Donald Jensen, MD, gives a 2014 Hepatitis C Update.
[MUSIC PLAYING] PROFESSOR JENSEN: I'll focus on obviously just hepatitis C. It's an update. And I'm going to start with a little background of two papers that sort of came out in the latter part of 2013, early 2014. This isn't really a DDW. But I think it's important for us to understand sort of the epidemiology of hepatitis C in the United States. And from this slide, if you'll look at the right side, the graphic side of this slide, the NHANES study, which is a large population-based study of hepatitis C that went from 1999 to 2002-- those middle two bars-- we saw that the number that we frequently used to say how many patients in the U.S. have hepatitis was 3.2 million. Now they didn't test incarcerated or homeless, so it's probably another million on top of that. But 3.2 is the number that we frequently throw out as the number of people in the U.S. with hepatitis C. The more recent data, with an updated NHANES from 2003 to 2010 said it's 2.7. Now some people think, well, 2.7-- it must be going down. That's good news. But really, when you look at this, the reason it's going down is because people are dying of their liver disease. So there's more people dying of their liver disease. Because the average age of a person with hepatitis C is 57. So more people are dying of the liver disease and other comorbidities going forward. So it's good news that there's fewer people with hepatitis C. It's bad news that more are dying with it. Now one of the interesting things is that in two studies looking at patients who have hepatitis C, about 57% of those estimated to have hepatitis C infection had already been tested. But less than half of those with two or more elevated ALTs were subsequently tested for hepatitis C. Now what that means is, patients that are going around with known hepatitis C, or without hepatitis C with two elevated ALT levels that have not been tested for hepatitis C. Now we know in that graph on the right, that fewer than 50% of people in the U.S. actually have been tested for hepatitis C. Relatively few of those-- only 7 to 11% have actually been cured of their hepatitis C with treatment. So there's a large untested population out there of hepatitis C patients. We know that 50% of those patients who had tested positive for hepatitis C were unaware of their status. And only 50% of positive individuals actually had a risk factor. So what has happened in the past, the indication for testing for hepatitis C was based on risk factor. Did you use injection drugs? Did you have a blood transfusion? Those well known risk factors for hepatitis C have really identified only a minority of patients with hepatitis C. And because of that, the CDC has implemented birth cohort screening. And it's now recommended by both the CDC and U.S. Preventive Services Task Force that everybody in the United States that's born between 1945 and 1965-- the baby boomer population-- should have a one-time test for hepatitis C. 75% of all hepatitis C patients fit in that age cohort. And if we test everybody in that age cohort, we'll identify at least 800,000 new patients who are appropriate for testing. Now let me switch and talk about therapy. Because this is the exciting area. But I wanted to have that awareness discussion with you first. So we know that with the discovery of the hepatitis C virus-- now, we only discovered hepatitis C virus in 1989. So it's been exactly 25 years since the discovery of the hepatitis C virus. We now know the replication machinery of the hepatitis C virus. And we have direct inhibitors to different parts of that machinery-- four different enzymes in the replication process of the hepatitis C, depicted on this slide as NS3, NS5A, and NS5B-- non-structural proteins. The NS3 is the protease enzyme. And we know that we've had inhibitors for that-- telaprevir and boceprevir-- which have been around since 2011. Last December, we added simeprevir as a third protease inhibitor for hepatitis C. We also have a number of NS5A inhibitors. And none of those are yet approved by the FDA. The only ones approved are red. We have a nucleoside inhibitor, sofosbuvir which is a chain terminator inhibitor of hepatitis C. There's three other chain terminator nucleoside inhibitors, or nucleotide inhibitors, in development. And finally, we have the non-nucleoside and non-nucleotide inhibitors-- two that are in late stage development, submitted to the FDA. And then some others that are in the process. Now what I'm going to show you is a little bit of what we currently have available for hepatitis C. And then I'm going to spend maybe the last five minutes talking about