WASH+, respectively); and schoolchildren without a school PC or WASH program (PC-/WASH-). Schoolchildren from PC+/WASH- (N = 218), PC+/WASH+ (N = 250) and PC-/WASH- (N = 254) schools were interviewed. Descriptive statistics were used to report demographics and survey responses. Chi-square or Fisher's exact test was used to compare PC+/WASH- schoolchildren with (i) PC+/WASH+ and (ii) PC-/WASH- schoolchildren. A lower proportion of PC+/WASH- schoolchildren used latrines and a higher proportion practised open defecation at school compared with PC+/WASH+ schoolchildren. A lower proportion of PC+/WASH- schoolchildren always washed their hands after toileting and before meals at school compared with PC+/WASH+ schoolchildren. However, the PC+/WASH- schoolchildren reported better toileting and handwashing practices at school compared to PC-/WASH- schoolchildren. Over 90% of PC+ schoolchildren agreed with schistosomiasis and STH control and accepted schoolteacher PC delivery. Expanding the integration of both school PC and WASH programs will improve health behaviours relevant to reduce the risk of schistosomiasis and STHs in schoolchildren. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Epidemiology of pediatric schistosomiasis in hard-to-reach areas and populations: A scoping review protocol.

Background: Schistosomiasis is a neglected tropical disease (NTD) that affects millions of people. Children are the most vulnerable group to developing overt disease. An estimated 779 million people are at risk of schistosomiasis and 50 million preschool-age children (PSAC) need treatment. PSAC are not currently targeted by national chemotherapy campaigns due to a lack of suitable pediatric formulations of praziquantel. The Pediatric Praziquantel Consortium has developed an orally dispersible praziquantel formulation (arpraziquantel) and is facilitating its adoption for schistosomiasis control by endemic countries through the ADOPT program - an implementation research program that paves the way for the large-scale delivery of the child-friendly formulation to treat schistosomiasis in preschool-aged children in endemic countries. A key challenge for comprehensive NTD control including schistosomiasis is reaching all at-risk populations, including those hard to reach. Main access barriers include geographic, social and economic conditions. Objective : This scoping literature review aims to document the epidemiology of schistosomiasis in children under 6 years of age living in hard-to-reach areas and populations. Methods : This review will adopt the five-stage scoping review process of identifying the research question, identifying relevant studies, study selection, charting data and collating, summarizing and reporting results. Electronic databases including Medline, Web of Science, Embase (Ovid), LILACS and African Journals OnLine (AJOL) will be searched for relevant articles. Two independent reviewers will screen identified articles using a two-stage approach of reviewing the title/abstract and then the full text of provisionally retained articles. Relevant literatures will be downloaded into EndNote X9 to maintain and manage citation and facilitate the overall review process. A meta-analysis will be conducted if indicated. Relevance : The results will provide insights into the burden of schistosomiasis among marginalized PSAC, aiming to produce evidence on the need for inclusion of this population when designing the expansion of preventive chemotherapy programs.

Epidemiology of pediatric schistosomiasis in hard-to-reach areas and populations: A scoping review protocol.

Background: Schistosomiasis is a neglected tropical disease (NTD) that affects millions of people. Children are the most vulnerable group to developing overt disease. An estimated 779 million people are at risk of schistosomiasis and 50 million preschool-age children (PSAC) need treatment. PSAC are not currently targeted by national chemotherapy campaigns due to a lack of suitable pediatric formulations of praziquantel. The Pediatric Praziquantel Consortium has developed an orally dispersible praziquantel formulation (arpraziquantel) and is facilitating its adoption for schistosomiasis control by endemic countries through the ADOPT program - an implementation research program that paves the way for the large-scale delivery of the child-friendly formulation to treat schistosomiasis in preschool-aged children in endemic countries. A key challenge for comprehensive NTD control including schistosomiasis is reaching all at-risk populations, including those hard to reach. Main access barriers include geographic, social and economic conditions. Objective : This scoping literature review aims to document the epidemiology of schistosomiasis in children under 6 years of age living in hard-to-reach areas and populations. Methods : This review will adopt the five-stage scoping review process of identifying the research question, identifying relevant studies, study selection, charting data and collating, summarizing and reporting results. Electronic databases including Medline, Web of Science, Embase (Ovid), LILACS and African Journals OnLine (AJOL) will be searched for relevant articles. Two independent reviewers will screen identified articles using a two-stage approach of reviewing the title/abstract and then the full text of provisionally retained articles. Relevant literatures will be downloaded into EndNote X9 to maintain and manage citation and facilitate the overall review process. A meta-analysis will be conducted if indicated. Relevance : The results will provide insights into the burden of schistosomiasis among marginalized PSAC, aiming to produce evidence on the need for inclusion of this population when designing the expansion of preventive chemotherapy programs.

