Improving the Cost-efficiency of Preventive Chemotherapy: Impact of New Diagnostics on Stopping Decisions for Control of Schistosomiasis.

BACKGROUND: Control of schistosomiasis (SCH) relies on the regular distribution of preventive chemotherapy (PC) over many years. For the sake of sustainable SCH control, a decision must be made at some stage to scale down or stop PC. These "stopping decisions" are based on population surveys that assess whether infection levels are sufficiently low. However, the limited sensitivity of the currently used diagnostic (Kato-Katz [KK]) to detect low-intensity infections is a concern. Therefore, the use of new, more sensitive, molecular diagnostics has been proposed. METHODS: Through statistical analysis of Schistosoma mansoni egg counts collected from Burundi and a simulation study using an established transmission model for schistosomiasis, we investigated the extent to which more sensitive diagnostics can improve decision making regarding stopping or continuing PC for the control of S. mansoni. RESULTS: We found that KK-based strategies perform reasonably well for determining when to stop PC at a local scale. Use of more sensitive diagnostics leads to a marginally improved health impact (person-years lived with heavy infection) and comes at a cost of continuing PC for longer (up to around 3 years), unless the decision threshold for stopping PC is adapted upward. However, if this threshold is set too high, PC may be stopped prematurely, resulting in a rebound of infection levels and disease burden (+45% person-years of heavy infection). CONCLUSIONS: We conclude that the potential value of more sensitive diagnostics lies more in the reduction of survey-related costs than in the direct health impact of improved parasite control.

The increased sensitivity of qPCR in comparison to Kato-Katz is required for the accurate assessment of the prevalence of soil-transmitted helminth infection in settings that have received multiple rounds of mass drug administration.

BACKGROUND: The most commonly used diagnostic tool for soil-transmitted helminths (STH) is the Kato-Katz (KK) thick smear technique. However, numerous studies have suggested that the sensitivity of KK can be problematic, especially in low prevalence and low intensity settings. An emerging alternative is quantitative polymerase chain reaction (qPCR). METHODS: In this study, both KK and qPCR were conducted on stool samples from 648 participants in an STH epidemiology study conducted in the delta region of Myanmar in June 2016. RESULTS: Prevalence of any STH was 20.68% by KK and 45.06% by qPCR. Prevalence of each individual STH was also higher by qPCR than KK, the biggest difference was for hookworm with an approximately 4-fold increase between the two diagnostic techniques. Prevalence of Ancylostoma ceylanicum, a parasite predominately found in dogs, was 4.63%, indicating that there is the possibility of zoonotic transmission in the study setting. In individuals with moderate to high intensity infections there is evidence for a linear relationship between eggs per gram (EPG) of faeces, derived from KK, and DNA copy number, derived from qPCR which is particularly strong for Ascaris lumbricoides. CONCLUSIONS: The use of qPCR in low prevalence settings is important to accurately assess the epidemiological situation and plan control strategies for the 'end game'. However, more work is required to accurately assess STH intensity from qPCR results and to reduce the cost of qPCR so that is widely accessible in STH endemic countries.

A cluster-randomised controlled trial comparing school and community-based deworming for soil transmitted helminth control in school-age children: the CoDe-STH trial protocol.

BACKGROUND: Current guidelines and targets for soil-transmitted helminth (STH) control focus on school-based deworming for school-age children, given the high risk of associated morbidity in this age group. However, expanding deworming to all age groups may achieve improved STH control among both the community in general and school-age children, by reducing their risk of reinfection. This trial aims to compare school-based targeted deworming with community-wide mass deworming in terms of impact on STH infections among school-age children. METHODS: The CoDe-STH (Community Deworming against STH) trial is a cluster-randomised controlled trial (RCT) in 64 primary schools in Dak Lak province, Vietnam. The control arm will receive one round of school-based targeted deworming with albendazole, while in the intervention arm, community-wide mass deworming with albendazole will be implemented alongside school-based deworming. Prevalence of STH infections will be measured in school-age children at baseline and 12 months following deworming. The primary outcome is hookworm prevalence in school-age children at 12 months, by quantitative PCR. Analysis will be intention-to-treat, with outcomes compared between study arms using generalised linear and non-linear mixed models. Additionally, cost-effectiveness of mass and targeted deworming will be calculated and compared, and focus group discussions and interviews will be used to assess acceptability and feasibility of deworming approaches. Individual based stochastic models will be used to predict the impact of mass and targeted deworming strategies beyond the RCT timeframe to assess the likelihood of parasite population 'bounce-back' if deworming is ceased due to low STH prevalence. DISCUSSION: The first large-scale trial comparing mass and targeted deworming for STH control in South East Asia will provide key information for policy makers regarding the optimal design of STH control programs. TRIAL REGISTRATION: ACTRN12619000309189 .

