Monitoring of drug efficacy in large scale treatment programmes for Human helminthiasis

Introduction

Helminth infections impose a great burden on poor populations in the developing world. Yet there are robust, low-cost and effective public health interventions to relieve that burden. The huge benefits of large scale deworming have been widely demonstrated. Such interventions are based on regular, large scale treatment of populations or sub-populations at high risk of morbidity with effective, safe, single dose drugs (preventive chemotherapy). Preventive chemotherapy aims at using available anthelminthic drugs¹ either alone or in combination as a public health tool for preventing morbidity due to multiple helminth infections. With the expansion of regular, large scale use of anthelminthic drugs, regular monitoring of drug efficacy becomes a crucial issue, in order to safeguard the effectiveness of interventions.

With integrated preventive chemotherapy as currently promoted by WHO, a massive scale up is expected in the coming years. However, the strategy is relying on a few (good) drugs with a limited number of new ones in pipeline. The area of human helminthology has also been neglected in many respects with respect to tools and surveillance systems to monitor drug efficacy, pharmacology, and even basic biology. An adequate response to this new challenge was urgently needed.

A meeting on "Monitoring of drug efficacy in large scale treatment programmes in human helminthiasis", jointly organized by WHO and the World Bank, took place in Washington, DC at the World Bank Headquarters from 31 October to 2 November 2007, with the aim of addressing the issue of monitoring of anthelminthic drug efficacy in a comprehensive way, in line with the WHO recommended strategy of preventive chemotherapy.

During the first day of the meeting, a situation analysis was carried out for each of the different drug/parasite combinations. This was complemented by a presentation on the dynamics of drug resistance in the treatment of helminth infections. The main conclusions of the first day were that: 1) anthelminthic drug resistance is a severe problem in veterinary medicine, and the lessons learned need to be applied to the human side; 2) although there have been reports of reduced efficacy in human helminthiasis (of benzimidazole on hookworm, of praziquantel on schistosomiasis and, more recently, of ivermectin on onchocerciasis), these reports have not been able to fully exclude the influence of (operational, methodological, statistical, and other) confounding factors on the observed results and therefore indisputably conclude that the reduced efficacy could be attributed to emerging drug resistance; 3) there is general agreement that we need to put a monitoring system in place, as in other fields; but 4) current detection tools are not ideal to deliver accurate monitoring. It was recommended to standardize and validate existing methods and procedures, to clearly define early signs of (potential) resistance, and to boost development of sensitive new (molecular) tools.The objectives of the meeting were: 1) to review the current status of drug efficacy for the different drug-parasite combinations (in veterinary medicine and in human public health); 2) to learn from drug efficacy surveillance in other fields (HIV, TB, malaria, and veterinary parasitology); 3) to review the adequacy of currently available tools and strategies for monitoring anthelminthic drug efficacy; 4) to plan for the development of an operational plan for more effective monitoring using current tools; 5) to discuss what cut-off levels could be set for action and what actions could be taken if efficacy was reduced; and 6) identify research priorities for the development of improved tools and strategies

On day 2, drug efficacy monitoring systems currently in place for TB, malaria, HIV and veterinary parasitology were presented. It was concluded that: 1) surveillance of drug efficacy is well established in other fields (TB, Malaria, HIV); 2) surveillance methods for identifying anthelminthic drug resistance are standardized and routinely used in veterinary parasitology, but there is no organized global surveillance system; 3) there are important lessons to be learned from the veterinary field in terms of the potential threat of resistance, management practices to delay or prevent it, and standardization of methodologies & procedures; 4) early detection of drug resistance is key to long term success of control programmes and 5) more basic research on the genetics and mechanism of anthelmintic resistance is required to enable the development of molecular detection tools.

During the third day, the discussions focused on how to operationalize this agenda in the short and medium term. Working groups were established to create standard operating procedures for surveillance tools for the different drugs/parasites, as well as to set clear definitions for the early detection of drug resistance. These should lead to the establishment of draft guidelines for anthelminthic drug efficacy monitoring. WHO would then organize a meeting to get consensus for such a manual. After having field-tested this manual, a monitoring network would progressively be set up. It was estimated that such a process could be completed within a time-frame of 12-18 months.

