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The Liver Meeting 2016

The Liver Meeting 2016 featured a wealth of data once again focused onon the new and emerging treatments and trends in hepatitis C. That so much can still be emerging testifies to the universal goal of curing every infected patient, including those who have failed our remarkable first-generation interferon-free direct-acting antiviral (DAA) regimen, and to accomplish this with the shortest duration of treatment if it can be done without compromising the opportunity for cure. Even after the quantum leap engendered by the advent of DAA regimens, new issues have emerged such as the chilling possibility that virologic cure might enhance the risk of recurrent liver cancer in patients previously treated for it, with some concerns raised (and addressed) about de novo cancer. The recent observation that hepatitis B can reactivate when HCV is rapidly suppressed after initial exposure to DAA therapy has resulted in a new warning within the labels for our current regimens and garnered much attention at The Liver Meeting. “Real world” studies continue to provide important information generally verifying the high level of efficacy demonstrated in trials. And, pressing needs such as linkage to care and expansion of the pool of providers were also a focus of interest.

HCV Next also spoke with Editorial Board members Paul Pockros, MD, director of the Liver Disease Center of the division of gastroenterology/hepatology at Scripps Clinic and clinical director of research at the Scripps Translational Science Institute, and Susanna Naggie, MD, associate professor of medicine at Duke University School of Medicine, about their take on the HCV presentations at the meeting. Additionally, we spoke with Paul Martin, MD, professor of medicine and chief of the division of hepatology at the University of Miami, about what is stirring beyond HCV.

– Ira M. Jacobson, MD

Co-Chief Medical Editor

HCV Next

Paul Pockros, MD

There were important and very exciting data presented at The Liver Meeting this year. In all, there were more than 480 abstracts about HCV.

Though we have amazing response with our current treatments, there were a few new therapies outlined at this meeting, each of which serves a unique purpose.

First, multiple abstracts covered glecaprevir/pibrentasvir (GP, AbbVie). We saw data EXPEDITION-4, ENDURANCE-1, SURVEYOR-2, ENDURANCE-2, ENDURANCE-4.

Overall, the studies showed that 97.5% of patients treated with GP for 8 weeks had an SVR, clearly showing a path forward for an 8-week regimen of a dual therapy without ribavirin that’s very, very effective. That will be important when it’s approved hopefully next year.

Of note, the data is in all genotypes but without cirrhosis. So while the presenters showed upwards of 97% and 99% SVR in all genotypes, a separate study called EXPEDITION-1 is ongoing in patients with cirrhosis, so it remains to be seen whether they will benefit.

Still, we will always sort out who has cirrhosis and who does not. If you can treat everybody who doesn’t have cirrhosis with an 8-week regimen that works for all genotypes without using ribavirin, that’s pretty compelling.

Additionally, Edward J. Gane, MD, showed important data on patients with chronic kidney disease. We have an approved direct-acting antiviral therapy for patients with end-stage renal disease in genotypes 1 and 4 — elbasvir/grazoprevir (Zepatier, Merck). However, all the other genotypes have unmet needs because our only approved treatment is pegylated-interferon and ribavirin. In showing the success in renal failure patients in all genotypes, presumably the approval will include for all genotypes regardless of renal disease. This would greatly help the patients reaching out to us about those other genotypes in end-stage renal disease. Of course, in this patient population, the data was at 12 weeks of therapy, not 8 weeks, so we will need to stay aware. In cirrhosis, we may see the same pattern of treatment.

Also, looking at treatment failures, the GP studies included interferon-ribavirin failures, sofosbuvir (Sovaldi, Gilead Sciences)-interferon-ribavirin failures, but they did not include NS5A failures. So, we don’t know if this regimen will be suitable for patients who fail an NS5A regimen. It likely will not serve as a salvage regimen, but that’s expected as it’s only a two-drug regimen.

That leads to the POLARIS study of sofosbuvir/velpatasvir (Epclusa, Gilead Sciences) plus voxilaprevir (Gilead Sciences). There was a bit of disappointment with this combination because their 8-week regimen did not meet the primary endpoint of noninferiority that they were trying to achieve. That means you would have to use 12 weeks of the regimen. They were hoping, I think, to shorten it to 8 weeks as an advantage over what they currently offer.

