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The International Liver Congress

Issue: June 2015

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The 2015 International Liver Congress celebrated its 50th anniversary by featuring some of the most up-to-date findings in the rapidly evolving field of hepatitis C virus therapies. More than 10,000 attendees gathered in Vienna, Austria, from April 22 to 26 to hear research on the latest pangenotypic direct-acting antiviral therapies emerging in the field as well as commentary on underserved populations finding higher cure rates than ever.

HCV Next board members in attendance offered varying viewpoints on the data presented. Nancy S. Reau, MD, associate professor of medicine at The University of Chicago Medical Center; Michael R. Charlton, MD, FRCP, professor of medicine at the Mayo Clinic in Rochester, Minn. and director of hepatology at Intermountain Medical Center in Salt Lake City, Utah; and Mitchell L. Shiffman, MD, head of the Liver Institute of Virginia, shared their thoughts on the most compelling data and topics discussed at this year’s meeting.

Nancy S. Reau, MD

Some of the biggest data coming out of this meeting is showing that treating a decompensated cirrhotic can be done successfully if we use sustained virologic response as a measure of success.

Unfortunately, the data is also allowing us to infer it might actually disservice a subset of end-stage liver disease patients by disadvantaging them from a MELD standpoint, as presented by Fred Poordad, MD, in the ALLY-1 study. Some of these patients are absolutely still going to require transplant even though you’ve cleared their hepatitis C, but now they’re less competitive within the transplant pool because their MELD score is lower.

Nancy S. Reau

We need to concentrate on this data and acquire more data that helps us identify patients we can salvage from transplant through SVR and, in turn, not treat those that can be treated post-transplant because they would be disadvantaged by a pre-transplant SVR.

The other thing I found very interesting was the data presented by Eric J. Lawitz, MD, in which he looked at the amount of resistance-associated variants (RAVs) that can occur after 24 weeks of ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) therapy. In this study, patients with no baseline NS5A RAVs experienced 100% SVR at 12 weeks, while those with baseline RAVs reached SVR12 at 60% and increasing numbers of NS5A RAVs led to a numeric decrease in SVR12. In 12 of the virologic failures, a new RAV emerged.

Even though it’s a small subset of patients that are going to fail, these RAVs can stack up and impact treatment decisions we are making with our current therapeutic arsenal.

Of course, when we get second generation NS5As and second generation protease inhibitors, we will have more options. But when we take these drugs to the real world, we know that our patients’ ability to be adherent is variable or maybe the prescribers don’t fully understand the complexities and the nuances about the length and ideal regimen. These situations can be potentially harmful due to the emergence of new RAVs.

Our guidelines, despite as black and white as we think they are for first-line treatment, need to help practitioners select the right first-line therapy. You really need to optimize that first shot to get a person cured.

At this meeting, we were also privy to quite a few studies of the Merck pipeline drugs — elbasvir and grazoprevir — and they look great. Along with the Gilead next wave of drugs, this looks like a very exciting place to be.

With drugs such as these and the success shown in the smaller RUBY-1 study, renal failure looks like it will be a challenge that will go away. Most of our difficult-to-treat populations are no longer going to be difficult to treat. As research moves on, we will uncover new difficult-to-treat populations, whether that’s patients who fail complicated therapy or individuals who might be harder to retain in care.

These are going to be our challenges along with trying to identify the best way to prioritize treatment. It will remain, though, that treating a patient with cirrhosis is not ideal. You want to treat them before they’re cirrhotic so they lose that risk of cirrhosis and hepatocellular carcinoma and having to be retained in that system. A cirrhotic patient is always my patient. Yet, if I can cure a patient that doesn’t have cirrhosis, then I can send them back to primary care with confidence.

We need to understand the window of budget constraints and how long we have to prioritize and as soon as we don’t have to prioritize because our treatments are that effective, we can rapidly expand our criteria, allowing us to treat more patients.

Michael R. Charlton, MD, FRCP

At the International Liver Congress this year, there have been three main areas of research that can be implemented now in daily practice or are on the verge of implementation.

