Establishing a Surveillance System to Monitor the Global Patterns of Drug Efficacy and Emergence of Anthelmintic Resistance in Soil-transmitted Helminth Programs

Soil-transmitted helminths (STHs) include Ascaris lumbricoides, Trichuris trichiura, and two hookworm species, namely Necator americanus and Ancylostoma duodenale. They are responsible for the highest burden among all neglected tropical diseases (NTDs). Recent global estimates indicate that in 2010 more than 1.4 billion people were infected with at least one of the four STH species, resulting in a global burden of approximately 3.3 million disability-adjusted life years (DALYs). To control the morbidity caused by STHs, preventive chemotherapy (PC) is the main strategy. This entails the periodical administration of a single-oral dose of albendazole (ALB; 400 mg) or mebendazole (MEB; 500 mg) to at-risk populations (ie., preschool-aged (preSAC), school-aged children (SAC) and women of reproductive age) (WHO, 2017). Accelerated by the London Declaration on NTDs, the global coverage of children in PC programs has increased from ~30% in 2011 to 63.6% in 2016, with the goal of covering at least 75% of children by 2020. The laudable long-term aim is to eliminate STHs as a public health problem (<1% moderate/heavy intensity infections), and to eventually declare targeted geographical areas free of infections.

This high level of drug pressure makes PC programs highly vulnerable to the development of anthelmintic resistance (AR). First, the community relies on two drugs (ALB and MEB) of the same class (benzimidazole (BZ) drugs), and with the same mode of action (the inhibition of the polymerization of microtubules). Hence the emergence of AR is likely to occur as drug donations expand. This has been substantiated in veterinary medicine, where AR has developed within a decade of the introduction of every anthelmintic class. Moreover, the development of AR against one BZ drug would most likely be accompanied by poor anthelmintic drug efficacy of the other BZ drug. Second, drugs are administered in single doses. Although a single dose is operationally justified, it never achieves 100% efficacy. Consequently, this practice may further select for the development of AR when suboptimal doses are widely applied over a significant period. Finally, only few anthelmintic drugs are licensed for the treatment of STH infections in humans Thus, should AR against BZ drugs eventually emerge and spread, PC-based control of STHs will be even more limited than at present with few acceptable alternative options. Hence, this re-enforces the urgent necessity for increased accessibility of anthelmintic drugs of different anthelmintic classes and thoroughly designed surveillance systems that allow detection of any changes in anthelmintic drug efficacy arising through the evolution of AR in these helminths.

Currently, any global surveillance system to monitor both drug efficacy and emergence of AR is lacking, and as a consequence it remains unclear to what extent the efficacy of drugs may have dropped and whether AR is already present. One of the main reasons for this lack of monitoring systems is the absence of a framework that guides and supports healthcare decision makers in planning, performing and reporting surveys. The development of such a framework is not straightforward. Moreover, PC programs typically operate in resource-limitedsettings, and therefore it is indispensable that health-care decision makers have some pliancy to minimize both financial and technical resources, while assuring a reliable assessment of the drug efficacy and spread of AR.

To conclude, AR is a real threat for PC programs targeting human STHs. To establish a surveillance system, and to hence further ensure the efficacy of the administered drugs, there is a need for diagnostic methods that effectively mitigate important obstacles of performing, analysing and reporting drug efficacy surveys in resource poor settings, and a validated molecular marker to detect emergence of AR at an early stage. Subsequently, a surveillance system should be established to assess global patterns of drug efficacy and AR. Finally, tools for planning routine AR monitoring, and for following up the global changes in drug efficacy and spread of AR over time should be made available.

The overall aim of this study is to pilot a surveillance system to assess anthelmintic drug efficacy and the emergence of AR in 11 countries were PC coverage has been high over a long period of time. The specific objectives are to: