The malaria medicine chest, part 2 1/10/02. By Nick White Nick White examines the possibilities offered by artemisinin and combination therapy.

With the rise of resistance in the malaria parasite, many antimalarial drugs are becoming useless (see part 1 ). But artemisinin and combination therapy are providing new hope.

Hope from China

The most important contributions to the treatment of malaria in the last 50 years have came from China. The Vietnam War provoked a major Chinese initiative to develop new antimalarial drugs, and the most important discovery to emerge from this productive era was qinghaosu or artemisinin.

This novel antimalarial peroxide is derived from a ubiquitous plant – Artemisia annua.

Facing the spectre of untreatable malaria by the end of the millennium, studies started in Thailand on combinations of mefloquine with the artemisinin derivatives, artesunate or artemether. Each of the combinations proved highly effective and their subsequent systematic use was associated with a dramatic reduction in the incidence of malaria.

Furthermore, resistance to mefloquine actually fell – something that had never happened before. Similar dramatic reductions in the incidence of malaria occurred in Vietnam where artemisinin derivatives were also deployed widely. These promising results sparked a global initiative to evaluate artemisinin-based combination treatments (usually referred to as ACTs) throughout Africa and in South America.

These trials have confirmed the South-east Asian results. The artemisinin combinations provide consistently rapid resolution of symptoms, they are highly effective and well tolerated, and in low transmission areas, use of the combinations provides the bonus of reducing malaria transmission and therefore the incidence of malaria.

Feature: Developing artemisinin

The discovery of artemisinin and the synthesis of piperaquine, lumefantrine and pyronaridine have provided us with a new generation of effective, and in some cases, affordable antimalarial drugs. (Indeed, they are so effective and so well tolerated that an epidemic of fake preparations has threatened malaria control efforts in South-east Asia.) When injected, these compounds are safer than the time-honoured quinine, and may be more effective.

Double act

Combination therapy – combining two drugs together – to prevent the evolution of resistance is a tactic already used for the treatment of tuberculosis, leprosy, HIV and many cancers. As the probability of the evolution of a mutant resistant to one compound is very low, resistance to a combination is extremely unlikely to emerge.

So, to prevent the advent of resistance to the artemisinins, these drugs are being combined with other, synthetic compounds. And as artemisinin works quickly and is removed from the body quickly, the other compounds should be those that last for longer in the body, mopping up any parasites that have escaped.

Of the available ACTs, artemether–lumefantrine has proved equally effective to artesunate–mefloquine and better tolerated. It is now at the centre of the World Health Organization Roll Back Malaria Initiative. Dihydroartemisinin–piperaquine is a very exciting newcomer from China. It is still in the development phase but it offers the prospect of a combination treatment for an adult of less than $1.

With these new combination preparations we have now several alternative treatments to choose from which provide highly effective treatment against malaria everywhere in the world, and to which resistance is unlikely to emerge rapidly.

A dose of realism

The unveiling of the complete genome sequence of Plasmodium falciparum offers new strategies in the battle against malaria. We can anticipate that new targets for drugs will be identified, and that drugs can be designed rationally to attack these targets. So, we can hope for new drugs, unrelated to those we already have, to replace our existing drugs if they do fall to resistance.

But we must be realistic too. It is highly unlikely that any drug that emerges from the genome sequencing effort will be generally available within the next ten years (just as it is unlikely that an effective malaria vaccine will be widely available within this time).

Thus we must make do with the drugs that we already have to combat malaria over the next decade. Fortunately we do have now several effective ACTs from China upon which we can rely.

The challenge now is to provide the evidence that will persuade the world to pay for these drugs, as it is certain that the majority of malaria-affected countries cannot do this on their own. There are powerful economic arguments that this is a cost-effective approach. If effective antimalarial drugs were available throughout the tropical world this would translate into a tremendous reduction in suffering and death.

Professor Nick White is Director of the Wellcome Trust's South-east Asia Overseas Unit.