Oct. 2, 1998 University of Illinois at Chicago researchers report in the Oct. 2 issue of Science magazine that increasing the amount of drug therapy early in the treatment of patients having the hepatitis C virus dramatically reduces production of the virus and strongly suggests that a new, more effective treatment strategy may readily be available.
Chronic infection with the hepatitis C virus affects 2 to 15 percent of the world's population and four million people in the United States. Standard treatment with the drug interferon eradicates the virus in just 10 to 30 percent of cases. Twenty to 30 percent of infected people may develop cirrhosis and 1 to 3 percent may develop liver cancer in 20 to 30 years' time. Hepatitis C is the leading cause for liver transplantation in this country.
The UIC researchers uncovered how interferon works against the hepatitis C virus using a mathematical model that enabled them to track the activity of the virus and predict which patients can most successfully be treated with the drug. They collaborated with scientists from Israel's Bar-Ilan University, the University of Washington, Seattle and Los Alamos National Laboratory in New Mexico.
Their research shows that the virus has a very high production rate (much higher than that of HIV and the hepatitis B virus) and that interferon works, in part, by halting production of the virus, said Nancy Lam, assistant professor of pharmacy practice in UIC's College of Pharmacy and co-lead author of the Science paper. Earlier studies had suggested that the drug works by preventing the virus from infecting cells.
These findings are likely to change the way doctors treat patients with this sometimes deadly virus.
"The current recommended treatment for hepatitis C virus has not been very effective," Lam said. "We now question the amount of interferon commonly prescribed and the timing of those dosages."
The standard approach to treating hepatitis C is to prescribe 3 million units of interferon three times a week. The UIC researchers used higher daily doses of 5, 10 and 15 million units in their study of 23 patients and found the 10- and 15-million-unit doses to be most effective over a two-week period.
During the first 24 to 48 hours of interferon treatment, the researchers observed a rapid dose-related decline in the viral load. In the following 12 days of treatment, the researchers noted a much slower viral decline. It is during this slower phase of decline that infected liver cells die.
"You want to treat the patients hard with drug therapy in the beginning and shut down production of the virus," said Dr. Thomas Layden, chief of digestive and liver diseases in UIC's department of medicine and a senior author of the Science paper. "This way you prevent drug-resistant mutations from developing. Then you prolong therapy while the cells already infected with the virus die."
The researchers also found it took from 1.7 to 70 days for infected cells to die. They observed that patients with high initial viral loads experienced slower cell death rates than patients with low baseline viral loads. They postulate that there may be a correlation between high cell death rates and immune response.
The researchers conclude that high cell death rates following the initial rapid decline in viral load may predict continued clearance of the hepatitis C virus after three months of interferon treatment. This finding suggests that it may not be cost-effective to continue interferon treatment in those patients who, after two weeks, exhibit low cell death rates. The standard approach to treating hepatitis C is to use interferon therapy for a year. The cost of year-long treatment, which requires, among other things, blood tests, doctor visits and liver biopsies, is $5,000 to $12,000 per patient.
The researchers say that studies with larger numbers of patients are needed to understand the impact of early anti-viral activity. Their next step will be to study immune function in people with the hepatitis C virus. The researchers expect to find that treating the virus with combination drug therapy, similar to that used against HIV, will be the most effective approach.
The UIC Medical Center, which uses combination drug therapy and other treatment approaches in its full-service liver clinic, is the leading center in the use of mathematical modeling to understand the dynamics of the hepatitis C virus. Since there are no hepatitis C virus cell cultures available for study in animals, mathematical modeling is among the most useful tools for understanding the virus.
The new Science study and previously published research by the team is enabling the UIC Medical Center to proactively design new, more effective therapies and has changed the way the medical community thinks about the virus, Layden said.
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