Malaria Matters

Kenya is facing at least two major and seemingly opposing changes in its malaria epidemiological profile.  SciDev.net reports on an article from The Lancet that confirms, “An analysis of data collected over 18 years from malaria-infected children at Kilifi District Hospital, on Kenya’s Indian Ocean coast, found that paediatric admissions for malaria had fallen by 75 per cent over a period of just five years.”

At the same time, “In recent years malaria has also appeared in the highland areas where it was previously unheard of,” according to Inter Press Service (Johannesburg).  Keeping pace with these changes is essential if the national malaria control services and its malaria donor partners are to provide appropriate interventions for each part of the country.

In the highlands where people are less used to malaria, Sumba and colleagues found that. “A significant proportion of this highland population chooses local shops for initial malaria treatment and receives inappropriate medication at these local shops, resulting in delay of effective treatment.”

Because highland residents, for example those in Kibera, Nairobi, travel back to their home villages in malaria endemic areas, they bring the parasites back. With the potential of global warming making the highlands more favorable to malaria transmitting mosquitoes, the highlands will face increasing risk, according to an IRIN news release. Furthermore, “As 20 percent of Kenya’s population — eight million people — living in the highland areas are now exposed to malaria, new plans for preparing and responding to an epidemic are needed” (Inter Press Service News).

In The Lancet article O’Meara and colleagues believe that the reduction in transmission in coastal Kilifi is multi-factorial and could be related to bednet use and changes in malaria drug policy among others. They conclude that, “Our results are consistent with comparisons between multiple sites and provide further evidence that reduction of trans mission leads to a change in pattern of severe disease but might not lead to immediate reductions in disease burden.” This means that …

Emphasis on use of insecticide-treated bednets, early treatment, and other control measures must be increased to maintain reductions in disease burden and prevent a potential resurgence of malaria in a population with far less immunity than before.

The experience in Kenya shows that changing climatic conditions and increasing effectiveness of malaria control interventions may in the short run put more people at risk of severe malaria due to reduced immunity levels.  The need for sustaining efforts in some parts of the country and focusing new interventions on others makes the elimination of malaria a challenging and ever shifting target.

A World AIDS Day approaches people in the field are giving a critical look at efforts to scale up ART. Jeremiah Norris in the Daily Times of Malawi raises the question of drug quality in the push for achieving widespread HIV/AIDS treatment goals. Could these same problems surface in the desire to scale up for impact (SUFI) that Roll Back Malaria partners are promoting? Some excerpts highlight the problem:

While activists have applauded the speed of this “scale-up,” it creates dangers. Many of the copies recommended by WHO are untested so patients cannot be certain that they act on the body in exactly the same way as the original (called bioequivalence). If the level of active ingredient is not absolutely correct, it can accelerate drug resistance and the mutation of the Aids virus. Under Indian law, drugs manufactured for export do not have to prove bioequivalence with the patented original.

Brazil is often held up as the model for universal Aids treatment. It too has based this largely on cheap, untested copy drugs. In July, the government acknowledged that one third of the 190,000 Aids patients under treatment were in what it called “a more advanced stage”–but medical studies had already shown even higher levels of drug-resistance.

 Norris worries that, “WHO, the Global Fund and the Clinton Foundation therefore sanctioned a drug that was not only unapproved and potentially sub-standard but also more expensive.” Most donors depend on WHO’s ‘prequalification’ program for ensuring drug quality, but maybe it is possible in the rush to achieve coverage some governments are buying drugs not on the prequalified list.

The pressure is on to scale up malaria treatment. The Global Fund Board has recently approved taking on management of the Affordable Medicine Facility – malaria (AMFm), which will among other things enhance the role of private sector in increasing access to malaria medicines. The Clinton Foundation has been negotiating with pharmaceutical manufacturers about making more lower coast malaria drugs available.

Norris’ concern that, “many poor countries … cannot carry out drug evaluation themselves” applies for malaria drugs as well as ARVs.  Even if a drug appears on a WHO or FDA list, one cannot guarantee that the medicine that found in a district hospital pharmacy or a local medicine shop in a malaria endemic country is actually of the quality required. Quick wins in scaled up medicine distribution can ultimately result in quick loss of life if capacity is not built to monitor drug quality at the front line.

