The fight against malaria is a fast-moving sector with all the political and ideological wrangling found in any field combining cutting-edge research, high donor input and the urgency to save lives. According to some experts, certain programmes to combat malaria are not only struggling to meet their ambitious targets.

In early 2004, an article appeared in the prestigious international medical journal the Lancet accusing the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) and the World Health Organization (WHO) of medical malpractice in malaria treatment. Its authors, some of the most highly respected scientists in the malaria field, berated the two organisations for continuing to accept and fund country proposals that included the use of ineffective antimalarials, such as chloroquine and sulfadoxine-pyrimethanine (SP).

The experts challenged both agencies to endorse immediately and unequivocally the more expensive artemisinin-based combination therapies (ACTs) as the first-line treatment against malaria. According to several studies in sub-Saharan Africa, the resistance of Plasmodium falciparum, by far the most lethal malaria parasite, to SP and chloroquine medicines exceeded 50 percent. In contrast, 90 percent of patients who were given ACTs in studies conducted on nearly every continent were cured. Delays in backing this new treatment, the Lancet authors said, had resulted in tens of thousands of children dying every year – and made the Roll Back Malaria (RBM) Partnership’s goal of halving malaria mortality by 2010 appear complete fantasy.

Robert W. Snow, of the Centre for Tropical Medicine at the University of Oxford, praised the article, calling it a “watershed moment”. Global Fund communication head Jon Liden, on the other hand, described the editorial as irresponsible and “a high-stakes gamble”. They agreed, however, that the piece had played an important role in raising awareness and funds, both of which were prerequisites to the RBM initiative meeting its ambitious target.

Four months after the Lancet piece appeared, the Global Fund held a closed-door meeting in Geneva. Afterwards, the organisation’s senior officials declared that African countries should retrospectively adjust all malaria grants awarded to specify ACTs. Global Fund officials estimated that the cost of this policy change would be more than a US $1 billion over five years. Beyond increasing the funding demands on donors, the implementation of ACTs as the treatment of choice promised to challenge ill-equipped health systems and to test the political will of all partner states in their long-standing battle to control the mosquito-borne disease.

Artemisia annua, from which artemisin, the key ingredient in a highly effective antimalarials is extracted. The drug acts as a deadly toxin on the parasite, quickly eradicating the intruder from a patient's blood stream.
Credit: Gregory Di Cresce/IRIN
Sweet wormwood

Artemisinin, the powerhouse of ACTs, is extracted from Artemisia annua, or sweet wormwood. The Chinese have used this two-metre-high weed to treat fevers for more than 2,000 years. It was not until the early 1970s, however, that scientists isolated artemisinin. Its derivatives, such as artemether and artesunate, were then studied throughout the 1980s for medicinal properties. In 1991, Geneva-based Novartis began collaborating with Kunming Pharmaceutical Corporation of China on the production of an ACT.

Artemisinin’s reaction to the malaria parasite is explosive. When the drug encounters the parasite, it immediately acts as a deadly toxin, swiftly eradicating the intruder from a patient’s bloodstream. Using the artemisinin in combination with other antimalarials improves the therapeutic efficacy of the treatment and delays the development of resistance.

WHO lists in its 2005 malaria control guide the following advantages of artemisinin derivatives:

• Rapid reduction of parasite densities;
• Rapid resolution of clinical symptoms;
• Effective action against multi-drug resistant P. falciparum;
• No documented parasite resistance to artemisinin and its derivatives;
• Few clinical adverse reactions; and
• Reduction of gametocyte carrier rate, which may reduce transmission (i.e., fewer of the parasite’s gametocytes within an infected person lowers the probability of a biting mosquito becoming a carrier).

As further evidence of artemisinin’s effectiveness, WHO’s latest treatment guidelines recommend only ACTs to fight falciparum. The combinations recommended are artemether-lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine,and artesunate plus sulfadoxine-pyrimethamine. Artemether-lumefantrine, known by the brand name Coartem by Novartis, is the only co-formulated ACT that WHO has prequalified, although this is likely to change in 2006.

From plant to pill, the production of Coartem takes about 14 to 18 months. Its shelf life, if properly stored, is two years. In contrast, chloroquine and SP last somewhere between five to 10 years. Coartem costs about $2.40 per adult treatment, or 10 to 15 times more than chloroquine or SP.

Funding and politics

“These changes are never easy,” said Peter Bloland, chief of the malaria case management unit for the Centers for Disease Control (CDC) in Atlanta, the UnitedStates. “There was lots of talk about a need to move to ACTs as far back as the late 1990s, but nobody knew where the money was going to come from. Cost was cited again and again as the chief stumbling block.”

That stumbling block seemed to have been cleared in early 2002, when the Global Fund, the brainchild of the Group of Eight leading industrialised countries (G8), held its first board meeting in Geneva which gave a green light to wider use of the drug. Two years later, however, the Fund was accused in the Lancet of being politically manipulated by donor countries to buy cheap, “useless drugs.”

According to Amir Attaran, of the Institute of Public Health at the University of Ottawa and lead writer of the Lancet article, donors such as Great Britain and the United States had previously discouraged African countries from implementing artemisinin because it cost too much; because there was a dearth of information on its effect on children; and because it was not needed in a region where other anti-malaria drugs “still worked.”