Effects, equity, and cost of school-based and community-wide treatment strategies for soil-transmitted helminths in Kenya: a cluster-randomised controlled trial.

BACKGROUND: School-based deworming programmes can reduce morbidity attributable to soil-transmitted helminths in children but do not interrupt transmission in the wider community. We assessed the effects of alternative mass treatment strategies on community soil-transmitted helminth infection. METHODS: In this cluster-randomised controlled trial, 120 community units (clusters) serving 150 000 households in Kenya were randomly assigned (1:1:1) to receive albendazole through annual school-based treatment targeting 2-14 year olds or annual or biannual community-wide treatment targeting all ages. The primary outcome was community hookworm prevalence, assessed at 12 and 24 months through repeat cross-sectional surveys. Secondary outcomes were Ascaris lumbricoides and Trichuris trichiura prevalence, infection intensity of each soil-transmitted helminth species, and treatment coverage and costs. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02397772. FINDINGS: After 24 months, prevalence of hookworm changed from 18·6% (95% CI 13·9-23·2) to 13·8% (10·5-17·0) in the annual school-based treatment group, 17·9% (13·7-22·1) to 8·0% (6·0-10·1) in the annual community-wide treatment group, and 20·6% (15·8-25·5) to 6·2% (4·9-7·5) in the biannual community-wide treatment group. Relative to annual school-based treatment, the risk ratio for annual community-wide treatment was 0·59 (95% CI 0·42-0·83; p<0·001) and for biannual community-wide treatment was 0·46 (0·33-0·63; p<0·001). More modest reductions in risk were observed after 12 months. Risk ratios were similar across demographic and socioeconomic subgroups after 24 months. No adverse events related to albendazole were reported. INTERPRETATION: Community-wide treatment was more effective in reducing hookworm prevalence and intensity than school-based treatment, with little additional benefit of treating every 6 months, and was shown to be remarkably equitable in coverage and effects. FUNDING: Bill & Melinda Gates Foundation, the Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, the Wellcome Trust, and the Children's Investment Fund Foundation.

Calculating the prevalence of soil-transmitted helminth infection through pooling of stool samples: Choosing and optimizing the pooling strategy.

Prevalence is a common epidemiological measure for assessing soil-transmitted helminth burden and forms the basis for much public-health decision-making. Standard diagnostic techniques are based on egg detection in stool samples through microscopy and these techniques are known to have poor sensitivity for individuals with low infection intensity, leading to poor sensitivity in low prevalence populations. PCR diagnostic techniques offer very high sensitivities even at low prevalence, but at a greater cost for each diagnostic test in terms of equipment needed and technician time and training. Pooling of samples can allow prevalence to be estimated while minimizing the number of tests performed. We develop a model of the relative cost of pooling to estimate prevalence, compared to the direct approach of testing all samples individually. Analysis shows how expected relative cost depends on both the underlying prevalence in the population and the size of the pools constructed. A critical prevalence level (approx. 31%) above which pooling is never cost effective, independent of pool size. When no prevalence information is available, there is no basis on which to choose between pooling and testing all samples individually. We recast our model of relative cost in a Bayesian framework in order to investigate how prior information about prevalence in a given population can be used to inform the decision to choose either pooling or full testing. Results suggest that if prevalence is below 10%, a relatively small exploratory prevalence survey (10-15 samples) can be sufficient to give a high degree of certainty that pooling may be relatively cost effective.

Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol.

Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03014167.

Economic Evaluations of Mass Drug Administration: The Importance of Economies of Scale and Scope.

It is recognized that changing the current approaches for the control of the neglected tropical diseases will be needed to reach the World Health Organization's (WHO) 2020 goals. Consequently, it is important that economic evaluations of the alternative approaches are conducted. A vital component of such evaluations is the issue of how the intervention's costs should be incorporated. We discuss this issue-focusing on mass drug administration. We argue that the common approach of assuming an intervention's cost per treatment is constant, regardless of the number of individuals treated, is a misleading way to consider the delivery costs of mass drug administration due to the occurrence of economies/diseconomies of scale and scope. Greater care and consideration are required when the costs are incorporated into such analyses. Without this, these economic evaluations could potentially lead to incorrect policy recommendations.

