Predicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy

Control of soil-transmitted helminths relies heavily on regular large-scale deworming of high-risk groups (e.g., children) with benzimidazole derivatives. Although drug resistance has not yet been documented in human soil-transmitted helminths, regular deworming of cattle and sheep has led to widespread benzimidazole resistance in veterinary helminths. Here we predict the population dynamics of human soil-transmitted helminth infections and drug resistance during 20 years of regular preventive chemotherapy, using an individual-based model. With the current preventive chemotherapy strategy of mainly targeting children in schools, drug resistance may evolve in soil-transmitted helminths within a decade. More intense preventive chemotherapy strategies increase the prospects of soil-transmitted helminths elimination, but also increase the speed at which drug efficacy declines, especially when implementing community-based preventive chemotherapy (population-wide deworming). If during the last decade, preventive chemotherapy against soil-transmitted helminths has led to resistance, we may not have detected it as drug efficacy has not been structurally monitored, or incorrectly so. These findings highlight the need to develop and implement strategies to monitor and mitigate the evolution of benzimidazole resistance.</p

Predicting the risk and speed of drug resistance emerging in soil-transmitted helminths during preventive chemotherapy

Control of soil-transmitted helminths relies heavily on regular large-scale deworming of high-risk groups (e.g., children) with benzimidazole derivatives. Although drug resistance has not yet been documented in human soil-transmitted helminths, regular deworming of cattle and sheep has led to widespread benzimidazole resistance in veterinary helminths. Here we predict the population dynamics of human soil-transmitted helminth infections and drug resistance during 20 years of regular preventive chemotherapy, using an individual-based model. With the current preventive chemotherapy strategy of mainly targeting children in schools, drug resistance may evolve in soil-transmitted helminths within a decade. More intense preventive chemotherapy strategies increase the prospects of soil-transmitted helminths elimination, but also increase the speed at which drug efficacy declines, especially when implementing community-based preventive chemotherapy (population-wide deworming). If during the last decade, preventive chemotherapy against soil-transmitted helminths has led to resistance, we may not have detected it as drug efficacy has not been structurally monitored, or incorrectly so. These findings highlight the need to develop and implement strategies to monitor and mitigate the evolution of benzimidazole resistance.</p

A general framework to support cost-efficient survey design choices for the control of soil-transmitted helminths when deploying Kato-Katz thick smear

Background To monitor and evaluate soil-transmitted helminth (STH) control programs, the World Health Organization (WHO) recommends screening stools from 250 children, deploying Kato-Katz thick smear (KK). However, it remains unclear whether these recommendations are suffi-cient to make adequate decisions about stopping preventive chemotherapy (PC) (preva-lence of infection &lt;2%) or declaring elimination of STHs as a public health problem (prevalence of moderate-to-heavy intensity (MHI) infections &lt;2%). Methodology We developed a simulation framework to determine the effectiveness and cost of survey designs for decision-making in STH control programs, capturing the operational resources to perform surveys, the variation in egg counts across STH species, across schools, between and within individuals, and between repeated smears. Using this framework and a lot quality assurance sampling approach, we determined the most cost-efficient survey designs (number of schools, subjects, stool samples per subject, and smears per stool sam-ple) for decision-making. Principal findings For all species, employing duplicate KK (sampling 4 to 6 schools and 64 to 70 subjects per school) was the most cost-efficient survey design to assess whether prevalence of any infection intensity was above or under 2%. For prevalence of MHI infections, single KK was the most cost-efficient (sampling 11 to 25 schools and 52 to 84 children per school). Conclusions/Significance KK is valuable for monitoring and evaluation of STH control programs, though we recom-mend deploying a duplicate KK on a single stool sample to stop PC, and a single KK to declare the elimination of STHs as a public health problem.</p

Tobacco control policies and respiratory conditions among children presenting in primary care

