The implementation of the Strongyloides stercoralis infection control plan is one of the goals of the World Health Organization's 2030 roadmap. The purpose of this work is to evaluate the possible impact of two different preventive chemotherapy (PC) strategies in terms of economic resources and health status on the current situation (Strategy A, no PC): Ivermectin for school-age children (SAC) and Adult dosing (strategy B) and ivermectin are only used for SAC (strategy C).
The study was conducted at IRCCS Sacro Cuore Don Calabria Hospital in Negrar di Valpolicella, Verona, Italy, University of Florence, Italy, and WHO in Geneva, Switzerland from May 2020 to April 2021. The data of this model is extracted from the literature. A mathematical model was developed in Microsoft Excel to evaluate the impact of strategies B and C on a standard population of 1 million subjects living in areas where strongyloidiasis is endemic. In the case-based scenario, a 15% prevalence of strongyloidiasis was considered; then the three strategies were evaluated under different epidemic thresholds, ranging from 5% to 20%. The results are reported as the number of infected subjects, the number of deaths, the cost, and the incremental effectiveness ratio (ICER). The periods of 1 year and 10 years have been considered.
In the case-based scenario, in the first year of the implementation of strategies B and C of the PCs, the number of infections will be significantly reduced: from 172 500 cases according to strategy B to 77 040 cases, and according to strategy C to 146 700 cases. The additional cost per recovered person is compared with no treatment in the first year. The U.S. dollars (USD) in strategies B and C are 2.83 and 1.13, respectively. For these two strategies, as the prevalence increases, the cost of each recovered person is on a downward trend. Strategy B has a greater number of announced deaths than C, but strategy C has a lower cost of announcing a death than B.
This analysis allows to estimate the impact of two PC strategies to control strongyloidiasis in terms of cost and prevention of infection/death. This can represent the basis for each endemic country to assess the strategies that can be implemented based on available funding and national health priorities.
Soil-borne worms (STH) Strongyloides stercoralis cause related morbidity in affected populations, and can cause death of infected persons in the case of immunosuppression [1]. According to recent estimates, about 600 million people worldwide are affected, with most cases in Southeast Asia, Africa and the Western Pacific [2]. According to recent evidence on the global burden of strongyloidiasis, the World Health Organization (WHO) has included the control of faecalis infections in the 2030 Neglected Tropical Diseases (NTD) road map goal [3]. This is the first time WHO has recommended a control plan for strongyloidiasis, and specific control methods are being defined.
S. stercoralis shares the transmission route with hookworms and has a similar geographic distribution with other STHs, but requires different diagnostic methods and treatments [4]. In fact, Kato-Katz, used to assess the prevalence of STH in the control program, has very low sensitivity to S. stercoralis. For this parasite, other diagnostic methods with higher accuracy can be recommended: Baermann and agar plate culture in parasitological methods, polymerase chain reaction and serological testing [5]. The latter method is used for other NTDs, taking advantage of the possibility of collecting blood on filter paper, which allows rapid collection and easy storage of biological samples [6, 7].
Unfortunately, there is no gold standard for the diagnosis of this parasite [5], so the selection of the best diagnostic method deployed in the control program should consider several factors, such as the accuracy of the test, the cost and the feasibility of use in the field In a recent meeting organized by WHO [8], selected experts determined serological evaluation as the best choice, and NIE ELISA was the best choice among commercially available ELISA kits. As for treatment, preventive chemotherapy (PC) for STH requires the use of benzimidazole drugs, albendazole or mebendazole [3]. These programs usually target school-age children (SAC), who are the highest clinical burden caused by STH [3]. However, benzimidazole drugs have almost no effect on Streptococcus faecalis, so ivermectin is the drug of choice [9]. Ivermectin has been used for large-scale treatment of onchocerciasis and lymphatic filariasis (NTD) elimination programs for decades [10, 11]. It has excellent safety and tolerability, but it is not recommended for children under 5 years of age [12].
S. stercoralis is also different from other STHs in terms of the duration of infection, because if not adequately treated, the special auto-infection cycle can cause the parasite to persist indefinitely in the human host. Due to the emergence of new infections and the persistence of long-term diseases over time, this also leads to a higher prevalence of infections in adulthood [1, 2].
Despite the particularity, combining specific activities with existing programs for other neglected tropical diseases may benefit from the implementation of strongyloidosis-like disease control programs. Sharing infrastructure and staff may reduce costs and speed up activities aimed at controlling Streptococcus faecalis.