This doesn’t offer any advantage. They’ve answered the previous questions in hard-to-treat populations with sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) and sofosbuvir/velpatasvir. Those two combination drugs are effective in all genotypes. You can prescribe 12 weeks of therapy and, with sofosbuvir/ledipasvir, you can prescribe for 8 weeks in the population without cirrhosis with a viral load < 6 million IU/ml.

It is likely that sofosbuvir/velpatasvir/voxilaprevir will be a salvage regimen as the data clearly points to that path. POLARIS included the most NS5A failures we’ve ever seen in any study (415 patients). That’s huge and they also studied 333 patients who failed other DAAs that were not NS5A containing regimens. Furthermore, the POLARIS studies also included compensated cirrhotics.

Lastly, is another triplet combination: grazoprevir/MK-8408/MK-3682 (Merck) or MK-3. In these studies, investigators showed a large number of patients with compelling SVR rates, but is was a complicated study.

In C-SEARCH, They looked at 8, 12 and 16 weeks, prior DAA exposures. With 94 patients that had NS5As, they showed 98% SVR with 16 weeks plus ribavirin and 100% SVR at 24 weeks without ribavirin. It clearly shows that this will be a salvage regimen for patients who have failed NS5A, which is an improvement over the current offering of NS5A drugs.

This regimen looks great in genotypes 1, 2 and 3, but they didn’t show other genotypes. They showed safety in the compensated cirrhosis cases and it was not tested in decompensated cirrhosis. (Many of these new triplet regimens include a protease inhibitor, so no one is anxious to do test them in patients with decompensated cirrhosis.)

In the C-ISLE study presented by Graham Foster, MD, we saw the efficacy of using the quad therapy of grazoprevir/elbasvir/sofosbuvir/ribavirin in patients with genotype 3 and cirrhosis. That’s great news, but we can’t get it for our patients in California. Payors will not approve 2 different DAA regimens at the same time as this is off-label.

By this time next year, I don’t think we are going to be discussing NS5A-experienced patients. Basically, NS3-experienced patients have had no different response to any of these regimens so that resistance is not posing an issue any longer. I think by this time next year, NS5A won’t be deemed a complication either. I’m not sure we will have anything important regarding resistance to focus on during next year’s meeting.

On the subject of monitoring patients, there was an important presentation regarding Fibrotest (BioPredictive) and Fibroscan (Echosens). Maria F. Donato, MD, showed that in her practice, they are reversing sinusoidal fibrosis without a parallel decrease in fibrosis. It really resonated with me because we are also seeing varices disappear and we are seeing patients’ Fibroscans get better, but if their cirrhosis is reversing, it’s only reversing to stage 3. It’s a word of caution to those using Fibroscan to release a patient from further monitoring for HCC.

Richard K. Sterling, MD, MSc, FAASLD, presented data on transmission and outcomes of HCV-positive donor kidneys transplanted into HCV-negative recipients. The data he showed was concerning, but it’s a new ballgame now that we have DAAs to be given post-transplant. He is going to do a study and it needs to be done because it’s a lot of kidneys that we could be utilizing.

On the hot topic of hepatocellular carcinoma and its linkage to DAA therapy, Andrew J. Muir, MD, FAASLD, showed more than 1,000 patients in the Gilead database remained in SVR and the incidence of HCC was 0.5% compared to the historical risk of 2.5%. He also showed reversal of Child-Pugh scores. To me, that made sense. The data from Canada supported the same idea of SVR reducing the risk of HCC but not eliminating it. The data from Italy also confirmed this, though the idea of an infiltrative three nodules type of HCC being more prominent in DAA patients was concerning. That seems like biologic behavior of a bad tumor, though, and may have no connection to DAAs.

Overall, I would have thought that a large database like Gilead’s would have picked up a signal between DAAs and HCC if it was real. That’s a lot of people with SVR and they were following them specifically for liver cancer.

More concerning, for me, was the presentation from Sally A. Tran, and Mindie Nguyen, MD, MAS, FAASLD, that says no one is getting screened. They showed that only 18.8% of patients received “optimal” screening every 6 months for HCC in a year of follow-up. Conversely, 45.8% fell into the “very poor or none” category. We need to improve those rates.

