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Prospects for elimination of soil-transmitted helminths

Ásbjörnsdóttir, Kristjana H.a,b; Means, Arianna R.a,b; Werkman, Marleena,c; Walson, Judd L.a,b

Current Opinion in Infectious Diseases: October 2017 - Volume 30 - Issue 5 - p 482–488
doi: 10.1097/QCO.0000000000000395
GASTROINTESTINAL INFECTIONS: Edited by A. Clinton White and Gagandeep Kang
Open

Purpose of review Soil-transmitted helminths (STH) are endemic in 120 countries and are associated with substantial morbidity and loss of economic productivity. Although current WHO guidelines focus on morbidity control through mass drug administration (MDA), there is global interest in whether a strategy targeting disease elimination might be feasible in some settings. This review summarizes the prospects for switching from control to an elimination strategy.

Recent findings STH control efforts have reduced the intensity of infections in targeted populations with associated reductions in morbidity. However, adults are not frequently targeted and remain important reservoirs for reinfection of treated children. Recent modeling suggests that transmission interruption may be possible through expanded community-wide delivery of MDA, the feasibility of which has been demonstrated by other programs. However, these models suggest that high levels of coverage and compliance must be achieved. Potential challenges include the risk of prematurely dismantling STH programs and the potential increased risk of antihelminthic resistance.

Summary Elimination of STH may offer an opportunity to eliminate substantial STH-related morbidity while reducing resource needs of neglected tropical disease programs. Evidence from large community trials is needed to determine the feasibility of interrupting the transmission of STH in some geographic settings.

aDeWorm3, The Natural History Museum, London, UK

bDepartment of Global Health, University of Washington, Seattle, Washington, USA

cDepartment of Infectious Disease Epidemiology, London Centre for Neglected Tropical Disease Research (LCNTDR), St. Mary's Campus, Imperial College London, London, UK

Correspondence to Judd L. Walson, Department of Global Health, University of Washington, Box 359931, 325 Ninth Avenue, Seattle, WA 98104, USA. Tel: +1 206 543 4278; e-mail: walson@uw.edu

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

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INTRODUCTION

Soil-transmitted helminths (STH) are a group of neglected tropical diseases (NTDs) that include hookworm (Necator americanus and Ancylostoma duodenale), roundworm (Ascaris lumbricoides), and whipworm (Trichuris trichiura). STH are endemic in at least 120 countries and are estimated to account for over 5 million disability-adjusted life years (DALY) [1▪,2] and substantial productivity loss [3,4] in endemic countries. The WHO Roadmap for NTDs [5] and 2012 London Declaration on Neglected Tropical Diseases [6] focus on the control of STH morbidity through mass drug administration (MDA) to school-age (SAC) and preschool-age (PSAC) children. There has been increasing interest in moving beyond morbidity control toward elimination of many NTDs, including STH [7–10]. We review recent literature relevant to the prospects for switching from a control to an elimination strategy for STH.

Box 1

Box 1

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SOIL-TRANSMITTED HELMINTHS MORBIDITY CONTROL

The current WHO endorsed strategy for the control of STH aims to eliminate STH as a public health problem, defined by the WHO as a reduction in prevalence to less than 1% of moderate or high intensity infection [11]. This target is based on evidence that severity of STH-associated morbidities is highly associated with an individual's intensity of infection. STH infections of moderate-to-high intensity are associated with diarrhea, anemia, chronic inflammation, and malnutrition and with disrupted growth and cognitive impairment in children [12,13▪].

Given that the diagnosis of STH infection requires laboratory capacity and skilled microscopists and that treatment with a single dose of albendazole or mebendazole is inexpensive, well tolerated, and can be delivered to high-risk groups by nonmedical personnel in schools or communities, the WHO recommends presumptive deworming through MDA in endemic areas [14]. Although there is ongoing debate about the economic, cognitive, and morbidity impact at the population level of this strategy [13▪,15,16,17▪,18], it can effectively eliminate infections of intensities understood to cause morbidity [19▪,20▪]. Specifically, current WHO guidelines focus on routine empiric deworming of all SAC, PSAC, and women of childbearing age without reliance on diagnostic testing of individuals before treatment [11]. The WHO recommends deworming of SAC annually in areas where pre-MDA prevalence is between 20 and 50%, and twice annually where pre-MDA prevalence is greater than 50% [5].

