Are WHO and Global Fund supporting sub-standard malaria treatment?

“At least tens of thousands of children die every year” because the World Health Organisation and the Global Fund for AIDS, Tuberculosis, and Malaria (GFATM) continue to fund (or support the funding) the purchase of old drugs by African countries rather than the newer, more effective and dramatically more expensive artemisinin-class combination therapies (ACT), according to an editorial “viewpoint” published in the January 17^th issue of The Lancet.

The editorial, written by academic malaria specialists and some researchers in the developing world accuses both organisations of “medical malpractice” and blames them for caving into pressure from donor “governments such as the USA, whose aid officials say that ACT is too expensive.” This “wastes precious international aid money, and at most, kills patients who have malaria.”

While the specialists make some valid points in their editorial, and ACT is indeed considered to be the state of the art in malarial treatment, there are a range of opinions as to when, which and how best to introduce them into different countries. Malaria treatment practices also have important implications for opportunistic infection prophylaxis for people with HIV, and vice versa. The accusations levelled at the Global Fund and WHO also have important implications for future confidence in decisions reached by both bodies regarding treatment choices that are funded or promoted by these institutions.

According to the editorial, WHO’s high profile “Roll Back Malaria Campaign” which seeks to halve malaria deaths worldwide by 2010 is “failing” and the burden of disease and death from malaria are actually increasing. The most important reason for this increase in malaria is drug resistance in the most deadly species, Plasmodium falciparum. WHO has acknowledged “global malaria control is being threatened on an unprecedented scale by continued use of outdated drugs such as chloroquine, which is ineffective in most parts of Africa, and sulfadoxine-pyrimethamine (SP), which is becoming so.”

The editorial writers say that it is now well established that the artemisinin-class combination therapies (ACT) are the preferred treatment option in situations where resistance to the older mainstay drugs has become established. They cite a large meta-analysis of nearly 6,000 patients published by The Lancet on January 3^rd, which demonstrated that adding three days of an artemisinin to existing malaria drugs can significantly reduce the patients' risk of treatment failure and lessen the pool of parasites in the gametocyte stage of life. Gametocytes are the form of parasite that infect the mosquitoes which then transmit malaria to humans. Reducing their numbers could potentially reduce transmission of the disease.

The “viewpoint” writers further state that: “ACT is now the preferred policy for WHO and the Roll Back Malaria campaign as a whole.” They quote a statement from WHO’s Roll Back Malaria Strategic Orientations 2004-08: “Recently WHO has formulated policy that elevates combination drug therapy to preferred first therapy for all malaria infections in areas where P. falciparum is the predominant infecting species of malaria. Combination therapy (CT) with formulations containing an artemisinin compound (ACT) is the policy standard.”

Despite this, the editorial claims: “WHO violates its own policy standard regularly.” As evidence of this they say that when countries in Africa “seek financial aid from the Global Fund for AIDS, Tuberculosis, and Malaria (GFATM) to purchase ACT, they are forcefully pressured out of it by governments such as the USA.”

But it is important to note that WHO and the Global Fund are distinct institutions and WHO has no say over what the Global Fund does or does not finance. However, the editorial claims that: “WHO signs its approval when GFATM funds cheap but ineffective chloroquine or sulfadoxine-pyrimethamine (SP) to treat P. falciparum malaria.”

The African countries that the article cites as examples of where WHO and the Global Fund have gone wrong are Senegal, Ethiopia, Uganda and Kenya. However, each case is unique.

In 2003, Senegal, on its own accord, switched from chloroquine, which had become largely ineffective, to the use of SP, which at present appears to still work in that country (laboratory surveillance data do not yet demonstrate significant resistance to that drug in Senegal). Chloroquine is only employed in cases when there is not an adequate clinical response to SP after a few days.

It’s not clear that this protocol can be called medical malpractice since SP is quite effective where there is no resistance. However, it could be argued that the addition of an artemisinin compound could delay the development of resistance. But such a choice would be expensive. SP costs $0.14 per treatment. ACT would cost the country ten to 30 times more.

Ethiopia and Uganda did indeed ask the Global Fund, in proposals developed at least two years ago, to fund the purchase of chloroquine and SP for their countries but these requests were only a small part of much larger comprehensive proposals to fund the development of healthcare infrastructure and management of HIV/AIDS, malaria and (in Uganda) TB. Furthermore, the wisdom of using SP and chloroquine has to be looked at in each country individually. In Ethiopia as in Senegal, no surveillance data indicate resistance to SP, although there is much resistance to chloroquine.

Resistance began in eastern South Africa, where the pyrimethamine component was first used on its own and, as resistance to monotherapy set in, sulfadoxine was later added to treat malaria. By the 90’s, resistance to both components became established and began spreading gradually northwards and westward. Thus SP resistance indeed may not be very well established in Senegal or Ethiopia.

The treatment strategy being employed in Ethiopia is, as in Senegal, first to use SP and if there is no response to treatment after three days, to add chloroquine, which still may be helpful even when there is resistance to it. If there is still no response, the patient is referred to a specialist who could treat the patient with quinine (a effective drug that is usually reserved for the treatment of severe malaria) or he or she perhaps could decide to use an artemisinin combination.

