HCV Rapidly Develops Resistance to Directing-acting Agents, Indicating Need for Multidrug Combos

SUMMARY: The hepatitis C virus (HCV) can rapidly develop mutations that confer resistance to multiple direct-acting agents such as HCV protease and polymerase inhibitors, according to a mathematical model described in the May 5, 2010 edition of Science Translational Medicine. Researchers suggested that effective oral therapy without interferon may require as many as 4 complementary drugs to avoid resistance.

Standard therapy for chronic hepatitis C using pegylated interferon plus ribavirin can cause difficult side effects and only clears the virus about half the time, leading researchers to evaluate a large number of direct-acting oral drugs that target specific steps of the viral lifecycle.

But HCV mutates easily and rapidly as it replicates, which allows for emergence of drug resistance mutations. Recent research indicates that resistance mutations are common, and in order for these agents to have prolonged effectiveness without interferon, some people may require "cocktails" of as many as 4 drugs that work in different ways.

Below is the text of a press release issued by the University of Illinois at Chicago summarizing the modeling study.

Combination of Direct Antivirals May Be Key to Curing Hep C

Chicago -- May 5, 2010 -- A combination of antiviral drugs may be needed to combat the drug resistance that rapidly develops in potentially deadly hepatitis C infections, a new study using sophisticated computer and mathematical modeling has shown.

Using probabilistic and viral dynamic models, researchers at the University of Illinois at Chicago, Oakland University and Los Alamos National Laboratory predict why rapid resistance emerges in hepatitis C virus and show that a combination of drugs that can fight three or more mutated strains may be needed to eradicate the virus from the body. They compared their model with data from a clinical trial of the new direct-acting antiviral medication telaprevir.

The findings are published in Science Translational Medicine.

Hepatitis C is a progressive liver disease that can lead to cirrhosis and liver cancer. Current standard treatment is a combination of the antiviral drugs interferon and ribavirin for a period of 24 to 48 weeks -- a regimen that is long and expensive, carries side effects, and is successful only in about half of patients.

Intensive effort has focused on developing direct antiviral drugs. But the virus is genetically diverse, and so may be particularly prone to develop resistance, said Harel Dahari, research assistant professor of hepatology in the UIC College of Medicine and one of the paper's co-authors.

One way to combat resistance would be to administer multiple drugs, each with a different mechanism of inhibiting the virus.

"We found that rapid emergence of resistance to these types of drugs is due to a population of viruses already present, allowing the resistant virus to become the dominant strain," said Dahari.

The researchers suggest that a combination of new antiviral drugs will be needed to fight all of the resistant virus strains and achieve better cure rates for the disease.

"We are moving to a new era where we can treat these patients with direct-acting agents against the virus, in which we specifically target the life-cycle of the virus," Dahari said.

To replace the standard treatment, four or more different types of direct drugs may be needed, Dahari said. However, some patients may need fewer drugs. It depends on the level of the virus in their blood, among other factors.

It is frustrating for patients to go through a long, difficult treatment and know that they might not be cured, said Dr. Scott Cotler, associate professor of medicine at UIC and a hepatologist who treats patients at the University of Illinois Medical Center's Walter Payton Liver Center.

"Patients are looking forward to a day when they don't have to take interferon and ribavirin," said Cotler. "But as we are learning with this study, if we are going to need four different direct drugs, it is going to be awhile before we get there. Now at least we know where the goal line is."

Dahari suggests that future treatment that includes the standard treatment and direct antivirals, such as telaprevir or boceprevir, will be tailored to each patient and that using direct antivirals may also shorten the duration of treatment.

Investigator affiliations: Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM; Department of Mathematics and Statistics and Center for Biomedical Research, Oakland University, Rochester, MI; Department of Medicine, University of Illinois, Chicago, IL.


6/18/10


Source

University of Illinois at Chicago. HCV Rapidly Develops Resistance to Directing-acting Agents Indicating Need for Multidrug Combos. Press release. May 5, 2010.


References

L Rong, H Dahari, RM Ribeiro, and others. Rapid Emergence of Protease Inhibitor Resistance in Hepatitis C Virus. Science Translational Medicine 2(30): 30ra32 (Abstract). May 5, 2010.

DL Wyles and RT Schooley. Rong's Numbers: Accelerating Progress in HCV Therapeutic Research (Editorial). Science Translational Medicine 2(33):33ps25. May 26, 2010.

http://www.hivandhepatitis.com/hep_c/news/2010/0618_2010_b.html