June 30, 2009 Dear Friends and Colleagues; As several major international gatherings loom, the global health and development communities are escalating activities in hopes of maintaining funding support for vital programs during this time of financial crisis. Among the major gatherings/events are:

• The G8 Summit in L’Aquila, Italy, July 8-10; • Barack Obama’s first Presidential trip to Africa, visiting Accra, Ghana, July 10-11; • UN Economic and Social Council (ECOSOC) Innovation Fair, Palais des Nations, Geneva, July

6-9. (Some details on ECOSOC are at the bottom of this Update.)

These events are occurring against a deeply challenging background globally that features financial crisis, food scarcities, widening spread of the H1N1 pandemic, empty chairs inside the Obama Administration, and historic events inside Iran. This Update from the Council on Foreign Relations Global Health Program covers:

• Activities at the Council’s Global Health Program • (Non)Expectations for the L’Aquila Summit • Pacific Summit on MDR-Tuberculosis • H1N1, H5N1 and the Future of Influenza • Bio(Non)Security • Searching for the Framework of U.S. Foreign Assistance: Who is in Charge? • HIV Virulence and Optimal Treatment Change • Climate Change and Health

Activities at the Council’s Global Health Program

On June 8th the Global Health Program convened a closed-door, full day meeting on the future of the United Nations Joint Programme on HIV/AIDS (UNAIDS). Mr. Michel Sidibé took leadership of the agency in January, following the nearly 13-year directorship of Dr. Peter Piot (1995-2008). UNAIDS was originally created to offset failures at the World Health Organization, and to harmonize anti-HIV activities across the range of UN organizations that had reason to play a role in combating the disease. At the time, the global budget for HIV prevention, care and treatment in developing countries amounted to about $400 million, and the global health landscape was barren.

2

In contrast, today UNAIDS sits in a very crowded global health landscape, inhabited by a plethora of new organizations, fueled by some $20 billion in public and private funding. The change of the agency’s leadership marked a wise time to take stock, and consider UNAIDS’ appropriate location in this new, claustrophobic health landscape. Recently the Center for Global Development and Oxford University’s Global Economic Governance Programme, under the leadership of Ruth Levine, released a detailed analysis of UNAIDS, listing recommendations for the organization’s foci in coming years: http://www.cgdev.org/content/publications/detail/1421429/. At the request of UNAIDS the Council’s Global Health Program invited a panel of some 40 experts to discuss the future goals and mission of UNAIDS. (The meeting, lasting some 10 hours, operating on Chatham House rules.)

On June 23rd Sidibé addressed the Board of UNAIDS, outlining his hopes for the agency’s future:

http://data.unaids.org/pub/SpeechEXD/2009/20090623_EXD_SP_24PCB_en.pdf. “Today I commit UNAIDS to act on three fronts, seeking: First, to increase results and their impact. Second, to optimize and expand partnerships. Third, to transform UNAIDS into a more efficient and effective organization,” Sidibé said.

“We need to define clearer objectives and metrics and strengthen monitoring and reporting to improve our ability to demonstrate impact.” In addition to the UNAIDS meeting the Global Health Program has also been engaged in a number of projects over the past month, including: Kammerle Schneider and Laurie Garrett were guest columnists for the Drug Resistance and Global Health Initiative led by Rachel Nugent at the Center for Global Development Non-Therapeutic Use of Antibiotics in Animal Agriculture, Corresponding Resistance Rates, and What Can be Done About It: http://www.cgdev.org/content/article/detail/1422307/ Peter Navario discussed the leveling off of South Africa's AIDS epidemic and its ability to step up HIV/AIDS treatments in light of "flatlined" global health funding in a CFR.org podcast interview. http://www.cfr.org/publication/19697/providing_hiv_treatment_in_an_uncertain_financial_climate.html Laurie Garrett discussed how technology is currently being used to fight disease all over the world with BigThink: http://bigthink.com/lauriegarrett/how-to-win-the-war-for-global-health

(Non)Expectations for the L’Aquila G8 Summit

While most Americans are chomping BBQ’ed hotdogs and swilling beer in celebration of the July 4th signing of the Declaration of Independence, the sherpas and assistants to the G8 leaders will be huddled in L’Aquila, Italy, hammering out final versions of documents that their bosses are meant to sign during the June 8-10th summit. A great deal of work has gone into trying to influence the Silvio Berlusconi government, host of this summit, in hopes that global health issues will not fall aside in this age of financial crisis. The Global Health Program has directly participated in some of these efforts,

3

including a meeting with Berlusconi’s Ministry of Foreign Affairs and Ministry of Finance staff. Especially aggressive efforts have been expended by Japan’s Health Policy Institute, Keizo Takemi of Tokai University, and a striking list of top Japanese policymakers, all hoping that the health systems commitments made last year by the G8 in Toyako will not be abandoned in L’Aquila. At this writing, expectations for the L’Aquila Summit are minimal. Berlusconi has been distracted by a long list of scandals, including his wife’s divorce filing and claims that the Prime Minister’s notorious sexual escapades have lately included a teenage girl. Italy seems to be in a national malaise, resigned to the Berlusconi leadership and despairing over the nation’s declining economic status. The G8 Summit, originally slated to take place on the island of Sardinia, has been moved to the earthquake-stricken L’Aquila area, drawing attention to Italy’s suffering. Even as Italy’s sherpa staff insisted the Summit would address vital issues like HIV and maternal survival, the nation’s Parliament voted to slash the country’s foreign assistance budget by 55% for 2009, and up to 80% by 2012. Several G8 Summits ago the leaders set a 2015 target of donating 0.7% of their respective GDPs to Official Development Assistance (ODA). Before cutting its ODA by 55%, Italy was contributing only 0.1% of its GDP, the lowest level attained by any of the European nations. According to the Italian press, Berlusconi’s domestic headaches have suddenly worsened. One of the Prime Minister’s close friends, Giam-paolo Tarantini, who allegedly brings teenage girls to the Italian leader’s villas for “parties,” is facing indictment on cocaine trafficking charges. The Bank of Italy this week is warning of possible economic collapse. Berlusconi’s scheme to broaden the G8, bringing in China, India and other nations, seems to be backfiring amid demands for participation from leader Colonel Muammar Gaddafi, and a host of Arab and Muslim leaders. Most Italians will be watching how Berlusconi and Obama get along, in light of the Italian leader’s racially dubious slur regarding President Obama’s “suntan.” The World Food Program, which is based in Rome, has lobbied hard for G8 financial commitments to offset the combined rise in basic food prices in poor countries, and increasing poverty due to the global recession. WFP says that its staff is logging 4 million new starvation cases per week this year, and nearly one out of every six people on earth now go hungry. WFP says it needs $6.4 billion to feed the people; it has just over $1 billion. Though food and agriculture are on the L’Aquila agenda, neither is expected to garner the level of financial attention WFP would like. “2009 will be a dangerous year,” warned World Bank President Robert Zoellick in a call for support of the health-related MDGs at the UN earlier this month. http://www.ausaid.gov.au/publications/pdf/lead_by_example.pdf.