Evaluating the variation in the projected benefit of community-wide mass treatment for schistosomiasis: Implications for future economic evaluations.

BACKGROUND: The majority of schistosomiasis control programmes focus on targeting school-aged children. Expanding the use of community-wide mass treatment to reach more adults is under consideration. However, it should be noted that this would require a further increase in programmatic resources, international aid, and commitment for the provision of praziquantel. Consequently, it is important to understand (i) where a change of strategy would have the greatest benefit, and (ii) how generalisable the conclusions of field trials and analytical studies based on mathematical models investigating the impact of community-wide mass treatment, are to a broad range of settings. METHODS: In this paper, we employ a previously described deterministic fully age-structured schistosomiasis transmission model and evaluate the benefit of community-wide mass treatment both in terms of controlling morbidity and eliminating transmission for Schistosoma mansoni, across a wide range of epidemiological settings and programmatic scenarios. This included variation in the baseline relative worm pre-control burden in adults, the overall level of transmission in defined settings, choice of effectiveness metric (basing morbidity calculations on prevalence or intensity), the level of school enrolment and treatment compliance. RESULTS: Community-wide mass treatment was found to be more effective for controlling the transmission of schistosome parasites than using a school-based programme only targeting school-aged children. However, in the context of morbidity control, the potential benefit of switching to community-wide mass treatment was highly variable across the different scenarios analysed. In contrast, for areas where the goal is to eliminate transmission, the projected benefit of community-wide mass treatment was more consistent. CONCLUSION: Whether community-wide mass treatment is appropriate will depend on the local epidemiological setting (i.e. the relative pre-control burden in adults and transmission intensity), and whether the goal is morbidity control or eliminating transmission. This has important implications regarding the generalisability of cost-effectiveness analyses of schistosomiasis interventions. Our results indicate that areas with poor school-enrolment/coverage could benefit more from community-wide treatment of praziquantel and should potentially be prioritised for any change in strategy. This work highlights the importance of not over-generalising conclusions and policy in this area, but of basing decisions on high quality epidemiological data and quantitative analyses of the impact of interventions in a range of settings.

Economic Considerations for Moving beyond the Kato-Katz Technique for Diagnosing Intestinal Parasites As We Move Towards Elimination.

While the need for more sensitive diagnostics for intestinal helminths is well known, the cost of developing and implementing new tests is considered relatively high compared to the Kato-Katz technique. Here, we review the reported costs of performing the Kato-Katz technique. We also outline several economic arguments we believe highlight the need for further investment in alternative diagnostics, and considerations that should be made when comparing their costs. In our opinion, we highlight that, without new diagnostic methods, it will be difficult for policy makers to make the most cost-effective decisions and that the potentially higher unit costs of new methods can be outweighed by the long-term programmatic benefits they have (such as the ability to detect the interruption of transmission).

How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?

Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements.

Cost-effectiveness of scaling up mass drug administration for the control of soil-transmitted helminths: a comparison of cost function and constant costs analyses.

BACKGROUND: The coverage of mass drug administration (MDA) for neglected tropical diseases, such as the soil-transmitted helminths (STHs), needs to rapidly expand to meet WHO's 2020 targets. We aimed to compare use of a cost function to take into account economies of scale to the standard method of assuming a constant cost per treatment when investigating the cost and cost-effectiveness of scaling up a STH MDA programme targeting Ascaris lumbricoides. METHODS: We fitted a cost function describing how the costs of MDA change with scale to empirical cost data and incorporated it into a STH transmission model. Using this cost function, we investigated the consequences of taking into account economies of scale on the projected cost-effectiveness of STH control, by comparison with the standard method of assuming a constant cost per treatment. The cost function was fitted to economic cost data collected as part of a school-based deworming programme in Uganda using maximum likelihood methods. We used the model to investigate the total reduction in the overall worm burden, the total number of prevalent infection case-years averted, and the total number of heavy infection case-years averted. For each year, we calculated the effectiveness as the difference between the worm burden or number of cases and the number in absence of treatment. FINDINGS: When using the cost function, the cost-effectiveness of STH control markedly increased as the programme was scaled up. By contrast, the standard method (constant cost per treatment) undervalued this and generated misleading conclusions. For example, when scaling up control in the projected district from 10% to 75% coverage of at-risk school-age children, the cost-effectiveness in terms of prevention of heavy burden infections was projected to increase by over 70% when using the cost function, but decrease by 18% when assuming a constant cost per treatment. INTERPRETATION: The current exclusion of economies of scale in most economic analyses must be addressed if the most cost-effective policies for the control of neglected tropical diseases are to be formulated. These findings are also relevant to other large-scale disease interventions. FUNDING: GlaxoSmithKline, Bill & Melinda Gates Foundation, Partnership for Child Development, and Wellcome Trust.

