The impact of community-wide, mass drug administration on aggregation of soil-transmitted helminth infection in human host populations.

BACKGROUND: Soil-transmitted helminths (STH) are intestinal parasites estimated to infect over 1.5 billion people. Current treatment programmes are aimed at morbidity control through school-based deworming programmes (targeting school-aged children, SAC) and treating women of reproductive age (WRA), as these two groups are believed to record the highest morbidity. More recently, however, the potential for interrupting transmission by treating entire communities has been receiving greater emphasis and the feasibility of such programmes are now under investigation in randomised clinical trials through the Bill & Melinda Gates Foundation funded DeWorm3 studies. Helminth parasites are known to be highly aggregated within human populations, with a small minority of individuals harbouring most worms. Empirical evidence from the TUMIKIA project in Kenya suggests that aggregation may increase significantly after anthelminthic treatment. METHODS: A stochastic, age-structured, individual-based simulation model of parasite transmission is employed to better understand the factors that might induce this pattern. A simple probabilistic model based on compounded negative binomial distributions caused by age-dependencies in both treatment coverage and exposure to infection is also employed to further this understanding. RESULTS: Both approaches confirm helminth aggregation is likely to increase post-mass drug administration as measured by a decrease in the value of the negative binomial aggregation parameter, k. Simple analytical models of distribution compounding describe the observed patterns well. CONCLUSIONS: The helminth aggregation that was observed in the field was replicated with our stochastic individual-based model. Further work is required to generalise the probabilistic model to take account of the respective sensitivities of different diagnostics on the presence or absence of infection.

Sampling strategies for monitoring and evaluation of morbidity targets for soil-transmitted helminths.

BACKGROUND: The current World Health Organization (WHO) target for the three major soil-transmitted helminth (STH) infections is to reduce prevalence of moderate-to-heavy infections to below 1% by 2020. In terms of monitoring and evaluation (M&E), the current WHO guidelines for control of STHs recommend evaluation of infection levels in school-age children (SAC) after five to six years of preventive chemotherapy (PC), using the standard Kato-Katz faecal smear. Here, we assess the predictive performance of various sampling designs for the evaluation of the morbidity target. METHODOLOGY/PRINCIPAL FINDINGS: Using two mathematical models for STH transmission and control, we simulate how the number of villages and SAC sampled affect the ability of survey results in sentinel villages to predict the achievement of the morbidity target in PC implementation units (e.g. districts). As PC is stopped when the prevalence of infection in SAC in sentinel villages is less than 1%, we estimate the positive predictive value (PPV) of this indicator for meeting the morbidity target in the whole district. The PPV varies by species and PC strategy, and it is generally higher in areas with lower pre-control prevalence. Sampling a fixed number of SAC spread out over 10 instead of 5 sentinel villages may increase the PPV by up to 20 percentage points. If every SAC in a village is tested, a higher number of villages may increase the PPV by up to 80 percentage points. Increasing the proportion of SAC tested per village does not result in a relevant increase of PPV. CONCLUSIONS/SIGNIFICANCE: Although the WHO guidelines provide a combined strategy to control the three STH species, the efficacy of PC strategies clearly differs by species. There is added value in considering more villages within implementation units for M&E of morbidity targets, the extent varying by STH species. A better understanding of pre- and post-control local STH prevalence levels is essential for an adequate M&E strategy including the definition of morbidity targets at the appropriate geographical scale.

Investigating the Effectiveness of Current and Modified World Health Organization Guidelines for the Control of Soil-Transmitted Helminth Infections.

Background: Considerable efforts have been made to better understand the effectiveness of large-scale preventive chemotherapy therapy for the control of morbidity caused by infection with soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura, and the 2 hookworm species, Necator americanus and Ancylostoma duodenale. Current World Health Organization (WHO) guidelines for STH control include mass drug administration (MDA) programs based on prevalence measurements, aiming at reducing morbidity in pre-school-aged children (pre-SAC) and school-aged children (SAC) by lowering the prevalence of moderate- to heavy-intensity infections to <1%. Methods: We project the likely impact of following the current WHO guidelines and assess whether the WHO morbidity goals will be achieved across a range of transmission settings. We also investigate modifications that could be made to the current WHO treatment guidelines, and project their potential impacts in achieving morbidity and transmission control. Results: While the standard guidelines are sufficient at low transmission levels, community-wide treatment (ie, involving pre-SAC, SAC, and adults) is essential if WHO morbidity goals are to be met in moderate- to high-transmission settings. Moreover, removing the recommendation of decreasing the treatment frequency at midline (5-6 years after the start of MDA) further improves the likelihood of achieving morbidity control in SAC. Conclusions: We meld analyses based on 2 mathematical models of parasite transmission and control by MDA for the dominant STH species, to generate a unified treatment approach applicable across all settings, regardless of which STH infection is most common. We recommend clearly defined changes to the current WHO guidelines.