“The first decline in the global economy since World War II. The largest decline in world trade in 80 years. What started as a financial crisis quickly spiraled into an economic crisis. Today, it is an unemployment crisis. This year, we forecast that economic growth in developing countries will slow sharply to 2.1 percent, down from 5.8 percent in 2008. Developing countries are being battered by successive waves radiating from contraction in growth and tightening of credit in the developed world. The global economy once

4

helped to lift hundreds of millions out of poverty – today, we risk development in reverse,” Zoellick continued. “These events could next become a social and human crisis, with political implications. The World Bank Group estimates that an additional 53 to 65 million people will be trapped in extreme poverty in 2009 because of the crisis. The number of chronically hungry people is expected to climb to over 1 billion this year. When poor families need to tighten their belts, they have to pull their children out of school, stop using health services, and cut back on providing nutritious food for their children. Women and girls suffer disproportionately. Our research shows that most of the eight Millennium Development Goals are unlikely to be met by 2015 – including those related to hunger and malnutrition, child and maternal mortality, education, and progress in combating HIV/AIDS, malaria, and other major diseases.”

In his remarks on June 15th at the UN Headquarters, Secretary-General Ban Ki-moon called on the G8 and the G20 to “stand by their promises,” noting that $60 billion worth of commitments to health, development and anti-poverty programs made in prior Summits remain unfulfilled. WHO Director General Margaret Chan issued starker warnings, citing the emerging H1N1 flu pandemic that, she predicted, will undermine “fragile health systems.” The “greed” of the wealthy world, Chan said, was pushing vaccines and medicines for the rich, at the expense of the poor, even as a pandemic threatens the entire world. This inequity, Chan argued, is pushing the world, “to the brink of social breakdown,” because H1N1 preparedness and medicines are, “strongly biased towards the richest countries.” In a document submitted to the June 15 UN gathering, Italy’s Berlusconi underscored the importance of the Millennium Development Goals (MDGs), and promised, “For this reason, the health-related MDGs continue to be one of the key thematic areas of the Italian G8 Presidency. Along with all G8 partners, Italy is promoting a comprehensive and integrated approach which combines different actions on the MDGs, maximizing synergies between health systems and global health initiatives. By recognizing that weak health systems obstruct progress, it is essential to continue to strengthen health systems for promoting universal access to health services.” At the time of this writing, we can report that the Summit sherpas have prepared a document on global health that is filled with wonderful language. But there are no specific monetary commitments. For further insights see: http://g8italy.wordpress.com/

Pacific Health Summit on MDR-Tuberculosis

Every June the Pacific Health Summit gathers in Seattle, focusing on a specific theme. The gathering brings together an auspicious group of leaders from the public and private sectors of global health, and is attended by Dr. Tachi Yamada, director of the global health portfolio of the Bill & Melinda Gates Foundation. This year the Summit focused on drug resistant tuberculosis, particularly XDR-TB – extensively drug resistant forms of the bacterium.

5

WHO estimates that 9.27 million people developed active TB in 2007; 1.4 million of them suffered from multidrug-resistant (MDR) or XDR-TB. For 1.32 million of the world’s tuberculosis sufferers in 2007 the illness proved fatal. Some 80% of the global burden of TB is concentrated in just 22 countries, primarily in Asia, sub-Saharan Africa and the former USSR nations. (For details on the breakdown of TB worldwide see the enormous surveillance analysis “Epidemiology of antituberculosis drug resistance 2002-07,” in The Lancet vol. 373:1861-1873, May 2009.) The current approach to TB involves a vaccine that is more than a century old; diagnostic technology that is six decades old, and a basic cocktail of medicines that hasn’t varied or improved in more than 40 years. Because the vast majority of tuberculosis sufferers are poor people, generally residing in poor countries, there has been no market incentive for improvement in this antique set of medical interventions. In 1985 the U.S. National Institutes of Health entire research budget for TB was less than $665,000 – a sum unlikely to produce any breakthroughs. In 2008 that budget was up to $130 million – still a paltry sum, given it takes years to glean biological results from experiments on the slow-growing mycobacterium. The Gates Foundation is the major contributor to TB research and drug development, donating $750 million in 2008. The list of basic scientific questions about the Mycobacterium tuberculosis is staggeringly lengthy. Earlier this month Tibotec, a subsidiary of Johnson & Johnson announced the discovery of the first serious, new candidate treatment for TB, dubbed TMC207. The drug is a diarylquinolone that kills the mycobacterium by inhibiting production of ATP, the vital energy source that drives cells. Details regarding exactly how the chemical exerts its effect are unknown. But in an early clinical trial, adding TMC207 to a standard TB treatment cocktail, the drug packed a whollap (See: Diacon AH, Pym A, Grobusch M et al, “The Diarylquinolone TMC207 for Multidrug-Resistant Tuberculosis,” NEJM 360:2397-405, June 2009.) In trials with MDR-TB sufferers in South Africa the addition of TMC207 caused a five-fold greater survival rate compared to standard therapy alone. Tibotec executives promise to get the drug through clinical trials and into the marketplace within 3 years. The new drug will be welcome, but cannot, alone, turn the global MDR-TB crisis around. The surge in drug resistance is driven in large part today by the HIV pandemic, as people with AIDS are especially vulnerable to the bacteria. TB is the number one cause of death of people with AIDS in Africa. A startling recent study from KwaZulu-Natal, South Africa, demonstrated that airborne recirculation of TB in communities hard-hit by HIV is resulting in reinfections of people previously, successfully treated for tuberculosis. In all too many cases the original infection involved a drug-susceptible strain of TB, but the subsequent reinfection was MDR, or XDR-TB. The implications of this are startling: The TB victims failed to make protective immunity against their original infection and in communities plagued by MDR-TB and HIV the risk of reinfections is profound. (See: Andrews JR, Ganhi NR, Moodley P, et al, “Exogenous Reinfection as a Cause of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Rural South Africa,” JID 2008:198: 1582-1588.)

