The major problem of emerging antimalarial drug resistance in Africa has been prioritised for concerted action under the Multilateral Initiative on Malaria (MIM). The objective of the meeting held in Geneva on 14-15th May was to discuss opportunities for greater integration of the full range of research, policy and implementation activities relating to antimalarial drug usage, and to develop clear plans for concerted action to address identified gaps that are not encompassed by current programmes. The meeting also provided a forum for examining on a broader basis options for enhancing the dovetailing of research and development activities, another specific priority to which the MIM has made a commitment. The meeting was attended by 37 individuals representing a total of 20 organisations. These organisations encompassed the spectrum of activities from malaria control programmes, through policy formulation, clinical and epidemiological research, and basic laboratory research. Participants included individuals with administrative and scientific responsibility for the activities of different agencies, together with a number of scientists supported by the agencies. Representatives of each of the participating agencies gave short presentations on their organisations’ activities. The role of these presentations was to increase awareness of ongoing activities, and to begin to construct an overview of how these activities interrelate and where there may be additional needs. This was followed by structured discussions on maximising the impact of research, policy and implementation activities on key areas.(back to top)

II PARTICIPATING ORGANISATIONS

The following organisations were represented:

Participants at the meeting recognised the urgent need for concerted action to address the severe challenges posed by emerging antimalarial drug resistance. Current malaria control programmes are heavily dependent upon chemotherapy, but the repertoire of drugs available for treatment of malaria is limited. The rapid spread of drug resistance in Africa could therefore potentially have disastrous public health consequences. It was recognised that governments in malaria endemic countries were faced with a number of fundamental problems both in selecting first and second line antimalarial drugs and in determining the criteria by which changes in drug treatment policies should be implemented. The meeting identified a range of critical research questions underpinning these policy decisions on drug usage that had not previously been adequately addressed, but were essential to the advancement of antimalarial drug policy at national and international levels. Factors contributing to the relative neglect of these research areas included the availability of chloroquine as a cheap and effective antimalarial drug for many years, and the expectation that further drugs and vaccines would shortly be available. However, a fundamental requirement was for a more effective mechanism to ensure that research agendas are orientated to the needs of policy makers. Constraints on implementation of policies included a general inadequacy of resources, but also a lack of trained personnel, particularly in health economics, sociology and demography, and insufficient ongoing activity to address essential operational research questions.

Participants at the meeting agreed on a number of actions to be taken to address key areas. Those agencies represented at a senior level were able to make immediate commitments to pursue particular areas.

The use of antimalarial drug combinations, and in particular of artemisinin derivatives with other antimalarials, was agreed to offer immense potential benefits for delaying the emergence of drug resistant parasites and possibly for reducing transmission and incidence of malaria in regions of low transmission intensity.

Recognising the need to take immediate action to delay the further spread of drug resistance, TDR/WHO and the Wellcome Trust made a commitment to support properly constructed safety and efficacy trials on combinations of artemisinin derivatives with other antimalarial drugs, in partnership with any other interested agencies. These studies were identified as essential preliminary steps to establish the acceptability and efficacy of using particular drug combinations, prior to considering their deployment.

A large body of data on malaria surveillance is available in a variety of forms and locations, but much of this is not in a format that is readily accessible or interpretable by policy makers. In view of the critical need for appropriate, up-to-date and accurate surveillance information on drug resistance and clinical malaria as a basis for policy decisions, it was agreed that there would be great benefit, at relatively low cost, from drawing together existing sources of data into a single database. The perceived requirement is for a multi-level database for African countries, formatted in such a way as to be accessible and relevant to ministries of health.

CDC agreed that it would be willing to offer its expertise in disease surveillance to facilitate the development of such a database in close collaboration with WHO and other partners actively involved in collecting and analysing malaria data. There was agreement that a meeting in Africa or email networking should be organised to discuss the development of such a database. Participants should include technical database experts, together with key partners involved in data collection in the range of different situations in Africa. It was agreed that the expertise developed for surveillance of other infectious disease should be fully utilised where possible.

Whilst optimising the use of existing data was considered to be essential, it was recognised that further effort was required to improve the quality and comparability of data that is collected, and ensure its relevance to policy makers.