Overall recommendations of the meeting:

• To establish standard operating procedures for surveillance tools
• To establish guidelines for monitoring systems
• To set up a network of laboratories with transfer of knowledge between North and South
• To set up a repository for clinical samples
• To resolve research versus control issues – and convince donors that monitoring of anthelminthic drug efficacy involves both
• To carry out research on molecular tools as a most pressing need

Working groups and update on progress since October 2007

Soil-transmitted helminthiasis (STH)
Coordinator: Jozef Vercruysse. Members: Marco Albonico, Jerzy Behnke, Donald Bundy, Gerald Coles, Tom Churcher, Lesley Drake, Peter Hotez, Ray Kaplan, Katherine Woo, Andrew Kotze, James McCarthy, Roger Prichard, Georg von Samson-Himmelstjerna, Michael Wilson

This working group has since written a position paper, summarizing in detail what is currently known about anthelminthic drug efficacy in human soil-transmitted helminthiasis, and making recommendations for: (1) the most appropriate coprological methods to be used to monitor the efficacy of anthelmintics used in control programmes; (2) the establishment of a checklist of confounding factors that may affect anthelmintic efficacy; (3) Standard Operating Procedures (SOPs), i.e. the appropriate design of studies to monitor efficacy of anthelmintics by Faecal Egg Count Reduction Tests (FECRT), including the statistical analysis to be used for the FECRT; (5) the (biological) laboratory methods to be considered to evaluate and confirm Anthelminthic Resistance (AR) for human STH, including the research needed on improved (molecular) tools for determining the presence of AR; and (6) the algorithms and referral processes needed for monitoring AR in endemic areas.

Studies have been planned to field-test these protocols in multiple settings with various history of large scale benzimidazole use. These field studies will be carried out during the second half of 2008 and should allow to validate the proposed methodologies for the monitoring of drug efficacy in large-scale treatment programmes for human infections with STH. They are also expected to shed light on threshold FECR values that should trigger the need for laboratory confirmation, and laboratory results that are conclusive of AR.

Onchocerciasis/ Lymphatic Filariasis
Coordinator: Uche Amazigo. Members: Hans Remme, Patrick Lammie, members of the Technical Consultative Committee of APOC (TCC/APOC), members of the Technical Advisory Group for the Elimination of Lymphatic Filariasis (TAG-ELF).

This working group has since organized a meeting, Geneva, 3-5 March 2008 in order to: (1) carry out a detailed analysis of all published reports on ivermectin efficacy in order to comprehensively assess the evidence of ivermectin resistance; (2) plan for follow-up studies in Ghana in order to assess confounding factors that may have affected the reported reduction in ivermectin efficacy stated in a recent Lancet article (Osei-Atweneboana et al., 2007); (3) formulate clear definitions of ivermectin resistance; (4) pèrepare guidelines for the monitoring of ivermectin efficacy in onchocerciasis (and lymphatic filariasis) control; and (5) suggest new sensitive tools for the early detection of drug resistance and define procedures for developing these tools.

The field studies in Ghana are also expected to be carried out during the second half of 2008, and a follow-up meeting has been planned to specifically plan for the development of molecular markers to survey for ivermectin resistance (Geneva, 16-17 June 2008).

Schistosomiasis
Coordinator: Paul Hagan. Members: Tim Anderson, Donato Cioli, Rodrigo Correa-Oliveira, Mike Doenhoff, Narcis Kabatereine, Frank Richards, Joanne Webster

No update on progress received so far.

Pharmacology
Coordinator: Tim Geary. Members: Nilanthi De Silva, Katherine Woo, Janis Lazdins-Helds, James McCarthy

This working group has prepared a draft position paper highlighting unresolved issues in the pharmacology of the anthelminthic drugs currently used in large scale control programmes, and proposing avenues to improve their efficacy and prevent or delay the development of resistance.

Indeed, although it is important to develop new anthelminthic compounds of a totally different family than existing anthelminthics, there is still ample room to reassess the pharmacology of existing anthelminthics in order to optimize their use, alone or in combination. Such improvements in the use of current products could require action with varying complexity, timelines and costs, such as: (1) human pharmacology (PK drug interaction) studies of co-administration of currently used drugs in humans for helminths, (2) the development of new formulations of available anthelminthics used in humans; (3) the development of fixed dose formulations; (4) the development of anthelminthic drugs currently used in veterinary field but not in humans.

The working group also addressed the issue of understanding drug mechanism of action to develop tools for the early detection of AR, which will require more basic research in molecular biology, biochemistry, and animal models.