Bednets failing to reduce malaria in Uganda, maybe everywhere

Since 2000, billions of dollars have been spent on a massive and multipronged anti-malaria effort supported by the World Health Organization, groups like Nothing But Nets, the Global Fund to Fight AIDS, TB and Malaria and other organizations. As a result, WHO says, malaria mortality has fallen by about 50 percent globally in the past 15 years.

But how certain are we of this success story, and what’s really driving it? Is it the hundreds of millions of bednets?

“That’s the million dollar question,”  said Moses Kamya, speaking recently at the University of Washington’s Institute for Health Metrics and Evaluation (IHME) in Seattle.

Kamya is a professor of medicine at Makerere University in Uganda. He presented an unpublished study showing persistently high transmission and increasing incidence of malaria in rural Uganda despite universal bednet coverage and effective anti-malaria treatment.

Kamya findings suggest that some experts are quietly, sometimes reluctantly, beginning to dig deeper into the assumption that bednets are as effective as claimed.

Read the rest at Humanosphere...

WHO Attacks Credibility of Suspected Drug-Resistant Malaria Case from Angola

[Note: See the latest developments here.]

The World Health Organization (WHO) rejects the findings of a paper describing suspected drug-resistant malaria in a Vietnamese migrant worker returning from Angola. (See previous post.) According to WHO's Pascal Ringwald, "It took 4 months for WHO to discover the truth and we will make sure that there will be retraction from the authors." But Patrick Kachur, chief of the Malaria Branch at the Centers for Disease Control (CDC), said "I doubt there will be a retraction," and that the CDC is going ahead with plans in Angola to search for similar cases and conduct tests on parasite clearance times.

Nearly all aspects of the case have been questioned. WHO has contended that the first line of treatment, artesunate, came from a batch recalled because of quality issues. The second line drugs, dihydroartemisinin and piperaquine, were delivered by nasogastric tube, a departure from preferred practice.  Also, the dose given, 1 mg/ kg given twice a day, achieves lower blood concentrations, according to mathematical models, than the recommended single dose of 2.4 mg/ kg once a day. The third line of treatment, quinine and doxycycline, were also delivered by nasogastric tube instead of intravenously as recommended. (Intravenous quinine was not available.) Still, nasogastric quinine worked, saving the patient's life. 

The apparent failure of the artemesinin-based drugs to clear the patient's malaria parasites has been attributed to hyperparasitemia which can impair clearance of parasites from the blood after they have been killed by the drug. Finally, genetic sequencing of the malaria parasites found them negative for K13, the biomarker associated with drug resistant malaria in Southeast Asia. 

The paper's authors have stood behind their research, refuting, for example, the claim that the artesunate used was of poor quality. But the battle continues. "Maybe," said WHO's Ringwald concerning the refutation. "But," when it comes to retraction, "CDC will," he continued.

All current containment efforts focus on Southeast Asia. The possible case from Angola threatens to expand an already fast-growing front, perhaps accounting for the heated debate.

Drug Resistant Malaria in Africa: A Suspected Case from Angola

[Note: See the latest developments here.]

A new paper suggests drug-resistant malaria might be present in Angola, perhaps brought there by an annual flow of some 40,000 Vietnamese migrant workers. Pockets of drug-resistant malaria, first found in Cambodia, now spot much of Southeast Asia, including Thailand, Vietnam, Myanmar and Laos. The expanding front comes despite containment efforts, begun in late 2008, aimed at preventing spread to Africa which already has the world’s highest malaria mortality.

A 58-year old Vietnamese construction worker returned from Angola after three years to his malaria-free village in Nam Dinh Province. Four days later, malaria symptoms appeared which went undiagnosed and eventually resulted in hospitalization. But artesunate, the frontline, fast-acting anti-malarial given to the patient, scarcely dented the number of teeming parasites. Even in severe malaria cases like this, patients usually begin to get better in just one day because artemisinin-based drugs act so quickly. (The patient also received the slower acting clindamycin to eliminate any parasites surviving the artemisinin onslaught, a combination approach meant to prevent drug resistance.)

Switching to a different combination of dihydroartemisinin and piperaquine also failed to knock down parasite levels. Only when subjected to quinine and doxycycline did malaria subside, allowing the once-endangered patient to return home about one month after admission.

The strength of resistance to the frontline artemisinin-based drugs seems considerably greater than that seen in Southeast Asia. As a rule of thumb, researchers suspect resistance if artemisinin doesn’t fully eliminate parasites after three days in cases of “uncomplicated” malaria. The Vietnamese patient’s severe malaria makes comparisons problematic. Still, Nick White, of Mahidol Oxford Tropical Medicine Research Unit, has "never seen such resistance, even in Cambodia." White, other researchers and the World Health Organization (WHO) are withholding final judgment as to whether this single case means artemisinin-resistant Plasmodium falciparum malaria is now present in Angola. According to White, “No, this doesn’t mean there is resistance in Africa—there may be but you need more than this.”

White raises the possibility that parasites actually killed by artemisinin might have remained in the patient’s blood, giving an appearance of resistance. Pascal Ringwald, WHO lead for the drug-resistant malaria containment effort, further explained: “the hyperparasitemia (10%) associated with insufficient drug blood levels could explain the extremely slow clearance after artesunate treatment...” Christopher Plowe, Howard Hughes Medical Institute investigator and professor at the University of Maryland, notes that “many factors other than intrinsic parasite resistance affect the treatment outcome, including immunity, fluid dynamics, pharmacokinetics and so forth.” But Plowe concludes: “This did look more like bona fide high-level resistance.” Continued Plowe:

“This is deeply worrying. It is just one case but the evidence of resistance is pretty good. It seems plausible that artemisinin-resistant parasites were carried to Angola from Vietnam and then locally transmitted among these migrant workers.”