The WHO NTD Roadmap has set a target of achieving 75% coverage of SAC and PSAC in all endemic countries by 2020 [5]. The success of the this ambitious strategy in treated populations is evident [14,21,22]: despite recent coverage estimates suggesting that only about half of all populations in need of treatment are being treated, global prevalence and intensity of infection in children have decreased significantly and school-based deworming has resulted in substantial reductions in STH-associated morbidity in many settings [2,19▪,23].

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THE CASE FOR COMMUNITY-WIDE MASS DRUG ADMINISTRATION FOR SOIL-TRANSMITTED HELMINTHS

Despite these gains, pediatric reinfection rates posttreatment are high [24,25▪,26], and school-based deworming has limited impact on overall community-wide prevalence [27] and intensity [28] of infection. When left untreated, adults continue to serve as reservoirs of STH infection in the community, ensuring continued reinfection of treated children, and sustaining transmission [29]. This is especially true in communities where hookworm is the predominant infection, as prevalence of hookworm infection peaks in adulthood [30]. Modeling of STH transmission under repeated rounds of MDA suggests that due to continued transmission at the community level, PSAC-targeted and SAC-targeted deworming programs will need to continue indefinitely – or at least until economic development, access to adequate water and sanitation, and other sociodemographic changes occur – to maintain benefit [10,31].

Expanding treatment with MDA to all individuals in a community has been shown to result in greater reductions in STH prevalence, even among children, than SAC-targeted and PSAC-targeted MDA [32▪]. Models (and some empiric data) suggest that transmission interruption may be possible through chemotherapy alone, provided that the treated population is expanded to all age groups and high coverage is achieved [8–10,31,33,34]. Experience from the Global Alliance to Eliminate Lymphatic Filariasis, which provides community-wide MDA with a package of drugs, including albendazole, has demonstrated that achieving high treatment coverage through community delivery of MDA is possible [35]. In fact, a substantial proportion of albendazole treatment worldwide is currently provided by MDA programs targeting lymphatic filariasis (LF), not by STH programs [9]. However, as LF programs achieve successful LF elimination and transition to post-MDA surveillance, community-wide MDA through the LF platform will cease. As a result, many populations in formerly LF and STH coendemic areas stand to lose the benefit to adults as well as the indirect benefit to children of community-wide treatment; and an estimated 14% of children are at risk of losing coverage altogether, as SAC-targeted and PSAC-targeted programs are not in place in all STH endemic areas covered by the LF program [36▪].

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WATER, SANITATION, AND HYGIENE

Although current WHO goals emphasize morbidity control, case studies of successful interruption of STH transmission do exist. STH were previously highly prevalent in the southeastern United States, South Korea, and Japan, where sustained control efforts through large-scale screening and MDA appear to have interrupted transmission [37–39]. It is important to note that though these successful programs relied heavily on mass chemotherapy, each of them took place during a time of significant economic development and improvements in access to water, sanitation, and hygiene (WASH). Improvements in WASH are critical from a human rights perspective [40] and have been advanced as crucial to the control or elimination of STH [41,42,43▪]. However, the evidence is mixed regarding the influence of WASH resources on STH prevalence and infection intensity [43▪,44▪,45,46▪▪,47,48]. The impact of WASH is influenced by the specific intervention(s) used, the quality of the intervention, consistent WASH usage, and other individual-level behaviors, as well as contributors to the environmental reservoir such as WASH usage and behaviors of other members of the community,[44▪] agricultural activities [49,50], and environmental factors such as precipitation and soil composition [43▪,51,52]. Successful WASH interventions are not only challenging to systematically measure but also costly to implement relative to MDA, so are rarely provided at sufficient scale; universal access remains a distant target [40,53]. Most available data on the effect of WASH interventions on STH prevalence or incidence come from observational and/or cross-sectional studies and there is limited high-quality trial evidence [54], although several randomized trials are ongoing or results pending publication [55].

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THEORETICAL POSSIBILITIES: WHAT DO THE MODELS TELL US?