The rapid development of resistance in Uganda and Kenya is indeed a cause for concern though a relatively recent phenomenon. HIV may actually play some role in this, or rather, the growing use of co-trimoxazole to prevent opportunistic infections related to AIDS (as well as to treat other common infections) may be partly responsible.

Co-trimoxazole is a very similar drug to SP. It has activity against malaria and shares the same malaria resistance profile. However, it is much less potent and also has a much shorter halflife in the body. WHO currently recommends that it be used by all symptomatic patients with HIV and all those with a CD4 cell count below 500 cells/mm³. In regions where it is being widely used in patients who are coinfected with both HIV and malaria, if adherence is poor, the selection of malarial resistance to SP could occur more rapidly. Numerous studies suggest that adherence to co-trimoxazole for its various uses is indeed often poor.

It is furthermore important to note that many people in areas with high transmission of P. falciparum harbour malaria infections without symptoms. In situations where only those with clinical symptoms are treated with SP resistance would probably become widespread only gradually, since much of the pool of the gametocytes that are being transmitted come from people who are not being exposed to the drug (where there is no selective pressure for resistance). But where cotrimoxazole use is widespread and adherence is low, and a proportion of the pool of gametocytes come from people without clinical malaria, SP resistance could be developing at an unusual pace.

This could partly explain why some areas of Kenya and Uganda have no or little evidence of resistance to SP, but why in some health districts, resistance to SP has developed within a very short period of time.

The Ugandan proposal to the Global Fund did indeed request substantial funding for chloroquine, where the clinical failure rate is on average 28% (and ranges from 9-89%) which will be used as firstline therapy – however in a different way than in most other settings. The strategy educates mothers and community workers to aggressively recognise and treat fevers in children and provides them with chloroquine specially packaged to ensure proper dosage and adherence. It is hoped that early treatment and better adherence will improve the response to treatment. The wisdom of this approach remains to be seen.

Meanwhile much of the SP purchased with Global Fund monies will be used as prophylaxis in pregnant women, a strategy that has been proven to work, while the safety of artemisinin combinations in this population in unproven. According to a commentary in the previous issue of The Lancet: “the safety of artemisinins during pregnancy remains unclear and a great worry.”

The editorial writers may disagree with medical wisdom of each country’s funding proposal, but to say that WHO supported these treatment choices is arguable. They write: “WHO's country representatives reviewed the funding proposals in which inappropriate drugs were sought--and signed their approval. Those signatures follow a declaration that WHO ‘has participated throughout the . . . process" of developing the proposal to GFATM, and that it "reviewed the final proposal and [is] happy to support it’.”

This implies that WHO has final sign-off authority on what the Global Fund supports and what it doesn’t. But it is important to understand these “declarations” in context. These proposals were for the management of HIV/AIDS, TB and malaria — not simply requesting funds to buy antimalarials. The actual “declaration” is a standard clause on many requests for funding from the Global Fund. In full, it states: “We the undersigned hereby certify that we have participated throughout the CCM process and have had sufficient opportunities to influence the process and this application. We have reviewed the final proposal and are happy to support it. We further pledge to continue our involvement in the CCM if the proposal is approved and as it moves to implementation.”

The claim that these funding decisions will lead to the death of thousands of children is based on an extrapolation from a study in Senegal that merely reported on the increase in death rate when chloroquine resistance occurred in that country. These data cannot be used to accurately predict the medical consequences of the models or strategies now being employed in Senegal, Uganda, Ethiopia and Kenya.

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 3^rd 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?”

Indeed, the role of the “market” and the pharmaceutical manufacturers in the “impending malaria crisis” is addressed nowhere in the January 17th editorial. Could this be because a number of the authors have close ties to the industry? In a conflict of interest statement following the editorial it was noted that lead author Amir Attaran “advises Novartis on its not-for-profit partnership with WHO for the joint distribution of ACT (Coartem) in developing countries. Two other authors are advisors to GlaxoSmithKline.”

They condemn "rich governments" for not wanting to pay the cost of the drug but nowhere do they condemn the pharmaceutical industry for charging such high prices for drugs derived from a natural product. Nowhere do the editorial writers call for these drugs to be put on the list of essential medicines so that governments can start producing them on their own.

The editorial also very quickly glosses over the dangers of resistance to this important class of drugs. It cites the fact that there is no evidence of resistance after 2000 years of usage in combinations (as most Chinese herbal preparations are) at different doses and for different purposes in China. But this may have little bearing on whether P. falciparum in areas where transmission is intense may or not become resistant to ACTs if it is too soon or recklessly employed.

ACT has great potential and must be introduced into these regions of the world — but in a rational fashion. As the authors of the meta-analysis study conclude: “funds for research into the best use of these compounds will also be necessary. Investigations will be needed to test specific strategies to enhance use of and adherence to 3-day combination regimens, to monitor their safety profile in widespread use, and to assess the costs, training, and organisational implications of introduction of such treatment, and the short and long term benefits.”