An economic evaluation of expanding hookworm control strategies to target the whole community.

BACKGROUND: The WHO treatment guidelines for the soil-transmitted helminths (STH) focus on targeting children for the control of morbidity induced by heavy infections. However, unlike the other STHs, the majority of hookworm infections are harboured by adults. This untreated burden may have important implications for controlling both hookworm's morbidity and transmission. This is particularly significant in the context of the increased interest in investigating STH elimination strategies. METHODS: We used a deterministic STH transmission model and parameter estimates derived from field epidemiological studies to evaluate the impact of child-targeted (2-14 year olds) versus community-wide treatment against hookworm in terms of preventing morbidity and the timeframe for breaking transmission. Furthermore, we investigated how mass treatment may influence the long-term programmatic costs of preventive chemotherapy for hookworm. RESULTS: The model projected that a large proportion of the overall morbidity due to hookworm was unaffected by the current child-targeted strategy. Furthermore, driving worm burdens to levels low enough to potentially break transmission was only possible when using community-wide treatment. Due to these projected reductions in programme duration, it was possible for community-wide treatment to generate cost savings - even if it notably increases the annual distribution costs. CONCLUSIONS: Community-wide treatment is notably more cost-effective for controlling hookworm's morbidity and transmission than the current child-targeted strategies and could even be cost-saving in many settings in the longer term. These calculations suggest that it is not optimum to treat using the same treatment strategies as other STH. Hookworm morbidity and transmission control require community-wide treatment.

Interrupting transmission of soil-transmitted helminths: a study protocol for cluster randomised trials evaluating alternative treatment strategies and delivery systems in Kenya.

INTRODUCTION: In recent years, an unprecedented emphasis has been given to the control of neglected tropical diseases, including soil-transmitted helminths (STHs). The mainstay of STH control is school-based deworming (SBD), but mathematical modelling has shown that in all but very low transmission settings, SBD is unlikely to interrupt transmission, and that new treatment strategies are required. This study seeks to answer the question: is it possible to interrupt the transmission of STH, and, if so, what is the most cost-effective treatment strategy and delivery system to achieve this goal? METHODS AND ANALYSIS: Two cluster randomised trials are being implemented in contrasting settings in Kenya. The interventions are annual mass anthelmintic treatment delivered to preschool- and school-aged children, as part of a national SBD programme, or to entire communities, delivered by community health workers. Allocation to study group is by cluster, using predefined units used in public health provision-termed community units (CUs). CUs are randomised to one of three groups: receiving either (1) annual SBD; (2) annual community-based deworming (CBD); or (3) biannual CBD. The primary outcome measure is the prevalence of hookworm infection, assessed by four cross-sectional surveys. Secondary outcomes are prevalence of Ascaris lumbricoides and Trichuris trichiura, intensity of species infections and treatment coverage. Costs and cost-effectiveness will be evaluated. Among a random subsample of participants, worm burden and proportion of unfertilised eggs will be assessed longitudinally. A nested process evaluation, using semistructured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system. ETHICS AND DISSEMINATION: Study protocols have been reviewed and approved by the ethics committees of the Kenya Medical Research Institute and National Ethics Review Committee, and London School of Hygiene and Tropical Medicine. The study has a dedicated web site. TRIAL REGISTRATION NUMBER: NCT02397772.

Cost and cost-effectiveness of soil-transmitted helminth treatment programmes: systematic review and research needs.