Burden and factors associated with schistosomiasis and soil-transmitted helminth infections among school-age children in Huambo, Uige and Zaire provinces, Angola

BackgroundSchistosomiasis and soil-transmitted helminths (STHs) contribute high disease burdens amongst the neglected tropical diseases (NTDs) and are public health problems in Angola. This study reports the prevalence, intensity and risk factors for schistosomiasis and STH infection in Huambo, Uige and Zaire provinces, Angola, to inform a school-based preventive chemotherapy program.MethodsA two-stage cluster design was used to select schools and schoolchildren to participate in parasitological and water, sanitation and hygiene (WASH) surveys across Huambo, Uige, and Zaire provinces. Point-of-care circulating cathodic antigen and urinalysis rapid diagnostic tests (RDTs) were used to determine the prevalence of Schistosoma mansoni and S. haematobium, respectively. Kato-Katz was used to identify and quantify STH species and quantify and compare with RDTs for S. mansoni. Urine filtration was used to quantify and compare with RDTs for S. haematobium. Descriptive statistics were used for prevalence and infection intensity of schistosomiasis and STH infection. Performance of RDTs was assessed through specificity and Cohen’s Kappa agreement with microscopy. A multivariate regression analysis was used to determine demographic and WASH factors associated with schistosomiasis and STH infection.ResultsA total 575 schools and 17,093 schoolchildren participated in the schistosomiasis survey, of which 121 schools and 3649 schoolchildren participated in the STH survey. Overall prevalence of S. mansoni was 21.2% (municipality range 0.9–74.8%) and S. haematobium 13.6% (range 0–31.2%), with an overall prevalence of schistosomiasis of 31.4% (range 5.9–77.3%). Overall prevalence of Ascaris lumbricoides was 25.1% (range 0–89.7%), hookworm 5.2% (range 0–42.6%), and Trichuris trichiura 3.6% (range 0–24.2%), with an overall prevalence of STH infection of 29.5% (range 0.8–89.7%). Ecological zone and ethnicity were factors associated with schistosomiasis and STH infection, with older age and female sex additional risk factors for S. haematobium.ConclusionsMost municipalities met World Health Organization defined prevalence thresholds for a schistosomiasis preventive chemotherapy program. A STH preventive chemotherapy program is indicated for nearly all municipalities in Uige and select municipalities in Huambo and Zaire. The association between ecological zone and ethnicity with schistosomiasis and STH infection necessitates further evaluation of home and school environmental, sociodemographic and behavioural factors to inform targeted control strategies to complement preventive chemotherapy programs.

Pharmacokinetic modelling and simulation to optimize albendazole dosing in hookworm- or Trichuris trichiura-infected infants to adults.

Albendazole is the most commonly used drug in preventive chemotherapy programmes against soil-transmitted helminth (STH) infections, with the standard dose of 400 mg resulting in suboptimal clinical outcomes. Population pharmacokinetic (PK) models that could inform dosing strategies are not yet available. A population pharmacokinetic model was developed based on micro-blood samples collected from 252 patients aged 2 to 65 years, infected with either hookworm or Trichuris trichiura and treated with albendazole doses ranging from of 200 to 800 mg. An exposure-response analysis was performed relating albendazole and its two metabolites to cure rates and egg reduction rates (ERR). Finally, model-based simulations were conducted to determine equivalent exposure coverage in infants to adults. A population PK model, with one distribution compartment for each compound and one peripheral compartment, following oral administration with a lag time, assuming first-order absorption and linear elimination, best described the concentration-time profiles. Clearance and volume parameters were scaled to body size (weight for albendazole and height for albendazole sulfoxide and sulfone). Dose proportionality was observed for the active metabolite, albendazole sulfoxide, but only in hookworm-infected individuals, with increasing exposure resulting in increased ERR. Exposure of sulfoxide was lowest in the tallest individuals. Pharmacometric simulations indicate that doses up to 800 mg could further increase albendazole efficacy in hookworm-infected adults, whereas the standard dose of 400 mg is sufficient in the youngest age cohorts. In the absence of evidence-based arguments for adjusting albendazole doses in T. trichiura-infected individuals, the search for new treatment options is further emphasized.