• Methodologies for malaria surveillance: for example sampling strategies and verification of methods for early detection and mapping of resistance (including exploitation of new and more rapid techniques).
• The aims of chemotherapy in the community at both the individual and population levels (e.g. parasite clearance, clinical cure, limitation of drug resistance)
• Criteria for switching drug treatments, including the relevance of different resistance indicators to policy decisions and the level of resistance that is ‘unacceptable’
• Factors determining the spread of drug resistance: complexity and intensity of drug pressure, drug quality, treatment regimens and compliance, disease transmission intensity
• Measurement of the health cost of drug resistance in terms of morbidity and mortality in communities and hence the health impact of the timing and nature of drug policy decisions
• The efficiency of the process by which scientific findings are translated into policies

• Studies of household treatment of malaria
• Optimising packaging and distribution of drugs
• Monitoring drug quality.

• The high quality of data gathered in a surveillance system was agreed to be paramount in ensuring that data will be employed in policy decisions. In this context, a smaller number of high quality sentinel sites would be preferable to gathering low quality information from a broad range of sites. However, it was acknowledged that data could be collected at different levels of sophistication at different sites, depending on the infrastructure available. It was agreed that detailed longitudinal data, perhaps including high quality patient data, characterised isolates and laboratory-based information, should be collected at a select few sites, but this would not be practicable or necessary at all sites. More basic, but high quality data, could be collected at locations with less-developed facilities. It was recognised that there are large areas without any form of monitoring and this inadequacy should be addressed where possible.
• Agreement needs to be reached on the type of data that is required to underpin policy decisions. A variety of different in vitro and in vivo methods are available for monitoring drug efficacy and resistance, and for mapping malaria. There is a need to simplify and verify these existing techniques and exploit new methodologies, particularly more rapid ones. Correlations between different types of data need to be examined with a view to establishing the relevance of the data to policy decisions. Tests need to be standardised in different areas and the importance of obtaining comparable multicountry data was emphasised.
• A consensus needs to be reached on the level of reliability in resistance data that would be acceptable as a basis for policy decisions on drug usage. This level will then determine the required sample sizes and number of sentinel sites that should be aimed for.
• Attention should be paid to the location at which data is collected. At present most data is obtained in a hospital setting, but the majority of malaria cases occur in households in communities.
• It was noted that a large proportion of current surveillance data was not published in peer reviewed journals, but was recorded in ‘grey’ literature.

• Participants at the meeting questioned who should take primary responsibility for carrying out monitoring of drug resistance and whether a new paradigm is needed for funding this activity. Monitoring is not usually regarded as pure scientific research, but nevertheless can involve a high degree of technical complexity and requires input of appropriate expertise. Large-scale surveillance is costly and would represent a high proportion of budgets available to national malaria control programmes.
• It was agreed that full use should be made of specialist technical expertise and funds available in research institutes and elsewhere for collecting and analysing malaria surveillance data. Such activities should complement the activities of ministries of health.
• A fundamental requirement is that data must be fully accessible to ministries of health for use in decision-making and this will require the involvement of these ministries from the initiation of a surveillance project. Appropriate communication links are necessary to ensure that data collected is relevant to policy decisions and disseminated in a clear and accessible form. Training should be provided to ensure that ministries of health have the necessary expertise in using databases. It was noted that the Mapping Malaria Risk in Africa (MARA) project has made efforts to establish links to ministries of health in each of the countries in which it is active and to ensure that maps and databases are in a form that is appropriate for policy makers. However, it was also noted that many research centres were not sufficiently proactive in making data available and accessible to ministries of health.
  

• 2.3 Databases

• Surveillance is carried out at different levels of sophistication, from basic drug efficacy tests, through to more detailed in vitro characterisation of drug resistant parasite strains and clinical information. This data, however, is collected by a range of organisations and is not always readily available to policy makers. Greater effort therefore needs to be made to put this data into a form that will be of value in policy decisions.
• Databases of surveillance data need to be constructed to allow entry of information at different levels of detail, which can then be stratified according to various criteria. For example, in vitro and clinical data might be linked where possible to data on drug consumption and selective pressure in populations, and to molecular characterisation of strains.
• Full use should be made of the opportunities to learn from surveillance databases that have been constructed for other diseases.
• It was recognised that with current technology, electronic databases could be transferred instantaneously to key locations in Africa, even if it were necessary for the database to be developed using expertise outside Africa.

