Combination Therapy in Global Strategy for Treatment of Malaria

Every year, malaria kills 1-2 million people. 90% of deaths occur in sub-Saharan Africa. The disease is present in over 100 countries and threatens 40% of the world population.

Treatments exist but, in recent decades, drugs such as chloroquine or sulphadoxine-pyrimethamine have become increasingly ineffective because of drug resistance. Resistance has spread so far that it now represents a serious threat to global public health.

> Artemisinin-based combination therapy (ACT)
Scientists now agree that the most effective treatment against malaria is a combination of drugs using artemisinin derivatives, highly potent extracts of the Chinese plant Artemesia annua. Artemisinin-based combination therapy (ACT) is the quickest and most reliable way of clearing malaria infection, and it is very well tolerated. Using a combination of drugs shortens the treatment course, and has also been shown to protect each individual drug from resistance.

The World Health Organization (WHO) is now actively encouraging malaria-endemic countries to switch to ACT, and many of them are starting to do so. Overall, 40 countries in the world have included ACT in their malaria treatment protocols and a further 14 are considering doing so.

> Why the need for fixed-dose combinations?
Compliance to treatment is crucial to ensure treatment effectiveness and prevention of future resistance to ACT. But when combinations are provided as two separate drugs, patients might take only of one the two drugs or fail to complete the whole course. The protection against resistance is also lost if one drug is taken without the other. To optimise patient compliance, it is therefore important to provide patients with fixed-dose combinations (two drugs combined into one tablet) rather than separate tablets.

So far, only one fixed-dose ACT exists, Coartem (an association of artemether and lumefantrine). Although extremely effective, it needs to be taken with a fatty meal, can cause gastric side-effects, and is relatively expensive. New fixed-dose combinations are therefore necessary to offer endemic countries a wider range of treatment options adapted to their needs. This is what the Drugs for Neglected Diseases Initiative (DNDi) in association with UNICEF-UNDP-World Bank-WHO's Special Programme for Research and Training in Tropical Diseases (TDR) has set out to do with its Fixed-dose Artesunate Combination Therapy (FACT) project, developing artesunate-amodiaquine and artesunate-mefloquine.

> Advantages of DNDi-TDR's FACT
The use of a fixed-dose combination, in strengths adapted to the patientsÕ ages, will allow a simple treatment of just three days, with a single daily administration of two tablets. The advantages are manifold:
• Rapid effect
• High cure rate (over 90%)
• Reduction of potential for transmission (less infective parasite in the blood)
• Ease of use (which increases compliance and therefore treatment effectiveness)
• Coverage of the whole population at risk (treatment can be used in both children and adults)
• Prevention of resistance and therefore further reduction of transmission
• Cheaper than buying combination of separate tablets or blister pack.

> Future use of fixed-dose combinations in malaria-endemic countries
Thirteen countries have already adopted the combination of artesunate + amodiaquine as their national first-line treatment1 and five have adopted artesunate + mefloquine2. These countries will undoubtedly choose to switch to fixed-dose combinations once they become available, and many other countries may choose to adopt them.

Assessing future need for ACT, the World Health Organization has forecast that in 2005, 90 to 150 million treatments will be needed (based on total morbidity estimates). Africa, the worst-hit continent, makes up 60-70% of this global requirement. To meet this huge need several industrial partners will have to be involved in the manufacture of both combinations at low cost.
All malaria-endemic countries will benefit from the availability of a wider range of safe, effective and easy to use fixed-dose combinations.

1. Indonesia plus Burundi, Cameroon, DRC, Equatorial Guinea, Gabon, Ghana, Liberia, Madagascar, Sao Tome, Sierra Leone, South Sudan, and Zanzibar.
2. Cambodia, Thailand, Bolivia, Peru, and Venezuela.

Malaria facts:
> Malaria kills between 1 and 2 million people every year
> Malaria kills one African child every 30 seconds
> Malaria is the first cause of death for children under 5 years of age
> Sickness and death from malaria account for 30-50% of hospital admissions and a yearly loss of US$412 billion on the African continent