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Lundi, 14 Novembre 2011 18:11

Hepatitis C: The Last Chimpanzee Research Battleground

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Hepatitis C: The Last Chimpanzee Research Battleground

When Katrina was nine months old, she was taken from her mother and sent to a laboratory in New York. At an age when young wild chimpanzees receive a level of maternal care not unlike the love provided by human mothers, she lived in a cage and was infected with hepatitis B and hepatitis C. Later she was infected with HIV.

By the time Katrina was 15 years old, she’d been sedated 268 times. During 36 of those episodes, doctors pushed a needle into her abdomen and took samples of her liver, and she didn’t receive so much as an aspirin after waking. Sometimes biopsies were taken from her lymph nodes or rectum. Once she went into respiratory arrest during sedation and had to be revived. Another time she self-mutilated her left thumb while coming out of anesthesia. Delirium is common among patients waking from a ketamine stupor.

When Katrina was 19, doctors observed that she had a tendency to compulsively groom herself, a behavior that — in humans, chimpanzees’ closest relative — often occurs in individuals with post-traumatic stress disorder. That condition also afflicts chimpanzees.

Over the next year, she lost nearly 40 pounds, one-third of her body weight. This was quite possibly due to the progression of her diseases, which now included shigella, rather than psychological distress. In 2002, at the age of 20, she was granted retirement and sent to an Air Force laboratory in Alamogordo, New Mexico — hardly an ideal setting for anyone, including a chimpanzee, but at least she wasn’t being knocked out anymore.

Eight years later, she was sent back into the lab.

Hepatitis C: The Last Chimpanzee Research Battleground

A government identification photograph of Katrina acquired through the Freedom of Information Act. Image: Physicians Committee for Responsible Medicine.

The story of Katrina isn’t representative of all chimpanzees used in medical research, but neither is it exceptional. And when it was discovered last year that she and 201 other chimps would be sent from Alamogordo to the Southwest National Primate Research Center, mostly for hepatitis C research duty, the controversy soon went national.

Ultimately the transfer would be halted — though not, as a Freedom of Information Act request found, before Katrina and 13 other chimps reached the research center, where they’re now kept. What’s followed has been a period of deep reflection among both the public for whose benefit research on chimpanzees is conducted and the scientists who conduct it, of whom many are troubled by its toll.

Before the year’s end, a panel convened by the Institute of Medicine to evaluate the scientific value of chimpanzee research will declare its findings. Their conclusions will shape the future of chimpanzee research in the United States, which aside from Gabon is the only country to permit invasive experiments on an animal that feels and suffers in human-similar ways.

“There must be overwhelming benefit for something that is truly injurious. I would think a requirement is to look upon these animals as very, very close to human research subjects,” said bioethicist Ronald Green of Dartmouth University. “You don’t impose the same standards of research as on human subjects — but you’re not totally remote from that. I’d want to ask what the alternatives are, and a clear demonstration that this information is crucial to the control of disease. I’m not an opponent, but the benefits need to be immense.”

At the Institute of Medicine’s hearings in May and August, scientists testified that chimpanzees are no longer necessary for progress in research on many diseases. In HIV, they simply didn’t prove useful; for malaria, better alternatives existed. But the one remaining exception, the ground over which the deciding scientific and ethical battles will be fought, is hepatitis C.

Spread by blood-to-blood contact, hepatitis C is, in the pantheon of mass killers, relatively less known. But a mass killer it is: An estimated 4 million people are infected in the United States, and at least 130 million worldwide. Some 10,000 Americans, and 340,000 more people around the world, die from hepatitis C-induced liver failure each year. No vaccine exists, and until recently there was only one drug of moderate effectiveness.

In developing drugs and vaccines for hepatitis A and B — two similarly-named but unrelated lethal viruses of the liver — chimpanzees were very useful. And even if hepatitis C researchers who use chimps might prefer to work with some other, less-troubling and less-expensive creature, chimpanzees are the only known non-human animal capable of being infected by the virus. They are the only animal model.

“In the U.S. today, there are far more deaths due to the hepatitis C virus than HIV,” said virologist Stanley Lemon of the University of North Carolina. “There’s no dispute about the ethical issues. The question is how you balance the need to recognize that with the potential for direct human benefit.”