Models of STH transmission under repeated rounds of community-wide MDA suggest that transmission interruption in a variety of transmission settings may be possible through chemotherapy alone [31,34]. STH species cannot autoinfect, meaning that successful reproduction requires at least one male and one female worm within a single human host [56]. At very low prevalence and mean intensity of infection, there is low likelihood of a single host being infected with both sexes. Therefore, it is not necessary for MDA to continue until all worms are eliminated [57]. The dynamics of STH infection in a population are defined by three parameters: the endemic prevalence that existed prior to the initiation of MDA, extinction of the parasites, and an unstable breakpoint – a theoretical threshold at which MDA may be ceased and where prevalence, rather than increasing until reaching equilibrium at pre-MDA levels, will instead decline over time and eventually reach extinction [58▪]. The breakpoint of transmission defines the moment at which reproduction cannot occur any longer and the helminth population collapses without further treatment of remaining infections.

Mathematical models can simulate this behavior and investigate the impact of MDA on the likelihood of transmission interruption. These models estimate the feasibility of transmission interruption and the frequency and the number of rounds of MDA required to achieve it. Key parameters include the dominant species of STH in each setting; the pre-MDA transmission intensity (R0) for the dominant species; the age profile of infection; effective coverage of MDA, a combination of coverage, compliance, and drug efficacy; and immigration of new hosts and parasites into the community being treated [31,34,57,58▪,59▪]. Each presents challenges for application to the real-world setting. Species distribution has implications for the persistence of infectious material in the environment [57], the age distribution of hosts and the importance of expanding chemotherapy to include adults [60], and the efficacy of each round of albendazole [61▪▪]. Pre-MDA data on species-specific STH prevalence are often unavailable, of low quality, or limited to SAC, whereas estimating pre-MDA transmission intensity based on post-MDA prevalence data introduces additional uncertainty [62▪▪].

Despite these challenges, models of STH transmission and the impact of repeated rounds of MDA have been compared and validated against declines in prevalence observed in real-world settings [59▪,63▪]. Two models fitted to the same baseline data obtained from a study of community-wide treatment in India – one a deterministic and the other a stochastic model – predicted the short-term impact of deworming with comparable accuracy and largely agreed on longer term predictions including the potential for transmission interruption despite differences in methodology [59▪].

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CHALLENGES TO INTERRUPTION THROUGH MASS DRUG ADMINISTRATION ALONE

There are several foreseeable challenges and risks to the success of an MDA-based transmission interruption strategy for STH. Even in moderate transmission intensity settings, models predict that high coverage and compliance, perhaps as high as 90% for SAC and PSAC and 80% for adults, are needed to achieve treatment interruption with MDA alone [56,58▪]. Achievement of high coverage in other NTD elimination campaigns, including in ongoing LF programs, is encouraging; however, compliance with offered treatment is equally important [64▪,65▪]. Estimates of compliance with MDA for helminths range from 19.5 to 99% [66▪] and highlight the need for more consistent definitions and longitudinal studies of compliance and coverage when MDA is delivered to communities and directly observed therapy may not always be feasible. In addition, systematic nonparticipation in MDA, in which some individuals are less likely to be offered [67,68] or to accept [69,70] MDA – as opposed to random distribution of noncompliance at a given coverage level – is particularly challenging, increasing the predicted number of rounds of MDA required to interrupt transmission even at levels of noncompliance less than 10% [58▪]. Noncompliance may increase with treatment fatigue in the community, particularly as morbidity, and perceived need for intervention is reduced.

Although models can provide estimates of the coverage and number of rounds needed to break transmission in a given setting, in practice, determining whether transmission has been interrupted presents a significant logistical challenge. The achievement of interruption can only be verified by removing drug pressure and ceasing MDA for a predefined period to monitor for recrudescence [58▪]. However, ceasing MDA activities in resource-limited settings carries a risk that program resources will be diverted elsewhere and programs difficult to restart in the event that recrudescence is observed [9]. For this reason, a threshold must be selected to optimally distinguish between areas where transmission has been interrupted and areas with continued transmission with a high positive predictive value (PPV) [58▪]. In this context, PPV is defined as the proportion of communities below the threshold in which prevalence will continue to decline toward elimination rather than bouncing back to pre-MDA levels. Assessment should ideally be timed so that programmed MDA activities can go forward in the event that a community does not meet the threshold; however, PPV is improved the longer the interval between MDA and assessment [58▪,71]. Modeling to compare several thresholds suggests that absolute prevalence, rather than change in prevalence or a prevalence ratio, best discriminates between communities that proceed to elimination and those that bounce back, and that a posttreatment prevalence of less than or equal to 2% has a PPV more than 80% for most pretreatment transmission intensity scenarios [71,72].