The William J Clinton Foundation is among the constituency members of the Roll Back Malaria Partnership. As such, the Clinton HIV/AIDS Initiative (CHAI), is not aimed at only one disease.  According to the website …

• CHAI’s first malaria price negotiations reduced the price of one ACT, an effective malaria drug, by 30% and reduced price volatility of artmesinin, the plant extract in ACTs, by 70%.
• CHAI initiated a pilot subsidy on ACTs in Tanzania which reduced the price in targeted areas by 95% and increased uptake by approximately 45% for people of all ages - 62% for children under 5.

In a conversation between Bill Gates and Bill Clinton on malaria at the Clinton Global Initiative meeting this year, the former President showed his clear interest in the disease by saying that, “Malaria is a good example of the sort of thing that we just celebrated on the stage here. This is something that you can break down into discrete units so no matter how much or little money you have, you can give it to an NGO that will buy a high-quality bed net, put it up, do it in the right way. And so, if you had $5 a year to give, you could still make a big difference in a family’s life.”

CBS News confirmed that, “Former President Clinton’s foundation has signed pricing agreements with several suppliers involved in making a malaria-fighting drug in an effort to stabilize the medication’s fluctuating costs and ensure more dependable availability.” Another side of the story, is that, “Besides benefiting from a more stable market, the suppliers that join the Clinton effort also get business and marketing assistance from the foundation.” Issues like the latter mean that questions are being raised as to how these accomplishments and those for HIV and other global health causes would be affected if Senator Hillary Rodham Clinton becomes Secretary of State in the upcoming Obama administration.

The Washington Post considers the possibility that major donations to the Foundation from international business tycoons, among others, “could present ethical concerns for Sen. Clinton if foreign governments believe they can curry favor with her by helping (such donors), or if they fear that restricting (such donors’) activities would damage their relations with her.” Suggestions range from revealing all donors, to reduced or no involvement by the former President in the Foundation and its fundraising and even to voiding existing standing donations.

The Clinton Global Initiative has posted on its own website a 2006 article from the New Yorker that describes Clinton’s continued international connections on a trip to Berlin. Attending one of the World Cup matches, “The Clintons took their seats in the ’statesman’s section,’ at midfield. While Clinton’s statesmanship has been strictly freelance for the past six years, he was not far from the German Chancellor, Angela Merkel, and he spent time during the game, and during the breaks, chatting with old friends-the schmoozer in excelsis.”

The Washington Post talked with Bill Clinton’s associates and concluded that, “those close to the former president said they would be reluctant to see him back away from charitable work that has provided a source of AIDS treatment for 1.4 million people, a major engine in the effort to reduce greenhouse gases and sponsorship of anti-obesity programs in American schools.”

Bill Clinton has been quoted as saying that he will do and disclose whatever is needed to enable Senator Clinton to become Secretary of State. Will this also be good for malaria?

The BBC reports that, “Around 100 million ACTs were sold in 2006, but forecasters say that demand will at least double over the next four years, potentially growing to over 300 million doses annually.This is partly due to a recent decision by the global malaria community to subsidise the cost of ACTs. There is already expected to be a shortage in 2010 owing to a lack of the Artemisia annua wormwood plant plant, the raw material for ACTs, being grown.”

The Artemisinin Enterprise is planning a three-pronged approach to address the problem as reported in Medical News Today.

• The Centre for Novel Agricultural Products at the University of York is using fast-track plant breeding to increase yields of artemisinin from the medicinal plant.
• The Institute for One World Health is using synthetic biology to produce artemisinin through fermentation and subsequent chemical conversion.
• The Medicines for Malaria Venture is developing novel synthetic artemisinin-like compounds.

RBM explains that, “All three approaches are needed to satisfy projected global demand for ACTs. The projects are collaborating to ensure maximum impact on ACT supply chains and to ensure the new technologies do not enter substandard drug or monotherapy supply chains.” A full report of the recent conference that explored these options can be found at the website of Centre for Novel Agricultural Products.

