Hepatitis C Information Central

Managing HCV in Nonresponders to Interferon Including Patients With Normal ALT Levels

BRUCE R. BACON, MD:

Thank you, Gene and Will, and for those of you who came tonight. Well, Ira said that the patients who responded and relapsed were a thorn in the side. I've said before at meetings like this that nonresponders are job security for hepatologists. And it has been really a frustrating problem for us to have so many patients that wouldn't respond to monotherapy. The relapsers gave us a little hint that maybe there was something that we were doing right, and then when combination therapy came around, I think we were all satisfied that patients who were re-treated did very well and frequently had a sustained response. But the nonresponders have been...continue...have continued to be fairly difficult to manage.

Now, what I'm going to do in the small amount of time allotted is just go over the results of work that we've done at St. Louis University. We...as many of you know, there have been a number of investigator-initiated protocols and trials done around the United States. And we set one up where we would re-treat interferon monotherapy nonresponders and relapsers for either 24 weeks of 48 weeks with combination therapy followed by a six-month follow-up. And I'm just going to show you tonight the nonresponder data, and this is still...this study is not completely finished yet, so this is an interim analysis as of a few months ago.

There were a total of 124 nonresponders. And our definition of a nonresponder here is someone who received standard doses of any of the alpha interferons for a minimum of 3 months and were still HCV RNA positive at the end of that 3-month period of time. As Gene has said, I...we did have patients who had normal ALT's and I've been a believer in treating liver disease not ALT levels over the years. And so we had a number of patients that had normal ALT's who have been in this...who were available for this study.

So there are 124 nonresponders, 64 percent men, mean age 44 1/2 years, with a range of 23 to 67 years. They were all RNA positive. Eighty percent of them had elevated ALT's so...or 19 percent with normal ALT's. And as would be expected in a nonresponder group of patients, a little bit more than the usual frequency of genotype 1 patients, so 81 percent were genotype 1, as opposed to the general population of the U.S., which is about 70 percent. And 27 of those had cirrhosis, or 22 percent.

Now, this is a little bit tedious to follow through, but I'll walk you through it. You see that the denominator changes, and that's because people were enrolled over time, and we looked at the analysis at a particular time. And this is what we have looked at. And the only number we're...the only parameter that we're really looking at here is negative HCV RNA by the NGI assay. So at treatment week 12, 122 patients...whether they had been treated for 24...started to be randomized in the 24-week treatment or the 48-week treatment group. At treatment week 12, 41 percent of patients were RNA negative. At treatment week 24, 46 percent were RNA negative. And this would follow through with what John had said about when to stop treatment. You get a few more if you treat patients for a little while longer with combination therapy. And 44 percent by end of treatment, whether it was for 24 weeks or for 48 weeks, were HCV RNA negative.

Now, the important time to really look and see how these patients are doing is in their follow-up, obviously. And at 12 weeks' follow-up, 31 percent were RNA negative, so several patients had relapsed. A few more relapsed when they were followed out for 24 weeks. But at 24 weeks of follow-up, 18 of 70 patients that had completed by this time period were still RNA negative for 26 percent sustained response rate...sustained virologic response. And this is all in previous monotherapy nonresponders.

Now, what difference does it make whether it's 24 weeks of treatment or 48 weeks of treatment? As you can see here...and if you just focus on the right hand side, which I think is the most important set of data, the 24-week follow-up data...there really isn't much difference for this group of patients so far between 24 or 48 weeks. The sustained response rate is about the same.

Well, genotype, as we've heard, makes a big difference, and this is again illustrated in our group, such that if we look at the 24-week follow-up data, non-1 genotype is 57 percent. But importantly, genotype 1 is about 18 percent, so if we take our genotype 1 patients that had previously not responded, we can get about a 20 percent sustained response rate with retreatment.

And finally, the business about normal or elevated ALT's. As you can see, at all points, whether it's at the end of treatment sustained response rate...sustained virologic response rate, at the 12-week follow-up or at the 24-week follow-up, there's no difference between whether or not patients had a normal ALT going into this or an elevated ALT.

So in conclusion, we're of the opinion that the combination of interferon and ribavirin may induce a sustained response in previous nonresponders to interferon monotherapy in at least 25 percent of patients. And we've now looked at a few more months of therapy, and this has actually gotten a little bit better as we follow patients...as we have more patients completing, and it's up to around 30 percent. And the same different-...the same issues are there relative to normal ALT or non-ALT, whether they have cirrhosis or not and the genotype differences. Those differences have remained the same. And of those with the sustained response at 24 weeks, many had a predictor of poor response. We shouldn't exclude cirrhotics from treatment because 28 percent of them...28 percent of the sustained responders were cirrhotics. Fifty-six percent were genotype 1, and several of them had high HCV RNA levels. But it seems to not make too much difference between 24 and 48 weeks of treatment. And I want to wait until the whole study is completely finished before we make too much of a conclusion about the 24 or 48 weeks. Thank you.