The purpose of this work is to estimate the costs and results of different strategies related to the control of strongyloidiasis, namely: (A) no intervention; (B) large-scale administration for SAC and adults; (C) for SAC PC.
The study was conducted at IRCCS Sacro Cuore Don Calabria Hospital in Negrar di Valpolicella, Verona, Italy, University of Florence, Italy, and WHO in Geneva, Switzerland from May 2020 to April 2021. The data source for this model is available literature. A mathematical model was developed in Microsoft® Excel® for Microsoft 365 MSO (Microsoft Corporation, Santa Rosa, California, USA) to evaluate two possible strongyloidosis-like interventions in high-endemic areas compared with (A) no intervention The clinical and economic impact of the measures (current practice); (B) PCs for SAC and adults; (C) PCs for SAC only. The 1-year and 10-year time horizons are evaluated in the analysis. The study was conducted based on the perspective of the local national health system, which is responsible for deworming projects, including the direct costs associated with public sector financing. The decision tree and data input are reported in Figure 1 and Table 1, respectively. In particular, the decision tree shows the mutually exclusive health states foreseen by the model and the calculation logic steps of each different strategy. The input data section below reports in detail the conversion rate from one state to the next and related assumptions. The results are reported as the number of infected subjects, uninfected subjects, cured subjects (recovery), deaths, costs, and incremental cost-benefit ratio (ICER). ICER is the cost difference between the two strategies divided by The difference in their effects is to restore the subject and avoid infection. A smaller ICER indicates that one strategy is more cost-effective than another.
Decision tree for health status. PC preventive chemotherapy, IVM ivermectin, ADM administration, SAC school-age children
We assume that the standard population is 1,000,000 subjects living in countries with a high prevalence of strongyloidiasis, of whom 50% are adults (≥15 years old) and 25% are school-age children (6-14 years old). This is a distribution frequently observed in countries in Southeast Asia, Africa and the Western Pacific [13]. In the case-based scenario, the prevalence of strongyloidiasis in adults and SAC is estimated to be 27% and 15%, respectively [2].
In strategy A (current practice), subjects are not receiving treatment, so we assume that the prevalence of infection will remain the same at the end of the 1-year and 10-year periods.
In strategy B, both SAC and adults will get PCs. Based on an estimated compliance rate of 60% for adults and 80% for SAC [14], both infected and uninfected subjects will receive ivermectin once a year for 10 years. We assume that the cure rate of infected subjects is approximately 86% [15]. As the community will continue to be exposed to the source of infection (although soil contamination may decrease over time since the PC started), re-infections and new infections will continue to occur. The annual new infection rate is estimated to be half of the baseline infection rate [16]. Therefore, starting from the second year of PC implementation, the number of infected cases each year will be equal to the sum of newly infected cases plus the number of cases that remain positive (ie, those who have not received PC treatment and those who have not responded to treatment). Strategy C (PC only for SAC) is similar to B, the only difference is that only SAC will receive ivermectin, and adults will not.
In all strategies, the estimated number of deaths due to severe strongyloidiasis is subtracted from the population each year. Assuming that 0.4% of infected subjects will develop severe strongyloidiasis [17], and 64.25% of them will die [18], estimate these deaths. Deaths due to other causes are not included in the model.
The impact of these two strategies was then evaluated under different levels of strongyloidosis prevalence in the SAC: 5% (corresponding to 9% prevalence in adults), 10% (18%), and 20% (36%) .
We assume that Strategy A has nothing to do with any direct costs to the national health system, although the incidence of strongyloidia-like disease may have an economic impact on the health system due to hospitalization and outpatient consultation, although it may be insignificant. The advantages from a social perspective (such as increased productivity and enrollment rates, and reduced loss of consulting time), although they may be relevant, are not taken into account due to the difficulty of accurately estimating them.
For the implementation of strategies B and C, we considered several costs. The first step is to conduct a survey involving 0.1% of the SAC population to determine the prevalence of infection in the selected area. The cost of the survey is 27 U.S. dollars (USD) per subject, including the cost of parasitology (Baermann) and serological testing (ELISA); the additional cost of logistics is partly based on the pilot project planned in Ethiopia. In total, a survey of 250 children (0.1% of children in our standard population) will cost US$6,750. The cost of ivermectin treatment for SAC and adults (US$0.1 and US$0.3, respectively) is based on the expected cost of prequalified generic ivermectin by the World Health Organization [8]. Finally, the cost of taking ivermectin for SAC and adults is 0.015 USD and 0.5 USD respectively) [19, 20].