In the meantime research needs to continue on other natural plant derivatives for curing malaria to avoid the dangers of having only one main tool for achieving and maintaining treatment levels needed to eliminate the disease. Of course, rational use of ACTs now is crucial.

During the first day of the 2008 Global Ministerial Forum on Research for Health in Bamako we were told that while not every country needs a national airline, all need indigenous health research capacity. How else could the unique ecological, cultural and administrative context for providing appropriate health services be discerned? The objectives for the forum follow:

• Strengthening leadership for health, development and equity
• Engage all relevant constituencies in research and innovation for health
• Increase accountability of research systems

While the forum is featuring improtant processes such as capacity building research ethics, civil society involvement, operations research application, among others, specific health issues like malaria are a subtext running throughout.  Mali itself has been developing strong malaria research capacity, and not surprisingly Ogobara Doumbo, the Director of the Malaria Research and Training Center (MRTC), University of Bamako, is a member of the program committee.

This month in The Lancet Stephen Pincock presents a short biography of Ogobara Doumbo, which starts with a childhood commitment to health care from someone clearly rooted in his culture and thus, able to ground his future health research in his country’s needs.

“One day towards in the late 1960s, a doctor came to visit a small village in eastern Mali where the young Ogobara Doumbo and his family lived. He asked the 10-year-old what he wanted to be when he grew up. “I said, ‘I am planning to be a doctor like you’”, Doumbo recalls. “He was very surprised for a small child to be so convinced he wanted to be a doctor.” Considering Doumbo’s father and grandfather were both traditional healers, perhaps his response was not really so surprising. From that year, Doumbo began travelling with his grandfather to other mountain villages, absorbing his strongly ethical approach to treating ailments ranging from infectious diseases to breast inflammation. “I spent enough time to see his practice and follow him carefully.”

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According to US National Institutes for Health, which is one of the supporter the MRTC, “The MRTC is viewed by many as a model for research centers in developing countries, as its research is planned, directed, and executed by African scientists.” Thus the MRTC can certainly hold pride of place equal to if not greater than a national airline. A small sample of findings from recent MRTC publications include -

• Artesunate-mefloquine is well-tolerated and is as effective as artemether-lumefantrine for the treatment of P. falciparum malaria. Artesunate-mefloquine also prevented more new infections (AMJMH).
• Maps provide valuable information for selective vector control in Mali (insecticide resistance management) and may serve as a decision support tool for the basis for future malaria control strategies including genetically manipulated mosquitoes (Malaria Journal).
• The magnitude of antibody response against Plasmodium falciparum may not be as important as it is believed to be. Instead, the fine specificity or function of the response might be more critical in protection against malaria disease (Acta Tropika)
• Given the delay in the time to first malaria episode associated with HbAS, it would be advisable for clinical trials and observational studies that use this end point to include Hb typing in the design of studies conducted in areas where HbAS is prevalent. (J Infect Dis)
• Altogether, these results suggest that indoor mating is an alternative mating strategy of the M molecular form of An. gambiae. Because naturally occurring mating couples have not yet been observed indoors, this conclusion awaits validation. (J Med Entomol)

Keep track of the Bamako Forum via TropIKA.net and learn more about health systems research, the challenges of eHealth and other health research issues that will affect the future of malaria research.

Approved Global Fund Round 8 Malaria Grants are listed in the chart below.  As we know, approval of a proposal does not mean that funds start flowing.  It is now necessary for the designated countries to prepare their plans and budgets so that formal grant signing can proceed.

Of the 29 Malaria grants approved in Round 7, five still have no designated Prinicpal Recipient since the grant has not been signed. These include Chad, Malawi, Sudan, East Timor and Nicaragua.

As we have stressed before, partners who help countries develop grant proposals should not abandon them after the proposal has been submitted. The work is just beginning once the proposal has been approved.

Various announcements have been made this week of a huge upcoming malaria vaccine trial among 16,000 African children. The Seattle Times describes the major health systems investments that have been underway to support this research trial.

The massive vaccine trials will be conducted in Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania. Dr. Christian Loucq, director of the Malaria Vaccine Initiative, said the project has been working over the past year to upgrade laboratory, computer and other equipment in those countries, train technicians, and even help develop local equivalents of the U.S. Food and Drug Administration to ensure the trials are properly monitored.

