Best Practices in the Management of HCV. 2015

Editor's Notes

• #5: HCV, hepatitis C virus.   I want to take you through the rationale for treatment initially. Then we’ll spend the bulk of the time talking through the treatments, spending most of our time talking about genotypes 1 through 4, and then a little bit about future directions and what you’ll see coming down.
• #6: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus.   So there’s been a lot of talk about whom to treat, and I think in general we would recommend that everybody with hepatitis C should get treated, and that is a clear statement that all of us would want to make. The AASLD/IDSA guidance group did look at the fact that there will be situations in which there are limitations on resources, and so how should you prioritize patients, and basically it’s on who’s most likely to have the complications in the near future. What we see with that is that the group with highest priority are those who already have advanced fibrosis (F3 or F4), those with organ transplants, and those with complications of some of the extrahepatic manifestations, whether it’s cryoglobulinemia or glomerulonephritis.   There are other groups with high priority, again based upon their risk for complications, including those with HIV, METAVIR F2, HBV coinfection, coexisting liver disease, type 2 diabetes, porphyria cutanea tarda, and also those with debilitating fatigue.
• #7: HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SVR, sustained virologic response.   And so what do we gain by treating hepatitis C? And this is the often-quoted study that was focused on patients with advanced fibrosis, and it was a multicenter study from 5 centers in Europe and Canada. And this was in the interferon era, so we have 530 patients who were treated with a median follow-up of 8.4 years. And when they looked at the 10-year cumulative incidence of events, they did see reductions in liver cancer, liver-related morbidity/mortality with transplant, but also they saw a decrease in all-cause mortality; that 10-year incidence is 26% down to 8.9%, so making the strong case that it’s more than just your liver, there’s a benefit to hepatitis C therapy.   But then what about the patients with early-stage disease? And we’re starting to see more data. We do see a benefit from the extrahepatic manifestations that I talked about, but we’re also starting to see more in patient-reported outcomes, and looking at the quality of life of patients and seeing there are benefits in the early-stage as well.
• #8: AFP, alpha-fetoprotein; BOC, boceprevir; DAA, direct-acting antiviral; DSV, dasabuvir; GT, genotype; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PR, peginterferon/ribavirin; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SMV, simeprevir; SOF, sofosbuvir.   And this has been looked at in a number of different ways, and we did want to highlight some recent data as well. The first study there is from TURQUOISE-II, which is a group of patients with cirrhosis, and this all-compensated cirrhosis. But what we’re seeing there is even in that group, early findings that by the end of the follow-up period, you’re seeing improvement in noninvasive markers, surrogate markers of liver function that are improved. And there was some modeling work that was done looking at the 2 major regimens that are out there right now, the 3-drug regimen and ledipasvir/sofosbuvir, demonstrating that there are benefits even in early-stages disease when you looked at some of the modeling data; improvement in their liver-related morbidity over time, so making the case that we should be aggressively treating even early-stage disease.
• #9: DSV, dasabuvir; HCV, hepatitis C virus; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response.   There was a very interesting paper that was presented at the European Liver Meeting which looked at the VA Clinical Case Registry as well, again trying to get at this concept of early vs delayed treatment. And seeing that there was a reduced risk of liver-related events and death began if you went with early treatment. And there‘s another Markov model, again highlighting that with early treatment we‘re seeing benefits in survival. So we‘re making the case for treatment.
• #10: So here we are again. It’s the early summer of 2015, so what treatments do we have? So we have sofosbuvir with ribavirin, sometimes with interferon; we have ledipasvir/sofosbuvir; we have ombitasvir/paritaprevir/ritonavir with dasabuvir; and we have simeprevir and sofosbuvir. And I did put in sofosbuvir/daclatasvir because we do expect to have that available towards the end of the summer. So, again, I’m just in the early summer here.
• #11: HCV, hepatitis C virus.   And I do remind you, the approach here is to take multiple drugs with different targets of hepatitis C and combine them together. So we have 2 protease inhibitors, simeprevir with paritaprevir; we have 2 polymerase inhibitors, a nucleotide with sofosbuvir, a nonnuc with dasabuvir. We have 3 NS5A inhibitors now, and notice that my table still includes ribavirin because it continues to play a role.