Table 2 and Table 3 respectively show the total number of infected and uninfected children and adults in the standard population of individuals over 6 years of age in the three strategies, and the related costs in the 1-year and 10-year analysis. The calculation formula is a mathematical model. In particular, Table 2 reports the difference in the number of infected individuals due to the two PC strategies compared with the comparator (no treatment strategy). When the prevalence in children is equal to 15% and 27% in adults, 172,500 people in the population are infected. The number of infected subjects showed that the introduction of PCs targeted at SAC and adults reduced by 55.3%, and if PCs targeted only SAC, it was reduced by 15%.
In the long-term analysis (10 years), compared with strategy A, the infection reduction of strategies B and C increased to 61.6% and 18.6%, respectively. In addition, the application of strategies B and C can result in a 61% reduction and a 10-year mortality rate of 48%, respectively, compared with not receiving treatment.
Figure 2 shows the number of infections in the three strategies during the 10-year analysis period: Although this number remained unchanged without intervention, in the first few years of the implementation of the two PC strategies, our number of cases decreased rapidly. More slowly afterwards.
Based on three strategies, an estimate of the reduction in the number of infections over the years. PC preventive chemotherapy, SAC school-age children
Regarding ICER, from 1 to 10 years of analysis, the additional cost of each recovered person increased slightly (Figure 3). Taking into account the decrease in infected individuals in the population, the cost of avoiding infections in strategies B and C was US$2.49 and US$0.74, respectively, without treatment over a 10-year period.
The cost per recovered person in the 1-year and 10-year analysis. PC preventive chemotherapy, SAC school-age children
Figures 4 and 5 report the number of infections avoided by PC and the associated cost per survivor compared with no treatment. The prevalence value within a year ranges from 5% to 20%. In particular, compared with the basic situation, when the prevalence rate is low (for example, 10% for children and 18% for adults), the cost per recovered person will be higher; on the contrary, in the case of higher prevalence Lower costs are required in the environment.
The first year prevalence values ​​range from 5% to 20% of the number of advertising infections. PC preventive chemotherapy, SAC school-age children
Cost per recovered person with a prevalence of 5% to 20% in the first year. PC preventive chemotherapy, SAC school-age children
Table 4 restores the number of deaths and relative costs in the 1-year and 10-year ranges of different PC strategies. For all prevalence rates considered, the cost of avoiding a death for strategy C is lower than strategy B. For both strategies, the cost will decrease over time, and will show a downward trend as the prevalence increases.
In this work, compared with the current lack of control plans, we evaluated two possible PC strategies for the cost of controlling strongyloidiasis, the potential impact on the prevalence of strongyloidiasis, and the impact on the fecal chain in the standard population. The impact of cocci-related deaths. As a first step, a baseline assessment of prevalence is recommended, which will cost approximately US$27 per test individual (ie, a total of US$6750 for testing 250 children). The additional cost will depend on the selected strategy, which may be (A) not implementing the PC program (current situation, no additional cost); (B) PC administration for the entire population (0.36 USD per treatment person); (C) ) Or PC addressing SAC ($0.04 per person). Both strategies B and C will lead to a sharp decrease in the number of infections in the first year of PC implementation: with a prevalence of 15% in the school-age population and 27% in adults, the total number of infected people will be in the implementation of strategies B and C Later, the number of cases was reduced from 172 500 at the baseline to 77 040 and 146 700 respectively. After that, the number of cases will still decrease, but at a slower rate. The cost of each recovered person is not only related to the two strategies (compared to strategy C, the cost of implementing strategy B is significantly higher, at $3.43 and $1.97 in 10 years, respectively), but also with the baseline prevalence. The analysis shows that with the increase in the prevalence, the cost of each recovered person is on a downward trend. With a SAC prevalence rate of 5%, it will drop from US$8.48 per person for Strategy B and US$3.39 per person for Strategy C. To USD 2.12 per person and 0.85 per person with a prevalence rate of 20%, strategies B and C are adopted respectively. Finally, the impact of these two strategies on the death of advertising is analyzed. Compared with Strategy C (66 and 822 people in the 1-year and 10-year range, respectively), Strategy B clearly resulted in more expected deaths (245 and 2717 in the 1-year and 10-year range, respectively). But another related aspect is the cost of declaring a death. The cost of both strategies decreases over time, and strategy C (10-year $288) is lower than B (10-year $969).