This is a indirect acknowledgment of the broader health systems challenges that create bottlenecks for implementing existing interventions such as long lasting insecticide treated nets, artemisinin-based combination therapy and intermittent preventive treatment for pregnant women.  The success of these current interventions is essential for bring malaria levels close to elimination levels in endemic countries so that when an effective vaccine arrives, it will be able to carry malaria control efforts to the next level - eradication.

GlaxoSmithKline, one of the vaccine trial partners, has an active malaria support program that addresses malaria prevention and treatment activities in 8 African countries and so is very likely aware of the systems challenges facing implementation of existing interventions. The researchers are also realistic about their own challenges because they have been involved in malaria vaccine trials since 2003.  The PATH Malaria Vaccine Initiative, the other partner in this endeavor, has other vaccine candidates in the pipeline ‘in case’.

Ultimately, the researchers realize that “even if their vaccine does not succeed, the widespread investment needed to conduct the trials means that Africa will be left with better communications, research and other infrastructure that could be used in the search for vaccines against other diseases such as AIDS.” What is needed though is ongoing, more thorough and concerted attention to improving health systems to deliver malaria and other primary health care interventions, not just building systems when and where a special research project is planned.

Better access to and use of health systems strengthening funds from the Global Fund is one step in this direction.

The Global Fund announced its Board’s decisions for Round 8 funding with the statement that, “The Global Fund to Fight AIDS, Tuberculosis and Malaria is pleased to announce that its Board has approved 94 new grants worth US$2.75 billion over two years.” the overall portfolio now totals US$ 14.4 billion and reaches 140 countries.

The good news is tinged with some bad, possibly arising out of the global financial crisis. As the Global Fund Observer reports, “because of financial shortfalls, the Board insisted on some cuts to the budgets in the Round 8 grants, and also delayed by six months the date at which Round 9 grants will be approved.” The current amount approved for two year Phase 1 grants is 90% of the requested US$3 billion. In a similar vein the Global Fund Observer reports that, “when it comes to negotiating Phase 2 for approved Round 8 proposals, the Fund will expect budgets to be cut by an average of 25% from what was originally proposed – unless the Fund receives sufficient donations that such cuts turn out not to be necessary.
Although there were fewer malaria proposals submitted, both the approval rate and total dollar value of these were greater than for the other two diseases as seen in the chart. The Global Fund Observer report shows that none of the malaria proposals from Latin America and the Caribbean were given immediate approval, and only three from Asia were approved. In contrast 70% of African applications were approved for immediate start.

There were at least four African countries that applied for both a malaria disease and a malaria health services strengthening component to their grant.  Two got both (Zanzibar in Tanzania and Zimbabwe) while two received only the disease component (Ghana and Rwanda)

Even with the cutbacks, the amount approved for Phase 1 grants in Round 8 was more than double that of Round 7, previously the largest amount ever approved.

Support from the Roll Back Malaria Partnership may likely explain the success of the malaria proposals from Africa.  Technical assistance was delivered for conducting needs assessments and proposal writing.  Partners need to remain vigilant in continuing that support for now delayed Round 9.

A discrepancy “between the perceived and actual level of transmission intensity” has been observed in the ‘Mosquito River’ area of Tanzania near Arusha by Mwanziva and colleagues. Specifically, they found …

Malaria transmission intensity by serological assessment was equivalent to < 1 infectious bites per person per year. Despite low transmission intensity, >40% of outpatients attending the clinics in 2006-2007 were diagnosed with malaria. Prospective data demonstrated a very high overdiagnosis of malaria. Microscopy was unreliable with <1% of slides regarded as malaria parasite-positive by clinic microscopists being confirmed by trained research microscopists. In addition, many ’slide negatives’ received anti-malarial treatment. As a result, 99.6% (248/249) of the individuals who were treated with ACT were in fact free of malaria parasites.