Development of a public geographical information system-based website to follow the impact of control activities of soil-transmitted helminths in endemic countries.

Soil-transmitted helminth (STH) infections are among the most common neglected tropical diseases worldwide causing high morbidity and mortality rates in endemic areas. Preventive chemotherapy (PC) programmes and health education are recommended by the World Health Organization (WHO) to reduce the impact of STH in endemic countries. Following our role as WHO collaborating centre (WHO CC ITA-116), we have developed a WebGIS and a dataset to support PC programmes to monitor the impact of STH control. This vHealth presentation shows the potentiality of these tools in improving communication among WHO's regional and country offices, Ministries of Health, pharmaceutical industries and other partners.

Progress towards control and elimination of neglected tropical diseases targeted by preventive chemotherapy in São Tomé e Príncipe.

The São Tomé e Príncipe government is committed to achieving neglected tropical disease (NTD) control and elimination as a public health problem by 2025. In 2014, the Ministry of Health led a national survey to determine the prevalence of soil-transmitted helminths (STHs) and schistosomiasis across the country. Following this survey, a preventive chemotherapy (PC) campaign with mebendazole and praziquantel reached 31 501 school-age children in 2015. A follow-up 2017 survey to determine the impact of the intervention showed success in controlling schistosomiasis, as no infections were found, but limited impact on STHs, with prevalence similar to pretreatment levels. The survey also investigated the prevalence of a third NTD, lymphatic filariasis (LF), which was found to be endemic in the country. Since then the Ministry of Health has developed the Strategic Plan for the Fight Against Neglected Tropical Diseases 2019–2025 and identified gaps to be addressed. This narrative review systematises the existing literature reporting on the epidemiology of NTDs for which there are PC programs in São Tomé e Príncipe. PubMed was searched for relevant papers that measured the prevalence of LF, schistosomiasis and STHs. Additionally, data provided by the Ministry of Health surveys were analysed. Finally, we discuss current NTD control, including the impact of the coronavirus disease 2019 pandemic and identify priorities for program strengthening and operational research.

Genetic uniformity, geographical spread and anthropogenic habitat modifications of lymnaeid vectors found in a One Health initiative in the highest human fascioliasis hyperendemic of the Bolivian Altiplano

BackgroundFascioliasis is a snail-borne zoonotic trematodiasis emerging due to climate changes, anthropogenic environment modifications, and livestock movements. Many areas where Fasciola hepatica is endemic in humans have been described in Latin America altitude areas. Highest prevalences and intensities were reported from four provinces of the northern Bolivian Altiplano, where preventive chemotherapy is ongoing. New strategies are now incorporated to decrease infection/re-infection risk, assessment of human infection sources to enable efficient prevention measures, and additionally a One Health initiative in a selected zone. Subsequent extension of these pilot interventions to the remaining Altiplano is key.MethodsTo verify reproducibility throughout, 133 specimens from 25 lymnaeid populations representative of the whole Altiplano, and 11 used for population dynamics studies, were analyzed by rDNA ITS2 and ITS1 and mtDNA cox1 and 16S sequencing to assess their classification, variability and geographical spread.ResultsLymnaeid populations proved to belong to a monomorphic group, Galba truncatula. Only a single cox1 mutation was found in a local population. Two cox1 haplotypes were new. Comparisons of transmission foci data from the 1990’s with those of 2018 demonstrated an endemic area expansion. Altitudinal, northward and southward expansions suggest movements of livestock transporting G. truncatula snails, with increasing temperatures transforming previously unsuitable habitats into suitable transmission areas. Transmission foci appear to be stable when compared to past field observations, except for those modified by human activities, including construction of new roads or control measures undertaken in relation to fascioliasis.ConclusionsFor a One Health initiative, the control of only one Fasciola species and snail vector species simplifies efforts because of the lower transmission complexity. Vector monomorphism suggests uniformity of vector population responses after control measure implementation. Hyperendemic area outer boundary instability suggests a climate change impact. All populations outside previously known boundaries were close to villages, human dwellings and/or schools, and should therefore be considered during disease control planning. The remarkable southward expansion implies that a fifth province, Aroma, should now be included within preventive chemotherapy programmes. This study highlights the need for lymnaeid molecular identification, transmission foci stability monitoring, and potential vector spread assessment.