How has it been missed, particularly if resistance is so strong? “Bit odd no one has noticed this before if this is a focus of the most artemisinin resistant parasites in the world,” observed White. Reports from Angola to WHO in 2013 found no evidence of resistance. There was “No sign of delayed clearance and 100% dihydroartemsinin-piperaquine efficacy,” according to Ringwald, who added that “Data were validated by CDC Atlanta.” However, Ringwald acknowledged that “the studies were not performed in the same province,” Luanda Sul, suspected as the origin of the drug-resistant malaria. The WorldWide Antimalarial Resistance Network (WWARN) has no data on Angola. WWARN is working on a study of three-day parasite clearance rates in Africa based on data from 15,000 patients, but fewer than one hundred are from Angola and come from a 2003 study in Kuito, well outside Luanda Sul province.*

A missing piece of the puzzle is whether malaria parasites in this case exhibit mutations in the K13 gene, a biomarker associated with artemisinin resistance in Southeast Asia. The status of such a test is far from clear. According to Ringwald, “It is not a WHO study and it not under our control,” who notes that the case occurred over a year ago. Conceivably, there are no samples to test. The corresponding author of the study did not reply to an email inquiry.

Ringwald downplays the importance of the case and asserts that “Artemisinin resistance is already reported in Africa.” But while mutations in K13 have been reported, clinical resistance in Africa has not. Also, the mutations reported there so far might merely be polymorphisms that are not part of a genetic network that confers resistance to artemisinin.

While Ringwald expressed skepticism about the Vietnamese case, “Nevertheless, we are investigating with CDC Atlanta in Angola if K13+ is also present like many other countries.” Further, in order “to reassure everybody we will specifically conduct [a study of parasite clearance rates] with dihydroartemisinin-piperaquine in the same province,” Luanda Sul .


Related: Drug resistant malaria takes new ground, raising fears of global spread

*This post has been updated. WWARN's study of three-day clearance in 15,000 people previously was said to have no data from Angola. The study includes 93 patients from Kuito, Angola in 2003.

Malaria eradication: How the Gates Foundation sets global health policy

Melinda Gates at the 2011 Gates Foundation World Malaria Forum 

For decades, following failed efforts in the mid-20th century to eradicate malaria, global policy aimed to control the disease. However, in a single moment late in 2007, Melinda Gates switched the world back onto eradication. Today that aim is more distant than five years ago because of drug resistance, a paucity of new drugs, the failure of bed nets, and slim prospects for an effective vaccine. These developments raise questions about eradication and how the world sets global health policies.

Speaking at the first World Malaria Forum, convened by the Gates Foundation in 2007, Melinda Gates said the moment represented a “historic opportunity not just to treat malaria or to control it—but to chart a long-term course to eradicate it.” Director general of the World Health Organization (WHO), Margaret Chan, converted on the spot and, from the audience, stood to voice her approbation. Thus was a policy decided that affected hundreds of millions people. The small audience of blue-ribbon researchers and policy makers sat stunned. Eradication had been embarrassing or even catastrophic decades before. In just minutes and without peer review, eradication was back.

The last disease officially targeted for eradication was polio. In May 1988, the World Health Assembly, governing body of WHO, unanimously endorsed a polio eradication resolution.  Regarding whether there would be a vote on malaria eradication, a Gates Foundation spokesperson said: “Not as far as I know.” However eradication remains the de facto goal of malaria policy.

Towards the end of 2007, the head of malaria at WHO, Arata Kochi, spoke out against these incursions on WHO turf. He circulated a memo describing a "cartel" of leading malaria researchers assembled and funded by the Gates Foundation. Kochi noted “intense and aggressive opposition” from Gates-backed scientists and the foundation. His memo recommended that WHO “stand up to such pressures and ensure that the review of evidence is rigorously independent of vested interests.” Kochi was replaced after his memo leaked to the New York Times.

Behavioral economics

Over the last dozen years, WHO has been slowly going broke. By the time of the 2007 Gates Malaria Forum, the purchasing power of WHO’s budget had fallen by almost 25 percent compared with 2000.

Going down: WHO’s weighted purchasing power. (Source: WHO)

Adding to these difficulties, half the WHO budget formerly came directly from member nation contributions. Increasingly, however, WHO has been forced to scurry, hat in hand, competing for grants with many non-government organizations and other entities. By 2006, such “voluntary” contributions tied to specific activities reached three quarters of WHO’s budget, and they have stayed there. By 2010, the Gates Foundation was the second largest voluntary contributor to WHO, providing $220m, more than the United Kingdom. According to Chris Murray, professor of global health at the University of Washington, “the behavior of organizations is profoundly affected by where they get their money from.” Most funding for global health comes from nation states, yet the foundation wields a disproportionate influence. According to Murray, “the influence of the Gates Foundation far exceeds the fraction of development of assistance for health that channels through their resources.” The reason, he continued, “is the way they have been funding and who they have been funding around the world.”

Gates’ man in Geneva

The United States is by far the largest funder of WHO, contributing 23 percent of WHO’s discretionary budget, nearly twice that of the next largest contributor, Japan. As the leading WHO funder, the US begins with more influence than any other nation.

Wielding that influence is Nils Daulaire. In late 2010, President Obama nominated Daulaire to be the US representative to the WHO executive board. Prior to his nomination, Daulaire served for more than a decade as president and CEO of the Global Health Council. In 2000, Daulaire’s non-profit became responsible for selecting the winner of the $1m Gates Award for Global Health. Since 2000 the Global Health Council received more than $36m from the Gates Foundation, about 40 percent of the Council’s revenue, according to Daulaire.

Daulaire said he "does not see the Gates Foundation or private entities as having a rightful role in establishing WHO’s priorities.” He dismisses suggestions that the Gates Foundation has an outsized role although he said: “There are member states who believe the Gates Foundation has more influence than it ought.” Daulaire said it is “entirely wrong” that the United States is increasing the foundation’s role.