• #12: HCV, hepatitis C virus.   So before we get into the treatment, there’s some key information that we need. We need to know the genotype; that clearly guides our treatment. But we also need to know the treatment history now. If the patient has been treated with interferon and ribavirin in the past, that will impact the regimen and the duration potentially. We have a lot of patients who failed those first-generation of protease inhibitors, even the more recent ones, and so again that will guide our treatment decision. And we’re starting to have patients who failed sofosbuvir, so we need to know some of the details of their history.   We need to know their fibrosis stage. There are a number of ways we can do this now: liver biopsy, transient elastography, there are the seromarkers as well. I think my main message would be how you stage fibrosis probably depends on what you have access to, and the key being that sound assessment of fibrosis needs to be made, it will guide your treatment. And also if it’s cirrhosis, then you’re going to want to know if they’re decompensated, and particularly if they have Child-Pugh B and C decompensated cirrhosis, then you need to know what role transplantation might have for that patient, and so they need that evaluation as well.
• #13: FDA, US Food and Drug Administration; HCC, hepatocellular carcinoma; HCV, hepatitis C virus.   So these are the FDA-approved regimens right now. And you notice the top one, there is simeprevir with peginterferon and ribavirin, and nobody’s going to suggest that we offer that to a patient today, but it just kind of shows you how hard it is—and even for our regulatory authorities if you just look at what’s in these package inserts, which is partly why the AASLD and the IDSA came together with this guidance committee to guide clinicians better about what are the regimens that we recommend.
• #14: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; BID, twice daily; HCV, hepatitis C virus; QD, once daily; QWK, once weekly.   So here we are for genotype 1, and you see now we have the 3 interferon-free regimens that are recommended there at the bottom that have become the basis for our treatment right now.
• #15: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; RBV, ribavirin.   And this focuses again on the AASLD/IDSA recommendations for treatment-naive genotype 1 patients, letting you know what the options are here. So you see it varies whether you’re genotype 1a or 1b, and also whether you have cirrhosis or not. If we do look at ledipasvir/sofosbuvir, in the guidance there it’s 12 weeks down the line for everybody. There is this option that if you have less than 6 million IU of HCV RNA, that you can consider 8 weeks. I will say in my area of the country, that’s not really a consideration; that is what our payers allow you to do, but when we can talk about that a little bit more.   If you go to ombitasvir/paritaprevir/ritonavir with dasabuvir, you see that 3 of the groups there do require ribavirin, it’s only the genotype 1b patients without cirrhosis who don’t. And also you see that the duration goes longer with the genotype 1a with the 3-drug regimen and for simeprevir plus sofosbuvir for both 1a and 1b if you have cirrhosis. And so this guides us about the approach.
• #16: GT, genotype; HCV, hepatitis C virus; SVR, sustained virologic response.   So I did want to show you a little bit about the data from the studies that support these recommendations. So the top there is ledipasvir/sofosbuvir, and ION-3 was one of the registration trials for that compound. And keep in mind, the 8-week regimen, this 6 million unit number there with the 8-week regimen was not something that was in the trial; that was a post hoc analysis from the FDA. And what they saw is that of the 123 patients who met those criteria of less than 6 million IU, the SVR rate was 97%; that led to that recommendation.   If we look at the 12-week group, we see that it’s 95% there as well. For simeprevir plus sofosbuvir, we put the OPTIMIST study that was recently presented at the European Liver Meeting. If you recall, simeprevir plus sofosbuvir was approved from the COSMOS data, which were quite a small study for the approval. OPTIMIST provides us a much bigger data set to look at with this regimen. They did look at an 8-week regimen for that and you see it was 83%, so that is not considered an acceptable duration for simeprevir plus sofosbuvir. If you look at the 12-week regimen, now we’re at 97%.   Coming down the table, the PEARL III study there provides the support for the 3-drug regimen for genotype 1b without ribavirin, seeing 99% as the SVR rate there. And then the PEARL IV study for genotype 1a patients with that regimen with ribavirin, with an SVR of 97%. I did put sofosbuvir plus daclatasvir in there just to remind you about that study. We anticipate that—and this is going for approval for genotype 3 in the United States, it’s not going for genotype 1. But just to remind you, it does have a broad coverage and the SVR rate is impressive in genotype 1, too.