The obvious one is the management of patients with liver failure and Child class B or C cirrhosis. Here in Vienna, Michael Manns, MD, presented the SOLAR-2 data, a European, Australian and New Zealand consortium using sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) with ribavirin before and after transplant in the sickest patients.

We’ve known for some time now that you can treat HCV infection in patients with Child A cirrhosis successfully. Those patients do very well, but there has been very little data on Child B and C and severe recurrence of hepatitis C following transplant.

Michael R. Charlton

What they’ve shown in a large number of patients (n = 327) in a randomized, prospective, multicentered study is that if you treat relatively compensated people with Child B, you get 95% SVR. Sicker patients, it’s a bit harder. In Child C, you lose about 10% in efficacy; that’s still really good. The data essentially showed the same thing that the North American study did.

The two interesting findings here were that if you do anything from F0 through to cirrhosis in Child A, there’s a 95% cure rate with 12 weeks of treatment. That’s fantastic. To use a non-interferon-containing regimen for 12 weeks with ribavirin and cure well over 90%, it’s an absolutely seminal observation.

In my field, no one really dies of F0 to F3; the people who are dying are cirrhosis and post-transplant. Post-transplant, a third of people die, lose ground or get retransplanted for HCV. With our new treatment arsenal, that should become a minor cause of death. What was our biggest challenge is going to become an area of minor interest. That’s an absolute game changer for patients and practitioners.

And that’s something we can start doing tomorrow because those drugs are approved.

The other major unmet need in treating patients with HCV has been those patients who are also in kidney failure. Though there are studies ongoing with sofosbuvir/ledipasvir, they are not yet complete and have not been presented in a meaningful way.

At this meeting, Paul J. Pockros, MD, presented the RUBY-1 study in which we saw that the combination of ombitasvir, paritaprevir, and ritonavir plus dasabuvir (Viekira Pak; Abbvie) demonstrated favorable tolerability outcomes in patients with chronic kidney disease. Though it was interim data and only two patients have reached SVR12, the patients have not discontinued treatment and no dose adjustments have been required.

Additionally, a poster looking at the combination of grazoprevir and elbasvir (Merck) showed that 99% of patients with HCV genotype 1 and chronic kidney disease achieved SVR12. The SVR rate was very high. It’s great to have a third option when discussing HCV treatment with patients in kidney failure.

When you go into renal failure, these drugs can be very complicated. When you give these drugs to a patient with liver disease and in renal failure, it’s very hard to predict what will happen.

In this study with elbasvir, an NS5A inhibitor, and grazoprevir, a protease inhibitor, there were high SVR rates and extremely good tolerability. That’s very reassuring. That cocktail is not approved yet, but everyone is assuming it will be approved shortly.

If a patient has fibrosis, kidney failure and hepatitis C, most centers in the United States will not perform kidney transplant. The 5-year survival rate if you’re on dialysis is about 50% to 60%. It’s not a death sentence, but it gives you a high possibility of mortality if you have hepatitis C and kidney failure. For that population, this is a real game changer.

You get more tearful patients when you tell them the news about being HCV-negative if they’ve had kidney failure or cirrhosis. It’s a scarring event for people; it’s a different level of response in this group.

While we await data from the sofosbuvir and ledipasvir combinations, this was very encouraging. This will be a nice tool to have.

The third topic is duration of therapy.

In a patient engagement group in our practice, we surveyed patients who have received hepatitis C therapy. We asked them, with no prompting, what their priorities are in treatment. No. 1, by far, was access. These drugs are very expensive; only a fraction of the 1% could afford these out of pocket.

Way down on their list was duration of therapy, but here there has been a big focus on shortening treatment durations with C-SWIFT and others looking at whether we can treat in 4, 6 or 8 weeks. Patients aren’t very concerned with this. Companies and providers are, but the truth is while it may impact how we practice, the studies are showing us that with the tools we have now at least, anything less than 8 weeks is unrealistic as a global approach for genotype 1. This may, of course, change.

