Bad blood: UW scientists unravel the mysteries of hepatitis C
The gruff circulation manager of the Spokane Spokesman Review was in trouble—Russ Ewan’s heart was failing him, and his doctor told him he had to go through heart surgery.
During his operation in 1983, Ewan had the usual blood transfusions but didn’t think much of it. When he left the hospital, he had a new lease on life. But he had no idea that the transfusions had given him an insidious disease that was lying in wait. He was in the early stages of what would become a chronic infection, one that would not reveal itself until the beginning of the next decade.
Ewan began having problems with his liver several years after his surgery. At that time, newspapers like the Spokesman Review were full of stories of people contracting AIDS through tainted blood transfusions. When he was tested, Ewan found out that the virus he had picked up from the transfusion wasn’t HIV. It was a newly discovered virus called hepatitis C.
Ewan is one of thousands of Americans who unknowingly contracted this mysterious virus from tainted blood in the 1970s and ‘80s, only to have it hang around for many years before showing its deadly potential. Country music star Naomi Judd is one hepatitis C carrier who was diagnosed in 1990, after being stuck with an infected hypodermic needle during her previous career as a nurse. Baywatch’s Pamela Anderson and Aerosmith’s Steven Tyler have announced that they, too, carry hepatitis C.
For many years, scientists and physicians have known about hepatitis A, which is spread through human feces, and hepatitis B, which is spread through bodily fluids via sexual intercourse, drug use and other contact. Both were prolific diseases, but they have since been reined in with protective vaccines and effective treatments.
“It’s a silent disease, in some ways — at least 50 percent of people in the United States with the chronic infection don’t know they have it.”
David Gretch, medical scientist
Hepatitis C, however, is a mystery disease. It was identified in the late 1980s, and it wasn’t until 1992 that scientists developed an adequate screening test. Since then, all donated blood and organs are screened for the hepatitis C virus.
In the U.S., about 12,000 people die every year from hepatitis C-related liver failure, making it a significant cause of death among the general population and the leading killer of people with HIV/AIDS. An estimated 3 million Americans, perhaps more, are carrying hepatitis C. It is even more prevalent in other countries, especially in Africa, Southeast Asia, and the western Pacific—about 170 million people around the world are chronically infected with hepatitis C.
The UW is a leader not only in treating the disease through drug therapies and liver transplantation, but also in unraveling the mysteries of how the virus affects the body.
Hepatitis C is very difficult to spot during the initial infection. People may have flu-like symptoms, nausea, back pain or fatigue, but most people who are infected have no symptoms at all. In fact, less than half will even develop jaundice, the yellowish skin tint that can indicate liver problems.
Naomi Judd, Pamela Anderson and Steven Tyler are among the celebrities who have said they carry hepatitis C.
“That’s why they often don’t know that they are carrying the virus,” says General Internal Medicine Professor Anne Larson, director of the Hepatology Clinic at UW Medical Center.
“It can take 20 to 25 years for patients to get cirrhosis,” says Laboratory Medicine Professor David Gretch, a medical scientist who studies hepatitis C. “It’s a silent disease, in some ways—at least 50 percent of people in the United States with the chronic infection don’t know they have it.”
In the 1960s and ’70s, up to 30 percent of people receiving blood transfusions mysteriously grew ill, suffering from liver inflammation—also known as hepatitis. Harvey J. Alter, a researcher at the National Institutes of Health, studied samples from the nation’s blood supply for years before finally determining an infection was responsible. Initially known as non-A/non-B hepatitis, the virus was eventually isolated and dubbed hepatitis C.
Before donated blood was screened for hepatitis C, it was probably quite common in the blood supply. Unfortunately, drug users donated blood at plasma centers in exchange for a quick buck. They were much more likely to carry the unknown virus, which – like HIV – can be passed through sharing of dirty hypodermic needles. Scientists estimate that during the 1970s and ’80s, as many as one in 10 units of blood was infected with the virus.
Some people who are exposed to hepatitis C virus don’t actually get infected, and of those who are infected, about 20 percent wind up beating the virus on their own during this so-called “acute” stage. The rest, about 55 to 85 percent, have the “chronic” form of the virus, which can hang around for years without causing any conspicuous signs of infection. They may have fatigue, or rare nausea, or other vague symptoms that don’t point to a particular cause. If they’re engaging in risky behavior, such as IV drug use, they may unknowingly pass the virus on to others, like someone who doesn’t know they’re HIV-positive having unprotected sex or sharing dirty needles.