6

Tragically, TB and HIV services are rarely synonymous. Patients should be worked up for both ailments at the same time, in the same place – but rarely are. This is partly due to donor funding streams, which are disease-specific, according to Dr. Peter Piot, former Executive Director of UNAIDS. It is also the result of strange separations in clinical practices, sometimes dating to colonial era policies. This week on Capitol Hill a report entitled “Deadly Duo: The Synergy Between HIV/AIDS and Tuberculosis,” from the Center for Global Health Policy www.idsaglobalhealth.org was released, documenting the death toll exacted by separation of HIV and TB clinical services. The TB situation in Africa is dire, fueled by severe shortages of drugs, protective gear for healthcare

workers, diagnostics and basic medical supplies. At King George V Hospital in KwaZulu-Natal, for example, 3,639 patients were treated for MDR-TB between 2003 and 2007; 235 of them were healthcare workers who contracted the disease on the job. Worse, 23 of those healthcare workers had XDR-TB. But supplies of basic protective gear for doctors, nurses, lab techs and other hospital personnel are so limited that the government issues them just one mask every thirty days, and nearly all other forms of protective gear are unavailable.

Drug shortages, resulting in interrupted or unavailable treatment, are all too common. Three weeks ago Dr. Joseph Sitienei, head of Kenya’s TB program, announced the nation had only enough drugs to treat 40 MDR-TB patients. All other tuberculosis patients suffering from multidrug-resistant bacteria are turned away. Uganda faces a similar crisis, and has turned away MDR-TB patients, because their illness is vastly more expensive to treat compared to normal TB. The head of Uganda’s TB program, Dr. Francis Adatu-Engwau, estimates a normal TB patient can be cured with about $30 worth of medicines; curing an MDR case costs $2,000. Sitieni, Adatu-Engwau, and their counterparts all over Africa are begging the Global Fund to Fight AIDS, Tuberculosis and Malaria for financial support, asking for orders of magnitude more funds for purchasing drugs. But the Global Fund is in trouble. (More on that, below.)

H1N1, H5N1 and the Future of Influenza

Anybody who has seen Margaret Chan lately can attest to the exhausting toll the officially-declared pandemic is taking on the world’s health leaders. The H1N1 “swine flu” may not be particularly deadly, but its inexorable spread around the world is exhausting the health resources of nations, and the personal stamina of pandemic leadership. Outside of Mexico and the flu offices of the CDC in Atlanta, most of the world has only been engaged in combat with H1N1 for 6-8 weeks, yet signs of fatigue, resource depletion and – predictably – political “they cried wolf” backlash have already set in. It is worth considering just how much more fatigue, financial pain, and organizational energy would be expended were this virus to transform into a far more lethal, yet still highly contagious, form.

7

As of June 28th the death toll due to “swine flu” has eclipsed that of “bird flu”, H5N1:

• H1N1 deaths: 311 • H1N1 denominator: More than 1 million in the

USA, alone, “millions” worldwide • H5N1 deaths: 262 • H5N1 denominator: 433 cases confirmed since

2003 The denominator matters, of course, and H5N1 remains the major virulence threat. But H1N1’s capacity to spread rapidly between human beings illustrates that the absolute numbers of dead can be large if the denominator is enormous. While these points may seem obvious to our readers, the denominator issue is often lost on the general public and policymakers. These are early days with H1N1, and the virus is still adapting to our species. If H1N1 follows the trajectory of the H5N1 “bird flu”, which first emerged in southern China in the mid-1990s, we can expect it to circulate around the world for years. On the other hand, were the 2009 version of H1N1 to mirror the historic arc of its 1918 predecessor, the virus will disappear from human circulation in a couple of years, after mutating into a virulent form and claiming the lives of tens of millions of people. Which will it be? We are in the season of tea-leaf-reading – or gene sequence-debating. Very smart, careful, experienced influenza virologists are now publicly arguing the likely mutational course of this virus, in an exercise

that is unparalleled. Never in the history of man/microbe relations have we known so much about the genetics and sequence variations of a real-time viral outbreak. Yet, much of this data is noise, and Science has yet to determine precisely how influenza viruses mutate, what selection pressures really matter, and precisely how these viruses change as they move between host species. The analogy that comes to mind is Hurricane Katrina: The National Weather Service had more satellite-captured data on the mounting Gulf of Mexico storm than had ever been amassed for a pending disaster, and could see hours before the hurricane hit shore that it was likely to

slam Louisiana and Mississippi with devastating force. But until it was just a few hours from landing nobody could precisely predict which piece of U.S. real estate would bear the brunt of Katrina’s force, with what outcome. Influenza and hurricane watching are both rapidly evolving sciences, aided by new tools that provide mountains of data, most of which is of dubious utility. History tells us influenzas move in waves around the world, often – like hurricanes – gaining strength and altering their form as they pass through the sea of humanity. The London Flu of 1889-92 struck in 1890 with a case fatality rate that was comparatively low – 10% of the total epidemic death toll occurred that year. But a year later it returned in deadlier form, killing about half of the epidemic’s total numbers during that winter. The 1918-19 pandemic came in three waves, the second of which claimed 60% of that epidemic’s total deaths. And the 1968 pandemic came in two waves, the second of which claimed 85% of all deaths. (See: Cohen J, “Past Pandemics Provide Mixed Clues to H1N1’s Next Moves,” Science 324:996-7, 2009.) Scientists are still puzzling out details regarding what