For genotype 3, it looks like 8 weeks might be sufficient. The C-SWIFT data presented by Poordad are preliminary, but showed that 93% of patients with genotype 3 treated with grazoprevir/elbasvir and sofosbuvir (Sovaldi, Gilead Sciences) achieved SVR12 after 8 weeks of treatment.

The follow-up isn’t quite long enough to be confident, but it looks promising. We knew that with genotype 1 from the ION-2 study that we could get away with 8 weeks in certain populations and we’re seeing the same thing with genotype 3.

As a provider, I’m not that invested in going from 12 weeks to 6 or 8 weeks. It’s interesting, but the impact is not there. If you’re getting 96% SVR at 6 weeks and 96% SVR at 12 weeks with few patients unable to tolerate a full 12 weeks, the impact on patients is not that great.

You’re not saving any additional lives. You’re just having the same outcome at a faster pace.

Mitchell L. Shiffman, MD

The International Liver Congress proved that we continue to do pretty well in hepatitis C. it looks like we will have a new addition to the marketplace shortly. The grazoprevir/elbasvir data presented here looks strong in high-risk populations, advanced and decompensated cirrhosis.

Mitchell L. Shiffman

All the presentations are showing exceptionally high SVR rates similar to the two- or three-drug combinations we already have, continuing the move toward pangenotypic treatment. In the aggregates put forward by Merck, this looks like a pan-genotypic, very efficacious compound, though like others, it might be weak in genotype 3.

The only genotype that didn’t do well was genotype 6, as seen in the C-EDGE data presented by Stefan Zeuzem, MD, but they had a very small number. They saw four out of six reach SVR12.

The general theme that’s coming out from all of the studies conducted in patients with cirrhosis is that although most patients improve, a small portion do not improve and may actually get worse during treatment and even after achieving a SVR. What everybody keeps talking about is: what is the point of no return? We need to look at all of these studies carefully to see if we can identify factors where patients deteriorate, where their MELD scores get higher despite achieving an SVR. These patients would be best served by going on to liver transplant first and then treating their HCV after the transplant. Clearly, we need to define what that point is

Yet, the SOLAR 2 study presented by Manns showed that all of the patients who went onto liver transplant had an improvement in the MELD scores. That may be counterintuitive. Why did these patients need a liver transplant if they had an improvement in the MELD score? It could be because the MELD was still very high, they had liver cancer, or debilitating symptoms of cirrhosis. The most difficult clinical question when you’re seeing a patient with decompensated cirrhosis is do we treat this patient’s HCV or do we just go to transplant and treat their HCV afterward? Or do we evaluate the patient for transplant and treat them along the way, using transplant as a safety net if they develop relapse?

The first study we saw regarding this was presented at The Liver Meeting in 2014 by Steven L. Flamm, MD. Those results looked fantastic in that about 90% of the Child C patients were achieving SVR. What we saw at this meeting and the general consensus particularly from the HCV TARGET study that K. Rajender Reddy, MD, presented, is that cure rates are not equal across the board. Clearly, the more advanced liver disease you have, the lower the SVR rates. It doesn’t drop precipitously like in the days of interferon, but the SVR rates do decline with worsening Child Class. For someone with Child C, we’re seeing in the upper 70% cure rates with Child B in the mid-80%.

That mirrors my own data on sofosbuvir and simeprevir (Olysio, Janssen) presented at the 2014 American College of Gastroenterology meeting (in press in the American Journal of Gastroenterology). Overall, in our study, we only treated patients with cirrhosis who had contraindications to receiving an interferon preparation. When we started this study, the approved treatments were sofosbuvir, PEG-ribavirin or simeprevir and PEG-IFN. We treated 120 consecutive patients with sofosbuvir/simeprevir. The overall SVR was 82% by intention-to-treat and 87% by a per-protocol analysis. Clearly, if you took the entire 12 weeks of treatment you did a bit better.

What we did show was very similar to what’s coming out of this meeting. The more advanced cirrhosis you have, the more the SVR drops off. Approximately 90%, 80% and 70% for Child A, B and C, respectively.