Epidemiological findings and policy implications from the nationwide schistosomiasis and intestinal helminthiasis survey in Sudan

BackgroundThe World Health Assembly endorsed the WHO Neglected Tropical Disease (NTD) Roadmap in 2013, in which NTDs were suggested as tracers of equity in the assessment of progress towards the Sustainable Development Goals. Nationwide surveys were undertaken in all 18 states of Sudan to identify the geographical distribution and to estimate the prevalence and intensity of schistosomiasis and other intestinal helminthiases from December 2016 to March 2017.MethodsWe used two-stage random sampling. Each district was subdivided into one to three different ecological zones (EZs) based on proximity to water bodies. Probability-proportional-to-size sampling was used to select schools from each EZ. We estimated schistosomiasis and intestinal helminthiasis prevalence by the centrifugation method and Kato-Katz smears. Multi-level mixed-effect models were used to investigate the relationship between the prevalence of infections and risk factors, including improved water or latrine status at the household or school level. We estimated the cost-effectiveness of a one-time mass drug administration (MDA) intervention with 75% coverage at the district and EZ levels.ResultsA total of 105,167 students from 1772 schools were surveyed. The overall egg-positive rates were: Schistosoma haematobium, 5.2%; S. mansoni, 0.06%; and intestinal helminths, 5.47%. Severe endemic areas were concentrated in East and South Darfur States. Children living in a house or attending schools with an improved latrine were less likely to be infected with schistosomiasis than those without a latrine (adjusted odds ratio, aOR: 0.45, 95% confidence interval, CI: 0.41–0.51 and aOR: 0.75, 95% CI: 0.70–0.81 at the household or the school levels, respectively). Open defecation was strongly associated with schistosomiasis (aOR: 1.50, 95% CI: 1.35–1.66). In community-wide mass treatment at the district level with an 8% threshold for schistosomiasis, 2.2 million people would not benefit from MDA interventions with 75% coverage despite high endemicity, whilst 1.7 million people would receive the MDA intervention unnecessarily. EZ-level MDA was estimated to be more cost-effective than district-level administration under all circumstances.ConclusionsOur findings provide updated prevalence figures to guide preventive chemotherapy programmes for schistosomiasis and intestinal helminthiasis in Sudan. Schistosomiasis was found to be common among the inhabitants of fragile and conflict-affected areas. In addition, we found that MDA interventions would be more cost-effective at the sub-district level than at the district level, and there was a strong association between schistosomiasis prevalence and latrine status, at both the household and school levels. This study will help the Sudanese government and its neighbouring countries develop adequate control and elimination strategies.

Association between Schistosoma mansoni infection and access to improved water and sanitation facilities in Mwea, Kirinyaga County, Kenya