8

changed inside the viruses with each deadlier wave, but Peter Palese of New York’s Mt. Sinai Medical Center feels confident that the PB1-F2 gene is the key to super-lethality in influenza A viruses. This gene was found when the 1918 flu virus was sequenced, and is believed to be key to influenza virulence: It is not present in the 2009 version of H1N1. What would it take for H1N1 to acquire that gene, or mutate its current PB1 sequence into the F2 form? Palese believes this transformation would entail such an unlikely set of events as to be considered improbable, if not impossible. But there are equally reputable virologists who disagree, and even Palese concedes that co-infection with the H5N1 “bird flu” and the H1N1 “swine flu” could well result in a mixing of viral RNA that would yield an extremely dangerous organism. It is worth noting, therefore, that both viruses are now circulating in Southeast Asia. The Indonesian co-circulation (on an environmental, if not individual animal level, is especially worrying. Over the last week Indonesian authorities reported 8 cases of H1N1 infection and fresh outbreaks of H5N1, though so far these events are occurring on different islands. The Ministry of Health has responded to the H1N1 emergence with airport-based strategies, demanding that all people arriving from countries with established “swine flu” outbreaks wear masks, and report to authorities if they develop fevers. Five of the 8 identified cases have involved individuals who recently arrived in Jakarta from Australia or Singapore. The regulation flies in the face of both WHO policy (no travel restrictions are warranted) and Chinese experience. In the later case, Beijing has imposed quarantines on planeloads of travelers from the U.S. and Mexico, but the actions have not prevented H1N1 entry into the country. Anecdotally we have heard of numerous examples of business travelers canceling trips to China out of fear they will be placed under quarantine. How likely is a H1N1/H5N1 reassortment event? Again, in trying to answer that question we encounter scientific confusion. The H5N1 virus has been around for at least 15 years, circulating primarily in wild bird populations and domestic poultry. Human cases have, thankfully, been rare – but very deadly. In Indonesia, for example, some 85% of people known to have been infected with H5N1 have died. (In contrast, the case fatality rate for H1N1 in Mexico is estimated at around 0.7%, possibly as low as 0.1%.) Over time the avian virus has mutated and evolved, now circulating in many forms around the world: The original trunk that took root in China in the mid-90s has now branched into a dense H5N1 evolutionary tree. Although the various strains of H5N1 scrutinized to date appear incapable of infecting the human nose, trachea or upper respiratory tract, this could change. The virus is currently adapted to the cells of bird beaks, but there have been far too many human cases to allow Homo sapiens nonchalance. Further, pig infections have been anecdotally reported from Indonesia. Though the H1N1 virus has genetic elements within it that originated in bird infections, the “swine flu” seems adapted to mammalian cell infection – and precisely the upper respiratory cells that the “bird flu” is currently incapable of infecting. In order for the virulent elements of the “bird flu” to mix with the contagion elements of the “swine flu” the two viruses would have to simultaneously infect not only the same animal (human, pig, chicken, duck, wild bird, or other species), but also the same cell within that animal. Since the two influenzas appear to be genetically adapted to infecting species-specific cell types this would seem to be a highly improbable event.

9

But it is not impossible. Learning exactly how likely such an event might be requires careful tracking of all known strains of H1N1 and H5N1, genetic analysis and on-the-ground epidemiology, particularly in pigs. Unfortunately, some countries (especially Indonesia) continue to erect barriers to such investigation. Surveys in 2002-2003 of H1N1 (and H3N2, H1N2) in European pigs reveal remarkably high rates of infection in the animals, based on the presence of antibodies in the swine. All but one of the 97 pigs surveyed in Belgium carried antibodies to H1N1; 93% of the German swine; 83% of the Italian. These may not have involved H1N1 strains identical to the currently dubbed “swine flu”, but they were at the very least, close cousins. This demonstrates that H1N1 viruses are endemic in European pigs. But even inside Europe, where disease surveillance is sophisticated and transparent, scientists are not sure what wild birds carry H5N1 “bird flu” or how other species of birds get infected and die. Almost everything that is known about the spread of H5N1 in Europe is based on forensic examination of dead animals. (See: Hesterberg U, Harris K, et al, “Avian influenza surveillance in wild birds in the European Union in 2006,” Infl and Other Resp Vir, 3:1-14, 2009.) Data on both animal and human cases in East and Southeast Asia is even sparser, and more difficult to interpret. It is known that H5N1 can infect a range of mammals, including domestic cats, ferrets and some rodents. Two years ago, European authorities reported “bird flu” deaths in cats, prompting warning that families keep their pets indoors. It would be useful to know whether H1N1 can also infect that range of mammals, and whether co-infection of the two viruses is possible in felines and rodents. Adding to the predictive confusion is data on the human immune response to influenza, some of which implies that a relatively benign virus can induce complicated decoy effects on antibodies, particularly if multiple strains of influenza are circulating in human populations at the same time. Much of this work is theoretical, and all of it is complex, but the bottom line is that the concept of “virulence” could have as much to do with how the infected host responds to the invading virus, as to the genetics of the virus, itself. (See, for example: Ndifon W, Wingreen NS and Levin SA, “Differential neutralization efficiency of hemagglutinin epitopes, antibody interference, and the design of influenza vaccines,” PNAS 106:8701-8706, and Lee HY, Topham DJ et al, “Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection,” J. Virol.10.1128/JVI.00098-09.) Key to the complexity of the immune response to influenza viruses is their constant mutation, due to the sloppy nature of their reproduction. There is a fundamental artifice in flu virology – the notion that a given, known genetic sequence is circulating in human beings at any given time. In reality people (or birds and animals, generally) are infected by “swarms” of viruses that may differ genetically by a significant percentage of their RNA. (Influenza is an RNA virus.) If members of the swarm have even minute genetic differences that alter the shapes of their hemagglutinin (HA) or neuraminidase (NS) proteins, the human immune system may “see” the microbes differently, and make competing antibodies.