The Global Fund disputed these allegations. Liden, insisted that changes to the new treatment were already underway before Attaran and his colleagues indulged in “exaggeration”. Liden felt the article was “unfair and irresponsible”, but he did acknowledge that the Global Fund was wrestling with a “very serious” funding deficit - another claim made by the article.

To keep current projects alive as well as fund new ones in 2006 and 2007, the Global Fund estimates it needs a total of $7.1 billion for the three areas it addresses – HIV/AID, TB and malaria. So far, it has about $4 billion in firm pledges from its donor countries, leaving a deficit of more than $3 billion.

One reason for this shortfall is the reluctance of the US government – which funds one-third of the Global Fund’s budget – to meet its international funding commitments.

In 2004, total world contributions to the fund came to $1.53 billion. In 2005, the global Funding for its work dropped to $1.28 billion. During the same period the US contribution dropped from $459 million to $352 million representing a fall of over 25 percent. For 2006, the US Congress has approved a $450 million donation, with the possibility of an additional $100 million if a pending budget bill is approved. Either way the funding gap between the Global Fund’s intentions and capacity based on contributions is significant and perennial.

Even if the Global Fund reached its $7.1 billion target for the next two years, the sum still would not be enough to fight malaria worldwide. WHO estimates it would cost $3.2 billion – more than half the Global Fund’s entire budget- to pay for all the ACTs, insecticide-treated bed nets and other interventions required to achieve the international targets on reducing malaria . The Global Fund estimated that last year it was able to disburse only $295 million fighting malaria.

Another wrinkle to the funding problems of the Global Fund and WHO, especially as they relate to ACTs, is WHO’s role as a procurement agent for African countries interested in purchasing Coartem. As noted earlier, Coartem is the only prequalified, co-formulated artemether-lumefantrine combination. Because of high levels of resistance to amodiaquine and SP treatments in East Africa, Coartem is essentially the only choice for countries such as Kenya, Uganda, Tanzania and Ethiopia. As Novartis is the sole pharmaceutical company that manufactures this drug, it essentially has a monopoly on the malaria treatment market in these countries, meaning countries who need it must buy from a single source.

To avoid this situation being exploited, WHO negotiated a memorandum of understanding with Novartis to purchase the drug at cost ($2.40 per treatment, as opposed to its retail price of about $7.50). Under the terms of this agreement, WHO must pool orders so that it can provide the Geneva-based company with a predictable and steady as well as to meet minimum order amounts. Novartis did not want to scale-up production of a costly drug with a short shelf life only to see it go to waste in the company’s storerooms.

In 2005, WHO asked Novartis to make 60 million treatments of Coartem. The pharmaceutical company replied that it could make only 30 million, given the global shortage of artemisinin. By the end of 2005, Novartis expected to release only 14 million orders for Coartem, leaving 16 million treatments, already prepared, in danger of being wasted.

“What happened? Money is not always the issue,” said Awa Marie Coll-Seck, executive secretary of the Roll Back Malaria Partnership. “Sometimes the problem is other things, like actually spending the money.” Suggesting that the release of the additional treatments was dependent on payment which was being delayed.

Challenges to implementation

Ministers of health or officials in charge of national malaria programmes struggle to access funding because they encounter bureaucratic obstacles within their own governments. “Many countries are not well equipped to spend Global Funds”, said Snow referring to bottleneck and capacity challenges in various countries.

Purchasing ACTs has been described as equivalent to taking a “leap of faith”. With no guarantees about how long the Global Fund will be around to subsidise the cost of the drugs; with other pharmaceutical companies – especially those based in countries planning to buy from Novartis – telling ministers of finance that buying from a single source “contravenes all good business principles”; and with most countries lacking the technical staff capable of properly distributing the drug, many experts, including Snow, agree it can be difficult to convince governments to place orders.

The latest two rounds of malaria funding for Kenya from the Global Fund amounted to $114 million. Of that, Sam Ocholo, head of the country’s division of malaria control, has had access to only $4.6 million. “There are conditions that the country has to meet,” Ocholo explained. “Sometimes they are very stringent to the extent that it affects the implementation. We also have our own in-country issues that may not be helping the process. … We needed to put in place processes and systems. We have taken a lot of time strengthening those systems to the detriment of achieving results.”

Before the Global Fund releases the bulk of any grant, it must be convinced that the country in question can effectively use the money. Among other things, this requires a country to prove it has the capacity, the human resources, to handle ACTs.

“The division of malaria control in Kenya is about six people,” Snow said. “That’s on a disease that accounts for about one-third of all hospitalisations, all out-patient admissions, and kills 36,000 to 38,000 children every year in this country. For this, you’ve got six people. That’s it. If a problem of this magnitude existed in the US, you’d have a Senate special committee on it. You’d have whole departments focused on it, and the CDC would be doing malaria and nothing else. You’d have not just a lot of financial resources at work, but human resources, too. That’s one of the things that falls through the cracks. You can provide as much money as you like to Kenya – you could double it – but you still only have six people to spend it, which include two medics and two technicians.”

