Hepatitis C Information Central

Introduction: Evolution of Therapy for Chronic Hepatitis C
Dr. John G. McHutchison, M.D.

JOHN G. McHUTCHISON, MD: Thank you, Dr. Schiff, Dr. Maddrey, everybody here this evening. It's my pleasure to briefly outline some of the important clinical facts related to the treatment of hepatitis C, particularly the initial treatment of the patient with chronic hepatitis C.

Now, what I've done here this evening is taken the liberty of combining the results of the two large, randomized controlled trials that were both reported last year, as Dr. Schiff has mentioned, and the other paper from an international trial by Thierry Poynard and other authors that was also published late last year. Now, all together treatment involved 1744 patients. As you can see there, those patients were randomized and enrolled to these trials. And this is really the key slide because it shows you four different groups of patients who were involved in these trials...we treated people with either interferon alone for six months or for 12 months or 48 weeks interferon alone, or we compared those response rates to interferon plus ribavirin, for either 24 weeks, as shown by the green bar, or 48 weeks, as shown by the purple bar. And what I've shown you here are sustained virologic response rates; that is, patients who cleared the virus six months after the end of therapy, or 24 weeks after the end of therapy. And as you can see, there's a step-wise progression or increase in the number of people who had a sustained response. The differences between the green bar and the purple bar are actually significant so more people were more likely statistically to respond to the combination of the two drugs to 48 weeks, and the difference between the green or the purple bar and either of the interferon bars is also significant. So you can see that the addition of ribavirin enhances the sustained response rate significantly.

Now, I must tell you that these figures or these percentages, as you can see here...40 percent and 33 percent for the two durations of combination therapy, include all the patients who didn't complete the study. That is, they dropped out because of the side effects, or there was some other reason they couldn't complete the study. And they were included as nonresponders on an intention-to-treat basis.

Now, in addition to these sustained virologic response rates, ribavirin, when you add it to interferon, does something else. And in that bottom box I've put on this slide, I've shown you the end treatment response rate; that is, the number of patients who managed to clear the virus by the end of the 24- or the 48-week treatment period. And as you can also see, the addition of ribavirin for either duration significantly enhances the response rate at the end of treatment. So, it appears that when you're putting interferon with ribavirin, two things happen: You initially increase the number of people who can eradicate or clear the virus when you use sensitive assays during or at the end of treatment, and subsequently you prevent relapse.

Now, the other end points of these studies...and again, I've shown combined results for the two studies...was a histologic improvement. And in all of these studies, we talk about histologic improvement in terms of improvement in the Knodell Inflammatory Index of greater than two points. And as you can see here, again, for the four groups of patients, the number of patients who had significant improvement in their liver biopsies was significantly higher for the combination therapy than it was for the interferon for either duration. In addition, the mean change, or the mean decrease or improvement in the Knodell Inflammatory score showed a step-wise progression so that the most improvement was seen in the individuals who received the combination of the two drugs for 48 weeks. But that is really a function of the larger number of virologic responders in these groups of patients. So as you can see, in the bottom line of figures in this chart, if you just look at patients who had a sustained response, indicated by SR there, you'll see that there's a significant and similar improvement in inflammation on the liver biopsy where the patients received interferon alone or interferon plus ribavirin, as you'd expect.

Now, I don't have time to go into all the subgroup analyses tonight, but as Dr. Schiff mentioned earlier, patients with genotype 1 are the most difficult patients to treat, or one of the most difficult groups to treat. And you can again see here for the four treatment groups in both of these studies, combined results, that there was a step-wise incremental increase in the number of patients who responded to combination therapy with genotype 1 infection. Twenty-nine percent for 48 weeks of the combination is shown by the purple bar; 17 percent the green bar for the combination of the two drugs for 24 weeks. Those differences were statistically significant, and a dismal two and nine percent for interferon alone. So it would appear on the basis of these results, being different, really different and statistically different, that patients with genotype 1 infection really benefit most from 48 weeks of the combination of interferon plus ribavirin.

Now, by comparison, patients with genotype 2 or 3 infection responded somewhat differently. And again, as you can see here by the green and the purple bars, the percentage of the patients who had a sustained virologic response was very similar and much much better; two-thirds of these patients actually had sustained viral eradication at the end of the 24-week follow-up, much better than either duration of interferon alone. So on the basis of the results for the patients with genotype 2 or 3 infection compared to genotype 1, it would make sense perhaps logically to determine the duration of interferon plus ribavirin therapy based on the presence of the patients being genotype 1 or not being genotype 1.

Now although it's not shown in this slide, genotype 1A and 1B patients responded similarly, and genotype 3 patients responded a little bit better, percentage-wise, than genotype 2 patients. We also did analyses, although I don't have time to show them tonight, of viral load being high or low, the presence of significant fibrosis or no significant fibrosis, and by stepwise logistic regression analysis in both of these studies, there were certain factors that were associated with greater efficacy: genotype non-1 infection, 2 or 3, predominantly; low viral load, no fibrosis on the liver biopsy; being young, less than 40 years of age; and being female.

Now, one of the things we used to do with interferon therapy was stop at 12 weeks' duration because patients had very little chance of responding if they were still PCR-positive at week 12 of therapy. That does not hold true for the combination of interferon plus ribavirin. And this slide needs a little bit of work because it's back to front, but basically if you just look at the colored portions of the pie charts...and you'll see here this is for interferon and ribavirin for 24 weeks or for 48 weeks...you'll see if you look at the people who were PCR-positive at week 12, there were four percent in this group that received the two drugs for 24 weeks, and there were 10 percent that would have gone on to have a sustained virologic response. So if we had stopped therapy...combination therapy on the basis of a positive PCR at week 12, we would have denied these 14 percent of patients the chance of a sustained virologic response and all its potential benefits.

By comparison, with combination therapy, if we measured serum HCV RNA by PCR at week 24, the chance of patients having a sustained response, whether they received 24 or 48 weeks of the two drugs, is much lower...two percent, three percent, and two percent...and somewhat more acceptable .

Particular side effects related to ribavirin that we don't...won't go through in great detail tonight, but they include the hemolytic anemia that we've talked about a lot, very manageable, about 10 percent of patients require a dose reduction; about 20 to 25 percent of people have cough and dyspnea that is also seen with other nucleoside analogues. It rarely requires dose reduction. Rash and itch occur in about 20 percent of patients, and rarely require us to interfere with therapy. Insomnia, about 40 percent of patients; anorexia, about 25 percent of patients; and also the teratogenicity that we have discussed and you all know about. So these are the side effects related to interferon...ribavirin particularly.

So in summary, this slide, I think, with the data that I've just presented, shows you some changes in practice for initial treatment of patients with combination therapy. First, I think we should state that it is the most effective initial therapy, obviously. The benefit is by enhancing the end-of-treatment response and subsequently by decreasing relapse to enhance the sustained virologic response. The benefit extends to the difficult or more difficult to treat patients, such as those with genotype 1 infection or fibrosis. I think HCV genotype is now an important clinical tool to help us determine the duration of therapy, as I hope I've shown you. We should measure response by measuring serum HCV RNA at 24 weeks, and obviously, because of the hemolytic anemia, we should monitor hemoglobin. Thank you very much.

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