Robert Fortner

Polio Eradication: Harder Than it Looks

Why it might require a new vaccine

The global campaign to eradicate polio crushed 90% of the disease in the space of a dozen years, by 2000. In the decade since, complete elimination has swung tantalizingly close—and then away again when case counts spiked and outbreaks reappeared in countries recently cleared of the virus. Once again, cases are ebbing and hopes rising. The New York Times recently reported that for four straight months, India has seen no new cases in its two most polio-burdened states. But the real news is the unnoticed opening of a new scientific front in vaccine research, portent of a longer battle.

The polio-free streak in the state of Uttar Pradesh, while encouraging, is actually only two months old and in the state of Bihar just over three. India as a whole did have zero cases in March. But in four of the last ten years, the country has started off with even fewer total polio cases only to see the tide turn. Nationwide, the total cases so far this year, 19, equals the number at this time in 2009. Polio incidence usually rises in May; given reporting delays, by July, the direction of the trend should be clearer.

The Times article cites extraordinary vaccination efforts to explain the new swing toward eradication. Polio vaccination campaigns in India are monumental undertakings, war-sized in scale involving an army of over two million vaccinators going house-to-house and overseen by a supervisor corps numbering greater than 100,000. However, the most enduring reason polio continues in India has not been a failure to vaccinate, but a failure of the vaccine.

If the population covered by campaigns is increasing, so too is the frequency of the campaigns. Vaccinations became monthly in Uttar Pradesh, for example, in 2007 in order to cover more quickly the 500,000 children born there each month.

Although the remarkable vaccination efforts have greatly pushed down polio cases, eradication has remained elusive because eight vaccine doses or even more don’t necessarily confer immunity. In India, the number of polio cases where the individual hasn’t been vaccinated has plummeted toward zero. Instead, increasingly the victims have been vaccinated over and over—to no effect.

In most places in the world—and many places in India—the Sabin oral polio vaccine works after two doses. No one knows what makes it go awry in Uttar Pradesh and Bihar. Those states are highly populous but low in income. Overcrowding and hygiene conditions help infection spread. But the vaccine's inability to elicit immunity is thought to be a product of malnutrition, immune suppression caused by other diseases and possibly genetic factors.

The World Health Organization just closed a call for research proposals to find out why, part of an ongoing large investment in improved vaccines. Critics of the eradication program have vociferated about the oral vaccine for some years. But developing new vaccines or drugs is time consuming, costly and not guaranteed to work, perhaps explaining the reluctance to open a scientific front in the war on polio. Previously, global eradication, while hugely daunting and complicated, came down to logistical execution, will power and funding.

Bruce Aylward, who heads the eradication effort at the World Health Organization, has ample willpower, but worries constantly about finances. He has steadily forecasted the imminent demise of polio for years. To fund the pursuit of eradication, he has learned that when there’s good news, like a favorable turn in case numbers, you cash it in. Aylward told the New York Times: “We’ve never had so many things looking so positive across so many areas.” Concerning a funding shortfall, he hastened to add: “I spend as much time in donor capitals as I do in infected countries.”

Hopefully his efforts will pay off. But if eradication remains unachieved, we will almost certainly be on the verge of it—still.

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Photo credit: Jean-Marc Giboux via quilty2010, Sub-National Immunization Day. Lucknow, Uttar Pradesh

Source, 2nd graphic: AFP Surveillance Bulletin—India Report for the week ending February 6, 2010

Source, 3^rd graphic: Paul, Y., Polio eradication in India: Have we reached the dead end?, Vaccine. 2010 Feb 17;28(7):1661-2.

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Heavy Lifting: Raising Health Beyond Polio's Reach (May 13, 2010)

Wall Street Journal: Pulling the plug on polio eradication? (April 26, 2010)

In Burma, the Wrong Kind of Resistance

Drug-resistant malaria may have spread to Burma and, worse, might now be impervious to current first-line drug defenses. Less than a year into the battle to contain resistance, everything that could go wrong may have.