Kenya is expected to introduce ACTs into its public health system early in 2006.

“These bottlenecks concerning the ability of countries to absorb funds are extremely variable,” said Melanie Renshaw, regional malaria adviser for the Eastern and South African Regional Office of the United Nations Children’s Fund (UNICEF).

Despite the logistical difficulties of its terrain, however, Ethiopia had managed to spend approximately 96 percent of an earlier round of funding.

“Zanzibar and Sudan also said they haven’t had any problems,” Renshaw noted. “Look, what this is all about is changing a country’s drug policy. When most of these malaria- endemic countries switched from chloroquine to SP, it took on average about five years. First you do your resistance testing. Then you have a meeting. Then you test for a new drug. Then you need national consensus. This has always been a very long process. What we’re experiencing with ACTs has been the most incredibly quick drug policy change I think we’ve ever seen.”

Obstacles to roll out

Corruption also stands in the way of successful implementation. The Global Fund suspended its funding to Uganda and demanded the country sack its management team, for example, after it was tipped off that money was being redirected into the pockets of in-country senior management. After an inquiry, the team was dismantled in November 2005 and the grant was immediately restored. Fortunately, projects for HIV/AIDS and malaria weren’t interrupted by the suspension, fund spokesman Liden.

Since the Lancet article in 2004, the Global Fund has given more resources to promote ACTs, promising to deliver 264 million doses over the next five years.
Credit: IRIN
Myanmar had its grants – totalling $35.7 million over two years – terminated because it had redirected that money into the military. The Global Fund learned of this from the UN Development Programme (UNDP), which was the principle recipient of the grant in Myanmar. Although one of the core principles of the Global Fund is to award grants to individual countries which, in turn, administer programmes themselves, Liden said in Myanmar’s case that principle just did not hold. “Normally a country is interested in the health of its citizens or is indifferent, permitting NGOs to take the lead. But when they actively obstruct efforts to help their population, we have no other alternative but to end funding.”

If a country can get past corruption, human resources issues and political infighting, it still has to address a host of challenges to “roll out” ACTs. First, there is the hurdle of getting the new drug into country. Then, there is the need to establish a distribution chain because, in many instances, existing networks are not systematic or reliable for routine medicines. New medical / dispersal guidelines need to be written to replace those that were adopted several years ago when countries switched from chloroquine to SP. People then need to be trained according to these new guidelines. In addition, there is a push to provide ACTs on a prescription-basis only, to ensure proper use of the drug and to prolong their effectiveness.

Finally, a campaign will have to be launched to convince the patient population to follow a complex dosing regimen (six pills, morning and night, three days in a row – at the right time with fatty meals). The rapid effectiveness of ACTs is, paradoxically, a potential detriment: Within about 12 hours of the initial dose, the parasite clearance is almost 100 percent and the patient feels instantly better. Such speedy improvement could discourage patients from completing a course of treatment. There is also considerable danger that patients may save the remaining pills or give them to somebody else. It is crucial that patients are well informed about using ACTs correctly. Early studies on compliance –in which supportive communication is stressed – have shown a high level of compliance.

Renshaw views the challenges of the treatment change as a “golden opportunity” to improve and expand healthcare systems not just vertically, but horizontally. “All of these demands will lead to significant improvements in health systems because the health system itself has to become much more efficient,” she said. “It is what Roll Back Malaria was always supposed to do – have malaria as a pathfinder for health system strengthening. ACTs will be a good way of demonstrating that.”

Looking back, looking forward

Since the Lancet article in 2004, the Global Fund has committed more resources to ACTs, vowing to deliver 264 million doses over the next two to five years. Kenya, Tanzania and Uganda have begun to cultivate sweet wormwood, Artemisia annua, to help offset the global shortage of artemisinin. Some 23 African countries have committed to ACTs are their frontline drug against malaria, and WHO has promised to work with Novartis to scale-up ACT production for 2006 and beyond.

“There’s a chance to take a huge step forward in the next five years,” said Liden. He insisted donor countries have come a long way in helping to finance a “revolution” against malaria. Liden qualified his enthusiasm, however, by acknowledging an urgent need to show “some big results soon.” Sudden significant reductions in malaria mortality across Africa and Asia could be a catalyst to draw even greater amounts of funding from the donor community, he said. Further setbacks would likely lead to a withdrawal of donor support.

Donor impatience and donor fatigue in the fight against malaria are not uncommon – they both were present after the failed attempt to eradicate malaria from sub-Saharan Africa in the 1950s. In this light, Liden viewed the emergence of new funding initiatives, such as US President George W Bush’s President’s Initiative and the World Bank’s Booster Program, with ambivalence. He recognised the positive contributions of these programmes but also saw them as signs of growing impatience among donors. They also add another layer of paperwork to already understaffed national malaria control programmes.

“As hopeful as I am about ACTs and other new tools we have to battle malaria, I’m nervous,” Liden said. “We’re moving too slowly. I’m nervous about a backlash in a year or two if the results are not there. And if the backlash comes, it will be huge. What does this all mean? Simply put, we can’t afford to fail.”
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