CME/CE Released: 09/04/2012; Valid for credit through 09/04/2013
Mark S. Sulkowski, MD: Hello. I am Dr Mark Sulkowski, professor of Medicine and medical director of the Viral Hepatitis Center at the Johns Hopkins University School of Medicine in Baltimore, Maryland. I would like to welcome you to this program, "Chronic Hepatitis C Infection: Treat Now or Wait?" Joining me today is Dr Donald Jensen, professor of medicine and director of the Center for Liver Diseases at the University of Chicago School of Medicine.
Before we get started, I would like to note that a lot of what we are going to discuss is on investigational drugs: not everything we are going to talk about is approved for prescription in the United States at this time. To have this discussion, we need to talk about what is currently approved for the treatment of chronic hepatitis C virus (HCV) infections and what we hope will be available for our patients in the near future. Don, why talk about whether to treat now or wait? Give us a scenario.
Donald M. Jensen, MD: As you know, 13 months ago, 2 new drugs, telaprevir and boceprevir, were approved for the treatment of chronic HCV infection in conjunction with the standard pegylated interferon/ribavirin backbone regimen. Telaprevir- and boceprevir-based triple therapy proved very effective in improving sustained virologic response (SVR) rates in patients with genotype 1 HCV infection, but also exacerbated some of the adverse effects associated with standard interferon-based therapy. The course of therapy is still relatively long in duration, usually 24 or 48 weeks. With the prospect of newer therapies becoming available sooner than anticipated, we need to consider that some of our patients may be able and inclined to wait for treatment with future therapies that might be easier to take, better tolerated, and have shorter courses of treatment compared with the standard regimens used today.
Dr Sulkowski: You raise a fascinating point. From 1998 to 2011, we went without a single new drug for HCV infection coming to market. Then, 2 new protease inhibitors -- telaprevir and boceprevir -- were approved in 2011. In the short time since their approval, half a dozen new investigational agents and regimens look quite promising. Information about these agents is being widely disseminated to physicians and patients, who often raise the topic when we sit down with them in the exam room.
Dr Jensen: Ten years ago we thought we were on the cusp of having newer, better therapies for chronic HCV infections. I can remember telling patients in the early 2000s, “In 3 to 5 years we are going to have a newer therapy.” I think there is a little bit of a false start with the present situation because none of these emerging therapies has been conclusively shown to be effective. Many are in phase 3 trials, but the promise of these agents is terrific and better than it was 10 years ago.
Dr Sulkowski: You raise a good point. I remember a conversation I had with a patient recently. I said, "We are expecting new therapies that are going to change how we treat hepatitis." He looked at me and said, “Doc, you told me that 5 years ago.” This brings up the question: Which patients should we treat now? Yes, new medicines are coming, but we have patients who can benefit from therapy now. Let us talk about those in your practice you are treating now.
Dr Jensen: When the first new therapies were approved last year, we looked at all the patients with chronic HCV infection we had seen over the previous 12 months and tried to decide who should be treated first. Who should be at the front of the line for treatment and who could we put at the back? We realized we could not treat everyone at once; some of our patients had been "warehoused" for several years.
We decided to treat the patients with the most urgent need for treatment first: patients with borderline decompensated cirrhosis and patients who needed treatment so they could get their kidney transplant. We put patients with more severe disease at the front of the line. Next, were the patients with favorable treatment characteristics, who we knew would have the very highest response rates to the newer therapies. Then, in the middle, were patients we knew could wait and/or would not have very good responses, even with the new therapies. That middle group is the most problematic.
Dr Sulkowski: Let us focus on the patients with more advanced disease. We are seeing more and more patients with compensated cirrhosis in their 60s and 70s. When you look back, you find that they had their HCV infection for 30 or 40 years. We are seeing the HCV epidemic in the United States play out. These patients have significant fibrosis and we are seeing a lot of them. Part of the debate with regard to these patients is, do we treat now, knowing that current therapies can lead to eradication in roughly 70% of genotype 1 infected patients, but likely at the expense of more adverse effects in patients with cirrhosis? How do you decide? Part of making that decision is determining each patient's prognosis over the next couple of years.
Dr Jensen: That is not an easy decision. You hit the nail on the head. The issue is that there are cirrhotic patients and then there are cirrhotic patients: some are well compensated and I would like to treat those patients now, but we are sometimes forced to treat patients with borderline decompensated cirrhosis. If I had a better therapy, I would treat the patients on the borderline -- I do not know if they can wait another 2 years for a new therapy. The patients that I think are going to "fall off the cliff," I need to treat now because the risk for the development of hepatocellular carcinoma or hepatic decompensation is too great. I try to put myself in that patient's position. I meld together what I know about the disease progression and that particular patient with what the literature states to make a recommendation.
