A small but potent research team at Georgetown University Medical Center (GUMC) is working on behalf of about one-tenth of the world’s population.
Four researchers in the Department of Microbiology and Immunology are key to efforts by drug developers in the U.S. and internationally to prevent or treat three viruses that sound like cousins, but which are not —hepatitis B, C, and D.
These viruses are distinct, but all are spread by blood and bodily fluids to infect and chronically inflame the liver — hence the label “hepatitis” — in as many as 700 million people around the world.
Even though hepatitis B (HBV) can be effectively prevented with a vaccine, it still infects roughly one out of every three people, most of whom clear the virus. But about a half billion people develop a long-lasting infection that significantly increases the risk of serious liver disease. Hepatitis C virus (HCV) is less prevalent around the world (infecting about 170 million people) but is difficult to treat and impossible, at this point, to prevent. Hepatitis D virus (HDV), the smallest known virus to infect humans, is relatively rare but it combines with hepatitis B to accelerate the progress towards liver disease.
These infections are so prevalent and dangerous — killing about 600,000 individuals each year — that the World Health Organization named July 28 as World Hepatitis Day. Their 2011 theme is: “This is Hepatitis…Know it. Confront it. Hepatitis affects everyone, everywhere.”
About 4.4 million Americans are living with chronic hepatitis, though most don’t know they are infected. But if left untreated, hepatitis damages the liver from an unceasing immune response, leading to liver cirrhosis (scarring) and liver cancer. HCV and HBV are responsible for most liver transplants in the U.S.
Which is why the work of these GUMC researchers is, and has been, so vital.
“We are a little hot bed of hepatitis research, a ground zero for testing potential treatments,” says research professorBrent Korba, PhD, a molecular virologist.
“The hepatitis virus research efforts at GUMC covers a very wide path — basic biology studies, preclinical drug discovery/evaluations, and the epidemiology,” he says.
Much of the work the researchers do is funded by the National Institutes of Health (NIH) through competing contract mechanisms. The NIH funds Korba to evaluate candidate anti-HCV and HBV agents in laboratory cultures —one of only three groups in the U.S. that do so. Paul Cote, PhD, a research professor, and Stephan Menne, PhD, a research associate professor, are the only researchers that the NIH supports to test HBV therapies in a “boutique” animal model – the woodchuck, also known as the groundhog. And John Casey, PhD, an associate professor and program director of Global Infectious Diseases, is the only researcher in the United States to be funded by the NIH to study HDV.
Between them, they have published 178 studies to date.
Their efforts continue a long and significant history of hepatitis research at GUMC. It began in 1988 with John Gerin, PhD, a world-renowned virologist and one of the earliest scientists to delve into HBV. At one point, before he retired in 2004, he worked with almost 70 scientists and assistants, including Korba, Casey and Cote. He further collaborated on woodchuck-related research with a group at Cornell University led by Bud Tennant, DVM, that had included Menne.
The issues the researchers deal with are unique because the viruses are so different from each other.
HCV, a virus in the family that includes Dengue Fever and West Nile pathogens, is the most common hepatitis virus in the U.S. But it cannot be prevented with a vaccine and is difficult to treat. Two decades ago, there was only one drug to treat the infection and a decade ago, a combination therapy came into use, curing less than 40 percent of patients.
But just this year, two new drugs were approved for use with the existing HCV therapy, and there are almost 40 candidate agents in more than 90 clinical trials, several of which have been tested in Korba’s GUMC lab. “We are at the first stage of drug development, the discovery of activity,” he says. Korba’s laboratory also tested most of the licensed anti-HBV drugs at their earliest stages. Since 1990, Korba and his team have been evaluating potential agents sent to them from all over the world, screening them for activity and mechanisms of action. If they pass muster, they will probably be tested in humans since there are no effective animal models for HCV. “Cultures have been very predictive of antiviral benefits,” he says.
“This is a very exciting time in hepatitis C drug development,” Korba says.
Even though hepatitis B can be effectively prevented with a vaccine, it still infects a half billion humans (of which about 2 million live in the U.S.), and the lifelong risk of developing liver disease from the virus is between 30-50 percent.
In contrast to HCV, HBV has an effective vaccine, but chronic infection is an issue, primarily due to neonatal transmission, says Cote. “More than seventy percent of babies who pick up the infection at birth can develop lifelong chronic infections,” he says. “Adults who become infected through other routes rarely develop a chronic condition.”
The drugs currently in use to treat chronic HBV infection are suboptimal for curing the infection, but can generally keep the infection under control if used over the lifetime of a patient.
Cote and Menne test potential HBV therapies, and study the basic pathogenesis of the virus, using the woodchuck, the only animal model that develops hepatitis B and liver cancer that is very similar to human HBV infection. Theirs is the only facility in the U.S. with this expertise that is currently funded by the federal government. New therapies are being tested that not only target the virus itself, but which also modulate the host immunological responses to effect a therapeutic recovery that more closely mimics a cure.
The investigators themselves have shown that a combination of antiviral drugs plus vaccine that modulates the immune response is very successful in “promoting a recovery, and even prevents liver cancer in woodchucks,” Menne says.
“We are very optimistic,” agrees Cote.
Casey researches HDV, or “delta,” the rarest of the hepatitis viruses, which is also one of the most dangerous and difficult to overcome.
This RNA virus, the smallest virus known to infect humans, piggybacks on top of HBV infection. “It is an incomplete virus that requires the helper function of HBV to replicate, so it occurs only among people infected with HBV,” says Casey.
About 5 percent of people infected with HBV are also infected with HDV— about 15 million people worldwide, including 75,000 in the U.S. — and no therapy is available to treat them, he says.
Casey’s work is basic, and he and his colleagues have come up with what they say is a “blueprint” for eradication of HDV in humans. “We want to use agents that reduce surface protein levels that HDV needs to survive,” he says. The approach was successful in a small study in woodchucks but the particular combination of drugs they tested was too toxic for human use. Still, there are other agents to test. “We have a way forward.”
As important as that is, Casey says it is the viruses themselves that intrigue him —a view shared by Korba, Cote, and Menne. “What really floats my boat is how interesting these viruses are,” Casey says. “All the hepatitis virus are fascinating, but delta is really unique. It is tiny, just a piece of nucleic acid that infects people and causes a very serious illness.”
By Renee Twombly, GUMC Communications