Interferon / Ribavirin Combination Therapy In Relapsers
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Ira M. Jacobson, MD
Good evening. I’d like to thank Drs. Schiff and Maddrey for inviting me to speak to you tonight. From the pioneering work led by Gary Davis in the late 1980s establishing the role of interferon, we gleaned what I called in the early days a kind of 50-50 rule. It seemed at that time that half the patients who were treated with interferon monotherapy responded and half relapsed, so we had the hubris to think that we were curing 25 percent of our patients. And we quickly learned with expanding use of interferon the next couple of years that that was an overestimate…it was overly optimistic…and that in almost all of our hands, the true relapse rate was over 70 or 75 percent, leaving me to call the relapse phenomenon the biggest thorn in the side of the clinical hepatologists in those days.
As Dr. Schiff showed in his first slide, we made a little leap forward in the mid-1990s with the recognition that if we took people who were having a good response at the 6-month point and extended therapy for 12 or 18 months, that we diminished the relapse rate somewhat, but we didn’t really achieve rates of sustained response in excess of about 15 percent, even so. We learned that predictors of relapse could be identified…the same sorts of things that predict initial responsiveness, like genotype, viral load, the presence of cirrhosis. There was some tantalizing evidence that hepatic HCV RNA might identify who’s at risk of relapse; that is, if the liver was still PCR positive at the end of treatment, those patients had a higher likelihood of relapse, but that never really came into use because of the logistical barriers to doing serial liver biopsies. And we learned that if you re-treated patients who had taken interferon monotherapy for 6 months and then relapsed, 30 to 60 percent of them had a sustained response if you re-treated them for 12 months after an initial course of 6 months preceding the relapse.
If you look at these studies, they’re very confusing. It’s very difficult to compare them with each other because they’re different sample sizes, different doses of interferon, and different selection criteria, particularly with regard to whether the initial relapse…response and relapse, that is…were defined by ALT normalization alone or RNA negativity at the end of treatment. And this is very important because the RNA status of the patient at the end of the first course of therapy is the biggest determinant of how likely the patient was to respond to interferon monotherapy for a longer period of time. This needs to be kept in mind when you look at the data for the U.S. and international multicenter relapse studies that we’re about to remind you of.
And of course, this study was formulated about 3 or 4 years ago, again led by Gary Davis. And it showed in a nutshell that if you re-treated somebody who’d taken interferon monotherapy and relapsed…and it could have been either one or two courses of monotherapy…that the sustained virologic response rate to a second course of interferon alone for 6 months was a meager five percent, and that there was a tremendous difference if you gave the patient 6 months of interferon and ribavirin, the response rate in those groups being…in that group being about 50 percent. And these compelling data led to the initial FDA approval of interferon and ribavirin for relapse patients back in June 1998, 6 months in advance of FDA approval for treatment-naive patients.
We were able to do the same kind of virologic profiling, kind of like a menu: You can choose a virologic parameter from column A and another one from column B and come up with a much more precise estimate of the likelihood of sustained response to interferon/ribavirin in relapsers than we were ever able to do before, and we’ve seen that repeated, of course, in the treatment-naive studies. We learned that if you re-treated a relapser who was genotype 1 with a high viral load, the sustained response rate was 25 percent…low, but much better than if you gave interferon along, of course; genotype 1 low viral load defined as 2 million or less on the NGI assay. The sustained response rate improved to 40 percent-Non-genotype 1, mostly genotypes 2 or 3 because of the demographics of the virus in the population study with a high viral load, 65 percent; and an impressive 100 percent sustained response rate in the 20 patients in the study who were genotype non-1 with a low viral load. And so here we saw really for the first time so impressively that the genotype was even more important than the viral load as a predictor of sustained response.
There were some features that I call notable features in that multicenter relapse study. The definition of relapse was based on ALT because when we gathered these patients, most of them had been treated before 1995 or ’96, when commercial PCRs weren’t really available. And this gets back to the point I made before: Some of these patients…all of these patients had had an initial response and then relapse defined by ALT, but we can reliably predict, based on historic data, that up to a quarter of these patients never cleared virus and so they were destined from the outset to have a much lower likelihood of response to repeat therapy with interferon/ribavirin, if you believe all the old data, than the patients who had truly cleared virus.