Tobacco control policies can protect child health. We hypothesised that the parallel introduction in 2008 of smoke-free restaurants and bars in the Netherlands, a tobacco tax increase and mass media campaign, would be associated with decreases in childhood wheezing/asthma, respiratory tract infections (RTIs), and otitis media with effusion (OME) presenting in primary care. We conducted an interrupted time series study using electronic medical records from the Dutch Integrated Primary Care Information database (2000-2016). We estimated step and slope changes in the incidence of each outcome with negative binomial regression analyses, adjusting for underlying time-trends, seasonality, age, sex, electronic medical record system, urbanisation, and social deprivation. Analysing 1,295,124 person-years among children aged 0-12 years, we found positive step changes immediately after the policies (incidence rate ratio (IRR): 1.07, 95% CI: 1.01-1.14 for wheezing/asthma; IRR: 1.16, 95% CI: 1.13-1.19 for RTIs; and IRR: 1.24, 95% CI: 1.14-1.36 for OME). These were followed by slope decreases for wheezing/asthma (IRR: 0.95/year, 95% CI: 0.93-0.97) and RTIs (IRR: 0.97/year, 95% CI: 0.96-0.98), but a slope increase in OME (IRR: 1.05/year, 95% CI: 1.01-1.09). We found no clear evidence of benefit of changes in tobacco control policies in the Netherlands for the outcomes of interest. Our findings need to be interpreted with caution due to substantial uncertainty in the pre-legislation outcome trends.</p

Tobacco control policies and respiratory conditions among children presenting in primary care

Tobacco control policies can protect child health. We hypothesised that the parallel introduction in 2008 of smoke-free restaurants and bars in the Netherlands, a tobacco tax increase and mass media campaign, would be associated with decreases in childhood wheezing/asthma, respiratory tract infections (RTIs), and otitis media with effusion (OME) presenting in primary care. We conducted an interrupted time series study using electronic medical records from the Dutch Integrated Primary Care Information database (2000-2016). We estimated step and slope changes in the incidence of each outcome with negative binomial regression analyses, adjusting for underlying time-trends, seasonality, age, sex, electronic medical record system, urbanisation, and social deprivation. Analysing 1,295,124 person-years among children aged 0-12 years, we found positive step changes immediately after the policies (incidence rate ratio (IRR): 1.07, 95% CI: 1.01-1.14 for wheezing/asthma; IRR: 1.16, 95% CI: 1.13-1.19 for RTIs; and IRR: 1.24, 95% CI: 1.14-1.36 for OME). These were followed by slope decreases for wheezing/asthma (IRR: 0.95/year, 95% CI: 0.93-0.97) and RTIs (IRR: 0.97/year, 95% CI: 0.96-0.98), but a slope increase in OME (IRR: 1.05/year, 95% CI: 1.01-1.09). We found no clear evidence of benefit of changes in tobacco control policies in the Netherlands for the outcomes of interest. Our findings need to be interpreted with caution due to substantial uncertainty in the pre-legislation outcome trends.</p

Appropriateness of strategy comparisons in cost-effectiveness analyses of infant pneumococcal vaccination: a systematic review

Objectives: Cost-effectiveness analysis (CEA) is the standard framework for informing the efficient allocation of scarce healthcare resources. The importance of considering all relevant intervention strategies and appropriate incremental comparisons have both long been recognized in CEA. Failure to apply methods correctly can lead to suboptimal policies. Our objective is to assess if CEAs of infant pneumococcal vaccination apply appropriate methods with respect to the completeness of strategies assessed and incremental comparisons between them. Methods: We conducted a systematic search of the PubMed, Scopus, Embase, and Web of Science databases and performed a comparative analysis of the retrieved pneumococcal vaccination CEAs. We checked the appropriateness of the incremental analyses by attempting to replicate the published incremental cost-effectiveness (CE) ratios from the reported costs and health effects. Results: Our search returned twenty-nine eligible articles. Most studies failed to recognize one or more intervention strategies (n = 21). Incremental comparisons were questionable in four CEAs and insufficient reporting of cost and health effect estimates was identified in three studies. Overall, we only found four studies that made appropriate comparisons between all strategies. Lastly, study findings appear to be strongly associated with manufacturer sponsorship. Conclusions: We found considerable scope for improvement regarding strategy comparison in the infant pneumococcal vaccination literature. To prevent overestimation of the CE of new vaccines, we urge greater adherence to existing guidelines recommending that all available strategies are evaluated to capture relevant comparators for CE evaluation. Closer adherence to existing guidelines will generate better evidence, leading to more effective vaccination policies