BackgroundSchistosomiasis remains a public health problem in Central Kenya despite concerted control efforts. Access to improved water and sanitation has been emphasized as important control measures. Few studies have assessed the association between access to improved water sources and sanitation facilities with Schistosoma mansoni infection in different environmental settings. This study assessed the association between S. mansoni infection and household access to improved water sources and sanitation facilities in Mwea, Kirinyaga County, Kenya.MethodsA cross sectional study was conducted between the months of August and October 2017. A total of 905 household heads from seven villages were interviewed and their stool samples screened for S. mansoni using the Kato Katz technique. Comparisons of demographic factors by S. mansoni infection were tested for significance using the chi-square test (χ2) or the Fisher exact test for categorical variables. Variables associated with S. mansoni infection were analyzed using univariable analysis and the strength of the association measured as odds ratio (OR) using mixed effects logistic regression at 95% CI, with values considered significant at p < 0.05.ResultsThe overall prevalence of S. mansoni was, 23.1% (95% CI: 20.5–26.0%), with majority of the infections being of light intensity. Rurumi village had the highest prevalence at 33.3%, with Kirogo village having the least prevalence at 7.0%. Majority (84.1%) of the households lacked access to improved water sources but had access to improved sanitation facilities (75%). Households with access to piped water had the lowest S. mansoni infections. However, there was no significant association between S. mansoni infections with either the main source of water in the household (Odds Ratio (OR) =0.782 (95% CI: 0.497–1.229) p = 0.285 or sanitation facilities (OR = 1.018 (95% CI: 0.705–1.469) p = 0.926.ConclusionOur study suggests that S. mansoni is still a public health problem among all age groups in Mwea irrigation scheme, Kirinyaga County, Central Kenya. Majority of the households lacks access to improved water sources but have access to improved sanitation facilities. This study recommends initiatives to ensure adequate provision of improved water sources, and the inclusion of the adult community in preventive chemotherapy programs.

Drug Combinations Against Soil-Transmitted Helminth Infections.

The soil-transmitted helminths (STHs), Ascaris lumbricoides, hookworm and Trichuris trichiura are common in areas with warm and moist climates with little access to adequate water, sanitation, and hygiene affecting the poorest populations. The current control strategy of the World Health Organization is preventive chemotherapy (PC), i.e.,the administration of the two benzimidazoles (albendazole and mebendazole) using single, oral doses to at risk populations without prior diagnosis. The recent success of PC is threatened by anthelmintic drug resistance and the low efficacy of the drugs against hookworm (mebendazole) and T. trichiura (albendazole and mebendazole). Only a handful of alternative drugs with anthelmintic properties are available, however, none of the drugs show high efficacy against all three STHs. The combination of two drugs with different activity profiles presents an attractive alternative, which could prevent the development of drug resistance and increase the efficacy compared to monotherapy. In this review, we summarize the efficacy of current and alternative anthelmintics, coadministrations and triple drug therapies assessed by means of network meta-analysis including only randomized controlled trials. Our results highlight that coadministrations have improved efficacy over monotherapy and the necessity of adapting current STH control strategies for the successful continuation of PC programs.

Pharmacokinetics of Praziquantel in Schistosoma mansoni- and Schistosoma haematobium-Infected School- and Preschool-Aged Children.

There is a growing consensus to include preschool-aged children in preventive chemotherapy programs with praziquantel to improve schistosomiasis control. However, pharmacokinetic data, crucial to establish a safe and effective dose for this age group, are sparse. The objective of this study was to establish and compare the pharmacokinetic parameters of praziquantel in preschool- and school-aged children with schistosomiasis. Two pharmacokinetic trials in school- and preschool-aged children infected with Schistosoma mansoni or S. haematobium were conducted in Côte d'Ivoire. Dried blood spot samples were taken from 492 children at 10 time points following a single oral dose of 20, 40, or 60 mg/kg of body weight of praziquantel and analyzed using liquid chromatography-mass spectrometry. Noncompartmental analysis (NCA) was performed to obtain the pharmacokinetic parameters of R-praziquantel (RPZQ), S-praziquantel (SPZQ), and R-trans-4-hydroxy-praziquantel. No significant differences in pharmacokinetic parameters between species-specific infections were observed. While pharmacokinetic parameters differed significantly between age groups for S. mansoni, this trend was not observed with S. haematobium Neither the area under the curve (AUC) nor the maximal blood concentration (Cmax) presented clear dose proportionality for R- and SPZQ. Logistic regression indicated a relationship between the RPZQ AUC and Cmax and the probability of cure. Praziquantel is subject to complex metabolic processes following erratic absorption. While the results of NCA are a very informative base for a better understanding of the drug, a more targeted approach in the form of population modeling is needed to quantify the factors influencing metabolic processes and draw conclusions.