The problem was there were no retrospective stored sera in these patients, and we’ve never been able to go back and prove this point. But because of this point, we believe that this study probably underestimated the true rate of sustained response to combination therapy in relapsers if the relapsers had been confined to those who had initially cleared RNA. And my own bias here is that the sustained virologic response rate in these patients would have been 60 to 70 percent if only those with an initial virologic response with their 6 months or 12 months of interferon monotherapy had been included in the study.
Also of note in this study is that the type dose and duration of initial interferon therapy did not influence the response to combination therapy. And I’ve always found the point about duration very interesting because I would have thought that somebody who’d relapsed following an initial 12 months of therapy rather than 6 months would have a lower chance of response to therapy. But it may be that ribavirin helps eliminate that difference.
There was a large U.S. investigators meeting…that is, people around the country using interferon/ribavirin…that convened in California in February 1999, and there were lots of intra-treatment response data, but very little data on sustained response. The treatment response rates ranged from 40 to 100 percent, but most of them were at the upper end of this range. There were a large number of studies on induction therapy, and I should add that there were studies on induction therapy in naive patients and nonresponders, as well as relapsers. In the relapsers, as well as in the other populations, there was always a trend toward a higher initial response rate with induction therapy, but there were really no data available yet on whether that…whether induction therapy induces higher rates of sustained remission later on. I think we’ll learn that in the next 6 to 12 months.
There was little difference in the abstracts presented at that meeting between 3 and 5 million units t.i.w. There was much more interest in the potential promise for induction therapy, though that remains to be proven. And most importantly perhaps from a practical viewpoint, the efficacy of 12 versus 6 months of combination therapy was still unproven in the relapser population.
So there are lots of unresolved issues. Firstly, would treatment for over 6 months be better for some patients? Well, we don’t know from any randomized trials because the national…the international studies that we just reviewed were confined to 6 months of re-treatment. But I strongly consider in my practice 12 months of therapy in relapsers with genotype 1, high viral loads, and/or advanced fibrosis or cirrhosis.
From a practical point of view, there are patients in whom you might consider induction therapy at the present time, and I do in fact consider it in patients who have advance liver disease and genotype 1 with high viral loads. Is there a role for PEGylated interferon? We have no data yet. As you all know, trials have just been initiated looking at PEG plus ribavirin for treatment-naive patients, and we’re all excited about the prospect of extending these studies to the relapser and the nonresponder populations in the near future.
And finally from the scientific viewpoint, I’m sure many of you who wonder in your offices as I have why some relapsers fail to respond to re-treatment. And I think here we need the molecular virologist to help us out. Has a change occurred in terms of endogenous host response? Is it a change in the quasispecies (?) profile of the patient? We really don’t know what the mechanisms of viral persistence are in these patients.
And I’ve talked about relapse after interferon monotherapy, but I think increasingly, even in the next few months…for those of us who started using interferon/ribavirin in treatment-naive patients within the past year, the typical relapser in our practice is not going to be a relapser after interferon monotherapy but a relapser after combination therapy.
And so I’m going to close with some thoughts about what to do with these patients. First, as Dr. McHutchison showed us, relapse is more likely with 6 versus 12 months of initial combo therapy in patients with genotype 1 and a high viral load. And I think all of us would now extend such therapy to 12 months in these particular patients. Whether we can stop at 6 months in every single patient with genotype 2 or 3 and a low viral load…or even a high viral load…remains unclear.
There are no data yet on re-treatment of relapsers after combination therapy. So what are we going to do from a practical viewpoint with these patients? Well, the options include re-treating for a longer time, and that would certainly be appropriate to think about if you’ve only treated the patients with 6 months initially of combination therapy. You might consider induction therapy, though there are no data to suggest that this is going to make a difference in the rate of sustained remission in the long run. You might keep the patient waiting for a few months for the hoped for combination trials with PEG plus ribavirin. You might consider maintenance therapy, particularly in those patients with very worrisome histology. And the theme of maintenance therapy is an increasingly intriguing and discussed one in this field. And then there’s the issue of whether you should consider maintenance therapy with interferon alone or with interferon and ribavirin together. We really don’t know. And finally, it might be perfectly appropriate to take a patient with very mild histologic change, who has relapsed after a course of combination therapy, and just keep them waiting for a while and see them in the office every 4 to 6 months. And with that, I’ll stop. And thank you for your attention.