Predictive Value of Microfilariae-Based Stop-MDA Thresholds after Triple Drug Therapy with IDA Against Lymphatic Filariasis in Treatment-Naive Indian Settings

Mass drug administration (MDA) of antifilarial drugs is the main strategy for the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple-drug therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is made based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS, one year after the last MDA round, provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves the predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in ≥95% predictive value even when the MDA coverage is relatively low.</p

How Does Treatment Coverage and Proportion Never Treated Influence the Success of Schistosoma mansoni Elimination as a Public Health Problem by 2030?

Background: The 2030 target for schistosomiasis is elimination as a public health problem (EPHP), achieved when the prevalence of heavy-intensity infection among school-Aged children (SAC) reduces to &lt;1%. To achieve this, the new World Health Organization guidelines recommend a broader target of population to include pre-SAC and adults. However, the probability of achieving EPHP should be expected to depend on patterns in repeated uptake of mass drug administration by individuals. Methods: We employed 2 individual-based stochastic models to evaluate the impact of school-based and community-wide treatment and calculated the number of rounds required to achieve EPHP for Schistosoma mansoni by considering various levels of the population never treated (NT). We also considered 2 age-intensity profiles, corresponding to a low and high burden of infection in adults. Results: The number of rounds needed to achieve this target depends on the baseline prevalence and the coverage used. For low-and moderate-Transmission areas, EPHP can be achieved within 7 years if NT ≤10% and NT &lt;5%, respectively. In high-Transmission areas, community-wide treatment with NT &lt;1% is required to achieve EPHP. Conclusions: The higher the intensity of transmission, and the lower the treatment coverage, the lower the acceptable value of NT becomes. Using more efficacious treatment regimens would permit NT values to be marginally higher. A balance between target treatment coverage and NT values may be an adequate treatment strategy depending on the epidemiological setting, but striving to increase coverage and/or minimize NT can shorten program duration.</p

A Comparison of Markov and Mechanistic Models for Soil-Transmitted Helminth Prevalence Projections in the Context of Survey Design

Globally, there are over 1 billion people infected with soil-transmitted helminths (STHs), mostly living in marginalized settings with inadequate sanitation in sub-Saharan Africa and Southeast Asia. The World Health Organization recommends an integrated approach to STH morbidity control through improved access to sanitation and hygiene education and the delivery of preventive chemotherapy (PC) to school-age children delivered through schools. Progress of STH control programs is currently estimated using a baseline (pre-PC) school-based prevalence survey and then monitored using periodical school-based prevalence surveys, known as Impact Assessment Surveys (IAS). We investigated whether integrating geostatistical methods with a Markov model or a mechanistic transmission model for projecting prevalence forward in time from baseline can improve IAS design strategies. To do this, we applied these 2 methods to prevalence data collected in Kenya, before evaluating and comparing their performance in accurately informing optimal survey design for a range of IAS sampling designs. We found that, although both approaches performed well, the mechanistic method more accurately projected prevalence over time and provided more accurate information for guiding survey design. Both methods performed less well in areas with persistent STH hotspots where prevalence did not decrease despite multiple rounds of PC. Our findings show that these methods can be useful tools for more efficient and accurate targeting of PC. The general framework built in this paper can also be used for projecting prevalence and informing survey design for other neglected tropical diseases.</p