• #17: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin.   Alright, so here’s the same table looking now at treatment-experienced patients. And if you look at the 2 right columns, you see that there actually hasn’t been a change. But the main issue is with ledipasvir/sofosbuvir with a couple of different options here. So we see that we have 24 weeks if we’re just doing ledipasvir/sofosbuvir for the patients who have cirrhosis for this, but there’s also in the guidance an option for 12 weeks—so half the duration—along with ribavirin. So let’s talk about that a little bit more.  
• #18: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus; PI, protease inhibitor; RBV, ribavirin.   This is also the same table for if you’ve failed a previous PI. You’ll notice because the 3-drug regimen is simeprevir, a protease inhibitor, we don’t recommend those regimens and so ledipasvir/sofosbuvir is what’s recommended if you failed a previous protease inhibitor.
• #19: HCV, hepatitis C virus; PI, protease inhibitor; SVR, sustained virologic response.   And these are some of the data that support some of that. So ION-2 is the registration trial of treatment-experienced patients for ledipasvir/sofosbuvir, and you see that these are the previous PI failure patients, and it did have quite a few patients who had failed protease inhibitors in it. And you see at the 12 week was 96%, 24 weeks—a small group there—but it was 100%. SIRIUS is the study that was presented last year, and it was already published that brings up this issue of could you shorten the duration of treatment there and add in the ribavirin? So this was a randomized trial, 24-week arm of just ledipasvir/sofosbuvir were at 97%, 12 weeks with ribavirin were at 96%; so again a very reasonable option, particularly if your patient can tolerate ribavirin.   I also put down at the bottom there again the experience with sofosbuvir plus daclatasvir. Some of the early experience with that regimen was in protease inhibitor failures and again highlights that it works well.
• #20: AE, adverse event; d/c, discontinuation; DSV, dasabuvir; GT, genotype; HCV, hepatitis C virus; OBV, ombitasvir; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SAE, serious adverse event.   This is TURQUOISE II, which is a study I think was really well done. It’s a huge study in patients with cirrhosis, 380 patients, treatment naive and experienced. Please remember they’re all compensated cirrhosis. And the study question here was 12 vs 24 weeks. And we know it works great, but if we focus on the safety data, these are patients with cirrhosis so they have serious adverse events. But the rate there is quite low. And I think one of the key things is the number of patients who had an adverse event leading to discontinuation is 1.9% to 2.3%, so very low. It was a well-tolerated regimen in patients with compensated cirrhosis. You do see some fatigue, you see a little bit more of that as you extend out the treatment, but well tolerated.
• #21: AE, adverse event; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; pegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; SOF, sofosbuvir.   This is the SIRIUS study, which I already mentioned. This is where we get the option for the 12 weeks of sofosbuvir/ledipasvir with ribavirin. And what was really also nice about this study is that there was the one group that was getting 24 weeks of ledipasvir/sofosbuvir and the other group got 12 weeks of the active drug. So the first 12 weeks of that study for that group was actually placebo. So it was a chance to look at ledipasvir/sofosbuvir against placebo. They didn’t start their real active treatment until week 13 essentially. And what we then were able to see, or what happens, I guess, the baseline in these patients with cirrhosis.   Overall, if you look at the study again, SIRIUS adverse events happens but they’re low—discontinuations were very low. The numbers there for headache and fatigue are actually in that first 12 weeks where that 12-week group there is actually really on placebo, and so you sort of see what the baseline headache and fatigue rate is with the patients with cirrhosis, and it’s a little bit more with the active drug; but again very well tolerated. We can feel very good.  
• #22: However, we have to watch all of these things to happen. This is some information that came out after sofosbuvir was approved. These came out of Europe. There were cases of serious symptomatic bradycardia when coadministered with amiodarone. So you’ll now see this in the sofosbuvir package insert, you’ll see in the ledipasvir/sofosbuvir package insert, and you’ll also see it in the simeprevir package insert because it can be paired with sofosbuvir. So again, there is ongoing monitoring of this, and we need to be cautious about this for our patients.
• #23: GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; pegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response.   What about in the patients who have experienced sofosbuvir failure? What do we know about them and what do the recent data tell us? So this was presented last year at the Liver Society Meeting. It’s already published and great to have out there. These are genotype 1 treatment–experienced patients who’d failed a prior sofosbuvir regimen, with most of them being sofosbuvir with peginterferon/ribavirin or sofosbuvir plus ribavirin. This group is mostly genotype 1a; it was 27% cirrhosis. It’s an open-label cohort where everybody received ledipasvir/sofosbuvir plus ribavirin for 12 weeks. And you see in the table, all but one of the patients achieved SVR; the one patient who didn’t was checked again and actually was genotype 3a. So all the genotype 1 patients were cured.