10

One of the signature features of 20th century pandemic strains of flu has been a shift from infection and death in elderly populations, to adolescents and young adults, marked by unusually high levels of mortality in younger members of the workforce. There is considerable debate among scientists regarding how much of this age-shift was due to host immunology, versus to viral virulence. Theoretically, both could be true. But to date no sign of past protective immunity among older adults against “swine flu” has emerged to explain why the majority of cases this year have been in younger populations. Despite speculation that prior vaccination or exposure twenty-plus years ago to some other form of H1N1 might have lent older adults immunity to the new “swine flu,” no such neutralizing antibody response has been demonstrated. H1N1 is now circulating widely in the southern hemisphere, in both humans and swine. It would be folly to underestimate both the likelihood that the virus will return to the north this fall, and that its genetic form will be different from that which circulated in Mexico in April. As we have reported in prior Updates, a concern for the Global Health Program is the likely spread of H1N1 within HIV+ populations in sub-Saharan Africa. Until this week it seemed Africa had been spared the scourge, but now reports of the influenza cases are pouring in from Kenya and neighboring countries. Most African countries have weak-to-nonexistent influenza reporting systems, so the modest numbers of cases reported to date should be considered underestimates. HIV+ individuals are far more likely to suffer and die from influenza. Even if appropriately treated with antiretroviral drugs to hold their HIV at bay, people infected with the AIDS virus are typically more likely to suffer unusual clinical events when exposed to influenza, and to harbor and shed virus for longer than HIV-negative individuals. The new flu pandemic is meeting up with the 25+ year old HIV pandemic: The outcome is not clear.

Also unclear is whether Tamiflu (oseltamivir) will prove effective in mitigating H1N1 illnesses and deaths five months from now. A form of drug-resistant H1N1 was found in a patient last week in Denmark, and genes for resistance to the drug are already present in other flu strains circulating in North America and Europe. Given most employer pandemic plans in the wealthy world are based on Tamiflu use, and many country schemes rely on the use of

the drug by first responders, it would seem wise to err on the side of assumed drug resistance. Certainly influenza strains all over the world have demonstrated the capacity to rapidly mutate, getting around the Tamiflu drug, without sacrificing transmissibility or virulence to do so.

11

The Obama Administration is taking the likely return of H1N1 very seriously. Last week both houses of Congress passed a war supplemental bill that included a White House requested flu pandemic package totally $7.7 billion. The funds will support purchase of vaccines and medical supplies, and bolster local and state capacities to respond to a pandemic. Nearly $2 billion of the overall package were immediately freed up for use this summer; the remainder will be released in FY2010 (which commences on October 1, 2009). The Administration is, meanwhile, trying to redesign the Bush-era pandemic plan for the nation. The Bush plan has already proven to have a fatal flaw, in that its staging system, triggering various federal and state responses to an outbreak, is based on case-fatality rates. H1N1 has not proven to be particularly virulent, however, so local officials have essentially bypassed federal guidance by closing schools and taking other actions reserved for more severely virulent microbes. One element under review concerns the

role, domestically, of the U.S. Armed Forces, including the National Guard. A new Congressional analysis envisions an extensive role for the Department of Defense in a domestic outbreak http://www.fas.org/sgp/crs/natsec/R40619.pdf though no specific triggers for action are identified. Under what circumstances is it appropriate to deploy armed forces inside the United States in response to a pandemic?

Bio(Non)Security Hundreds of companies, large and small, are now vying to produce flu drugs and vaccines, and many are using novel techniques that offer hope of one day being able to rapidly and cheaply produce vaccine for the entire human population. Before reaching that point, however, researchers in the private sector will need to study flu strains, and grow them in laboratories under various conditions. For some multinational companies this means shipping viral strains from a lab in one country, to a collaborating lab located in another country. Such a transfer in February between facilities contracted to Baxter International led to a major “goof” that could have caused the spread of human “bird flu” inside Europe. Baxter mistakenly shipped live H5N1 from their lab in Vienna to subsidiaries in Germany, the Czech Republic and Slovenia, where researchers thought they were handling crippled forms of the virus that would not be dangerous. The error was discovered when experimental ferrets in the Czech lab died of “bird flu”. While the flu vaccine world tries to figure out ho such a potentially catastrophic error occurred, the Obama Administration has reopened policy debate about biosecurity, overall. The American Association for the Advancement of Science (AAAS) argues that the existing regulations, promulgated during the post-9/11 and anthrax-mailings period, have stifled scientific collaboration and slowed the pace of basic research. AAAS points to Mexico’s decision to send flu

12

samples in April to Canada for analysis, rather than the CDC in Atlanta, because of the cumbersome biosecurity regulations in the U.S. Canada then made the H1N1 “swine flu” diagnosis. The White House in January ordered creation of an interagency group that is now reviewing all biosecurity regulations, and Congress has its own review process underway. But the Institute of Medicine is now reviewing biosecurity in the context of the anthrax mailings of 2001, and the FBI’s insistence that Dr. Bruce Ivins was the culprit responsible. Ivins, who committed suicide last summer following months of intense FBI scrutiny, worked at the U.S. Army Medical Research Institute on Infectious Diseases (USAMRIID), located in Ft. Detrick, MD. An anthrax vaccine researcher, Ivins was allegedly able to hide anthrax samples from the FBI and USAMRIID authorities for years. If true, the Ivins case points up grotesque biosecurity flaws. Five months ago the Defense Department ordered all research at USAMRIID stopped, pending thorough investigation. A systematic scouring of the freezers, fridges and shelves of the facility has turned up a staggering 9,220 vials of pathogens that had never been logged into the USAMRIID system. The vials, which represent 13% of the entire USAMRIID pathogen inventory, contained everything from useless slurries to dangerous toxins and viruses. In a June 16th press conference Col. Mark Kortepeter, USAMRIID’s deputy commander, said, “The vast majority of these were working stocks that had accumulated over several decades.” A similar investigation a decade ago showed that many researchers at USAMRIID hoarded, and hid, their pathogen samples because they feared official registration might interrupt the progress of their research. This begs the question of whether the 9,220 newly discovered vials represent everything that was made and saved at USAMRIID, or some other samples have been moved by scientists to other

facilities over the years. Similar lapses have occurred in labs outside the U.S. In May, for example, Canada’s National Microbiology Laboratory in Winnipeg admitted that it failed to report theft of vials full of Ebola viruses. The samples turned up in the trunk of Konan Yao’s car, found by U.S. Customs officials as the scientist tried to cross the border between Manitoba and North Dakota. Yao was arrested for smuggling and is in the custody of the U.S. Marshal.