New Advances in the Treatment of Trichuriasis

Purpose of review Infection with the intestinal nematode Trichuris trichiura is a common public health relevant human infection. Since the commonly used drugs show low efficacy against this infection, recent literature about the state-of-the-art treatment of trichuriasis is reviewed particularly with regard to current efforts to improve the situation. Recent findings The drugs albendazole and mebendazole are widely used in preventive chemotherapy in high-risk areas around the world, since they are easy to administer and also effective against other soil-transmitted helminth (STH) infections. Unfortunately, both drugs show poor efficacy against T. trichiura, and the efficacy tends to decrease over time. New treatment options including combinations of the available drugs or drugs used in veterinary medicine are emerging and currently tested. A novel potential antihelminthic drug class has been recently identified, which could possibly aid also in the environmental control of the infection. Summary Due to the low and decreasing effectiveness of the commonly used drugs, more effective drugs against trichuriasis are urgently needed. There have been attempts to increase the efficacy of currently used drugs by combining them. Furthermore, new drugs are being tested against STH infections. Dihydrobenzoxazepinones could be a promising new class of antihelminths with potential use in environmental infection control, too. Future research should concentrate on developing broad-spectrum treatments effective against several worm species in order to broaden the impact of current preventive chemotherapy programs.

Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-transmitted helminths: A systematic review, meta-analysis and individual patient data analysis.

BackgroundThe soil-transmitted helminths (STH), Ascaris lumbricoides, Trichuris trichiura and hookworms, infect 1.5 billion people worldwide and cause an estimated burden of 3.3 million disability-adjusted life years (DALYs). Current control strategies focus on morbidity reduction through preventive chemotherapy (PC) but the most commonly used recommended drugs (albendazole and mebendazole) are particularly inefficacious against T. trichiura. This, together with the threat of emerging drug resistance, calls for new control strategies, including co-administration with other anthelminthics. Ivermectin plus albendazole is widely used against lymphatic filariasis, but its efficacy and safety against STH infections has not yet been fully understood.Methods and findingsWe conducted a systematic literature review and meta-analysis on the efficacy and safety of ivermectin-albendazole co-administration in five different databases (i.e. PubMed, ISI Web of Science, ScienceDirect, CENTRAL and clinicaltrials.gov) from 1960 to January 2018. Four studies reporting efficacy of ivermectin-albendazole against STH infections and five studies on its safety met the selection criteria and were included for quantitative analysis. Ivermectin-albendazole was significantly associated with lower risk (risk ratio (RR) = 0.44, 95% confidence interval (CI) = 0.31–0.62) for T. trichiura infection after treatment compared to albendazole alone. The co-administration revealed no or only a marginal benefit on cure and egg reduction rates over albendazole alone for A. lumbricoides and hookworm infections. Adverse events (AEs) occurring after ivermectin-albendazole co-administration were mostly mild and transient. Overall, the number of individuals reporting any AE was not different (RR = 1.09, 95% CI = 0.87–1.36) in co-treated and albendazole-treated patients. However, although not statistically significant, sub-group analysis showed a tendency for slightly more AEs in patients with filariasis treated with ivermectin-albendazole compared to those treated with albendazole alone (RR = 1.29, 95% CI = 0.81–2.05).ConclusionsOur findings suggest a good tolerability and higher efficacy of ivermectin-albendazole against T. trichiura compared to the current standard single-dose albendazole treatment, which supports the use of this co-administration in PC programs. Large-scale definitive randomized controlled trials are required to confirm our results.

Soil-transmitted helminth infections and nutritional status in Ecuador: findings from a national survey and implications for control strategies

ObjectiveThe estimation of prevalence and intensity of soil-transmitted helminth (STH) infections at a country-level is an essential prerequisite for the implementation of a rational control programme. The aim of this...

Preventive chemotherapy to control soil-transmitted helminthiasis averted more than 500 000 DALYs in 2015.

