However, combination therapy with artemisinins is promising and may indeed be a better treatment choice in some of these countries. Ironically, the drug is quite ancient. Artemesinin (qinghaosu) is the antimalarial extract of Artemesia annua (sweet wormwood) used for centuries in traditional Chinese medicine. First isolated in 1971 by Chinese chemists, artemisinin is chemically unrelated to quinine or other existing antimalarial agents. Artemisinin and its derivatives, artemether and artesunate, can clear parasitaemia and reverse coma more rapidly than other drugs, but parasite recrudescence is common after monotherapy unless treatment is extended to 7 days or unless the drug is combined with other drugs that are eliminated from the body more slowly.
According to the commentary in the previous Lancet: “In southeast Asia, an epicentre for drug-resistant malaria, artemisinin combination treatment (ACT), particularly artesunate-mefloquine, has been a highly effective, safe, and durable regimen. Provision of artesunate-mefloquine as standard therapy in western Thailand and Vietnam has coincided with the reduced incidence of falciparum malaria and the stabilisation or reversal of mefloquine-resistance rates. The reduced incidence of malaria and the containment of resistant parasites have been attributed to the ability of artesunate to kill gametocytes … and thereby reduce transmission.”
However, the editorial writers somewhat misrepresent the meta-analysis study findings, at least in how they apply to Africa. This meta-analysis includes three studies from Thailand, twelve studies from sub-Saharan Africa, and one from Peru. According to the Lancet commentary “In most studies (but not all), the addition of 3 days of artesunate significantly increased parasite clearance rates at days 14 and 28 after treatment, and reduced gametocyte carriage rates at day 7.”
Most but not all — in countries where there was resistance to the antimalarial that artesunate was added to, the approach often did not work so well, while conversely in other settings where the antimalarial that artesunate was added to worked well, the effect of the addition was often negligible. According to the study authors: “Resistance therefore compromises effectiveness of artemisinin-based combination treatments using the failing drugs as partners. If the partner drug is effective in a particular region, then the benefit of addition of artesunate will be small, which might make the strategy unappealing to policymakers. But this is the optimum setting in which to use such combination treatments to prevent the emergence of resistance, and to ensure longlasting effectiveness.”
Adding artesunate to existing antimalarials adds about $1 to the cost of each treatment course (vs. $0.13 or $0.14). This is a difficult choice for nations where the burden of disease is high, funds for healthcare are limited and there is a wide range of health care needs that must be addressed with that funding. To simply blame WHO, the Global Fund, and the USA, a convenient target of late, is too easy. To claim, as the editorial authors do, that nations: “hesitate to change their treatment policies and request funding for ACT when that displeases the powerful donor governments who warn them - usually in private - that ACT is too expensive,” is an oversimplification, at the very least. It then seems a contradiction when the editorial concludes with the statement that unless WHO and the Global Fund change their policies “the reputations of both will be tainted such that rich governments lose confidence and cease funding them.”
As noted, the meta-analysis found that adding artesunate to a short course of a failing drug doesn’t always work that well. A better approach might be a different combination regimen. In fact, a recent study in Uganda suggested that amodiaquine-sulfadoxine-pyrimethamine was superior to artesunate-sulfadoxine-pyrimethamine for preventing late recrudescences. According to the January 3rd Lancet commentary: “This combination is also much cheaper, and thus would free resources for other pressing health needs in poor countries.”
Another approach could be a switch to a new ACT. Most of these are even more expensive than simply adding artesunate and not as widely tested. One exception, dihydroartemisinin-piperaquine, formulated in a single tablet, costs only $1 for an adult treatment. The same issue of the Lancet contained a study that demonstrated that combination worked very well in Vietnam, where multidrug-resistant malaria is common. Nevertheless, that is still much more than the price of chloroquine and SP, and the combination is relatively untested in other regions.
The editorial authors condemn WHO for not issuing clear malaria management guidelines as they have done for HIV/AIDS and TB. However, part of the reason why WHO does not dictate individual country malaria policies is because the disease is very different from region to region.
As the January 3rd commentary notes: “will ACT reduce malaria incidence and prevent the emergence and spread of drug-resistant parasites in Africa, as occurred in southeast Asia? Only additional research will answer these questions. However, because of differences in epidemiology and intensity of transmission, reducing malaria incidence in Africa will be challenging. Whereas infected individuals in Thailand usually become symptomatic, many Africans carry heavy infections without symptoms and thus act as a reservoir for continued transmission of parasite.”
Furthermore, results of ACT in South-east Asia have been “generally superior to the results from other countries…Whether (or which) ACT is the best combination therapy for first-line treatment in a particular country has not been adequately studied. Under the circumstances, different countries could reasonably make different choices for first-line therapy--which is precisely the current state of affairs. Zanzibar and Burundi have recently adopted artesunate-amodiaquine as first-line therapy, Zambia has adopted artesunate-lumefantrine, and Rwanda has adopted amodiaquine-sulfadoxine-pyrimethamine as a short-term strategy. These countries have each decided to act, but not all have chosen ACT. And if all countries were to deploy ACT in the near future, is there sufficient artemisinin to supply this enormous market?”