In May, the Defense Science Board of the Task Force on Department of Defense Biological Safety and Security Program issued a startling assessment of U.S. biosecurity, arguing that, “a determined adversary cannot be prevented from obtaining very dangerous biological materials intended for nefarious purposes, if not from DoD laboratories, then from other sources. The nation needs to recognize this reality and be prepared to mitigate effects of a biological attack. Today, we as a nation are not prepared.” The view from the State Department’s Office of International Health and Biodefense is very different. Writing in the International Journal of Risk Assessment and Management (Vol. 12: 204-221), the Department’s Marc Ostfield argues that “biosecurity” that seeks to control scientists and pathogens is doomed to failure, and may provide nations with false senses of safety. Ostfield insists that the

13

expertise to use and manipulate organisms, the pathogens themselves, and both natural and manmade vectors for their spread can be found all over the world. Most, he insists, can be extracted from nature by individuals who have rather minimal technical skills. On a policy level, Ostfield argues, this “biosecurity” focus on pathogen containment is a direct outgrowth from Bush Administration emphasis on “weapons of mass destruction” and control of nuclear weapons. Imposing nuclear disarmament policies on biological organisms, Ostfield says, is pure folly. A far wiser course of action would involve improving disease surveillance and response worldwide, and strengthening diplomatic tools aimed at preventing nations of from preparing or using biological weapons.

Searching for the Framework of U.S. Foreign Assistance: Who

is in Charge? The U.S. foreign assistance mess, including PEPFAR, the Millennium Challenge Corporation and pandemic surveillance, shows no immediate sign of resolution. Global health advocates ignore the U.S. foreign assistance debate at their peril. Back in the 1990s when HIV, TB, malaria, child health programs, multilateral support for WHO, vaccine campaigns and the rest of what we now call global health garnered $5.6 billion a year, from all sources, it was easy to ignore things like UK or French development policy. But by 2007, global ODA for health topped $21.8 billion, and health targets -- especially HIV, TB and malaria -- rivaled the scale of such development efforts as child literacy, agricultural campaigns and transportation systems.

Steady readers of the Global Health Program’s Updates will recall that we have engaged in review of U.S. foreign assistance, and advocated sweeping reforms. Hope for bold change ran high in January following Obama’s inauguration, but has diminished considerably over recent months. The framework of foreign assistance is, indeed, under review inside the State Department right now. But the process does not include the Bureau of African Affairs, the U.S. Agency for International Development (USAID), PEPFAR or any part of the Department of Health and Human Services (HHS). Whatever shape global health and development programs will take in the Obama Administration is being decided now, by Secretary of State Hillary Clinton and her Deputy Secretary Jack Lew. Inside the National Security Council, Gayle Smith, a long time advocate for African development, has quietly tried to exert influence over the process. As Afghanistan and Pakistan take center stage in U.S. foreign policy attention, development and health are increasingly seen as elements in the State Department’s diplomatic toolkit. This is not to say that Africa will be a forgotten continent in the administration of a President whose father was from Kenya: Far from it. The President will travel to Ghana immediately after the G8 Summit (July 10-11), and Secretary Clinton will lead a very high level mission to Kenya and three

14

other unannounced African nations in August. No other American administration has put official African engagement so high on its diplomatic list, so early in its term. Moreover, Smith and the NSC successfully pushed a White House Global Health Initiative that commits the U.S. to spending $63 billion over the next 6 years on a range of health efforts; more than 70% of the spending will go to PEPFAR for HIV programs. To put this in perspective, in FY08 OGAC, or the Office of the Global AIDS Coordinator (a position now filled by Dr. Eric Goosby), garnered 48% of total U.S. global health spending. Combined with small amounts meted thru other agencies, HIVAIDS commanded 51.6% of U.S. global health spending in FY08. According to an analysis from the Kaiser Family Foundation (April 2009, http://www.kff.org/globalhealth/7881.cfm ) the steady increase in HIV-targeted funding over the last ten years has been the key element of overall increases in U.S. support for health. That might sound like something fiscally impressive, but global health remains an almost trivial piece of the overall foreign assistance package. In FY2008 the U.S. budget was $3 trillion – global health garnered $9.6 billion, or less than 0.4%, though between FY04 – FY08 the global health budget soared from $4.4 billion to nearly $10 billion. Overall, Kaiser found, 51% of global health funding in 2007 was handled by the State Department; 28% by USAID; 12% by HHS.

The Obama Administration endorsed the International Health Partnership in January, and committed to supporting health systems improvement and recipient country leadership in deciding appropriate targets for donor resources. In theory, that means that U.S. dollars ought to be apportioned according to country needs, not U.S. Congressional mandates. But let’s be serious, and face political realities.

15

Reality Number One is that nothing will substantively change in U.S. foreign assistance targets or organization unless dynamic, savvy leadership is in place to guide the health and development agenda through politically tumultuous waters. Which brings us to the Paul Farmer question. The Harvard physician, creator of Partners in Health, recipient of Clinton Global Initiative support for HIV programs in Rwanda, guiding light for health initiatives in Haiti – yes, that Paul Farmer. The Obama Administration has reportedly asked Farmer to serve as director of USAID, and the Bostonian is mulling it over. If Farmer takes the job he will inherit an agency with the lowest morale in the federal government, devastated budget, greatly reduced professional staffing, and a frightening agenda. He will find himself in a political struggle even before he faces Congressional confirmation hearings, fighting for control of the agency’s budget and management. And he will have to manage development programs executed inside embattled areas, such as in Afghanistan and Taliban-contested parts of Pakistan. Even for a seasoned veteran of Washington insider politics the USAID job would be a tough one: Several such individuals have been approached, but turned the position down. One such individual reportedly decided there was a 50/50 chance of turning the agency around after 8 years of Bush Administration devastation, but only if the director lived and breathed the job 18 hours a day, 7 days a week. If that is the key, Farmer’s stamina is legendary. But unlimited energy isn’t enough: Knowing how to play and win the games in Washington and in the multilateral sphere of global health is crucial.

Dr. Michel Kazatchkine, director of the Global Fund to Fight AIDS, Tuberculosis and Malaria has proven a savvy political operator, fighting for donor support. But the global financial crisis has defeated even his wise charm. The Fund has approved $2.5 billion more in grants for 2009 than it has actual monies to cover, and 2010 grants lacking real funds bring the total shortfall to more than $4 billion. Kazatchkine hoped that the U.S. Congress would approve enough support to cover the 2009 shortfall – about $2.1 billion. But only $700 million was voted through Congress in late June.