Dr Sulkowski: When we look at the outcomes with treatment, the data consistently show that achieving SVR is a cure and, perhaps more importantly, decreases the risk for liver cancer, liver failure, and death. Data from the HALT-C trial, which enrolled patients with advanced fibrosis, convincingly showed that if you could achieve eradication, you had fewer adverse outcomes.[1] . The idea that we can make a difference and possibly offer life-saving therapy to patients with cirrhosis is what keeps us going.
Dr Jensen: The average age of the patient with chronic HCV infection today is around
55 years.[2] As this group of patients ages, the percentage with cirrhosis will increase. It is estimated that, of the approximately 4,000,000 people with chronic HCV infection in the United States, about 1,000,000 will have cirrhosis by the year 2020.[3] That is an incredibly high number. There is an urgent need for us to treat those patients and cure them so that we do not have 1,000,000 people in need liver transplants or treatment for liver cancer in the future.
Dr Sulkowski: Let us talk about the other side of the question. A patient's liver biopsy shows METAVIR stage F1, portal fibrosis with no evidence of bridging or septae. What factors would you consider in deciding whether to treat that patient?
Dr Jensen: Patients such as that have both options open to them. I am not worried about those patients decompensating over the next 2 to 3 years while waiting for new therapies. On the other hand, patients with a favorable genetic genotype (interleukin[IL]28B CC or 1b), have mild disease, or of a younger age have a great response to current therapies. And patients who have relapsed after a previous course of therapy have an approximately an 80% chance of SVR with triple therapy, maybe even with a shorter therapy duration (eg, 24 weeks). Would the patient with an 80% probability of SVR, of being cured, want to be treated now or wait for new therapies to avoid interferon?
Dr Sulkowski: I agree. We have been using data from a subanalysis of pivotal studies published in TheNew England Journal of Medicine for guidance.[4-7] One of the tests that I now order for most of my patients is IL28B genotyping, because I find it helpful. It is not that I am going to defer therapy in all my patients with the CT or TT genotype (those with less favorable response rates), as they may respond well to current triple therapy. But when you look at the CC genotype patients, the majority -- approximately 80% to 90% -- qualify for 24 or 28 weeks of treatment and have cure rates in the range of 90%. That is something patients need to know. I tend to look more at the histology of patients with CT and TT genotypes to determine whether or not to defer treatment.
You raised the issue of prior response to therapy. Patients who have relapsed after previous treatment have the highest response rates to retreatment with current triple therapy regimens.[5,8] But, what about patients with cirrhosis, for example, those have had a null virologic response to pegylated interferon/ribavirin? How do you treat them?
Dr Jensen: They are in a difficult position. The data both on boceprevir and telaprevir in previous null responders with cirrhosis show SVR rates of approximately 14% to 15%.[5,8,9] Treating a patient with a difficult and potentially toxic therapy for 48 weeks (all cirrhotic patients require 48 weeks of therapy) with only a 14% chance of SVR is difficult to reconcile. I would do 1 of 2 things for that patient. If I think the patient needs to be treated now, I would use a 4-week pegylated interferon/ribavirin lead-in phase, possibly with telaprevir. If the patient responded during the lead-in phase, I would continue the therapy because that points to a better outcome on triple therapy. If the patient did not respond, then I would probably discontinue treatment, at which point I would try to get them into a clinical trial that takes patients with cirrhosis (which there are not many of) or wait for future therapies to become available.
Dr Sulkowski: That is the group that really needs treatment. We have talked about sitting down with patients and reviewing their disease, viral characteristics, genotype 1 subtype, IL28, and race. The other point is how the patient feels about treatment. I have had patients say, "I do not want to live with this virus, and the interferon side effects I have read about do not bother me that much." That is a patient I would treat. On the flip side, patients have told me that tell me, "I am very busy; I do not want to commit to a treatment with a lot of side effects. I read online that better treatments are coming." Let us talk about the other side of the equation, the wait side. You used the term warehousing, which generally refers to the idea of telling a patient, “We are going to defer therapy until we have different and, perhaps, better options.” Tell me, what is driving that?
