Facts on ACTs (Artemisinin-based Combination Therapies)
JANUARY 2006 UPDATE |
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Facts on ACTs (Artemisinin-based Combination Therapies)
JANUARY 2006 UPDATE |
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I. MALARIA BURDEN, DRUG RESISTANCE AND PATTERNS OF DRUG USE
Recent estimates of the global malaria burden have shown increasing levels of malaria morbidity and mortality, reflecting the deterioration of the malaria situation in Africa during the 1990s. About 80% of all malaria deaths occur in Africa south of the Sahara, and the great majority of them in children under five (1).
Key among the factors contributing to the increasing malaria mortality and morbidity is the widespread resistance of Plasmodium falciparum to conventional antimalarial drugs, such as chloroquine, sulfadoxine–pyrimethamine (SP) and amodiaquine. Multidrug-resistant falciparum malaria is widely prevalent in south-east Asia and South America. Now Africa, the continent with highest burden of malaria, is also affected. Resistance to inexpensive monotherapies such as chloroquine and SP has developed or is developing rapidly, with increased mortality as a result.
The inappropriate use of antimalarial drugs during the past century has contributed to the current situation: antimalarial drugs were deployed on a large scale, always as monotherapies, introduced in sequence, and were generally poorly managed in that their use was continued despite unacceptably high levels of resistance.
Over the past decade, a new group of antimalarials – the artemisinin compounds, especially artesunate, artemether and dihydroartemisinin – have been deployed on an increasingly large scale. These compounds produce a very rapid therapeutic response (reduction of the parasite biomass and resolution of symptoms), are active against multidrugresistant P. falciparum, are well tolerated by the patients and reduce gametocyte carriage (and thus have the potential to reduce transmission of malaria). To date, no resistance to artemisinin or artemisinin derivatives has been reported, although some decrease in sensitivity in vitro has been detected in China and Viet Nam (2). If used alone, the artemisinins will cure falciparum malaria in 7 days, but studies have shown that in combination with certain synthetic drugs they produce high cure rates in 3 days with higher adherence to treatment. Furthermore, there is some evidence that use of such combinations in areas with low to moderate transmission can retard the development of resistance to the partner drug.
II. WHO RECOMMENDATIONS ON MALARIA TREATMENT
As a response to increasing levels of resistance to antimalarial medicines, WHO recommends that all countries experiencing resistance to conventional monotherapies, such as chloroquine, amodiaquine or sulfadoxine–pyrimethamine, should use combination therapies, preferably those containing artemisinin derivatives (ACTs – artemisinin-based combination therapies) for falciparum malaria (3, 4).
As yet another step towards combating drug resistance in Africa, WHO has lowered the resistance-threshold recommended for treatment policy change from 25% to 10% as assessed by standard WHO protocols in children under 5 years of age (5), meaning that a more effective treatment should be adopted when the proportion of treatment failures to the old treatment reaches 10%.
WHO currently recommends the following combination therapies (in alphabetical order):
Note: Amodiaquine plus sulfadoxinepyrimethamine may be considered as an interim option where ACTs cannot be made available, provided that efficacy of both is high.
III. MALARIA ENDEMIC COUNTRIES ADOPT COMBINATION THERAPIES
WHO provides technical cooperation to ministries of health on all aspects of national treatment policy change – monitoring the therapeutic efficacy of medicines, updating, implementing and monitoring ACT-based treatment policies. Adoption is not immediately followed by implementation: in Africa a total of 10 out of the 34 (29%), and outside Africa 13 out of the 20 countries (65%) which have adopted ACTs are deploying these medicines in the public sector.
The countries which are currently deploying ACT in the general health services to some extent are the following:
Since 2001, a total of 56 countries have adopted one of the WHO recommended artemisininbased combination therapies, several as first-line treatment and a few as second-line (see table below, last updated on 1st November 2005).
The Figure 1 shows the trend of adoption of ACTs as fi rst-line treatment (the line represents the cumulative number of countries).
IV. SUPPLY AND DEMAND FOR ACT
The exponential increase in the number of countries adopting ACTs has led to a rapid increase in demand for artemisinin and its derivatives. The global consumption of ACTs has increased from a few hundred thousands in 2001 and 2002 to tens of millions in 2005. The rapid increase in demand produced a global supply shortage of artemether/ lumefantrine (4), the product which was in greatest demand. This shortage which lasted for a period of about 12 months has been overcome by its manufacturing company by introducing major changes in the critical steps of manufacturing, from sourcing to supply chain management. No supply shortages are foreseen for any of the ACTs in the near future.