The choice of a PC strategy to control strongyloidiasis will be based on a variety of factors, including the availability of funds, national health policies, and existing infrastructure. Then, each country will have a plan for its specific goals and resources. With the PC program in place to control the STH in the SAC, it can be considered that the integration with ivermectin is easier to implement at a reasonable cost; it is worth noting that the cost needs to be reduced to avoid one death. On the other hand, in the absence of major financial restrictions, the application of PC to the entire population will definitely lead to a further reduction in infections, so the number of deaths of the total strongyloides will drop sharply over time. In fact, the latter strategy will be supported by the observed distribution of Streptococcus faecalis infections in the population, which tends to increase with age, contrary to the observations of trichomes and roundworms [22]. However, the ongoing integration of the STH PC program with ivermectin has additional benefits, which can be considered very valuable in addition to the effects on strongyloidiasis. In fact, the combination of ivermectin plus albendazole/mebendazole proved to be more effective against trichinella than benzimidazole alone [23]. This may be a reason to support the combination of PC in SAC to eliminate concerns about the lower prevalence of this age group compared with adults. In addition, another approach to consider might be an initial plan for SAC and then expand it to include adolescents and adults when possible. All age groups, whether included in other PC programs or not, will also benefit from the potential effects of ivermectin on ectoparasites including scabies [24].
Another factor that will profoundly affect the cost/benefit of using ivermectin for PC therapy is the infection rate in the population. As the prevalence value increases, the reduction in infections becomes more obvious, and the cost for each survivor decreases. Setting the threshold for PC implementation against Streptococcus faecalis should take into account the balance between these two aspects. It must be considered that for other STHs, it is strongly recommended to implement PC with a prevalence rate of 20% or higher, based on significantly reducing the incidence of the target population [3]. However, this may not be the right target for S. stercoralis, as the risk of death of infected subjects will persist at any intensity of infection. However, most endemic countries may think that even if the cost of maintaining PCs for Streptococcus faecalis is too high at a low prevalence rate, setting the treatment threshold at about 15-20% of the prevalence rate may be the most appropriate. In addition, when the prevalence rate is ≥ 15%, serological testing provides a more reliable estimate than when the prevalence rate is lower, which tends to have more false positives [21]. Another factor that should be considered is that large-scale administration of ivermectin in Loa loa endemic areas will be challenging because patients with high microfilaria blood density are known to be at risk of fatal encephalopathy [25].
In addition, considering that ivermectin may develop resistance after several years of large-scale administration, the efficacy of the drug should be monitored [26].
The limitations of this study include several hypotheses for which we were unable to find strong evidence, such as the reinfection rate and mortality due to severe strongyloidiasis. No matter how limited, we can always find some papers as the basis for our model. Another limitation is that we base some logistics costs on the budget of the pilot study that will begin in Ethiopia, so they may not be exactly the same as expected expenditures in other countries. It is expected that the same study will provide further data to analyze the effects of PC and ivermectin targeting SAC. Other benefits of ivermectin administration (such as the effect on scabies and the increased efficacy of other STHs) have not been quantified, but endemic countries may consider them in the context of other related health interventions. Finally, here we did not measure the impact of possible additional interventions, such as water, sanitation, and personal hygiene (WASH) practices, which can further help reduce the prevalence of STH [27] and indeed the World Health Organization Recommended [3]. Although we support the integration of PCs for STH with WASH, the evaluation of its impact is beyond the scope of this study.
Compared to the current situation (untreated), both of these PC strategies resulted in a significant reduction in infection rates. Strategy B caused more deaths than strategy C, but the costs associated with the latter strategy were lower. Another aspect that should be considered is that at present, in almost all strongyloidosis-like areas, school deworming programs have been implemented to distribute benzimidazole to control STH [3]. Adding ivermectin to this existing school benzimidazole distribution platform will further reduce SAC's ivermectin distribution costs. We believe this work can provide useful data for countries wishing to implement control strategies for Streptococcus faecalis. Although PCs have shown a greater impact on the overall population to reduce the number of infections and the absolute number of deaths, PCs targeting SAC can promote deaths at a lower cost. Considering the balance between the cost and effect of the intervention, a prevalence rate of 15-20% or higher may be recommended as the recommended threshold for ivermectin PC.
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