• WHO/AFRO and CTD: monitoring of therapeutic efficacy of antimalarials across Africa and in vitro studies of parasite drug susceptibility.
• CDC collaborating with WHO and others to develop a database system to facilitate country-level entry and analysis of in vivo drug efficacy data.
• CDC monitoring activities in Mozambique, Tanzania, Kenya, Peru and the USA.
• WRAIR: in vivo and in vitro antimalarial drug sensitivity testing at sites in Southeast Asia, Africa and South America.
• East African Network for Monitoring Antimalarial Treatment Efficacy: an initiative that brings together scientists and representatives of Ministries of Health from Tanzania, Kenya and Uganda to strengthen regional information on parasite chemosensitivity as a base for rational and effective malaria treatment policies in East Africa. The network is supported in part by the UK DFiD.
• Mapping Malaria Risk in Africa (MARA): network of six sites across Africa which act as regional data collection centres. The aim is to construct a map of malaria endemicity in Africa using geographical information system (GIS) platforms. Activities are also being extended to include some drug resistance data. Sources of support include the Canadian IDRC, the MIM Task Force for Malaria Research Capability Strengthening and the Wellcome Trust.
• MIM Task Force for Research Capability Strengthening in Africa (co-ordinated by TDR) has supported five multicentre studies in Africa which have a focus on research on markers of drug resistance (involving Mali, Benin, Guinea, Ghana, Nigeria, Tanzania, Malawi). A meeting of the investigators involved in these projects is planned by TDR to discuss validation and standardisation of markers of resistance.
• USAID: In partnership with CDC, WHO/AFRO and WHO/CTD, USAID has been supporting the development and use of standardised tools and protocols for drug resistance surveillance. Africa integrated malaria initiative (AIMI) is a programme in four countries (Benin, Kenya, Malawi and Zambia) to improve management of malaria.
• German Technical Co-operation (GTZ): malaria programmes in Mauritania, Mali, Uganda and Viet Nam to improve antimalarial drug use, monitor drug resistance, promote the use of bednets, and improve laboratory diagnosis for malaria case management and surveillance.
• Proposed concerted action towards a global surveillance network of anti-malarial drug resistance (EC funds sought). This network has the objective of improving the monitoring of antimalarial drug resistance and establishing a system for rapid dissemination of information (Planned network includes sites in West Africa and Asia).
  

• 2.5 Next steps

• It was agreed that a major advance could be made, at relatively low cost, by drawing together the available sources of monitoring and mapping data. This data should be linked to the NIH-supported repository of characterised parasite strains.
• CDC agreed to offer its expertise in disease surveillance to facilitate the development of a database of available sources of information in a form that would conform to the principles outlined above and that would be freely accessible to Ministries of Health. This would involve working in close collaboration with WHO programmes and other partners such as MARA and the East African Network for Monitoring Antimalarial Treatment Efficacy to assess the information available and construct a suitable database. The aim would be to put in place a more intensified effort to establish a surveillance network for Africa, with input of technical expertise from outside Africa, where necessary. CDC had already begun to work with WHO/AFRO and CTD to develop a database for entry and analysis of drug efficacy data, and expressed willingness to explore possible ways in which it might facilitate a more comprehensive and concerted effort to optimise the use of currently available data sources.
• Representatives of ‘SHARED’, an information system on research relevant to developing countries, indicated willingness to assist in transferring surveillance data to developing countries with which it has active links.
• USAID has ongoing close collaborations with CDC, WHO/AFRO and CTD relating to antimalarial drug usage and expressed a keen interest in enhancing these collaborations. The offer by the Africa Bureau of USAID to commit some funds to explore the issues outline above was enthusiastically received.
• It was agreed that continual efforts should be made to focus discussions of approaches to developing an appropriate set of databases for monitoring drug resistance in Africa. This could be done through a meeting of, or email networking between, the participating agencies and the major sites collecting data that might be incorporated into a database, including representatives of ministries of health. CDC and other interested partners might provide support and co-ordination for such discussions.
• It was agreed that a technical workshop should be convened to address some of the detailed scientific questions relating to collection of appropriate high quality surveillance data, including sampling strategies. This might be held in conjunction with the planned series of CDC meetings on ‘Confronting the Challenge of Antimalarial Drug Resistance in Africa’.