According to animal advocates like the Humane Society and the Physicians Committee for Responsible Medicine, whose FOIA requests first revealed Katrina’s transfer, just because they are the only animal model for hepatitis C doesn’t mean chimps are a good one. They note substantial differences in how the virus behaves in chimpanzees, whose immune systems seemingly do a better job of fighting it off and protecting their livers.

Scientists disagree strenuously, pointing to a series of chimpanzee-derived fundamental advances in understanding how hepatitis C attacks cells and replicates. “Chimpanzees are very useful for questions of basic virology,” said Robert Thimme, a University of Freiburg hepatologist who worked with chimpanzee tissue samples in the U.S. before returning to Germany. Alexander Ploss, a Rockefeller University virologist developing mouse alternatives to chimpanzees, called them “the gold standard.” According to Lemon, “the chimp is an excellent model.”

However, the usefulness of chimpanzees for studying molecular mechanisms of the hepatitis C virus, or HCV, leads to another question: Could a time come when we’ve learned enough? If so, it might already have arrived.

“Chimpanzees for many reasons are no more the most important model for HCV infection,” said Hubert Blum, a University of Freiburg hepatologist who has studied hepatitis since the late 1970s. “The possibility to infect cells in culture has revolutionized HCV research, especially in terms of testing antiviral agents.”

A decade ago, studying the life cycle of hepatitis C required tissue samples taken from chimpanzees like Katrina. Now it can be done in lab-grown human cell cultures. This advance, combined with insights already derived from chimpanzees, plus progress in other areas of virology and molecular biology, has fueled a new generation of hepatitis C drugs developed without direct chimp testing.

These include Merck’s Victrelis, which was approved in May by the U.S. Food and Drug Administration and appears twice as effective as traditional hepatitis C treatments, and Vertex Pharmaceuticals’ Incivek, also approved in May. Two more drugs — Pharmasset’s PSI-7977 and Bristol-Myers Squibb’s BMS-790052 — are in late-stage clinical trials.

“The chimpanzee model has been very valuable in leading up to where we are now with drug development,” said Lemon. “But it’s not necessarily on the critical path to discovery now. The need for chimpanzees in antiviral drug development is much less than it was five years ago. You could argue that it’s not there any more.”

'The need for chimpanzees in antiviral drug development is much less than it was five years ago. You could argue that it's not there any more.'

Lemon’s assessment resembled that of Robert Hamatake, director of hepatitis C biology at GlaxoSmithKline, who in August told the Institute of Medicine that chimpanzees were not critical to their work. The company stopped using chimps in 2008.

But while chimpanzees are no longer necessary to develop hepatitis C drugs, vaccines pose a more complex challenge. Vaccine development requires studying a living body’s immune system response. New systems like Sanofi Pasteur’s MIMIC offer an immune-system-in-a-dish alternative, but haven’t yet delivered even an experimental hepatitis C vaccine. Mice engineered to possess human-like immune systems also remain in early stages of development. “For vaccine development, chimps are clearly the best model,” said Blum.

A possible chimp-free vaccine approach would be to test safety in animals and efficacy in humans, but this would pose a different set of ethical challenges, said Lemon. Such studies would also take longer to complete than chimp studies. But Lemon also said continued chimpanzee research is no guarantee of a successful vaccine. And whatever one’s final ethical calculation on chimpanzee research, the existence of new hepatitis C treatments does change the equation. Whether it’s justifiable to inflict suffering on a human-like animal in order to develop vaccines for a treatable disease is a different question than if the disease were untreatable.

“The researchers who do this would love to have everything available and at hand. But they cannot show that there’s no other way of doing it,” said Physicians Committe for Responsible Medicine president John Pippin. “And since these are chimps and not toaster ovens, there needs to be some consideration given to them. I imagine you’re aware of how like us chimpanzees are psychologically. Imagine life in a laboratory for 40 or 50 years.”

“There’s still a need for these animals in vaccine work,” said Lemon. Without using chimpanzees, “I think we’d get there. But it would take us longer. Probably a lot longer.”

Image: Chimpanzee mother and child at the Singapore Zoo. (Shiny Things/Flickr)

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