Another logistic consideration is how to accurately determine when the absolute prevalence reaches the threshold with a high PPV for transmission interruption. Microscopy-based diagnostic methods are not sensitive at low intensity [73,74] and given that prevalence of infection is highly correlated with infection intensity, mean intensity is expected to be extremely low as populations approach the transmission breakpoint [2] and current microscopic methods would likely be inadequate for the documentation of transmission interruption. Although the assessment of novel diagnostics for STH is somewhat hampered by the lack of a gold standard [75], in field-based studies, quantitative polymerase chain reaction (qPCR) consistently detects more infections than microscopy-based methods. Using PCR as a pseudogold standard, these studies have found sensitivity of two-stool two-slide Kato-Katz as low as 70% for Ascaris and 32% for N. americanus relative to multiparallel qPCR [73], whereas sensitivity of sodium nitrate flotation was 83% for Ascaris and 34% for hookworm relative to multiplex PCR [73,76]. Detection of DNA by qPCR is possible at concentrations as low as 1 fg/μl [77] and qPCR appears to have superior sensitivity [78▪▪] at known concentrations of eggs corresponding to low-to-moderate intensity of infection, as well as reduced variability [79] when compared with Kato-Katz. Recent advances in molecular diagnostics, including qPCR, may meet the necessary performance characteristics to be useful for the documentation of an absolute prevalence 2% or less.

Transmission interruption through MDA relies on the continued efficacy of benzimidazoles. Although the cure rate of a single dose of benzimidazoles is as high as 97% for Ascaris[80], the efficacy against hookworm is variable and may be linked to nutritional status [25▪,26]. Albendazole alone has a low cure rate for Trichuris infection [80,81] and MDA has only a moderate impact on mean infection intensity [82], suggesting that transmission interruption in areas where Trichuris is dominant may require the use of combination therapy [25▪,61▪▪].

The potential emergence of resistance to benzimidazoles is a major concern when expanding MDA to the whole community [83,84] particularly given the lack of availability of second-line treatment options and the potential for the success of the STH morbidity control strategy to be undermined. Anthelmintic resistance, including multidrug resistance [85], is a well documented issue in animal populations [86] and some mutations associated with benzimidazole resistance have been identified in eggs from human stool [87]. Although any large-scale MDA with benzimidazoles may risk producing resistance [54], in animal husbandry, strategies to combat resistance include the exclusion of a subset of the population from deworming to maintain refugia [88,89]. The exclusion of adults from MDA mirrors this strategy in human populations, suggesting that expansion of MDA to include all age groups risks accelerating the emergence of resistance unless transmission is interrupted within a fairly small number of rounds.

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CONCLUSION

Interrupting the transmission of STH in some geographic areas could theoretically eliminate substantial morbidity and productivity loss while also the reducing resource burden that STH programs demand. Transmission interruption would eliminate the need for continued MDA, freeing up resources for other public health activities in resource-limited settings and limiting the need for pharmaceutical company donation programs which are currently planned through 2020. An elimination strategy through MDA only, while requiring substantial investment, is nevertheless potentially more achievable in many settings than universal WASH improvement. However, there are many foreseeable challenges to such a strategy, and most evidence for its feasibility comes from mathematical models. Although these provide crucial information to inform a roadmap of the strategy and its requirements, given the risks to existing morbidity control efforts, assumptions must be tested in well conducted population-based trials before the merits of such a strategic shift can be determined.

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Acknowledgements

None.

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Financial support and sponsorship

All authors are supported by the DeWorm3 Project, which is funded by a grant to the Natural History Museum from the Bill and Melinda Gates Foundation (OPP1129535, PI Walson).

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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58▪. Anderson R, Farrell S, Turner H, et al. Assessing the interruption of the transmission of human helminths with mass drug administration alone: optimizing the design of cluster randomized trials. Parasit Vectors 2017; 10:93.

An individual-based stochastic model of a cluster randomized controlled trial of transmission interruption suggests that resolution between those populations where prevalence bounces back and those where it progresses toward elimination – positive predictive value – is highest if prevalence is assessed a minimum of 2 years post-MDA and an absolute prevalence threshold used.