“Many are diagnosed based on routine blood screening and are very surprised to know they’re infected,” Larson explains. “Some people are diagnosed because they reported to their doctor a history of risk factors—like transfusions before 1992, or IV drug use—or they were incidentally noted to have abnormal liver enzymes on routine lab tests.”
Some people may not realize they have the virus at all, and could carry it their entire lives without knowing. Of the estimated three million people in the United States with chronic hepatitis C infection, between 20 and 40 percent will eventually develop cirrhosis or scarring of the liver.
Medical experts believe that in the next decade, the burden of the disease on society will grow as more and more longtime carriers of the virus begin developing cirrhosis and liver disease. But hepatitis C is not a death warrant. The disease is treatable, at least for most patients. The early-stage acute infection can be cured in most people, if it’s caught then. But even in patients with the chronic infection, such as Naomi Judd, there are treatment options that can eliminate the virus from their bodies entirely.
The artificial version of interferon, a compound made by the body to fight infection, can help hepatitis C patients by improving the body’s immune response against the virus. Since the virus makes billions and billions of copies of itself every few hours—a discovery made by Gretch and his UW colleagues—researchers have developed a time-release interferon treatment to deal with this rapid regeneration.
Now, most chronic hepatitis C patients receive a combination of interferon and ribavirin, a drug that interferes with virus reproduction. The combination therapy can cure many patients of the virus, depending on the type of hepatitis C they’re carrying.
Unfortunately, only about half of the patients with one strain of the virus will respond to the combination therapy. The others will continue to carry the virus, and some may eventually develop liver cirrhosis and end-stage liver disease.
The only known treatment at that point is a difficult yet potentially lifesaving one for patients: a liver transplant. UWMC is a regional center for liver transplants, and is one of only two such hospitals in the northwestern United States. UW doctors performed 124 liver transplants last year, and could have performed many more if there were more liver donors. About two thousand Americans die each year while waiting for a liver transplant.
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Now that physicians have followed hepatitis C patients for decades, they have gained a good understanding of how the chronic disease affects people. But the virus itself remains mysterious in many ways.
“We know a lot about the disease itself—its symptoms, how it progresses and those sorts of things,” says Pathology Chair Nelson Fausto. “What we do not know are the real mechanisms through which the virus affects the liver and the immune system.”
Gretch and his colleagues are studying why the virus seems to act differently in different patients—those who get advanced liver disease, for instance, compared to those who carry the infection for years without major liver problems.
In all chronic hepatitis C patients, the virus mutates very rapidly to adapt to the host’s immune system. But one out of every five people eventually reaches a point where their immune system stops affecting the virus at all. Like an escaping criminal fleeing from the law, the virus changes its disguise over and over again until it blends in perfectly and stays hidden from the immune system. The virus then quits mutating and becomes a “major variant.”
“At that point, the virus has adapted to become the best variant for that particular host,” Gretch explains. “In that 20 percent of cases, it goes bad for the host.”
Learning how the virus adapts to the point where it drops off the radar of the immune system may help scientists determine how to disrupt that process, and perhaps delay or even prevent the onset of advanced liver disease.
Scientists have not yet created a vaccine for hepatitis C, though recent findings by UW researchers may help pave the way for one.
One significant difference between hepatitis C virus and its relatives is the lack of a vaccine—both hepatitis A and B can be prevented by protective vaccines. In fact, it was UW Geneticist Ben Hall who created a method in which yeast cells could be used as tiny biochemical “factories” for the replication of hepatitis B vaccine.
Scientists have not yet created a vaccine for hepatitis C, though recent findings by UW researchers may help pave the way for one. Fausto and his UW colleagues recently created a method for culturing hepatitis C virus in a research-friendly environment—human liver cells, known as hepatocytes. Previous studies have relied on special strains of the virus that can grow in cell culture systems, but could not replicate for long periods of time or produce more virus.
Putting the virus in the old culture system was like putting the seed of a plant in a tiny puddle or piece of soil—it might sprout, but could only grow so far. The new method is more like a pot filled with soil—the seed can keep growing into a fledgling plant. In this case, the virus can keep replicating for months at a time in human liver cells, a venue that is very close to the setting for the real infection.
“We maintained it for three months, which is very helpful when studying chronic infections,” says Jean Campbell, an instructor in pathology and a scientist in Fausto’s lab. “This setting is so much closer to your liver or my liver, that you can now start asking questions about the progression of the virus in a patient. Before you couldn’t even really ask those questions.”