• #24: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; pegIFN, peginterferon; RBV, ribavirin.   We’re going to shift gears a little bit and talk to you about genotype 2 and 3 on our tour. So here’s the table from AASLD/IDSA. So genotype 2, pretty straightforward; sofosbuvir plus ribavirin is recommended for 12 week—16 weeks if the patient has cirrhosis. Same for the peginterferon/ribavirin nonresponders. You see there is an option there as an alternative regimen to add in interferon for your nonresponder patients. Genotype 3 at the bottom there is where we get more interesting. We’re at 24 weeks for sofosbuvir plus ribavirin, and then we do have the option for both of adding in interferon.
• #25: GT, genotype; pegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; Tx, treatment.   So let’s talk a little bit about some of the data with genotype 3. This study was presented at the European Liver Society Meeting in April and again another very interesting study. This looked at these patients with different sofosbuvir regimen. It’s a randomized controlled trial. The patients could receive sofosbuvir and ribavirin for 16 weeks, sofosbuvir and ribavirin for 24 weeks, or sofosbuvir with peginterferon and ribavirin for 12 weeks. It includes treatment-experienced and treatment-naive patients with and without cirrhosis. And if we look across the groups—I realize there’s overlapping confidence intervals here—but you see in our range, the 24-week group of sofosbuvir/ribavirin does pretty well. But you see that the best outcomes in each of the groups are when you throw interferon into the mix there in green; that’s the highest numbers that we see there. So an interesting finding and consideration for our practices.
• #26: GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response.   This is a study that was presented a year ago at the European Liver Society Meeting. These are genotype 3 patients and previous sofosbuvir failures. These are patients who came from the FISSION, POSITRON, and FUSION trials. This is an open-label cohort, so it’s not randomized; the clinician and their patient decided. They could get sofosbuvir and ribavirin for 24 weeks or peginterferon and ribavirin and sofosbuvir for 12 weeks. So there’s 91% there of the patients who received the interferon regimen vs 63% who just received sofosbuvir and ribavirin. The genotype 3 treatment–experienced cirrhotic group remains our biggest challenge, and you see a consistent theme in the lower rates in that group.  
• #27: HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response.   Some of you may ask what about ledipasvir/sofosbuvir with ribavirin; what is the experience there? This is a study that was presented in the last Liver Society Meeting of treatment-experienced patients. Again, open-label cohorts here, small studies. And the patients without cirrhosis were at 89%, were again down lower in the patients with cirrhosis. If you look overall at ledipasvir/sofosbuvir for genotype 3, it’s not as good a regimen. It doesn’t have as good of activity. It did not see that move forward as a recommendation. So we would not routinely recommended ledipasvir/sofosbuvir for genotype 3.
• #28: DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; SOF, sofosbuvir; SVR, sustained virologic response; Tx, treatment.   I did want to mentioned daclatasvir and sofosbuvir because we did talk about that being available at the end of the summer. This is the ALLY-3 data that were presented. These are treatment-naive and -experienced patients, some with prior sofosbuvir and alisporivir included here as well. Cirrhosis in 21% of these patients. These are essentially 2 open-label cohorts where they received daclatasvir and sofosbuvir once daily for 12 weeks. And if you looked, patients without cirrhosis SVR rates of over 90% for that group. It’s again, with this regimen as well, when we come to those patients with cirrhosis, whether naive or treatment experienced where we see the lower response rates for that as well.   We don’t know what’s going to be the recommendation yet, obviously, because it’s not been approved. But I can tell you from the European Liver Society, we have the recommendations in the bottom right there in which for patients without cirrhosis; they recommend daclatasvir and sofosbuvir for 12 weeks. With compensated cirrhosis, they’re recommending daclatasvir plus sofosbuvir plus ribavirin for 24 weeks.
• #29: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; FDA, US Food and Drug Administration; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.   This is a little bit of the data again to support the treatment for genotype 4 recommendations. The NEUTRINO study did have some sofosbuvir plus peginterferon/ribavirin for genotype 4 in there, 27 out of 28 patients with SVR. Sofosbuvir plus ribavirin has been studied. It’s a different series now and it looks like an effective regimen; it is 24 weeks. Ledipasvir/sofosbuvir as multiple studies now again have shown that this is a very effective regimen for it, as is ombitasvir/paritaprevir/ritonavir and ribavirin, the PEARL-I study, again 12 weeks, very effective regimen.