59▪. Coffeng LE, Truscott JE, Farrell SH, et al. Comparison and validation of two mathematical models for the impact of mass drug administration on Ascaris lumbricoides and hookworm infection. Epidemics 2017; 18:38–47.

Comparison of an age structured partial differential equation deterministic model and an individual-based stochastic model of Ascaris lumbricoides and hookworm transmission and the impact of MDA. Both models largely agreed on the potential for transmission interruption.

60. Turner HC, Truscott JE, Bettis AA, et al. An economic evaluation of expanding hookworm control strategies to target the whole community. Parasit Vectors 2015; 8:570.
61▪▪. Turner HC, Truscott JE, Bettis AA, et al. Analysis of the population-level impact of co-administering ivermectin with albendazole or mebendazole for the control and elimination of Trichuris trichiura. Parasite Epidemiol Control 2016; 1:177–187.

Model demonstrating that adding Ivermectin to SAC-targeted and preschool-age children-targeted MDA increased the feasibility and reduced the time required to break transmission of Trichuris through MDA only. Adding adults only minimally reduced time required.

62▪▪. Werkman M, Truscott JE, Toor J, et al. The past matters: estimating intrinsic hookworm transmission intensity in areas with past mass drug administration to control lymphatic filariasis. Parasit Vectors 2017; 10:254.

Describes the estimation of hookworm transmission intensity pre-MDA using LF MDA coverage data; quality data on coverage can improve predictions of the effectiveness of STH elimination programs.

63▪. Montresor A, Deol A, À Porta N, et al. Markov model predicts changes in STH prevalence during control activities even with a reduced amount of baseline information. PLoS Negl Trop Dis 2016; 10:e0004371.

Validated a simiplified Markov model to predict changes in STH prevalence in the presence of MDA, taking into account drug, frequency, and the population targeted.

64▪. Dyson L, Stolk WA, Farrell SH, Hollingsworth TD. Measuring and modelling the effects of systematic nonadherence to mass drug administration. Epidemics 2017; 18:56–66.

Introduces a method to analyze the impact of noncompliance with MDA; this article is not disease specific.

65▪. Farrell S, Truscott J, Anderson RM. The importance of patient compliance in repeated rounds of mass drug administration (MDA) for the elimination of intestinal helminth transmission. Parasit Vectors 2017; 10:291.

Model estimating the impact of noncompliance with MDA on transmission of Ascaris and schistosomiasis; the latter appears to be more sensitive to noncompliance.

66▪. Shuford KV, Turner HC, Anderson RM. Compliance with anthelmintic treatment in the neglected tropical diseases control programmes: a systematic review. Parasit Vectors 2016; 9:29.

This systematic review highlights the wide range of compliance with MDA for helminths, as well as the differences in definitions and reporting, which is likely to pose an important challenge to reframing routine programs around elimination.

67. Macharia JW, Ng’ang’a ZW, Njenga SM. Factors influencing community participation in control and related operational research for urogenital schistosomiasis and soil-transmitted helminths in rural villages of Kwale County, coastal Kenya. Pan Afr Med J 2016; 24:136.
68. Chami GF, Kontoleon AA, Bulte E, et al. Profiling nonrecipients of mass drug administration for schistosomiasis and hookworm infections: a comprehensive analysis of praziquantel and albendazole coverage in community-directed treatment in Uganda. Clin Infect Dis 2016; 62:200–207.
69. Chami GF, Kontoleon AA, Bulte E, et al. Community-directed mass drug administration is undermined by status seeking in friendship networks and inadequate trust in health advice networks. Soc Sci Med 2017; 183:37–47.
70. Cabral S, Bonfim C, Oliveira R, et al. Knowledge, attitudes and perceptions regarding lymphatic filariasis: study on systematic noncompliance with mass drug administration. Rev Inst Med Trop Sao Paulo 2017; 59:e23.
71. Truscott JE, Werkman M, Wright JE, et al. Identifying optimal threshold statistics for elimination of hookworm using a stochastic simulation model. Parasit Vectors 2017; 10:321.
72. Truscott J, Farrell S, Anderson RM. Using transmission models in study design: detecting elimination and the impact of preexisting treatment programs. Presented at American Society of Tropical Medicine & Hygiene 65th Annual Meeting, Atlanta, Georgia, USA, 2016.
73. Easton AV, Oliveira RG, O’Connell EM, et al. Multiparallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming. Parasit Vectors 2016; 9:38.
74. Medley GF, Turner HC, Baggaley RF, et al. The role of more sensitive helminth diagnostics in mass drug administration campaigns: elimination and health impacts. Adv Parasitol 2016; 94:343–392.
75. O’Connell EM, Nutman TB. Molecular diagnostics for soil-transmitted helminths. Am J Trop Med Hyg 2016; 95:508–513.
76. Llewellyn S, Inpankaew T, Nery SV, et al. Application of a multiplex quantitative PCR to assess prevalence and intensity of intestinal parasite infections in a controlled clinical trial. PLoS Negl Trop Dis 2016; 10:e0004380.
77. Pilotte N, Papaiakovou M, Grant JR, et al. Improved PCR-based detection of soil transmitted helminth infections using a next-generation sequencing approach to assay design. PLoS Negl Trop Dis 2016; 10:e0004578.
78▪▪. Easton AV, Oliveira RG, O’Connell EM, et al. Multiparallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming. Parasit Vectors 2016; 9:38.