Helminth lifespan interacts with non-compliance in reducing the effectiveness of anthelmintic treatment.

BACKGROUND: The success of mass drug administration programmes targeting the soil-transmitted helminths and schistosome parasites is in part dependent on compliance to treatment at sequential rounds of mass drug administration (MDA). The impact of MDA is vulnerable to systematic non-compliance, defined as a portion of the eligible population remaining untreated over successive treatment rounds. The impact of systematic non-compliance on helminth transmission dynamics - and thereby on the number of treatment rounds required to interrupt transmission - is dependent on the parasitic helminth being targeted by MDA. RESULTS: Here, we investigate the impact of adult parasite lifespan in the human host and other factors that determine the magnitude of the basic reproductive number R 0 , on the number of additional treatment rounds required in a target population, using mathematical models of Ascaris lumbricoides and Schistosoma mansoni transmission incorporating systematic non-compliance. Our analysis indicates a strong interaction between helminth lifespan and the impact of systematic non-compliance on parasite elimination, and confirms differences in its impact between Ascaris and the schistosome parasites in a streamlined model structure. CONCLUSIONS: Our analysis suggests that achieving reductions in the level of systematic non-compliance may be of particular benefit in mass drug administration programmes treating the longer-lived helminth parasites, and highlights the need for improved data collection in understanding the impact of compliance.

Testing for soil-transmitted helminth transmission elimination: Analysing the impact of the sensitivity of different diagnostic tools.

In recent years, an increased focus has been placed upon the possibility of the elimination of soil-transmitted helminth (STH) transmission using various interventions including mass drug administration. The primary diagnostic tool recommended by the WHO is the detection of STH eggs in stool using the Kato-Katz (KK) method. However, detecting infected individuals using this method becomes increasingly difficult as the intensity of infection decreases. Newer techniques, such as qPCR, have been shown to have greater sensitivity than KK, especially at low prevalence. However, the impact of using qPCR on elimination thresholds is yet to be investigated. In this paper, we aim to quantify how the sensitivity of these two diagnostic tools affects the optimal prevalence threshold at which to declare the interruption of transmission with a defined level of confidence. A stochastic, individual-based STH transmission model was used in this study to simulate the transmission dynamics of Ascaris and hookworm. Data from a Kenyan deworming study were used to parameterize the diagnostic model which was based on egg detection probabilities. The positive and negative predictive values (PPV and NPV) were calculated to assess the quality of any given threshold, with the optimal threshold value taken to be that at which both were maximised. The threshold prevalence of infection values for declaring elimination of Ascaris transmission were 6% and 12% for KK and qPCR respectively. For hookworm, these threshold values are lower at 0.5% and 2% respectively. Diagnostic tests with greater sensitivity are becoming increasingly important as we approach the elimination of STH transmission in some regions of the world. For declaring the elimination of transmission, using qPCR to diagnose STH infection results in the definition of a higher prevalence, than when KK is used.

Identifying optimal threshold statistics for elimination of hookworm using a stochastic simulation model.

BACKGROUND: There is an increased focus on whether mass drug administration (MDA) programmes alone can interrupt the transmission of soil-transmitted helminths (STH). Mathematical models can be used to model these interventions and are increasingly being implemented to inform investigators about expected trial outcome and the choice of optimum study design. One key factor is the choice of threshold for detecting elimination. However, there are currently no thresholds defined for STH regarding breaking transmission. METHODS: We develop a simulation of an elimination study, based on the DeWorm3 project, using an individual-based stochastic disease transmission model in conjunction with models of MDA, sampling, diagnostics and the construction of study clusters. The simulation is then used to analyse the relationship between the study end-point elimination threshold and whether elimination is achieved in the long term within the model. We analyse the quality of a range of statistics in terms of the positive predictive values (PPV) and how they depend on a range of covariates, including threshold values, baseline prevalence, measurement time point and how clusters are constructed. RESULTS: End-point infection prevalence performs well in discriminating between villages that achieve interruption of transmission and those that do not, although the quality of the threshold is sensitive to baseline prevalence and threshold value. Optimal post-treatment prevalence threshold value for determining elimination is in the range 2% or less when the baseline prevalence range is broad. For multiple clusters of communities, both the probability of elimination and the ability of thresholds to detect it are strongly dependent on the size of the cluster and the size distribution of the constituent communities. Number of communities in a cluster is a key indicator of probability of elimination and PPV. Extending the time, post-study endpoint, at which the threshold statistic is measured improves PPV value in discriminating between eliminating clusters and those that bounce back. CONCLUSIONS: The probability of elimination and PPV are very sensitive to baseline prevalence for individual communities. However, most studies and programmes are constructed on the basis of clusters. Since elimination occurs within smaller population sub-units, the construction of clusters introduces new sensitivities for elimination threshold values to cluster size and the underlying population structure. Study simulation offers an opportunity to investigate key sources of sensitivity for elimination studies and programme designs in advance and to tailor interventions to prevailing local or national conditions.