During the Bush Administration it was clear who Kazatchkine and other global health leaders should turn to for support and financing. Mark Dybul ran OGAC/PEPFAR and commanded respect both inside the White House and on the Hill – in a crunch, he could be counted on to help mobilize money. And inside HHS Bill Steiger ran the Office of Global Health Affairs (OGHA) with an iron fist. He was tough to work with, but could be counted on to mobilize Republican support when it suited him. Today Dybul’s job is filled by Goosby, whose political savvy is yet to be tested. And nobody knows what Sebelius plans to do with the OGHA.

16

Without a strong OGHA in the Obama Administration it is unclear who runs strategic global health overseas operations. For example, were an outbreak to occur in Country A, and the leader of said country formally requested help from the U.S. CDC, who processes that request, through what channels, and with what budgetary considerations? In the absence of clear answers Tom Frieden, the new Director of the CDC, will have to figure this out, no doubt working through the State Department. Sebelius may be abdicating authority of international disease interventions. These chain-of-command and structural questions regarding U.S. foreign assistance mirror confusion at the UN and multilateral level. The June 20 issue of The Lancet featured four important studies aimed at tracking money for global health, setting priorities for future health development and asking who is in charge. A follow-on meeting in Venice this week seeks to find a balance between targeted health initiatives (e.g. GAVI, PEPFAR, Global Fund) and overall health systems support. WHO’s Chan argues this is a false dichotomy:

Venice, Italy 22 June 2009 Why the world needs global health initiatives Dr Margaret Chan, Director-General of the World Health Organization I think we can now let a long-standing and divisive debate die down. This is the debate that pits single-disease initiatives against the agenda for strengthening health systems. As I have stated since taking office, the two approaches are not mutually exclusive. They are not in conflict. They do not represent a set of either-or options. It is the opposite. They can and should be mutually reinforcing. We need both. We need them to work together to facilitate what I believe we all agree is the most important goal: to save lives and improve health outcomes....Global health initiatives were established with a strong sense of purpose and great ambition. They set out to save lives, on an emergency basis, even though not everything was known at the start about everything that needed to be done, or the best way to do it. And there was a clear moral imperative to act. The AIDS epidemic demonstrated the relevance of equity and universal access in a substantial way. With the advent of antiretroviral therapy, an ability to access medicines and services became equivalent to an ability to survive for many millions of people. This is the essence of the equity argument: people should not be denied access to life-saving interventions for unfair reasons, including an inability to pay. These global health initiatives have gathered knowledge along the way, and in so doing, they have shed light on a cause of much ill health in this world: weak and inequitable health systems. Weak health systems are wasteful. They waste money, and dilute the return on investments. They waste money when regulatory systems fail to control the price and quality of medicine.

17

They waste training when workers are lured away by better working conditions or better pay. They waste efficiency when needless procedures are performed, or when essential procedures are precluded by interruptions in the supply chain. They waste opportunities for poverty reduction when poor people are driven even deeper into poverty by the costs of care or by the failure of preventive services. Above all, weak health systems waste lives. Weak health systems are almost certainly the greatest impediment to better health in the world today. They are the central obstacle that blunts the power of global health initiatives.

According to the studies in The Lancet total global health funding in 1990 was $5.6 billion; by 2007 that reached nearly $22 billion. The number of players on the field has increased dramatically over that time, and the role of UN agencies has diminished. The majority of financial resources are now channeled through disease-specific initiatives, such as GAVI (child vaccination) and the Global Fund (AIDS, TB and malaria). In 2007, more than half of all ODA for health targeted HIV/AIDS ($5.1 billion). The actual amounts of money directed to WHO and other UN agencies has changed little over the last 17 years, but NGO support has grown more than ten-fold. The other area of major growth has been in bilateral programs, such as PEPFAR, USAID, DIFID and other OECD aid. In one lengthy analysis found in The Lancet the authors examine how this growth and shift in financing of health has affected local country programs. It is a mixed bag: some targeted initiatives have augmented broader medical and public health programs, while others have drained resources and personnel away from country-directed efforts. Because the study focused on direct health programs we do not know what their impact has been for health-related development efforts, such as water treatment, construction of transport systems between health facilities, food supply and child education. The take-home message seems to be the following: In this era of financial crisis every single entity – public or private – that is engaged in health and development should try to work together, avoid duplications, harmonize efforts, and listen carefully to what the people in recipient countries say they most need. Donors are demanding efficiency and evidence of outcomes that can be linked to dollars. No aspect of health should be sacrificed – or needs to be forfeited. It is possible to have financing flow through many pipelines without causing damage to health systems, if every player on the field shares that goal. The U.S. is by far the biggest donor, both from its government and private sector. If the goal of synergizing health services to maximize the numbers of lives saved is to be realized, the U.S. leadership in foreign assistance and health must be solidified. The urgency is real. Last week the Los Angeles Times reported that Kenya is running out of health financing, and has set up “patient prisons” to jail people who are unable to pay their hospital bills. Some mortuaries in Kenya are now refusing to release patients for burial, pending payments from relatives of the deceased, and others decline to accept bodies from over-loaded hospital morgues until family payments are guaranteed.

18

Tanzania has announced a 25% cutback in HIV services. A new Ugandan government study finds that the majority of that country’s hospitals and clinics are severely deteriorated, and should be replaced. Meanwhile, the HIV pandemic on the continent continues to swell, guaranteeing that costs of care and treatment will escalate for many years into the future. The stress on already-impoverished health infrastructures and ODA needs will only increase.