Nils Daulaire at the 2011 World Health Assembly (Source: US Mission Geneva)

Following Daulaire’s nomination, reform of WHO rose to the top of its agenda. WHO “hit a financial wall” in 2011,” according to Daulaire. He said the United States was not a prime mover on reform which he described as driven by economic considerations. But in a statement before the 2011 World Health Assembly, Daulaire said the "financing discussion has sparked an important discussion on the role of WHO at the center of global health and how to ensure the organization is best placed to respond to the challenges of the 21st century." Making these determinations would be a private consulting firm paid by the Gates Foundation.

WHO's executive board passed a proposal that addressed “the overall design of the program of reform,” one which would reengineer WHO head offices and the entire organization. The comprehensive review and changes would extend to “all expected results, indicators, targets and baselines.” Money for this rewrite of WHO’s institutional DNA had “been secured from the Bill & Melinda Gates Foundation,” according to the resolution. Daulaire said he had no involvement arranging the Gates funding. WHO staff are “given the license to hunt” for funds, he said. The Gates Foundation declined comment concerning its involvement in WHO reform.

The reform resolution also called for creation of a new entity, the World Health Forum. Its charter was to “define the rules of engagement in global health,” particularly among its many players. The Forum might potentially have revised the central role of WHO and the World Health Assembly, perhaps institutionalizing a role for privately-funded organizations, including corporations. Planning for the first World Health Forum, originally scheduled for the end of 2012, was to be funded by the Gates Foundation. But the proposal “received little support,” Margaret Chan told the executive board in November 2011, and the idea was shelved.

Nonetheless, the World Health Assembly (WHA) has adopted key policies initiated by the Gates Foundation, setting the global health agenda in the near and long term. The WHA adopted the foundation’s “Decade of vaccines” vision, first articulated by Bill Gates. Vaccines are hardly new to global health. But the idea of placing at them at the center of global health for the next ten years originated from the Gates Foundation. A foundation press release referred to “the January 2010 call by Bill and Melinda Gates for the next ten years to be the Decade of Vaccines. “ In 2011, Gates addressed the WHA, pressing for his vaccines vision. "Our priorities are your priorities," he said. He pointed to a shared interest in child and maternal mortality before talking "about how you can provide the leadership to make this the Decade of Vaccines." In 2012, the WHA gave Gates' vision its stamp of approval.

Shorter term, the Gates Foundation’s highest priority is polio eradication. Following a vote at the 2012 WHA, polio eradication is now the sole health emergency worldwide. The US delegation co-sponsored both the decade of vaccines and polio resolutions. “We were an early mover on polio,” said Daulaire of the polio resolution.  But Daulaire claimed that on polio, WHO led and the foundation followed. In email he wrote: “The Gates Foundation's wishes and priorities were not a consideration in the WHO debate, but it's nice that they are on board.” Chronologically, however, the Gates Foundation ratcheted polio to its top priority in 2010, with WHO following two years later.

With WHO’s disempowerment has come a drift toward irrelevance. “WHO would like to be a partner and work with you,” Margaret Chan importuned at a Gates-funded gathering of global health influentials in 2010. But confidence in WHO’s capacities has dwindled. In a particularly embarrassing revelation, academics Chris Murray and Alan Lopez reported in 2004 that WHO couldn’t count: “The sum of deaths claimed by different WHO programs exceeded the total number of deaths in the world.” Each disease department exaggerated deaths in a bid to maximize funding. Also, because WHO is comprised of member states, political considerations also influenced estimates, according to Murray and Lopez. They concluded: “the only viable solution will be to create a new, independent, health monitoring organization.”

Independent of who(m)?

In 2007, the Gates Foundation awarded Murray a 10-year, $105 million grant for a new Institute for Health Metrics and Evaluation (IHME), affiliated with the University of Washington. Murray’s group took a wrecking ball to WHO’s already crumbling credibility. Using new methods, IHME published different estimates than WHO for child, maternal and, most recently, malaria mortality. 

IHME has become an alternative, perhaps preferred alternative, for global health metrics, displacing WHO and other UN-related entities. The Lancet endorsed IHME’s methods and results by cosponsoring a conference with IHME on maternal and child mortality in 2010. At the conference, Lancet editor Richard Horton said global health metrics had “broken out of traditional citadels,” bringing a “democratization of health.”

IHME's Murray had lectured his students that “the behavior of organizations is profoundly affected by where they get their money from.” And IHME’s research and publicity on malaria, specifically bednets, may reflect Gates Foundation influence. IHME claimed bednets prevented deaths from malaria in a press release although their research did not support such a claim. (See the previous story in this series: Bednets are failing.)

From overstatement, IHME passed to non-statement on bednets. Earlier this year, a headline-making IHME paper in the Lancet on malaria mortality was silent on whether bednets saved the lives of African children even though hundreds of millions of nets have been distributed in one of the world's largest health interventions.

The paper did say, however, that bednets did not reduce deaths of adults in Africa. Only in email did IHME's Stephen Lim write  “ITNs [bednets] were a statistically significant predictor of African child mortality,” meaning bednets did save children under five in Africa from dying of malaria. If true, however, it is unclear why the peer-reviewed paper omitted such an important finding. IHME declined to answer questions in email regarding the statistical basis for the claim. Lead author of the paper, Chris Murray, did not reply to an email asking for confirmation of Lim's statement.

Lancet editorial accompanying the IHME study said that "One aspect of the findings that is unlikely to raise objections is the implication that interventions scaled up since 2004 have been phenomenally successful in reducing the number of malaria deaths." The successful interventions included, said the editorial, the distribution of anti-malarial drugs and 230 million bednets. But the only finding on bednets in the IHME paper was a negative one, that nets did not save adults.