• Firstly, the goal of chemotherapy in different epidemiological contexts requires clear definition. This might be to effect a clinical cure or parasitological clearance or to limit the development of drug resistance. The goal of chemotherapy needs to be assessed both at the individual patient level and at the population level, in order to take into consideration factors such as the development and influence of immunity in populations. Hence, the immediate and long-term goals of chemotherapy might differ. Drug toxicity was identified as an important factor in assessing the potential benefit of a change in drug usage.
• Participants emphasised that further work is required to examine the validity in policy decisions of different in vitro and in vivo parameters for monitoring drug efficacy, and molecular markers of resistance, and to establish correlations between different parameters. It was recognised that a particular parameter was unlikely to be universally valid, but would be influenced by the epidemiological situation, particularly the disease transmission intensity. There was a call to explore molecular options for early detection of resistance that could predict resistance prior to the emergence of serious clinical problems. It was noted that TDR was conducting research on new, simplified methods to detect resistance, and on the validation and use of these methods as predictors of resistance. The more complex question of how information on accumulation of mutations conferring drug resistance should be translated into policies is a further area to be explored.
• A fundamental aspect of drug usage recommendations is the impact of resistance on morbidity and mortality from malaria in communities and hence the impact of the timing and nature of a policy decision on the health of a population. Participants highlighted the very limited extent of information on the true health cost of drug resistance to countries.
• It was recognised that a major factor determining the acceptability of a proposed policy change is the cost of the alternative drug recommendation.
• It was agreed that a concerted effort was required to address in depth the research questions identified above underpinning policy decisions and to ensure that mechanisms are in place for such research to be carried out.
• It was agreed that the planned MIM Pan-African Malaria Conference would be an important opportunity to encourage dialogues between researchers and ministries of health to assist in the definition of research required to underpin policy decisions. It would therefore be essential to ensure the full involvement of ministries of health at the conference.

3.2 Strategies for delaying the emergence of antimalarial drug resistance

• It was agreed that a technical workshop should be organised to address in depth the factors determining the spread of resistance through populations. The Wellcome Trust and TDR/WHO expressed particular interests in pursuing this area in conjunction with any other interested organisations.

• Potent, rapidly acting and well-tolerated
• Short half-life. Artemisinin derivatives are very rapidly eliminated and hence when used in combination with other drugs they are rarely present in the blood alone; reducing the likelihood of parasites emerging that are resistant to the derivatives.
• Reduce biomass by approximately 10,000 fold per asexual life-cycle, ensuring that the residuum of parasites exposed to the second drug (e.g. mefloquine) alone is very small and selective pressure for the emergence of mutants is reduced considerably.
• Reduce gametocyte carriage, and hence the capacity of the parasite to be transmitted to another host, by approximately 90%. Deployment of artemisinin derivatives appears to have reduced the incidence of falciparum malaria in areas of Viet Nam and Thailand.
• Rapid therapeutic response ensures that patients are able to return to school or work earlier
• There is no evidence either in clinical or laboratory experiments for significant resistance developing in parasites exposed to artemisinin derivatives.

• It was agreed that the proposal to deploy all antimalarial drugs in combination with artemisinin derivatives offered immense potential benefits and urgent action should be taken to establish whether this approach would be effective and feasible. TDR/WHO and the Wellcome Trust therefore agreed to explore, with any other interested agencies, opportunities to support properly constructed clinical studies on the safety and efficacy of artemisinin derivatives in combination with other antimalarial drugs.

• The Wellcome Trust volunteered to explore opportunities to promote training of personnel in malaria endemic countries in health economics, operational research, demography and sociology.