Dr Jensen: It is a discussion you have with patients. I do not think we ever say we are warehousing, we say are going to wait for future therapies. Some patients want to be treated now, regardless. Some patients do not want interferon in any situation. The fear of interferon is often seen in patients who have been previously treated; maybe it was very difficult for them to work or to carry on a full life when they were on interferon therapy. We go through that discussion. I tell patients that can wait that it is probably going to be 2 or 3 years until we have new therapies. We are all hoping that, by 2014, we will have an interferon-free therapy, but there is no guarantee.
Dr Sulkowski: A lot of patients have read about these new therapies in the headlines. For example, headlines from the European Association for the Study of the Liver (EASL) annual meeting in April 2012 read that 1 regimen, a nucleotide analog plus and NS5A inhibitor, taken by mouth once daily for 24 weeks had a 100% rate of patients remaining virus negative 4 weeks after stopping therapy (ie, SVR 4).[10] But when you dig deeper, you see that the study included a relatively small number of patients: 44 with genotype 1 and none of them had cirrhosis. Patients are not aware these factors may make a difference. We don't know when that regimen and other regimens that look promising will be available in the clinic.
One of the things we saw in data presented at the same meeting was that for some regimens, the genotype 1a subtype became resistant pretty readily, whereas the 1b responded better.[11] Perhaps we will use interferon-α in genotype 1a patients because it is a good antiviral agent. Is interferon-α completely off the table or will we still be using it in 2 or 3 years?
Dr Jensen: We will still be using interferon-α in a few years, either interferon-α or interferon-λ. I think there will be a role, hopefully a minor role. Some patients have greater benefit from an interferon-containing regimen than 1 without interferon. The goal is to minimize the adverse effects to make therapy more tolerable, perhaps by truncating the interferon duration to less than 48 weeks.
Dr Sulkowski: We have interferon-α as a tool if we need it for certain patient groups. A 45-year-old woman has chronic HCV genotype 1a. Her biopsy shows stage 1 fibrosis. She is a busy person. She works and has a family. She does not want to have hepatitis. She makes it very clear to you that she wants to be cured. What conversation do you have with her?
Dr Jensen: I might measure her IL28B genotype to see whether she is in that very easy to cure group that can truncate triple therapy to 6 months. If she is, then we talk about treating now: What that would involve? What adverse effects could be anticipated? A lot of patients come to me who have never been treated and worried about the adverse effects. When they are actually on therapy, they find it is not as bad as they thought it would be. Everyone on interferon has some adverse effects, but some are not as bad as others.
Dr Sulkowski: What about the complexity of therapy with the current treatment: an interferon injection once a week, ribavirin pills twice daily, and telaprevir or boceprevir (2 or 4 pills every 7 to 9 hours with food requirements). How much is that influencing the decision to defer treatment?
Dr Jensen: It is a huge problem. Patients may be ready to begin therapy, but when I start spelling the dosages out, the pill burden and the complexity can make a difference for some patients.
Dr Sulkowski: And included in the adverse effect profile that we alluded to, there is more anemia. Sometimes I draw a scale and put pros and cons on it, and we work through that. The option of waiting is really watching and waiting. I tell the people that I am not treating today, but I want to see them back in 6 months to talk about their disease, know what is going on with their lives, and update them on what we have learned, good and bad, about new therapies.
Dr Jensen: We have just written an editorial that has been accepted for publication by Hepatology on informed deferral.[12] When we defer a patient for future therapy, we should inform them of all the risks and benefits, exactly as you have pointed out. It is important. We have informed consent for treatment, and we ought to have informed deferral.
Dr Sulkowski: Sometimes patients and their healthcare providers focus on the adverse effects of therapy while failing to understand the risk of deferral. We all have had patients with cirrhosis who declined treatment because of adverse effects. At least in our view, they are not appreciating the real risk they are taking by deferring treatment.
Dr Jensen: Absolutely.
Dr Sulkowski: I want to thank Dr Jensen for this engaging discussion about what we are currently experiencing in clinical practice. We are in a unique and fortunate situation after a decade of suboptimal treatments, ie, pegylated interferon/ribavirin for 48 weeks with a 40% SVR achieved in genotype 1 patients. We have leapt forward with the addition of telaprevir and boceprevir to a 70% SVR rate in genotype 1 patients. We worked a long time to get this far. We are seeing cures in patients that, 5 years ago, I would not have thought possible. At the same time, we have a very dynamic and rapidly moving field of research; the clinical trials are testing combinations of direct-acting antivirals that are providing exciting possibilities. There is much work to be done, but we have seen a glimpse of the future. It is highly encouraging for our patients with chronic HCV infection.
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