Lancet, heal thyself

In 2010, the Lancet ran a series on malaria elimination. An accompanying comment, co-written by Horton, concluded that the goal of elimination was “worthy, challenging, and just possible.” Although none of the Lancet articles carried notice that the series was externally funded, support came at least in part from the Malaria Elimination Group (MEG) which is funded by the Gates Foundation.

The series labeled MEG as a "collaborating partner." Other Lancet series, health and climate change, for example, identify collaborators and funders separately. Other series (e.g. health in Brazil) have neither collaborators nor funders.

Asked about funding of the malaria series, Lancet spokesperson Tony Kirby initially said in email that “ 'supported' means led, devised, and written by members of MEG.” The usual financial connation of "supported" did not apply.

However, in subsequent correspondence, Kirby acknowledged a funding role for MEG: “All external funds are raised by the partners we work with to do the academic work and analysis that forms the basis of the Series, to have a peer review meeting, and for a launch.” Asked whether the external funds for the malaria series ought to have been disclosed to readers, Kirby did not reply.

Readers were told, regarding the series: 

The Lancet puts malaria elimination under the microscope and examines the technical, operational, and financial challenges that confront malaria-eliminating countries.

However, a group with malaria elimination as its goal largely authored and provided funding for the series published in the Lancet which provided no disclosure of the external funding.

"There is a definite lack of transparency," wrote Ana Marusic in email of the non-disclosure by the Lancet. Marusic co-authored a New England Journal of Medicine paper updating the conflict of interest policy for the International Committee of Medical Journal Editors (ICMJE). The Lancet, according to its website, is a signatory to ICMJE's guidelines. "Financial relationships," read the ICMJE requirements, "are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself."

Alongside the malaria series, the Lancet published a laudatory profile of the head of MEG entitled, “Richard Feachem—scaling the heights of global health leadership.” MEG is coordinated by the Malaria Elimination Initiative, part of the Global Health Group at the University of Califormia, San Francisco. Feachem declined say to what portion of his funding for malaria comes from the Gates Foundation. His group won Gates grants for malaria of $9 million in 2010 and $5 million in 2007.

More ambigously yet still potentially worrisome, in late 2011, the Lancet received a paper reporting the spread of drug resistant malaria to western Thailand. Recognizing the importance of the findings, the Lancet fast-tracked the submission for publication within four weeks. However, the paper was then taken off the fast track. It languished for months. According to one of the paper’s authors, who did not wish to be identified, only the publication of a related paper in Science caused the Lancet to publish it, nearly six months after submission. The authors wondered if their paper had been intentionally suppressed because it seemed like bad news for malaria elimination efforts. “We never comment on internal procedures relating to our papers,” wrote Lancet spokesperson Tony Kirby in email.

Oversight: Congress and malaria

Gates Foundation: well-represented at congressional hearing on malaria (Source: CSPAN)

The United States is one of the largest funders of anti-malaria efforts through the $5 billion President's Malaria Initiative. In December of 2011, the House Committee on Foreign Affairs held a hearing on global efforts to eliminate malaria. The goal of elimination was set by the Gates Foundation—and the committee mostly heard from the Gates Foundation concerning progress. Only one member of the six-person panel came from an organization not funded by the foundation: Richard Bate of the American Enterprise Institute.

By contrast, panelist Regina Rabinovich served as the Gates Foundation's director of infectious diseases. The other panelists came from PATH, Malaria No More, the Medicines for Malaria Venture and the US Global Leadership Coalition, each recipient of $10 million or more from the Gates Foundation.

PATH runs the Gates-backed Malaria Vaccine Initiative which has shepherded the RTS,S vaccine into final clinical trials. PATH won the very first Gates Foundation grant in global health, $250,000 for family planning and birth control in 1995. In 2011, PATH received 14 grants totaling $81 million, according to the Gates Foundation website. (See the third story in this series: The long struggle: vaccines against malaria.)

Malaria No More has won more than $10 million in Gates funding to support advocacy efforts. In 2009, Malaria No More partnered with Ashton Kutcher who raced CNN to one million Twitter followers to raise awareness for bednets.

The Medicines for Malaria Venture has received significant Gates Foundation funding in its pursuit of new anti-malarial drugs, most recently a $134 million grant. (See the second story in this series: After artemisinin: searching for the next front-line malaria drug.) 

The US Global Leadership Coalition (USGLC) lobbies Congress on foreign aid, "advocating for increases in the International Affairs Budget," according to its website. USGLC has received more than $11 million in Gates funding for advocacy since 2007.

The 2011 panelists raised concerns and caveats about progress against malaria, but the hearing represented an "opportunity to testify on the great strides we have made and are making toward eliminating malaria," as Malaria No More's David Bowen testified. Bowen echoed the comment of an earlier panelist and emphasized that malaria was "an underpublicized and underappreciated success story..."

Some testimony overstated progress. The Gates Foundation’s Regina Rabinovich testified: “When I visited The Gambia ten years ago, there were three children to a bed for a disease that has almost disappeared from The Gambia ten years later.” However, malaria “is far from disappearing,” according to Umberto Dalessandro, who works on control and elimination for the Medical Research Council in The Gambia. Malaria has been greatly diminished but most of the country remains at medium-high levels of transmission, according to the Malaria Atlas Project. The Gambia is not pursuing elimination.

Malaria in The Gambia: Darker means more malaria. Areas in white are neighboring countries (Source: Malaria Atlas Project)

Richard Bate of the American Enterprise Institute was the only panelist without financial ties to the Gates Foundation. Bate also testified about malaria in 2004. The composition of the panel then was very different. Besides Bate, the other two panelist came from government organizations, representatives from USAID and the World Health Organization. By 2011, Congress heard mostly the voice of the Gates Foundation. WHO has been supplanted. And USAID, which directs most of the US foreign aid budget, today is helmed by Rajiv Shah who spent seven years at the Gates Foundation.