In Southeast Asia, malaria has overrun--twice--the pharmaceutical defenses erected against it, evolving resistance to previously potent anti-malarial drugs and ultimately rendering them useless worldwide. Last year, portents of a third such performance appeared. In cases along the Thai-Cambodia border, the first-line drug artemisinin began taking longer to completely clear malaria parasites, suggesting that today's champion had lost a step against a strengthening disease. (See Once again, it's 'Apocalypse Now' in Southeast Asia.)

Plans quickly developed to crush this new threat before it spread globally--again. Efforts to eradicate malaria from the affected areas of Cambodia have markedly reduced prevalence of the disease. But preliminary reports now suggest that parasites in some regions of Burma and Vietnam may also respond poorly to artemisin, meaning the original lines of containment might already be breached.

In the past, drug-defeating strains originated in Southeast Asia and then spread by human carriers to Africa. Worryingly, researchers are currently working to determine whether artemisinin-resistant malaria has arrived in other parts of the world and if there is a connection to Southeast Asia.

On top of news of a faster-than-expected spread, some evidence suggests that artemisinin is getting slower and slower in some cases. If the trend continues, eventually treatment failure will result, meaning complete resistance to artemisinin when there are no new drugs to take its place.

On the other fronts of the war on malaria, a vaccine candidate, called RTS,S, has moved into final clinical trials. However, the protective effects of the vaccine have varied widely, from 40% to 60%, creating a difficult decision on whether to undertake large and costly vaccination campaigns when RTS,S emerges from clinical trials in 2014. The bright spots at present are insecticide-treated bednets. The bednet campaign has raised awareness, money and most importantly actual usage of the nets in malarial regions of the world.

If heart drugs keep improving, will we be able to tell?

Even under high magnification, new drug benefits are vanishing

By the end of the 20^th century, modern medicine was fending off 190,000 deaths a year from otherwise fatal heart conditions. Funding poured into cardiovascular research, more than doubling from $3.8b in 1995 to $8.4b in 2005. Now from this richly oxygenated drug pipeline, two new heart drugs have emerged. Massive clinical trials depict, at IMAX scale, medicines that seem better, faster, stronger. But it still takes squinting to see the improvements. And even tests in tens of thousands of people aren’t large enough to show that the new drugs actually save lives.

Once, life-saving effects were visible to the naked eye. In the 1980s, a clinical trial of 17,000 people demonstrated unequivocally that aspirin prevented hundreds of deaths. After a heart attack, aspirin cuts the subsequent risk of death, stroke or heart attack by 2.0%. Improving on aspirin took nearly a decade and a trial of over 19,000 people for the faint effects of a new drug, Plavix, to surface. Plavix surpassed aspirin by a hard to see, Braille-like bump of 0.5%. But the benefits of Plavix and aspirin, taken together, are additive. After Plavix gained FDA approval in 1997, it won for drug-maker Sanofi-Aventis the second largest pharmaceutical franchise in the world.

The scent of that $8 billion market brought competitors loping, ears-back in pursuit. First came Effient from Eli Lilly. Perhaps to magnify small differences between Effient and Plavix, the company-funded study put heart attacks under a microscope. The trial looked not only at heart attacks with chest pain and other classic symptoms, but also those detectable only by a blood test measuring levels of cardiac enzymes. The precise definition of these invisible heart attacks varies and even changed mid-trial. And whether they matter is disputed. But largely because of the tally of non-fatal heart attacks, the Eli Lilly study showed Effient beating Plavix.

Neither drug, however, defeats death. Enter Brilinta, a new antiplatelet drug from AstraZeneca. A recent clinical trial showed Brilinta not only besting Plavix but saving lives—maybe. The study of nearly 19,000 people still wasn’t big enough to attribute the 89 fewer deaths among Brilinta patients to the new drug or to chance.

Chance is not why cardiovascular clinical trials funded by drug companies tend to report results favorable to the funder. AstraZeneca paid for the Brilinta trial, and two of the study’s authors were employees of the company. AstraZeneca also managed the trial data itself, contrary to good practice. Britain’s National Health Service has expressed doubt about the trial’s blinding—which could suggest that the new drug might have been given to patients who were healthier to begin with. Also raising eyebrows, the trial’s 1,800 North American patients fared worse on Brilinta, although that too could owe to chance. (Brilinta is currently wending through the FDA approval process).