Susanna Naggie, MD

In the HCV sessions, by far the pending next generation programs moving forward took the spotlight. There are two general approaches with either dual or triple therapies being the focus.

It seemed that the GP combination was center stage here in Boston. It performs very well and is a very safe combination in patients without decompensated liver disease. It’s pangenotypic and a fixed-dose combination. It is a three-pill combination, but wow. The researchers reported high SVR after 8 weeks in those without cirrhosis and 12-16 weeks in some special populations such as those with renal impairment including hemodialysis and difficult to treat genotype 3 infected patients. Which cirrhosis study from AASLD is referred to here? The Endurance studies were mostly noncirrhotic. I think the statement is true, but it should be referenced to the latest available data.

We also had a chance to see phase 2 data with the triple regimens.

Sofosbuvir/velpatasvir/voxilaprevir looks to be a great salvage regimen, as will MK3682+MK8408+grazoprevir, as mentioned previously. Still, I have my reservations about triplet regimens overall and when they should be used.

Looking forward, we have some great first-line dual regiments. That’s what GP will become, and already approved we have ledipasvir/sofosbuvir, sofosbuvir/velpatasvir and grazoprevir/elbasvir. Dual therapy will probably be the primary approach to treatment and then the triples will be behind them to salvage those that fail (and there are so few of those).

What we are starting to see is when the triples fail, people don’t fail with resistance, which is different than what we see with the dual regimens. Even with a sofosbuvir backbone, which has a high barrier of resistance, the high barrier isn’t conferred for the regimen as a whole in that when you fail, you still fail with NS5A resistance.

In the studies presented here, both triples did not have resistance at the time of relapse or viral breakthrough and that’s an appealing aspect to think about if this remains true as more data come in.

That being said, my HIV training makes me wary. If you don’t need a third drug, why use it? When you add a third drug, there’s a risk of toxicity or drug-drug interactions that may be more complicated. With the three together in sofosbuvir/velpatasvir/voxilaprevir, we saw an increased incidence of diarrhea compared to sofosbuvir/velpatasvir alone. It is a sign of possible toxicity, while not serious, but this is a burden patients have to bare.

What I would see as more likely is that we keep those triples for salvage and use these really well tolerated dual regimens as our primary therapies.

It also remains to be seen how the FDA approves these new regimens. If the triple regimens are approved for treatment-naïve patients, then some providers will use them as first-line treatment. Or perhaps we will consider those patients with multiple negative baseline predictors to push us toward the triple regimens from the beginning. It did make me feel better that resistance does not seem to be an issue with the triple regimens, but I think for the vast majority of patients only 2 drugs are needed.

If you treat HCV/HIV coinfection, the take home from this meeting was there wasn’t a single coinfection presentation on the podium. Yet, there were studies with HIV patients in them. This is what we are seeing.

The FDA has removed HIV as a population of unmet need. For example, when sofosbuvir was approved, part of the post-marketing requirement for the FDA was that they conduct a study with HIV patients.

Now the bar for approval is different and they view DAAs differently. Studies may only include 3% to 5% patients with HIV. In the G/P study, for example, there were just 20 patients with HIV.

My concern is that patients with HIV will become another minority population. In some ways, it’s a step forward, but given the nuances around safety and drug interactions, we may be limiting our knowledge of how antiretroviral and HCV antiviral medications interact in actual patients.

Once you include a protease inhibitor in an HCV treatment, the number of antiretrovirals that you can use is limited. For the majority, if not all of, the regimens pending NDA submissions choices of compatible antiretrovials are few, primarily unboosted integrase inhibitors (dolutegravir or raltegravir) or rilpivirine. You can’t have ritonavir or cobicistat. You can’t have protease inhibitors. You’re now looking for patients with HIV where you there are fewer ARV options. These triple regimens may not be as feasible for heavily experienced HIV patients, which argues for a need on more data not less. If we as clinicians don’t have enough safety data and we will be limited on how we can apply these next generation treatments in the HIV population.