• #30: AASLD/IDSA, American Association for the Study of Liver Diseases/Infectious Diseases Society of America; HCV, hepatitis C virus.   Alright, just a little bit about genotypes 5 and 6. These are the current guidance to suggest sofosbuvir plus peginterferon/ribavirin is the recommended regimen right now. We did see some data at EASL that’s showing ledipasvir/sofosbuvir did very well for that as well. Genotype 6, the ledipasvir/sofosbuvir is recommended for 12 weeks. And you see the alternative regimens there, but we see less of this in our practices obviously.
• #31: So I did want to say a little bit about the future because I have the ones on the bottom there plus some things that are in development and we’ll talk a little bit about sofosbuvir with GS-5816, which is a new NS5A inhibitor. Grazoprevir and elbasvir, a protease inhibitor with an NS5A inhibitor. And daclatasvir/asunaprevir/beclabuvir, so NS5A inhibitor with a protease inhibitor and a nonnuc polymerase inhibitor.
• #32: HCV, hepatitis C virus; LDV, ledipasvir; SOF, sofosbuvir.   So what’s the general thought here? So I think on one hand, we may see regimens that are similar to what we have, maybe with some nuances, but also there’s a lot of discussion how much shorter can we make treatment. This was an interesting study looking at the concept of taking the 12 weeks of what we have now, ledipasvir/sofosbuvir, but could we get down to 6 weeks if we added another mechanism of action drug, so another polymerase inhibitor. And you see in this proof of concept, it could be done. Then again, can we do that broadly?
• #33: SVR, sustained virologic response; Tx, treatment.   This was another study looking at this again with sofosbuvir with GS-5816, which is the new NS5A inhibitor, and with GS-9857, which is a protease inhibitor. And what we see is we were there at 6 weeks, treatment naive, no cirrhosis, 14 out of 15. When we start to push the envelope, when we get to the treatment-experienced cirrhosis or when we get down to 4 weeks is where we drop off. But I think it’s great to see that there’s these efforts to figure out what can be done.  
• #34: ASV, asunaprevir; BCV, beclabuvir; DCV, daclatasvir; GT, genotype; SVR, sustained virologic response.   This is one of the regimens I talked about, which is probably trying to do similar to what we have right now. But this was all without ribavirin. This is daclatasvir/asunaprevir/beclabuvir regimen. These are noncirrhotic genotype 1 treatment-experienced patients. Again, we’re hitting the 90% range there for most of the groups without ribavirin.
• #35: FDC, fixed-dose combination; EBV, elbasvir; GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; SOF, sofosbuvir.   This is C-SWIFT, which I think is another very well done and interesting study. These are genotype 1 and genotype 3 patients looking between 4 and 8 weeks for the genotype 1, and then 8-12 weeks for the genotype 3, really looking again at how much we can push the envelope there. And with the 8-week group, you see for the genotype 1s we’re doing well—a small study. But as we push the envelope down to 4 weeks, that’s too short. So, again is it the duration? Is it the drugs we’re using? But it’s nice to see that all these questions are being addressed.
• #36: EBV, elbasvir; GT, genotype; GZR, grazoprevir; HCV, hepatitis C virus; RBV, ribavirin; Tx, treatment.   This is the C-EDGE study which is, again, I mentioned, the grazoprevir/elbasvir you will see soon. This is looking at this with its larger trials. On the left, you see the treatment-naive patients for genotypes 1, 4, and 6, and then on the right, you see the treatment-experienced patients, again there for 1, 4, and 6. On the right, they looked at 12 vs 16 weeks, and what you see again in general, we’re seeing great outcomes there. Don’t be worried about the genotype 6 group. That’s 10 patients, that’s 2, but still I think overall we’re pleased with the outcomes there.
• #37: DAA, direct-acting antiviral.   Alright, so there’s much coming here. There’s many other things under investigation. I think we continue to be challenged by keeping up, and I think the AASLD-IDSA guidance will help, and programs like this will help. But I think it remains a wonderful time in which we’re seeing that there are many options that we can offer our patients, and things continue to get better.