what's on the near horizon. So when we think about the attributes of a good therapeutic regimen for hepatitis C, the most important thing is really the sustained viral response. And sustained viral response-- we're talking about after treatment, if we wait three months or six months after treatment, if that virus remains undetectable for three or six months after treatment, we call that a cure. If we follow those patients with a sustained viral response to any therapy, if they're undetectable three or six months after therapy-- we follow them 10 years later, 98 to 99% remain undetectable. There's no virus detected in their liver. And their liver histology reverts towards normal. Even cirrhosis, even fibrosis can improve over time, if they're a sustained viral responder. So the difference between hepatitis C and a lot of other viral infections is that we can cure hepatitis C. This is a curable disease. And a lot of patients come to me saying, well I know it's not a curable disease. And I say, no. This is a curable disease. So I think there's some misinformation that we need to correct. Current standard of care. And we have guidelines that came out , published in January of this year, looking at the new agents-- sofosbuvir and simeprevir. Abbreviated here SOF for sofosbuvir and SMV for simeprevir. For patients who are interferon eligible-- interferon's still in the mix for patients who are eligible to take interferon. But in patients who are ineligible, that may have autoimmune disease or other contraindications to interferon, we can combine simeprevir and sofosbuvir without interferon in a common and that's based on the COSMOS study. There's relatively few numbers of patients in that study-- only 174 patients. But they had a 93% sustained viral response rate. For treatment-experienced patients, the same thing holds true. Although since they've been previously exposed to interferon, we tend not to use interferon as our recommended approach. And it becomes the sofosbuvir, simeprevir, with or without ribavirin strategy. And saving interferon means that those patients have a potential shorter treatment course-- 12 weeks-- and potentially much less in the way of side effects and interferon related problems. We know that there are six major genotypes, 1 through 6. One is the most common. But we do have genotypes 2, 3, 4, 5, and 6. And the regimens, I'm not going to go through this in detail. You can find this easily on our website for our guidelines, hcvguidelines.org, where the recommended regimens for the other genotypes are listed here. Again, relatively short duration. Many of them without interferon based, either sofosbuvir and ribavirin alone for 12 or 24 weeks. Same thing with treatment-experienced patients, for two, three, four, five and six. Two accounts for about 15% or 20% of patients with hepatitis C in the U.S. Three, about 10 or 15%. Genotype 1 is about 70% percent of patients. We rarely see five and six. So now what's on the horizon? And the exciting news is that there are terrific therapies that are just around the corner. And thinking that we've just discovered hepatitis C in 1989, we're actually on the cusp of being able to cure virtually 100% of patients without interferon, with just eight of 12 weeks of therapy. And to think that that's possible in such a short time is truly amazing. The interferon-free regimens for Genotype 1-- the most common genotype-- are listed here. The classes of the inhibitors on the left column-- protease inhibitors, NS5A, nukes, non-nukes, and ribavirin. And I'm going to show you some of the data on each of these different regimens. Notice there's no interferon in any of these regimens. And that's the good thing. There's no injectable, no side effects associated with interferon. So the first study-- and this was presented at EASL in April, and again was updated at the presentation at DDW in May-- the ION study which is a study of two oral agents, sofosbuvir, which is a nucleoside, and ledipasvir, which is an NS5A inhibitor. Co-formulated. These are two medicines in one pill taken once a day. For patients with Genotype 1, they had four arms- the combination with or without ribavirin for 12 weeks, and the combination with or without ribavirin for 24 weeks. And look at the sustained response rates on the right column. 97 to 99% cure rates in patients previously untreated. 16% of patients in those studies actually had cirrhosis. So we can cure, with one pill a day, for as short as 12 weeks, 99% of patients with hepatitis C, without ribavirin. The ION-2 study said, well, yeah. Those patients are probably the ideal patients to treat. What about patients that were previously treated with pegylated based therapies? How good are we at treating those? So they had also a similar study, about 400 and some odd patients. 