Zobair M. Younossi, MD


November 12, 2010

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Hello, I'm Zobair Younossi, Executive Director of the Center for Liver Diseases and Vice President of Research at the Inova Health System in Falls Church, Virginia.

Today, I'm at the 2010 American Association for the Study of Liver Diseases (AASLD) meeting in Boston. We're going to discuss some of the new developments, both here and around this meeting, related to hepatitis C.

As you know, the current standard treatment for hepatitis C is to use a combination of pegylated interferon-alpha-2A or 2B and ribavirin. When you use this combination, you will achieve a 50% to 55% sustained virologic response (SVR) rate with sustained viral eradication. In fact, these rates are lower in patients who have genotype I and who receive a full year of treatment, with 40% to 45% of them achieving sustained virologic response.

However, in 2010, we're entering a new era in the treatment of hepatitis C. The recent developments in hepatitis C, including those discussed at this liver meeting, will bring us closer to the practice of personalized medicine for patients with chronic hepatitis C. There are 3 important areas of advancement: first, response-guided therapy for chronic hepatitis C treatment; second, biomarkers for predicting response to treatment of hepatitis C; and third, development of targeted therapy for hepatitis C.

Response-guided therapy. Response-guided therapy really uses HCV [hepatitis C virus] RNA testing during treatment to predict response and guide treatment for patients with chronic hepatitis C. This information can be summarized by documenting that the earlier the HCV RNA becomes negative for these patients during treatment, the higher the chance of achieving SVR or durable response. [In addition], those patients who achieve rapid virologic response, for example, by 4 weeks they are undetectable in terms of HCV RNA, they may need an even shorter course of treatment. In fact, these data seem to be applicable to newer regimens that are being developed for hepatitis C.

Predicting response. The next advance in hepatitis C is the development of biomarkers that are capable of predicting SVR in patients with hepatitis C who are scheduled to be treated with antiviral therapy. Recently, a new genomics biomarker called IL-28B was developed that predicts SVR in genotype I patients who are treated with pegylated interferon and ribavirin. Those patients with HCV genotype I whose IL-28B test shows that they have the "C-C allele" rather than the "T-T allele" will have a much higher chance of achieving SVR. In fact, 70% to 80% of them will achieve SVR vs approximately 20% to 25%. This allele may explain the great deal of heterogeneity that we have been seeing over the past few decades in the treatment of hepatitis C.

Targeted therapy. The third exciting area of advancement in hepatitis C is the development of targeted therapy. Specifically, we have seen data on the new direct-acting antivirus for hepatitis C, also called STAT-C [specifically targeted antiviral treatment for hepatitis C] treatment. These agents are new drugs that will target viral enzymes that are important for replication of hepatitis C and block these enzymes from allowing the hepatitis C virus to replicate.

There are 2 categories of direct antivirals, one category is called protease inhibitors, and the other one is polymerase inhibitors. Protease inhibitors that are furthest along in development are telaprevir and boceprevir. Telaprevir is an inhibitor of NS3/NS4 HCV serine protease. The best efficacy of this agent has been seen when it's used in triple combination regimen, combined with standard of care pegylated interferon and ribavirin, for the first 12 weeks followed by another 12 or 36 weeks of treatment.

Boceprevir is an NS3 serine protease inhibitor. It is most efficacious when it is used in triple combination, also with pegylated interferon and ribavirin. In fact, most of the studies require that this drug be used after a full week lead-in phase of combination standard treatment followed by 44 weeks of triple combination therapy.

When you're looking at the efficacy of these triple combination therapies, they are similar and they are significantly higher than what you see with double combination therapy for patients with genotype I. For patients who have never been treated before, or so-called "naive" patients, the sustained virologic response is somewhere between 70% and 75%. In fact, if you use response-guided therapy, as I mentioned earlier, the response rate is even higher, especially for telaprevir. SVR for nonresponders or treatment-experienced patients is as high as 65%. However, if you categorize patients in terms of whether they will relapse or are nonresponders, meaning they have never responded before, the response rate of these drugs in relapsers is 85% to 90%, and in those who are called nonresponders, about 30% to 35%.

One important difference between these 2 regimens is duration of the combination that is required. With telaprevir, 12 weeks of triple combination is required. With boceprevir, triple combination must be provided for the full course (44 weeks) of treatment.

Of course, by adding new drugs you'll see added side effects, which are anemia for both drugs and rash for telaprevir.

In summary, these exciting data suggest that we have already entered or will shortly enter the new and exciting area of personalized medicine in treatment of hepatitis C patients by using response-guided therapy, IL-28B biomarkers, and once approved, regimens that would include targeted therapy with triple regimens that include protease inhibitors.

Thank you again for joining us. This is Dr. Zobair Younossi for Medscape.


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