The virus culture system should make significant improvements in the study of hepatitis C virus, Fausto says. He and Campbell are optimistic that this step could one day help lead to the creation of a vaccine, or perhaps the creation of other, better treatments. Similar advancements in HIV research have led to a few promising candidates for a vaccine against that virus.
“HIV vaccines got such a foothold when Robert Gallo developed a culture system for that virus,” Campbell explains. “This set up a huge response in the pharmaceutical industry.”
Culturing the virus in human liver cells may also help researchers figure out why the combination therapy of interferon and ribavirin only works with certain strains of hepatitis C, and why people with other strains don’t respond as well or at all to that treatment.
Another option would be to create a therapeutic vaccine—a type of vaccine that would be given to people who are already infected—in the hope of eliminating the virus from their body or diminishing its effects. One possible approach for a therapeutic vaccine would be to begin attacking a portion of the virus that doesn’t adapt or mutate well.
“By studying the genetic sequence of the virus, we can learn where it doesn’t like to mutate,” says Gretch. “If we can get the immune system to attack that area, then it may get rid of the virus.”
In the meantime, much research on hepatitis C virus is aimed at increasing the survival rate of the chronic infection and its companion condition, liver disease. Gretch is taking part in a study called HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis), which is studying whether low-dose interferon can help stave off liver cirrhosis in patients with advanced disease who haven’t responded to other treatments.
Now, such patients who progress to full cirrhosis are left with essentially one option: the chance of a liver transplant. Researchers hope that low-dose interferon can help stave off cirrhosis, even in patients who previously received full interferon treatment but weren’t able to clear the infection.
Projects like this at the UW and other institutions could make a significant impact on a global disease. But hepatitis C carries a bad reputation. Though some who contracted the virus in the United States during the 1970s, ’80s and ’90s were unfortunate victims of infected organs or blood transfusions, others got it through sharing needles during intravenous drug use. The sharing of dirty needles has become the biggest source of hepatitis C transmission around the world, as well.
Supporting research on drug addiction-related diseases can be a political hot-button. Consequently, some researchers have had difficulty receiving funding for their hepatitis C work. Fausto and his colleagues, for example, have no further resources to continue their work on the virus culture system. Though the field of hepatitis C research has done well in recent years, trying to fight or eliminate this deadly virus can be a hard sell in the politicized world of biomedical research funding.
How the UW helped defeat hepatitis B
For many years, hepatitis B was one of the most prevalent infectious diseases in the United States, attacking about a quarter-million people each year in the 1980s. The virus is transmitted through the blood, and can be spread through risky behavior like unprotected sex or the sharing of dirty needles, or can be passed from mother to child during birth.
Like today’s outbreak of hepatitis C, the hepatitis B virus spread relatively easily, and treatment options were not always successful. The virus harms people through either an acute or chronic infection, in each case striking the liver. As the virus spread here in the United States and around the world, a protective vaccine seemed the best bet for stopping the disease.
However, scientists had been relying on the blood of infected people to create a vaccine for hepatitis B. This led to concerns that it might contain new strains of the virus that slipped past purification methods, and could inadvertently infect the people who were being vaccinated. Scientists also needed far more blood plasma than was available to create enough vaccines for people at risk.
Meanwhile, at the University of Washington, geneticist Ben Hall and post-doc Gustav Ammerer were studying a seemingly unrelated topic: how yeast cells used genetic information to perform basic processes. Hall and his colleagues and a company called Genentech discovered a way to insert genetic information for a human protein into the yeast cell, and get the yeast to produce that protein (see “Rising to the Occasion,” March 1994).
The groundbreaking achievement allowed scientists to turn yeast cells into miniature biochemical factories, churning out copy after copy of human proteins like interferon and insulin.
Hall and his colleagues then used the method to get yeast cells to produce something called a surface antigen for hepatitis B. This superficial coating on the cell makes the human body think it is encountering the hepatitis B virus, so it mounts an immune response to the cells, which are actually harmless. This response then vaccinates the body from future hepatitis B infections.
Hall’s work has led to many other biomedical advances, but has already made a huge impact on hepatitis B. New infections in the U.S. have dropped from about 250,000 per year in the 1980s to only about 60,000 per year today. The UW has received more than $87 million in royalties since 1990 as millions of lives around the world have been saved through the prevention of new infections.