HIV Virulence and Optimal Treatment Change A consortium of U.S. researchers has found evidence that HIV is evolving towards greater virulence. Surveying clinical data on thousands of HIV patients seen between 1985-2007, the researchers found a striking difference in the CD4 immune system cell counts immediately following sero-conversion. The mean CD4 count back in 1985, when diagnosing and testing was comparatively primitive and patients typically were identified after they acquired an opportunistic infection, was 632 cells/mm. By 2007, in an era of rapid testing and diagnosis, mean count had dropped to 118 cells/mm. (See: Crum-Cianflone N, Eberly L et al, “Is HIV Becoming More Virulent?” CID 48: 1285-1292.) The virulence study relies on rich-country data (USA, Canada, Australia, Europe). After factoring for a number of possible confounders, the researchers conclude that, “the initial CD4 cell counts among HIV seroconverters in the United States have significantly decreased during the epidemic. The decrease in the post-seroconversion CD4 cell counts occurred early in the epidemic, with stabilization since the advent of HAART. These data may provide an important clinical correlate to studies suggesting that HIV may have adapted to the host, resulting in a more virulent infection.” In a previous Update we cited a host of papers in the April 30th New England Journal of Medicine that pointed to the need to start HIV treatment before CD4 counts fall below 350 cells/mm. In mid-June African AIDS experts gathered in Namibia, confirming the need to commence treatment far sooner than is the current norm, which stipulates CD4 of 200 cells/mm. One NEJM study found that waiting until CD4 counts fall to 200 increases the probability of death by 69%. In the short run, finding and treating individuals at this earlier stage – especially in rural Africa – will increase costs considerably. But the American College of Physicians has concluded that long term costs will decrease considerably. In the US, for example, commencing HIV treatment when an individual’s CD4 count is below 50 costs $36,500 per year. But patients that get into the system when their CD4 count is above 350 can be cared for at an average cost of $13,900/year. Capturing patients early, and treating them effectively, saves money in the U.S. A recent survey of African HIV programs found that most patients are commencing treatment when their CD4 counts are below 130 – in South Africa the median CD4 at start of treatment is only 87. Between 7 to 30% of the African patients are lost to follow-up within 2 years, but among those still tracked by the health system about 12 percent have died by the 2-year point. This high mortality rate may reflect imperfect care and a late start to treatment. (See: Brinkhof MWG, Boulle A et al, “Mortality of HIV-Infected Patients Starting Antiretroviral Therapy in Sub-Saharan Africa: Comparison with HIV- Unrelated Mortality,” PLoS Medicine 6:e1000066, April 2009.) A recent assessment of PEPFAR outcomes between 2004-2007 found that HIV-caused deaths in focus countries were 10.5% lower than in neighboring African nations that do not receive PEPFAR funds. But no statistically significant difference in incidence or prevalence of infection was seen between PEPFAR and control countries, indicating PEPFAR has failed to have an impact on new

19

infection rates. (See: Bendavid E and Bhattacharya J, “The President’s mergency plan for AIDS Relief in Africa: An Evaluation of Outcomes,” Ann Int Med 150: May 19, 2009.) One of the agonies of AIDS in Africa is the direct relationship between spread of the virus and the ill treatment of women. Six weeks ago Catherine Nyirenda, the first openly HIV+ woman in Zambia, was beaten to death in Lusaka by an ex-boyfriend. She had the courage to face HIV stigma, but could not defend herself against the sort of male abuse that is tolerated in many pockets of Africa.

A recent, disturbing study of sexual violence in Swaziland, where HIV prevalence in young adults exceeds 25%, demonstrates how serious abuse of girls and women is. A survey of 1,244 females, aged 15-24 years, found that a third of them had been a victim of sexual violence before reaching the age of 18. Most of the rapes and sexual assaults were carried out by members of the girls’ families, school mates or men living in their neighborhoods. The mean age of first assault or coerced sex was 15

years. (See: Reza A, Brieding MJ et al, “Sexual violence and its health consequences for female children in Swaziland: a cluster survey study,” Lancet 373: 1966-1972, 2009.) Sadly, female leadership in much of Africa has not turned this crisis around. It may be a reflection of the quality of that leadership. For example, Manto Tshabalala-Msimang has just been named the African Union’s Goodwill Ambassador for maternal and child health. Manto served as Minister of Health for South Africa during the terrible HIV denialism years, justifying Thabo Mbeki’s policies of ignoring the epidemic. During her tenure more than 300,000 people died needlessly of AIDS, according to a Harvard study, because she refused to make medicines available to her people.

Climate Change and Health The Lancet and University College London Institute for Global Health jointly executed a large and comprehensive analysis of the likely impacts of climate change on the health of populations worldwide. The report, which occupies the bulk of the May 16th edition of The Lancet, sets aside a lot of the dubious science forecasts previously asserted, and offers a fresh, challenging look at the problem. The study concludes that:

• While climate change will shift infectious disease patterns, due to changing rainfall patterns, the net impact will be minor compared to other, harsher catastrophes caused by increasing atmospheric CO2.

• Food security and resultant malnutrition will be severe. Poorer countries that already have weak agricultural sectors may face famine and mass starvation.

Sexual violence victims in a special women’s hospital in

South Kivu, Congo

20

• Water supplies in some regions will become increasingly contaminated, as severe weather events overwhelm purification, sewage and irrigation facilities. In other parts of the world climate shifts will cause life-threatening droughts.

• Mass migrations of humanity will occur, as regions of the world become uninhabitable wither due to water shortages, severe weather events or rising sea levels. Migrant health and housing will become a major governance issue throughout the world.

• Few countries have sufficiently resilient healthcare capacity to handle the increase in traumatic injuries and exposure ailments that will be caused by catastrophic weather events.

As always, the Global Health Program of the Council on Foreign Relations will endeavor to keep you informed on these and other related events. We wish our northern hemisphere readers a happy summer, and hope that those in the southern hemisphere are not unduly stressed by the spread of H1N1 flu. (Details on the upcoming ECOSOC Summit are below.) Sincerely,

Laurie Garrett *** ECOSOC Innovation Fair (from the ECOSOC website)

The high-level segment of the annual substantive session of the Economic and Social Council (ECOSOC) is designed to showcase innovative projects and practices in the area of global public health by a wide range of stakeholders in support of successful global public health activities. Objective of the Fair:

21

• Share innovative solutions and best practices in the area of global public health; • Demonstrate the strong links between public health and the other IADGs / MDGs; • Promote broad multi-stakeholder engagement in the work of the Council; • Encourage interaction among participants in the Fair and member States which could

possibly lead to the launching of initiatives.

The Annual Ministerial Review, under which the Fair is organized, will consider the following broad thematic areas:

• Accelerating the achievement of Millennium Development Goals 4, 5 and 6, including their relationship with other MDGs;

• Strengthening health systems of developing countries, particularly strong and stable primary healthcare facilities;

• Strengthening the global health workforce through human resources development of the sector, including responding to the challenge of brain-drain, managing migration and increasing access to and quality of training;

• Promoting health security in order to minimize vulnerability to acute public health events that endanger the collective health of populations at the global level (emerging and epidemic-prone diseases, outbreaks of food borne diseases, natural disasters and climate change, and chemical or radioactive events);

• Raising the profile of neglected tropical diseases.