20% had cirrhosis. They had been previously treated with interferon based therapies. And again, the same regimen-- fixed dose combination for 12 or 24 weeks, with or without ribavirin. Again, amazing sustained response rates-- which are cure rates-- between 94 and 99%. The next question that was raised is, what about treatment-experienced cirrhotics? What if we look at the cirrhotic, specifically? And even patients with known cirrhosis, we have success rates between 82 and 100%. And it looks in this study that although ribavirin didn't really change the response rates, perhaps cirrhotic patients may benefit from 24 weeks as opposed to 12 weeks. Again, one pill a day. Almost no side effects associated with this fixed dose combination pill. If we look at previous patients who were exposed to protease inhibitors-- telaprevir and boceprevir-- as a breakdown from these studies, we see again between 94 and 100% of patients with sustained response rates. So even if they've been exposed to telaprevir and boceprevir in the past, this therapy can still cure a high percentage of patients in those groups. So if 12 weeks is good, what about eight weeks? Can we shorten the treatment duration? So the ION-3 study was undertaken. This was presented at DDW. Looking at two doses-- sofosbuvir ledipasvir with and without ribavirin for eight weeks, versus the 12 weeks sofosbuvir ledipasvir. And again, on the right column you can see that the sustained response rates-- the cure rates-- varied between 93 and 95%. So it looks as if eight weeks is probably just as good as 12 weeks in curing patients with Genotype 1 treatment-naive. Now this group had no cirrhosis. And they were all treatment-naive. So it is a more selective group. The question came, well, can we go even shorter? What about six weeks? So the ELECTRON trial done in New Zealand looked at three-dose-- sofosbuvir, ledipasvir fixed-dose combination-- adding ribavirin. And can we shorten it even to six weeks of therapy? And there, the sustained response rates dropped to 68%. So at this period of time, even though 68%-- we would have given our eye teeth for 68% a few years ago. We're now thinking this is an inferior duration, that we're probably dealing with at least eight weeks or 12 weeks in treatment-naive patients. Now there's another combination of agents that's also right around the corner. Now I should say that that ION combination, the sofosbuvir/ledipasvir combination, is at the FDA for approval. The FDA has set October 10 as the date that they will give their panel recommendations for approval of sofosbuvir/ledipasvir. So we're looking at this as potentially available this fall, this combination. This combination by AbbVie has three agents, a protease inhibitor-- ABT 450; an NS5A inhibitor-- ABT 267, which are co-formulated in one pill; and ABT 333, which is a non-nucleoside inhibitor, with and without ribavirin. These studies were done with ribavirin. Again, treatment-naive patients without cirrhosis and treatment-experienced patients without cirrhosis-- 96% cure rate with just 12 weeks of this three-drug combination. The TURQUOISE study looked at treatment-naive and treatment-experienced, but all with cirrhosis. This paper just came out in the New England Journal and suggested that 92 to 96% of patients-- 100% with cirrhosis-- can be cured with a very short treatment duration of these medications, with very few in the way of side effects. Further studies looking at patients with Genotype 1B versus 1A-- there are differences between 1A and 1B-- looking at the same three-drug combination with and without ribavirin for 12 weeks, again demonstrates that 90 to 100% of these patients can be cured with this therapeutic regimen. So this is my take on where we're going and where the future is going to be, that the AbbVie combination is also in front of the FDA. The FDA has said, just in a press release yesterday or today, that they're giving it breakthrough status. So it will also likely be approved before the end of the year. So hopefully before the end of this year, we will have the combinations sofosbuvir/ledipasvir by Gilead. And by the end of the year we should have AbbVie combination, their three-drug combination, all oral, no interferon. All of these drugs are associated with a success rate between 90 and 100% in all types of patients-- cirrhotic, non-cirrhotic, treatment-naive, and treatment-experienced. And I think over the future, this is the pattern that we're going to see going forward. Thank you very much.