Artemisinin compounds are derived from a raw substance extracted from the plant Artemisia annua. Cultivation of the plant requires a minimum of 6-8 months from planting to harvesting, and extraction, processing and manufacturing of the final products require at least 2 to 5 months depending on the product formulation. In 2005, there has been a major expansion of the agricultural production and extraction facilities from the existing sites and sources in China and Viet Nam to several in Africa and other parts of the world.
WHO forecasts that for 2006 at least 120 million ACT treatment courses will be required globally. The Roll Back Malaria Medicines and Supply Services is consolidating all ACT country forecasts, including anticipated demands from international funding institutions and procurement agencies and plans to make this information publicly available in early 2006. The sources of information and estimations for these forecasts will be provided to help both manufacturers and health development partners.
V. HOW ACCESS TO ACT IS ENSURED
| QUALITY ASSURANCE Prequalification and Sourcing Project |
In May 2002, in collaboration with other United Nations agencies, WHO established an international mechanism to pre-qualify manufacturers of artemisinin compounds and ACTs on the basis of compliance with internationally recommended standards of manufacturing and quality (6). Products and manufacturers that meet these standards are included in a list considered acceptable for procurement by United Nations agencies. The list is published as a guide to governments, NGOs and other partners, e.g. the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), procuring ACTs. To date, one ACT – artemether–lumefantrine (Coartem®) – has been pre-qualified. |
| WHO-UNICEF CALL FOR TENDERS OF ACTS | WHO and UNICEF place regular calls for tenders of co-blistered combinations of the following products for which there are not yet pre-qualified manufacturers: i) artesunate plus amodiaquine; ii) artesunate plus sulfadoxine/pyrimethamine; iii) artesunate plus mefloquine; and iv) amodiaquine plus sulfadoxine/pyrimethamine. Several manufacturers have been inspected by WHO, and GMP-certified products for all of the above ACT are being procured by both WHO and UNICEF, including for GFATM supported programmes. |
| NEGOTIATED PRICES AND CENTRALIZED PROCUREMENT artemether/lumefantrine (Coartem®) | WHO and Novartis, the manufacturer of artemether/lumefantrine (Coartem®), have a special pricing agreement since 2001: Novartis provides the drug at cost price (US$ 0.9 and 2.4 per child and adult treatment course respectively) for use in the public sector in malaria-endemic countries (7). WHO, through a panel of experts, reviews requests for supplies of Coartem®. Through the special price agreement WHO and UNICEF procure the drug for governments of malaria-endemic countries, United Nation agencies, bilateral agencies, and NGOs. |
| FINANCING OF ACTS Global Fund expenditure on ACTs |
GFATM, established in 2002, is up to now the largest funder of ACTs for public health. In first four rounds of funding, a total of US$ 230 million has been approved over the first 2 years of GFATM Board-approved proposals for the purchase of ACTs, mostly for African countries. Since January 2004, the GFATM has promoted:
Other sources of funds for ACT purchases available to endemic countries include development banks, multilateral and bilateral agencies and NGOs. Recent new and expected sources of funding for malaria control include the World Bank’s Booster Programme for Malaria Control, which amounts to between US$500 million and US$1 billion over the next five years, and USA’s President’s Malaria Initiative (PMI) for US$1.2 billion over five years for 15 countries. It is expected that some of these funds will be available for the purchase of ACTs. |
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References
1. The world malaria report. Geneva, Geneva, World Health Organization, 2005 (unpublished document WHO/HTM/MAL/2005.1102)
2. Susceptibility of Plasmodium falciparum to antimalarial drugs. Report on global
monitoring, 1996-2004. Geneva, World Health Organization, 2005 (unpublished
document WHO/HTM/MAL/2005.1103)
3. The use of antimalarial drugs. Report of a WHO Informal Consultation. Geneva,
World Health Organization, 2001 (WHO/CDS/RBM/2001.33).
4. Antimalarial drug combination therapy: Report of WHO technical consultation, 4-5
April 2001. Geneva, World Health Organization (WHO/CDS/RBM/2001.35).
5. Assessment and monitoring of antimalarial drug effi cacy for the treatment of
uncomplicated falciparum malaria. Geneva, World Health Organization, 2003
(WHO/HTM/RBM/2003.50).
6. WHO Prequalifi cation Project - http://mednet3.who.int/prequal/
7. Procurement of artemether/lumefantrine (Coartem®) through WHO. - http://www.
who.int/malaria/cmc_upload/0/000/015/789/CoA_website5.pdf
| For further information, please contact: WORLD HEALTH ORGANIZATION 20, avenue Appia – 1211 Geneva 27 – Switzerland Tel. +41 22 791 3419 Web site: http://www.who.int/malaria |