Bill & Melinda Gates: peerless, reviewless

When Melinda Gates switched the world to malaria eradication in 2007, it wasn’t on the basis of peer-reviewed science but because she was able to see “all the way to the horizon,” as she put it at the 2011 Gates Malaria Forum. By contrast, she does not advocate tuberculosis eradication because of scientific unknowns.

But the scientific examination of what would be needed for to eradicate malaria came three years after commitment to that goal, and science has put the horizon much further out than Melinda Gates’ own estimate. Pedro Alonso, who oversaw the Gates-funded MalERA initiative delineating the science needed for eradication, described it as a “massive research agenda.” Even the half-way point lies an unknown distance ahead. Brian Greenwood, of the London School of Hygiene and Tropical Medicine, said: “What needs to be done scientifically is more challenging than what has been done.”

Meanwhile, to sustain the eradication vision, Bill Gates leaned on non-peer-reviewed science. At the 2011 Gates Malaria Forum, he described models as “quite exciting” and presented one developed by Intellectual Ventures, run by Nathan Myhrvold the former chief technology officer at Microsoft. Myrhvold's training is in theoretical physics and mathematical economics. His two peer-reviewed papers are on dinosaurs. Based on Myhrvold’s malaria model, Gates said that adding a 50 percent effective vaccine—like the Gates-backed RTS,S—to existing interventions of insecticides, bednets, and antimalarial drugs, could locally eliminate malaria.

Bill Gates at the 2011 Gates Foundation World Malaria Forum 

The foundation does not have an eradication plan. “The bigger the aspiration the more ambiguous the solution,” said Jeff Raikes in opening remarks at the 2011 forum. Raikes is a former Microsoft executive and now CEO of the Gates Foundation. Shrinking the malaria map by eliminating malaria where possible is part of the strategy, one which targets malaria where it is weakest.

Remarkably, elimination advocates are uncertain which country represents the greatest victory so far over malaria. Asked what country overcame the most intense malaria transmission so far, MEG’s Richard Feachem said that was “a very good question.” He did not know the answer. No one does. The best guesses are Taiwan or Singapore, which got rid of malaria decades ago, in 1965 and 1982 respectively. Both are islands (greatly aiding elimination) and comparatively wealthy. Malaria is at least ten times more powerful in its African strongholds. However, Feachem believed that the world had paid insufficient attention to the recent accomplishments of Morocco and Turkmenistan in eliminating malaria.

Modern day Cassandra

Nearly every aspect of malaria from research to policy and advocacy is influenced and sometimes controlled by the Gates Foundation. “Everyone is a client,” Chris Murray, lectured his global health students in 2008. (Murray did not mention that IHME is as well. In 2011, Murray received a salary of $460,000 according to state records, making him the highest paid tenured professor at the University of Washington.) Vocal opponents like the former head of malaria at WHO, Arata Kochi, are removed. Many rank-and-file scientists keep quiet. “I’m not sure if I would tell a journalist I don’t believe eradication is possible,” said one anonymous Gates-funded researcher.

A number of Kochi’s 2007 allegations seem supported by current evidence. He claimed the foundation “takes its vested interest to seeing the data it helped generate taken to policy.” The foundation has funded testing and development of the RTS,S vaccine. That vaccine seems not only part of Bill Gates’ modeling exercise: the foundation’s continued support suggests it may push for licensing and deployment of the vaccine. Acting as judge, jury and advocate, warned Kochi years ago, “could have implicitly dangerous consequences on the policy-making process in world health.” He described the foundation’s decision-making as “a closed internal process, and as far as can be seen, accountable to none other than itself.” For this series, the Gates Foundation declined comment on the spread of drug resistant malaria, the failure of bednets, concerns about the effects of RTS,S on transmission and the foundation’s involvement in the remaking of WHO.

Bill and Melinda Gates are following in the footsteps of the Rockefeller Foundation, which arguably invented global health roughly a century ago. However, with the advent of the World Health Organization in 1948, the Rockefeller Foundation ceded its de facto leadership to that new institution of civil society. Today, global health appears to be passing back into private hands.

The Gateses are noble people embarked on an admirable and exceedingly difficult mission. Their foundation is a force for good. The best way to save lives, however, is not to dominate science or democratic institutions. A surfeit of zeal can actually harm the battle against malaria: “The history of special antimalarial campaigns,” reads a 1927 League of Nations report, “is chiefly a record of exaggerated expectations followed sooner or later by disappointment and abandonment of the work,” a cycle that has already been repeated.

A new one seems to have begun. In 2012, American Idol finalist Katharine McPhee told USA Today "I feel like (ending) malaria – like hunger here in the United States – is easily attainable." McPhee's statement is simply false. Although Bill and Melinda Gates are much more circumspect, their support underlies the misleading USA Today story: the article arose from McPhee's trip to Africa with Malaria No More—fueled by a $7.3 million grant from the Gates Foundation.

Bednets are failing

Undefeated (© IRD / M. Dukhan)

Bednets seemed the perfect malaria intervention: cheap, needing no doctors or needles but saving the lives of perhaps five children for every thousand covered. But unfurling hundreds of millions of mosquito-killing nets across Africa has provoked a wave of insecticide resistance. Resistant mosquitos pass through and bite instead of dying. Also, children eventually come out from under bednets when they are older which might be worse than having had no protection to begin with in areas with intense malaria transmission. Remarkably, the most recent and comprehensive research on malaria mortality shows weak or no evidence that bednets save the lives of children in Africa.