A similar experience was found in urban Lagos, Nigeria ten years ago*:

• Blood film investigation of 916 children between the ages of 6 months and 5 years yielded a parasite prevalence rate of 0.9%.
• Night knockdown collections of mosquitoes in rooms yielded only C. quinquefasciatus and A. aegypti
• Very low densities of A. gambiae larvae were found in breeding sites (between 0.3 and 0.7)
• Community members, during focus group discussion identified malaria, in it various culturally defined forms, as a major health problem.
• Among the children examined clinically, 186 (20.3%) reported an illness, which they called “malaria” in the previous two weeks, and 180 had sought treatment for this illness.
• Data obtained from 303 shops in the area documented that a minimum of US $4,000 was spent on purchases of antimalarial drugs in the previous week.

This contrasts with a report from Médecins Sans Frontières (MSF) that “ weak distribution and health systems and a lack of qualified staff” are reasons why poor people in many malaria endemic areas do not receive appropriate treatment.

During a recent visit to Mozambique I observed that antenatal clinic staff had Rapid Diagnostic tests. Some explained that if the test was negative, they would send the client to the lab. If the lab results were negative, they would still treat to be on the sfae side.  This reinforces the conclusion by Mwanziva that “rational drug-prescribing behaviour” must be reinforced. Of course as seen in Lagos, this concern goes well past the behavior of orthodox prescribers.

This malaria treatment gap poses serious threats to both lives and resources.  The shame is that health workers and program planners bear as much of the responsibility as the patients themselves, if not more. This is a challenge may be met through development and enforcement of better treatment performance standards.

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*Brieger WR, Sesay HR, Adesina H, Mosanya ME, Ogunlade PB, Ayodele JO, Orisasona SA. Urban malaria treatment behaviour in the context of low levels of malaria transmission in Lagos, Nigeria. African Journal of Medicine and Medical Sciences 2002; 30(suppl): 7-15.

Uganda’s New Vision newspaper points out that …

UGANDA has lost $12m (about sh25b) from the Global Fund over poor accountability. Out of $36m allocated to the country in 2003 for HIV/AIDS activities under Round One, over $10m has not been released as the Fund was not satisfied with how the first installments were used. Another $24m was allocated in 2004 for malaria activities under Round 2, but $2m has not been disbursed, according to the Fund’s website www.theglobalfund.org.

The Round 2 Malaria grant apparently was intended for only 3 years. It started in 2004 and the last progress report was posted in August 2007. In that last report the GFATM rated the project with its lowest grade, a ‘C’.  The currently running Round 4 malaria grant is rated at B1 as of February 2008.  There is no record that a grant agreement has been signed and disbursement commenceD on the Round 7 malaria grant that was awarded a year ago.

The Guardian reminds us that, “In 2005 Uganda was suspended from the Global Fund over irregularities in the administration of funds. This year, the Ugandan government began proceedings to prosecute those accused of embezzling Global Fund money, including two former health ministers.” The Guardian also points to health system challenges may be at the root of some grant performance problems:

Uganda’s decentralised health system is to blame for the poor delivery of health services across the country, according to health minister Stephen Mallinga. Speaking at the 14th health sector joint review meeting in Kampala on Monday, Mallinga said the decentralised recruitment of health workers had led to a culture of “tribalism”, with many health workers recruited and remaining within their own home regions.

Global funds are urgently needed in Uganda because as The Guardian pointed out, “Uganda’s economic woes continued this week with an estimated 114bn Ugandan shillings ($54m) wiped off the local stock market in one day.” The Global Fund website also featured Uganda’s economic problems by explaining that, “The future of Uganda’s recently launched five-year strategic plan aimed at reducing new HIV/AIDS cases in the country is uncertain because of the global financial crisis, which could lead donors to allocate funding more conservatively.”

Currency problems were also highlighted by The Guardian: “Last week the shilling collapsed against the dollar, falling to a low of Shs 2,200. As a result fuel prices have spiked, with a litre of petrol rising by nearly Shs 300.” Inflation is a major challenge to donor funding - assuming the $12 million in HIV fund are ‘found’, they would be worth much less today than when first awarded.

If GFATM malaria funds stop, the burden will likely fall on families. The Uganda Ministry of Health estimated that, “A poor malaria-stricken family may spend up to 25% of its income on malaria treatment and prevention.”

In these times of economic crisis donors like the Global Fund need to stress even greater accountability and performance than before to make every Dollar, Pound and Euro count.