We did have a poster showing that real-world data from four cohorts showed the same SVR rates in HIV coinfection as those in clinical trials, confirming that HIV patients achieve the same cure rates, but drug interactions remains the critical difference that must be understood to manage these patients and ensure they have the access they need to HCV curative therapies.

In the Medicaid session, Robert Greenwald of Harvard’s Center for Health Law and Policy Innovation, presented the group’s report on access to HCV treatments. In general, it’s good news and things are opening up. You’re seeing the shift to decrease the restriction on fibrosis, but less so on alcohol and drug use or allowable prescribing providers. Medicaid is still maintaining restrictions on providers, social habits and stigmas. We have a long way to go. There are still a lot of states restricting by fibrosis—too many.

Other studies came out showing that once you have severe fibrosis, you are at a higher risk of developing liver cancer even after a cure. In the Canadian cohort presented here, they showed a 2.5-fold increased risk of developing HCC if cirrhosis is present. This means that those insurers restricting access to F3/4 fibrosis are asking patients to assume this risk of liver cancer for 8 to 10 years or longer. That data is important to make a selling point: patients with severe liver disease have an irreversible risk. We need continued evidence that this restriction on treatment due to fibrosis is hindering patient health.

Additionally, we had the ASCEND trial in a predominantly African American population who were sent to either a nurse practitioner, general practitioner or specialist and the researchers showed there was not a significant difference in SVR rates. Interestingly, there was a significant difference in adherence to visits, with NPs (73%) outperforming the primary care (63%) and specialist physicians (56%).

Similarly we saw several reports from VA data. The VA (similar to the ASCEND trial noted above) reflects providers who are not just specialists. There are general practitioners, internists, physicians’ assistants on the front lines of treatment HCV in the VA. In many ways, the VA results may be the most real-world of any we’ve seen.

In a Duke University study, they saw 94.9% SVR12 after ledipasvir/sofosbuvir while a University of Washington study showed just 92.8% SVR12 in 2015 with both ledipasvir/sofosbuvir and paritaprevir/ombitasvir/ritonavir/dasabuvir (Viekira Pak, AbbVie). Our expectations are so high at this point that many of us would say that 92% is sufficient. With this mix of providers, we need to figure out how we get up to 97% and 98%. I’d like to believe in this day and age, regardless of comorbidities, we can get people through and cure them all.

The last topic was cancer in the setting of DAA therapy. There has been a lot of concern about reports suggesting an association with DAA therapy and cancer. We should never ignore potential signals of safety, but at this point in time, we have several publications from the last 6 months and some podium presentations here that suggest this is not a signal at all. We need to continue to collect additional data and hopefully get to a point where we all feel comfortable that these drugs don’t actually cause cancer, but are being used in very high risk patients who are at risk of developing cancer as part of the natural history of their disease.

• References:
• Chan AW. Abstract 931. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Donato MF. Abstract 256. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Emmanuel B. Abstract 22. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Foster GR. Abstract 258. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Gane EJ, et al. Abstract LB-11. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Ioannou GN. Abstract 21. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Janjua NZ. Abstract 175. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Muir AJ. Abstract 880. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Naggie S. Abstract 892. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Romano A. Abstract 19. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Sterling RK. Abstract 178. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.
• Tran SA. Abstract 57. Presented at: The Liver Meeting; Nov. 11-15, 2015; Boston.

• For more information:
• Ira M. Jacobson, MD, can be reached at 10 Union Square E #2g, New York, NY 10003; email: ijacobson@CHPNET.org.
• Susanna Naggie, MD, can be reached at 40 Duke Medicine Circle, Clinic 1K, Durham, NC 27710; email: susanna.naggie@duke.edu.
• Paul Pockros, MD, can be reached at 10666 N Torrey Pines Rd, La Jolla, CA 92037; email: Pockros.Paul@scrippshealth.org.

Disclosures: Jacobson reports financial relationships with AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Intercept and Roche. Naggie reports financial relationships with AbbVie, Bristol-Myers Squibb, Gilead, Jenssen, Merck and Tacere. Pockros reports financial relationships with AbbVie, Beckman Coulter, Bristol-Myers Squibb, Gilead, Intercept, Janssen, Lumena, Merck and RMS.