In 2000, health officials set a goal to protect 60 percent of the population at greatest risk of dying from malaria, children under five and pregnant women.  Compelling studies had shown that bednets dramatically reduced malaria and saved lives. In 2005, the World Health Assembly voted to hoist the target to 80 percent. Distribution of nets leapt to 47 million in 2006, up from 17 million the year before. In 2007, Melinda Gates called for the total global eradication of malaria. In 2008, the world spun up and delivered more than 60 million nets. Nets became a cause célèbre, with Ashton Kutcher leading the charge on Twitter in 2009. In 2010, more than 140 million nets were shipped to sub-Saharan Africa, where more than 750 million people are at risk for malaria.

Insecticide treated nets (ITNs) distributed to sub-Saharan Africa. WHO, World Malaria Report 2011

Scale-up drives resistance

But living organisms try to stay that way. And the immense selective pressure of mosquitocidal nets drove a proportionate resistance pushback. More nets, deployed for more time, select for a more resistant mosquito population. For example, in a large trial in Asembo, Kenya, as bed net coverage ascended, a key mutation conferring insecticide resistance expanded through the mosquito population. When bednet coverage reached 100 percent, the resistance mutation also neared 100 percent frequency.

Adapted from Mathias et al., “Spatial and temporal variation in the kdr allele L1014S in Anopheles gambiae s.s. and phenotypic variability in susceptibility to insecticides in Western Kenya,” DOI: 10.1186/1475-2875-10-10

Treated nets all use pyrethroids, a class of insecticides originally derived from chrysanthemums. Pyrethroids are enormously toxic to mosquitos but comparatively safe for humans. Pyrethroids act on nerve cells by binding to a receptor site on a sodium channel, inhibiting its deactivation. In susceptible mosquitos, pyrethroids trigger rapid paralysis or “knockdown,” then death.

Not all die, however. Mosquitos have evolved a number of defenses. Some are metabolic — insects rapidly detoxifying or sequestering poisons. In addition, researchers looking at mosquito feet with an electron microscope have even detected “cuticular thickening” which slows or blocks insecticide absorption when mosquitos touch down on nets. Mosquitos might be evolving their behavior as well to avoid bednets. A recent study of two villages in Benin found that mosquitos shifted their peak feeding time from the middle of the night, when nets protect people sleeping under them, toward dawn when villagers are waking up and exposed. 

More important, however, are mutations that reconfigure the sodium channel to prevent the short-circuiting effects of pyrethroids. A sufficient dose of pyrethroids kills up to 100 percent of susceptible mosquitos but in some “knockdown resistant” phenotypes, as many as 100 percent survive.

The frequency of resistance genes within a population ebbs and flows, and pyrethroids can still do serious damage even where resistance is present. Although the large number of nets drives selection for resistance, the insecticide onslaught also kills huge numbers of mosquitos, reducing transmission. Against susceptible mosquitos, bednets radically reduce bloodfeeding, by 90 percent or more. By contrast, bloodfeeding of knockdown-resistant mosquitos is essentially unaffected by the pyrethroids on bednets. And, by itself, the physical barrier presented by nets provides only very partial protection.

The search for alternatives

Venerable pyrethroids are now roughly half a century old. There are efforts to find new insecticides, but none are in sight. The Innovative Vector Control Consortium (IVCC), set up and funded by the Bill and Melinda Gates Foundation, has been working on the problem since 2005.  IVCC’s current portfolio shows no new chemicals entering into a development or registration for use phase. If there are any promising candidates further upstream, IVCC chief operating officer Tom McLean won’t talk about them. He fielded a question on status by saying: “At this early stage of the development process it is not appropriate to publish specific chemical structures of what is in the pipeline because it is essential to preserve the commercially competitive nature of these products.”

The Gates Foundation directly funded out-of-the-box projects like “click chemistry” in which two non-toxic chemicals bind together lethally inside mosquitos. But that clever idea did not pan out.

According to Helen Pate Jamet, senior scientist for bednet maker Vestergaard Frandsen, “ideally we need at least 2-3 new insecticides from completely different insecticide classes in order to have a real impact on resistance and have the ability to rotate/mix different classes.”

Meanwhile, Vestergaard Frandsen is testing nets impregnated with chlorfenapyr which comes from a new class of insecticides called pyrroles. Unfortunately, they aren’t as good as pyrethroids. Chlorfenapyr is less toxic to mosquitos and more harmful to humans than pyrethroids. Chlorfenapyr is a "prodrug" that has to be broken down before starting the chain of events that, in time, kills the mosquito. Consequently, chlorfenapyr-treated nets provide little to no personal protection from malaria. Mosquitos still bite, only dying later. “Any inhibition of blood feeding associated with the insecticide treatment was not statistically significant,” according to one study of chlorfenapyr–laced bednets. To work, much of the community must also sleep under a net, thereby reducing the mosquito population. The direct life-saving benefit of pyrethroid bednets is lost.

Geographic extent and implications

Pyrethroid resistance has been found all over the African continent. Mosquitos have developed resistance to other insecticides, but according to WHO's most recent report, "Resistance to pyrethroids seems to be the most widespread." And it's worsening. Previously there were pockets of resistance; now there are pockets of susceptibility. 

Adapted from:  Ranson, et al., “Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control?” DOI: 10.1016/ and WHO, “Global Plan for Insecticide Resistance Management in Malaria Vectors”

Yet remarkably there is debate about whether insecticide resistance impacts malaria control. “[T]here is broad consensus that the degree of resistance that has developed and its likely trajectory are a cause for serious concern,” according to Scott Filler, senior advisor at the Global Fund for Aids, TB and Malaria. The trajectory, Filler says is toward “widespread control failure,” but “the pace of this process and the degree of reduction in malaria control effectiveness remains unknown.” The Global Fund purchases the majority of the world’s bednets, some 56 million in 2010.

Janet Hemingway, director of the Liverpool School of Tropical Medicine concurs that there is “undoubtedly a rapid increase” in pyrethroid resistance in Africa and that “at some point we will get failure.”