Not only are the benefits of these drugs diminishing and arguable. The number of new drugs is plummeting. From eight in 1995, the number of novel chemical entities approved for heart conditions crashed to zero in 2005. All newly-approved drugs tumbled, from 53 in 1996 to just 18 by 2005.

Surprisingly, it’s not the drug companies’ fault. Huge updrafts of research funding did little to arrest the drug free fall. Not only did cardiovascular research funding double, government funding of all biomedical research ballooned, also doubling between 1998 and 2003. The biomedical research engine now gulps $100 billion annually in the United States. Reassuringly, it powers more scientists than ever and generates 200,000 research papers a year, nearly twice the output of 1995. But research and funding have clearly broken away from drug production. Why?

Research has dived deeper and deeper in search of the fundamental causes of disease. This fantastic voyage ever downward in scale was expected to conclude with the sequencing of the human genome and the molecular pinpointing of the genes that cause disease. Instead, the search is still on. Only 3% of the heritable, genetic basis for early heart attack has been discovered. Scrutinizing the DNA of nearly 3,000 sufferers turned up just nine genes in common, suggesting that there are hundreds more. Worse, early heart attacks have a stronger genetic basis than those occurring after age 65 which represent 90% of all heart attacks.

The research odyssey continues deeper and gets murkier. The genes with the strongest influence on early heart attack don’t, say, produce artery-blocking plaque. Instead they appear to control other, unidentified genes of unknown function. Disentangling this self-referential interplay of genes with each other and genes with environment is the daunting task of epigenetics. Like drug trials, research projects are becoming enormous. Inevitably, there is a Human Epigenome Project, vaster in scope than even its parent, the Human Genome Project.

But as research dives deeper, the medical payoff has become fainter. The tether connecting research to new drugs and health benefits began stretching a quarter century ago. In 1984, a group at Oxford quietly and presciently called for megatrials in the 10,000- to 20,000-person range because most trials were “too small to be of much independent value.” In other words, drug benefits had become too small to be detected without a large trial. In 1985, new drug approvals climbed to record heights. They held there, helped by the arrival of the last key heart medication, the statins, which began lowering cholesterol in 1987. In 1988, the Oxford team published the 17,000-person study of aspirin’s antiplatelet credentials. The era of megatrials began. In 1989, as if on cue, new drug approvals began dropping from their all time highs and have not recovered.

In the realm of heart medications, only modest refinements have ensued. Plavix and other antiplatelet drugs improved very slightly on venerable aspirin but lifesaving benefits have vanished even from megatrials. Similarly, new anticoagulants (with names like bivalirudin and fondaparinux) mostly burnished the achievements of heparin which began saving lives in its first, tiny 1960 trial of 35 patients.

A similar pattern holds for cancer, the number two killer in the United States after heart disease. For breast cancer, the 1960s delivered the biggest breakthrough ever: chemotherapy. It cut mortality by 14% and finally displaced 19^th-century radiation treatment as front line therapy. Every therapeutic discovery for breast cancer since chemotherapy has produced only smaller benefits. In the 1970s, modified chemotherapy pared mortality just another 3.1% by employing more toxic drugs developed in the 1950s. Those treatments remain front line to this day. The biggest news since has been tamoxifen, which reduces mortality by 9.2% but only for about three quarters of patients with a particular type of breast cancer. Tamoxifen dates to 1977. The more recent aromatase inhibitors marginally improve on tamoxifen but not in a life-saving way.

The latest generation of cancer drugs, “targeted agents” like Tykerb, approved in 2007, exploit the new, high-definition molecular knowledge. But targeted agents, while higher in precision, have generally lost even the occasional power to cure wielded by older, cruder chemotherapy.

Seemingly the last thing to decouple from new drugs is expectations. In 1998, on the 50^th anniversary of the first clinical trial, the Oxford trialists looked ahead to the next half century. They called once again for “greatly increasing” trial size. The reason, they said gently and soberly, is simple: “when it comes to major outcomes it is generally unrealistic to hope for large therapeutic effects.” Instead expectations, like new drug prices, continue to soar, high above shrinking health benefits below.

Photo credit: Buttersweet on Flickr

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