Demonstrates increased sensitivity of qPCR for STH compared with Kato Katz, particularly at low intensities of infection, observed for samples collected from field studies as well as laboratory spiked samples.

79. Easton AV, Oliveira RG, Walker M, et al. Sources of variability in the measurement of Ascaris lumbricoides infection intensity by Kato-Katz and qPCR. Parasit Vectors 2017; 10:256.
80. Muller I, Beyleveld L, Gerber M, et al. Low efficacy of albendazole against Trichuris trichiura infection in schoolchildren from Port Elizabeth, South Africa. Trans R Soc Trop Med Hyg 2016; 110:676–678.
81. Okoyo C, Nikolay B, Kihara J, et al. Monitoring the impact of a national school based deworming programme on soil-transmitted helminths in Kenya: the first three years, 2012–2014. Parasit Vectors 2016; 9:408.
82. Pion SD, Chesnais CB, Weil GJ, et al. Effect of 3 years of biannual mass drug administration with albendazole on lymphatic filariasis and soil-transmitted helminth infections: a community-based study in Republic of the Congo. Lancet Infect Dis 2017; 17:763–769.
83. Furtado LF, de Paiva Bello AC, Rabelo EM. Benzimidazole resistance in helminths: from problem to diagnosis. Acta Trop 2016; 162:95–102.
84. Coffeng LE, Stolk WA, Bakker R, de Vkas SJ. Soil-transmitted helminths (STH) control, elimination and development of drug resistance: repercussions of systematic nonparticipation to preventive chemotherapy, in American Society of Tropical Medicine & Hygiene 65th Annual Meeting. 2016: Atlanta, Georgia USA.
85. Garcia CM, Sprenger LK, Ortiz EB, Molento MB. First report of multiple anthelmintic resistance in nematodes of sheep in Colombia. An Acad Bras Cienc 2016; 88:397–402.
86. Redman E, Whitelaw F, Tait A, et al. The emergence of resistance to the benzimidazole anthlemintics in parasitic nematodes of livestock is characterised by multiple independent hard and soft selective sweeps. PLoS Negl Trop Dis 2015; 9:e0003494.
87. Rashwan N, Bourguinat C, Keller K, et al. Isothermal diagnostic assays for monitoring single nucleotide polymorphisms in Necator americanus associated with benzimidazole drug resistance. PLoS Negl Trop Dis 2016; 10:e0005113.
88. Berk Z, Laurenson YC, Forbes AB, Kyriazakis I. Modelling the consequences of targeted selective treatment strategies on performance and emergence of anthelmintic resistance amongst grazing calves. Int J Parasitol Drugs Drug Resist 2016; 6:258–271.
89. Cornelius MP, Jacobson C, Dobson R, Besier RB. Computer modelling of anthelmintic resistance and worm control outcomes for refugia-based nematode control strategies in Merino ewes in Western Australia. Vet Parasitol 2016; 220:59–66.
Keywords:

disease elimination; soil-transmitted helminths; transmission interruption

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