However, according to Christian Lengeler, it is “probably right” that “we have already now some detrimental effect...” because of pyrethroid resistance. Lengeler is director of the health interventions unit at the Swiss Tropical and Public Health Institute. Together with WHO, Lengeler advocated for bednets in the mid-1990s. He also authored the influential meta-analysis of bednet trials in 2004 showing 5.5 lives could be saved for each 1,000 children covered by nets.

Uncertainty principle

Getting a grip on the actual effects of bednets is difficult. The Global Fund’s Filler gave a mixed message on whether a decline in effectiveness can be measured. “No – no such [study] design exists,” said Filler. But he then added: “This can be accomplished in carefully designed trials but these are complex, expensive and need a high level of epidemiological expertise to conduct….”

A study of bednets in the village of Dielmo in Senegal published last year showed nets rapidly reduced malaria when first introduced, consistent with many previous studies. However, within two years, 48 percent of mosquitos had a mutation for pyrethroid knockdown resistance, up from 8 percent at the beginning of the study. Cases of malaria rebounded to just below pre-bednet levels.

Controversy ensued. “This paper is bad,” Lengeler said of the Dielmo study. The study, Lengeler continued, “has no credit whatsoever in the malaria community.” A commentary accompanying the Dielmo study applauded the rigor of the research but cautioned against extrapolating its conclusions to the rest of Africa.

However, the authors of the commentary themselves produced a study just a few months earlier which appeared to show bednet failure. In Luangwa, Zambia, bednet use rose dramatically in two years from about half the population to 86 percent. However, malaria infections went up. Although the paper seemed to demonstrate some kind of failure, one of the authors, Thomas Eisele, wrote in email: "That is not accurate.” Eisele, of the Tulane University School of Public Health and Tropical Medicine, did not reply to subsequent requests to elaborate. He pointed instead to research from the Institute for Health Metrics & Evaluation (IHME) showing more favorable results.

Claims on nets overstretching evidence

The IHME study found that bednets were associated with a statistically significant reduction of mortality from any cause of 23%. However, the study did not examine the effect of insecticide treated nets (ITNs) on death from malaria. As the study authors pointed out, "we were only able to examine the relationship between ITNs and all-cause mortality as the surveys we used do not include information on cause-specific mortality." 

However, a press release from IHME about the study used less cautious language, claiming: "researchers found clear evidence that bed nets reduce the number of child deaths from malaria." That statement did not appear in the peer-reviewed paper and is not supported by evidence in the paper.

IHME recently published a more comprehensive, exhaustive malaria mortality study. It made global headlines, reporting a higher death toll for malaria than previous estimates. Part of the difference came from a much larger estimate of deaths among adults. However, the study found that bednets did not reduce adult deaths from malaria in Africa: "coverage of insecticide-treated bednets," read the report, "was not a statistically significant predictor of African adult malaria mortality." But on the even larger question of whether bednets save children in Africa, the study is silent.

Asked that question in email, however, one of the paper’s authors, IHME’s Stephen Lim, replied that “ITNs [bednets] were a statistically significant predictor of African child mortality.” In other words, bednets worked to save the lives of the largest and most vulnerable group, children in Africa.

But the basis for this unpublished claim isn’t clear. The IHME study incorporates data from many smaller studies of particular geographic areas and then extrapolates as needed to country and continent levels using sophisticated, computationally-intensive modeling techniques. IHME actually generated many hundreds of models which were then averaged together into an ensemble to most closely approximate reality. However, Lim said IHME did not calculate an average hazard ratio for the effects of bednets. (A  hazard ratio is a number that indicates whether an intervention increases or decreases risk, in this case the risk of dying from malaria.) “Analytically,' said Lim in email, "we can calculate an ‘average’ hazard ratio but it is not something we have currently in place and would involve a considerable amount of work.” 

Not having a hazard ratio raises the question of how the statistical significance of bednets was assessed. IHME spokesperson William Heisel wrote in email that 131 models found bednet coverage to be a significant predictor of malaria mortality for children under five in Africa. However, at one point in the analysis, there are a total of 214 models for children under five in Africa. IHME did not reply to an email asking if this meant 131 models were and 83 models were not significant for bednets. 

A greater number of models does not necessarily mean the variable being tested is statistically significant because models are weighted differently. IHME had earlier cautioned against simply counting the models in their list: “This list by itself," wrote Lim, "is not easily interpretable as different individual models are given more weight in generating the ensemble model.”

Asked whether IHME had based their assessment of statistical significance on a count of models, Heisel replied that IHME would not answer any more questions in email, .

Possible mistake?

Although difficult to countenance, distributing bednets in high transmission areas—like much of sub-Saharan Africa—might have been a mistake.

Intensity of malaria transmission worldwide. Darkest color indicates very high (>40 percent) infection prevalence and high transmission.  Gething, et al., “A new world malaria map: Plasmodium falciparum endemicity in 2010” DOI: 10.1186/1475-2875-10-378

Where malaria is intense, being bitten is a kind of deadly hazing ritual with survival conferring a degree of immunity. In very young, non-immune children, malaria infection leads to fever—and possibly death. The fatality rate of malaria infections is, perhaps contrary to expectations, very low. Only an estimated 0.3 percent of infections globally cause death. But infections are so numerous that hundreds of thousands of children die each year. Children who survive, however, generally can better control infections later in life and even show no symptoms while carrying perhaps millions of parasites.

Research in the late 1990s concluded that “a critical determinant of life-time disease risk is the ability to develop clinical immunity early in life…” Malaria, including cerebral malaria and severe malaria, declined as children got older. Risk for severe malaria was highest where transmission was less intense, likely because people don’t acquire immunity without exposure to considerable infective biting.