The importance of patient compliance in repeated rounds of mass drug administration (MDA) for the elimination of intestinal helminth transmission.

BACKGROUND: Systematic non-compliance to chemotherapeutic treatment among a portion of the eligible population is thought to be a major obstacle to the elimination of helminth infections by mass drug administration (MDA). MDA for helminths is repeated at defined intervals such as yearly or every 2 years, as a consequence of the inability of the human host to develop fully protective immunity to reinfection. As such, how an individual complies to these repeated rounds of MDA can have a significant impact on parasite transmission. The importance of this factor is poorly understood at present. Few epidemiological studies have examined longitudinal trends in compliance in the many communities in areas of endemic helminth infection that are undergoing MDA. Reducing systematic non-compliance will obviously increase the number of individuals treated, but it may also alter the dynamics of parasite transmission. METHODS: Here we develop an individual-based stochastic model of helminth transmission and MDA treatment to investigate how different patterns of compliance influence the impact of MDA for two groups of helminths, the soil transmitted nematode infections and the schistosome parasites. We study the effect of several alternative treatment and compliance patterns on the dynamics of transmission. RESULTS: We find that the impact of different compliance patterns, ranging from random treatment at each round of chemotherapy to systematic non-compliance by a proportion of the population, is very dependent on both transmission intensity in a defined setting and the type of infection that the treatment is targeted at. Systematic non-compliance has a greater impact on the potential for elimination of Schistosoma mansoni transmission by intensive MDA, than it does on Ascaris lumbricoides. CONCLUSIONS: We discuss the implications of our findings for the prioritisation of resources in MDA programmes and for monitoring and evaluation programme design. The key message generated by the analyses is that great care must be taken to record individual longitudinal patterns of compliance at each round of MDA as opposed to just recording overall coverage.

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.

Comparison and validation of two mathematical models for the impact of mass drug administration on Ascaris lumbricoides and hookworm infection.

The predictions of two mathematical models of the transmission dynamics of Ascaris lumbricoides and hookworm infection and the impact of mass drug administration (MDA) are compared, using data from India. One model has an age structured partial differential equation (PDE) deterministic framework for the distribution of parasite numbers per host and sexual mating. The second model is an individual-based stochastic model. Baseline data acquired prior to treatment are used to estimate key transmission parameters, and forward projections are made, given the known MDA population coverage. Predictions are compared with observed post-treatment epidemiological patterns. The two models could equally well predict the short-term impact of deworming on A. lumbricoides and hookworm infection levels, despite being fitted to different subsets and/or summary statistics of the data. As such, the outcomes give confidence in their use as aids to policy formulation for the use of PCT to control A. lumbricoides and hookworm infection. The models further largely agree in a qualitative sense on the added benefit of semi-annual vs. annual deworming and targeting of the entire population vs. only children, as well as the potential for interruption of transmission. Further, this study also illustrates that long-term predictions are sensitive to modelling assumptions about which age groups contribute most to transmission, which depends on human demography and age-patterns in exposure and contribution to the environmental reservoir of infection, the latter being notoriously difficult to empirically quantify.

Measuring and modelling the effects of systematic non-adherence to mass drug administration.

It is well understood that the success or failure of a mass drug administration campaign critically depends on the level of coverage achieved. To that end coverage levels are often closely scrutinised during campaigns and the response to underperforming campaigns is to attempt to improve coverage. Modelling work has indicated, however, that the quality of the coverage achieved may also have a significant impact on the outcome. If the coverage achieved is likely to miss similar people every round then this can have a serious detrimental effect on the campaign outcome. We begin by reviewing the current modelling descriptions of this effect and introduce a new modelling framework that can be used to simulate a given level of systematic non-adherence. We formalise the likelihood that people may miss several rounds of treatment using the correlation in the attendance of different rounds. Using two very simplified models of the infection of helminths and non-helminths, respectively, we demonstrate that the modelling description used and the correlation included between treatment rounds can have a profound effect on the time to elimination of disease in a population. It is therefore clear that more detailed coverage data is required to accurately predict the time to disease elimination. We review published coverage data in which individuals are asked how many previous rounds they have attended, and show how this information may be used to assess the level of systematic non-adherence. We note that while the coverages in the data found range from 40.5% to 95.5%, still the correlations found lie in a fairly narrow range (between 0.2806 and 0.5351). This indicates that the level of systematic non-adherence may be similar even in data from different years, countries, diseases and administered drugs.