BACKGROUND: In this time of rapidly expanding mass drug administration (MDA) coverage and the new commitments for soil-transmitted helminth (STH) control, it is essential that resources are allocated in an efficient manner to have the greatest impact. However, many questions remain regarding how best to deliver STH treatment programmes; these include which age-groups should be targeted and how often. To perform further analyses to investigate what the most cost-effective control strategies are in different settings, accurate cost data for targeting different age groups at different treatment frequencies (in a range of settings) are essential. METHODS: Using the electronic databases PubMed, MEDLINE, and ISI Web of Knowledge, we perform a systematic review of costing studies and cost-effectiveness evaluations for potential STH treatment strategies. We use this review to highlight research gaps and outline the key future research needs. RESULTS: We identified 29 studies reporting costs of STH treatment and 17 studies that investigated its cost-effectiveness. The majority of these pertained to programmes only targeting school-aged children (SAC), with relatively few studies investigating alternative preventive chemotherapy (PCT) treatment strategies. The methods of cost data collection, analysis and reporting were highly variable among the different studies. Only four of the costing studies were found to have high applicability for use in forthcoming economic evaluations. There are also very few studies quantifying the costs of increasing the treatment frequency. CONCLUSIONS: The absence of cost data and inconsistencies in the collection and analysis methods constitutes a major research gap for STH control. Detailed and accurate costs of targeting different age groups or increasing treatment frequency will be essential to formulate cost-effective public health policy. Defining the most cost-effective control strategies in different settings is of high significance during this period of expanding MDA coverage and new resource commitments for STH control.

Mitigation strategies for pandemic influenza A: balancing conflicting policy objectives.

Mitigation of a severe influenza pandemic can be achieved using a range of interventions to reduce transmission. Interventions can reduce the impact of an outbreak and buy time until vaccines are developed, but they may have high social and economic costs. The non-linear effect on the epidemic dynamics means that suitable strategies crucially depend on the precise aim of the intervention. National pandemic influenza plans rarely contain clear statements of policy objectives or prioritization of potentially conflicting aims, such as minimizing mortality (depending on the severity of a pandemic) or peak prevalence or limiting the socio-economic burden of contact-reducing interventions. We use epidemiological models of influenza A to investigate how contact-reducing interventions and availability of antiviral drugs or pre-pandemic vaccines contribute to achieving particular policy objectives. Our analyses show that the ideal strategy depends on the aim of an intervention and that the achievement of one policy objective may preclude success with others, e.g., constraining peak demand for public health resources may lengthen the duration of the epidemic and hence its economic and social impact. Constraining total case numbers can be achieved by a range of strategies, whereas strategies which additionally constrain peak demand for services require a more sophisticated intervention. If, for example, there are multiple objectives which must be achieved prior to the availability of a pandemic vaccine (i.e., a time-limited intervention), our analysis shows that interventions should be implemented several weeks into the epidemic, not at the very start. This observation is shown to be robust across a range of constraints and for uncertainty in estimates of both R(0) and the timing of vaccine availability. These analyses highlight the need for more precise statements of policy objectives and their assumed consequences when planning and implementing strategies to mitigate the impact of an influenza pandemic.

Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings.

BACKGROUND: The potential impact of pre-exposure chemoprophylaxis (PrEP) on heterosexual transmission of HIV-1 infection in resource-limited settings is uncertain. METHODOLOGY/PRINCIPLE FINDINGS: A deterministic mathematical model was used to simulate the effects of antiretroviral PrEP on an HIV-1 epidemic in sub-Saharan Africa under different scenarios (optimistic, neutral and pessimistic) both with and without sexual disinhibition. Sensitivity analyses were used to evaluate the effect of uncertainty in input parameters on model output and included calculation of partial rank correlations and standardized rank regressions. In the scenario without sexual disinhibition after PrEP initiation, key parameters influencing infections prevented were effectiveness of PrEP (partial rank correlation coefficient (PRCC) = 0.94), PrEP discontinuation rate (PRCC = -0.94), level of coverage (PRCC = 0.92), and time to achieve target coverage (PRCC = -0.82). In the scenario with sexual disinhibition, PrEP effectiveness and the extent of sexual disinhibition had the greatest impact on prevention. An optimistic scenario of PrEP with 90% effectiveness and 75% coverage of the general population predicted a 74% decline in cumulative HIV-1 infections after 10 years, and a 28.8% decline with PrEP targeted to the highest risk groups (16% of the population). Even with a 100% increase in at-risk behavior from sexual disinhibition, a beneficial effect (23.4%-62.7% decrease in infections) was seen with 90% effective PrEP across a broad range of coverage (25%-75%). Similar disinhibition led to a rise in infections with lower effectiveness of PrEP (< or = 50%). CONCLUSIONS/SIGNIFICANCE: Mathematical modeling supports the potential public health benefit of PrEP. Approximately 2.7 to 3.2 million new HIV-1 infections could be averted in southern sub-Saharan Africa over 10 years by targeting PrEP (having 90% effectiveness) to those at highest behavioral risk and by preventing sexual disinhibition. This benefit could be lost, however, by sexual disinhibition and by high PrEP discontinuation, especially with lower PrEP effectiveness (< or = 50%).