Such natural tolerance is a mystery. There is no definitive set of biomarkers for it. And it’s no free pass: immunity may wane without some amount of continued infective biting, making severe disease a possibility.

One of the authors of the study, Robert Snow, now head of the public health group at the Kenya Medical Research Institute/Wellcome Trust Program, said recently, “I remain convinced that a certain degree of parasite exposure is required to develop functional immune responses to reduce risks of death and severe disease from malaria.”

Nets were originally targeted at children under five because most deaths from malaria occurred in that age range. But where malaria is intense, infection is unavoidable, with bednets deferring it to a later age. The age range least likely to sleep under a net is age 5 to 19. The most protected become the least protected—with potentially more adverse health consequences. Studies have found a shift in disease burden to older age groups following introduction of bednets. Trape and colleagues found this in Dielmo, Senegal. Other researchers, in an earlier 2009 paper, showed that nets reduced malaria risk in younger but not older children, a finding “consistent with older children having used [bednets] when they were younger, and therefore having acquired less immunity.” Thus to the extent bednets have saved lives in high transmission settings, they may also have created a population with reduced natural immunity, possibly setting the stage for a rebound of malaria.

“The issue of rebound and building up a time-bomb of susceptibles is interesting and you will find people willing to argue either side,” said Simon Hay, of Oxford University where he heads the Malaria Atlas Project.

The Global Fund’s Scott Filler said rebound concerns were “one major progenitor to move from targeted distribution of [bednets] to children under five to the goal of achieving universal coverage…” WHO switched to recommending universal coverage in 2007. (As the graph above shows, however, bednets distributed actually declined in 2011.)

Gerry Killeen of the Ifakara Health Institute in Tanzania believes rebound “is highly implausible unless the interventions themselves fail (resistance) or are withdrawn.”  His parenthetical mention of resistance, however, could mean trouble. Azra Ghani, of Imperial College London, and colleagues concluded that “If the effectiveness of the intervention gradually wanes, the impact on immunity is likely to be minimal and the incidence of clinical disease will return to pre-intervention settings,” perhaps ten years later.

Diaphanous nets and ghosts of the past

Bednets were hoped to be a precise, stealthy intervention beneath the notice of mosquitos. But protecting even a portion of the population appears to have engaged their evolutionary attention.  The switch to universal coverage also shifted the strategy: the purpose of the nets has become to kill mosquitos. “In order for their full potential to be realized,” reads the WHO position statement, bednets “should be deployed as a vector control intervention.”

However, if the goal was to knock transmission into an unrecoverable tailspin, it hasn’t worked. Transmission in high intensity areas dropped, but the force of infection still “needs a bit more help get it over a hump of stability that will impact on disease burden in the longer term,” said Robert Snow. The question is how because, continued Snow, the “expectation that [bednets] alone were to be the panacea in high transmission areas was misplaced.”

Resistance to DDT caused the technical failure of the mid-20th century effort to eradicate malaria. Nonetheless, over time, bednet policy has taken on a worrying semblance to this unsuccessful strategy. The previous effort didn’t even attempt to take on the heartland of malaria in sub-Saharan Africa, with some researchers arguing success was impossible using DDT. Also, planners of the oft-maligned effort actually knew resistance would be a problem where DDT was used and consequently they set a blitzkrieg timeline for achieving victory in a few years before resistance rose up. In comparison, the bednet strategy seems ad hoc and improvisational.

The coverage targets, initally 60 percent and then 80 percent, “were moved because we weren't going to meet them on time,” said David Smith of the University of Florida. “Instead of admitting nothing was happening, the intervention coverage target was increased and the date moved back—seeming to have some thought behind it, but mostly just saving face.”

Pyrethroid resistance was not part of the agenda at the Gates World Malaria Forum last October nor was it mentioned in congressional hearings on malaria last December. That omission may come from a concern, expressed by Killeen, “that doom-and-gloom stories will kill public enthusiasm for things that have saved many lives,” which he estimates to be half a million in Tanzania over the last five years. Scaling up such interventions “took a long time to get in place.” He concludes, “I am the father of two under fives and I live in a part of rural Tanzania where over 80 percent of people use [bednets] so this is a very real issue for me.”

Malaria is horrific, nature unsentimental. Sustainably reducing or ridding the disease from the world is unquestionably desirable. “But as we are now seeing,” say other researchers, controlling mosquitos with chemical killing agents comes at a price, “and the price is resistance.”

The long struggle: vaccines versus malaria

Photo: Caitlin Kleiboer 

"After clean water, vaccines may have saved more lives than any other public health intervention. Eradication of malaria, a disease that may have killed more humans than any other single cause, likely requires a malaria vaccine. However, after nearly a century of research, today’s only candidate might not pack enough immunological punch to win deployment. Sadly, there are no obvious successors. Goals for vaccines set in 2006 are now approaching, but may not be possible to meet."

Read the rest @ Ars Technica

Third in my series on malaria.

1) Drug resistant malaria takes new ground, raising fears of global spread

2) After artemisinin: searching for the next front-line malaria drug

Drug resistant malaria takes new ground, raising fears of global spread

Photo: Robert Semeniuk

In Southeast Asia, drug-resistant falciparum malaria may have evolved resistance to another frontline therapy and established itself in new territory in western Thailand, according to the World Health Organization. The new area in Thailand joins previous hot spots in Cambodia, Vietnam, and Myanmar, with the latter being badly equipped to stanch further spread. Despite containment efforts, the possibility this strain may spread to Africa, which has the most significant malaria burden, remains very real.

From my article in Ars Technica, first in a series on malaria.

Read the full story

Robert Semeniuk's stirring photo shows a man from Myanmar with severe malaria who walked with his wife for four days to cross the border into Thailand, coming to the Mao Tao clinic in the village of Mae Sot. A forthcoming Lancet paper will describe the detection of artemisinin resistance arising in that region of Thailand.