Preventive chemotherapy (PC), the large-scale administration of anthelminthics, is recommended by the World Health Organization (WHO) for the control of soil-transmitted helminthiasis (STH). Since 2010, donated anthelminthics for STH have boosted the implementation of PC programmes in children, achieving global coverage of more than 60% in 2015. The WHO Global Health Estimates attribute an annual loss of over 3.3 million disability-adjusted life-years (DALYs) to STH. The aim of this study is to estimate the impact of PC programmes on child morbidity. We used data from the WHO Global Health Estimates, national coverage data on PC and the results of an evaluation of the impact of PC in 17 countries on morbidity previously conducted by our group. We estimated that the implementation of PC averted in 2015 over 44% of the DALYs that would have been caused in children by STH without the control intervention. A reduction in morbidity of over 75% is expected, if the global target is reached in 2020. If the programme is subsequently maintained, morbidity from STH will be almost totally removed by 2025. In endemic areas, preventive chemotherapy provides a significant health benefit. We consider this estimation potentially useful to evaluate the cost utility of the investment made by several endemic countries on PC to control STH.

Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the Schistosoma mansoni mouse model.

After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed. In addition, efficacy of PZQ in the presence of the CYP inducer, dexamethasone (DEX), was determined. Plasma samples were obtained by tail vein bleeding at 4 time points. The (R)-PZQ levels were determined using a LC-MS/MS method. Non-compartmental pharmacokinetic analysis was performed using PKsolver. In addition, experiments using an enhanced in vitro assay were conducted. We found that the use of ABT increased (R)-PZQ plasma exposures in the systemic circulation by ~10 to 20 fold but the latter were not predictive of efficacy. The use of DEX decreased plasma exposures of (R)-PZQ in the systemic circulation by ~10 fold without reducing efficacy. We extrapolated the (R)-PZQ concentrations in mouse portal vein / mesenteric veins from the systemic exposures and found that a free exposure of (R)-PZQ of ~ 20 μM*h in the portal vein was needed to obtain a worm burden reduction >60%. It is suggested that the high (R)-PZQ concentrations available before the hepatic first pass metabolism drive the efficacy against S. mansoni adult worms residing in the mesenteric veins. It is then possible that the current dosing regimen of 40 mg/kg in preventive chemotherapy programs may provide suboptimal concentrations in low-weight patients such as children, due to smaller total amounts of drug administered, and may consequently result in lower cure rates.

Treatment of preschool children for schistosomiasis.

Treatment of preschool children for schistosomiasis.

Reduced efficacy of albendazole against Ascaris lumbricoides in Rwandan schoolchildren

Control of human soil-transmitted helminths (STHs) relies on preventive chemotherapy of schoolchildren applying the benzimidazoles (BZ) albendazole or mebendazole. Anthelmintic resistance (AR) is a common problem in nematodes of veterinary importance but for human STHs, information on drug efficacy is limited and routine monitoring is rarely implemented. Herein, the efficacy of single dose albendazole (400 mg) was evaluated in 12 schools in the Huye district of Rwanda where Ascaris is the predominant STH. Ascaris eggs were detected by wet mount microscopy and the Mini-FLOTAC method to assess cure rate (CR) and faecal egg count reduction (FECR). Blood and faecal samples were analysed for co-infections with Plasmodium sp. and Giardia duodenalis, respectively. Ascaris positive samples collected before and after treatment were analysed for putatively BZ-resistance associated β-tubulin gene single nucleotide polymorphisms. The overall CR was 69.9% by Mini-FLOTAC and 88.6% by wet mount microscopy. The FECR was 75.4% and the 95% calculated confidence intervals were 50.4–87.8% using sample variance, 55.4–88.8% by bootstrapping, and 75.0–75.7% applying a Markov Chain Monte Carlo Bayesian approach. FECR varied widely between 0 and 96.8% for individual schools. No putative BZ-resistance associated polymorphisms were found in the four Ascaris β-tubulin isotype genes examined. Since FECRs <95% indicate reduced efficacy, these findings raise the suspicion of BZ resistance. In the absence of respective molecular evidence, heritable AR in the local Ascaris populations cannot be formally proven. However, since FECRs <95% indicate reduced efficacy, BZ resistance may be suspected which would be alarming and calls for further analyses and routine monitoring in preventive chemotherapy programs.