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The Take Home: Digestive Disease Week 2014

Issue: July/August 2014

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Each year, Digestive Disease Week brings together an international group of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy and Society for Surgery of the Alimentary Tract, the 2014 conference showcased more than 5,200 abstracts and hundreds of lectures on the latest advances in research, medicine and technology from each of DDW’s sponsoring societies.

HCV Next was onsite during the meeting and spoke with several experts about exciting data and sessions that provide insight into the management and treatment of hepatitis C virus. Among them were Bruce R. Bacon, MD, professor of internal medicine and co-director of the Liver Center at St. Louis University School of Medicine, and HCV Next Editorial Board members Douglas T. Dieterich, MD, professor of medicine in the division of liver disease at Icahn School of Medicine at Mount Sinai; Paul Y. Kwo, MD, medical director of liver transplantation in the gastroenterology/hepatology division at Indiana University; Paul J. Pockros, MD, director of the Liver Disease Center in the division of gastroenterology/hepatology at Scripps Clinic and clinical director of research at the Scripps Translational Science Institute; and Nancy S. Reau, MD, associate professor of medicine at University of Chicago.

Paul Y. Kwo, MD

At this conference, there were several landmark presentations regarding therapeutic efficacy in HCV. Two very important studies presented here were SAPPHIRE-II and ION-2. Both treatment trials looked at their respective direct-acting antiviral (DAA) agents in the treatment of patients who had failed pegylated interferon- and ribavirin-based therapies.

Paul Y. Kwo

SAPPHIRE-II evaluated the NS3/4A protease inhibitor ABT-450 dosed with ritonavir (ABT-450/r) plus the NS5A inhibitor ombitasvir and NS5B RNA polymerase inhibitor dasabuvir (all AbbVie) with ribavirin. This is a study that examined the efficacy in treatment-failure patients, predominantly nonresponders to pegylated interferon and ribavirin. Importantly, cirrhotics were not included in this study; they were treated in a separate study. Overall, outstanding sustained virologic response rates were seen with 12-week durations. SVR rates were above 95% in both genotypes 1a and 1b. The regimen of the combination DAAs was well tolerated. Importantly, this was a placebo-controlled trial. There was a 12-week observation period during which therapy was delayed for a certain percentage of the cohort. The majority of side effects were attributed to the known side effects of ribavirin, which is part of the regimen. This was identical in results to the phase 3 SAPPHIRE-I study presented at International Liver Conference, the annual meeting of the European Association for the Study of the Liver (EASL), in which, again, identical SVR rates were seen in genotype 1 treatment-naive patients with HCV. This demonstrates that we go into the era of DAA agents, we are finding that when you add potent DAAs together previous treatment history becomes irrelevant and you can get high SVR rates regardless.

Another important study presented was ION-2. Four hundred forty patients were randomly assigned a fixed-dose formulation of sofosbuvir (Sovaldi, Gilead) and ledipasvir (Gilead) with or without ribavirin for 12 weeks, or sofosbuvir and ledipasvir with or without ribavirin for 24 weeks. This was a treatment-failure population which included patients with cirrhosis. Outstanding SVR rates were seen, ranging from 94% to 99%. The addition of ribavirin did not make a difference in the overall efficacy rate. ION-2 demonstrates that the majority of individuals can be treated safely with a 12-week course of sofosbuvir and ledipasvir. A subanalysis suggested that 24 weeks may offer some advantage in treatment-experienced cirrhotic patients. This provides the first large clinical trial that examines the efficacy of a combination to treat patients who have failed the previous first-generation protease inhibitors telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck), prior exposure to which did not have any impact on the likelihood of SVR.

At DDW, we saw other presentations, including many helpful symposia on special populations. One of the take-home messages for treating clinicians is that DDW, in combination with the recent EASL conference, have shown us that the therapeutic challenges have largely been solved. We are soon going to have all-oral therapies available for all of the genotypes, 1 through 6. The challenge will be to make sure we have access to patients and now go into patient populations that we have previously neglected simply because they couldn’t tolerate the previous pegylated interferon/ribavirin backbone. There were symposia on the elderly, those who use injection drugs, those with renal disease, those who are post-transplant, and other difficult-to-treat patients. There were also presentations on efforts to treat prisoners, as well as other genotypes. These are all efforts as we move into the era of new DAA agents that are going to be necessary for us to be able to treat and reduce the burden of HCV in the United States and globally. Therapeutically, we have largely solved HCV. There are still some populations, including those with genotype 3, that remain somewhat of a challenge. In addition, patients with advanced fibrosis may require additonal therapeutic strategies, as preliminary data suggest that such patients seem to have lower SVR rates. Again, it will likely be that the combination of DAAs will be required to achieve SVR in these individuals, and of course will require additional follow-up. As we move forward in the next year though, one can expect that we will have approval of multiple DAAs that will allow us multiple options to treat our patients. This is a good time to screen your patients and let them know they are going to have highly effective, well-tolerated therapies available, regardless of any comorbidities that they may have.

Bruce R. Bacon, MD

One of the most exciting concepts going around at this meeting and [recently in April] at [EASL] are the tremendous advances in treatment of viral hepatitis with the new interferon-free regimens. At DDW, we have seen results of the AbbVie ‘3D’ three DAA combination plus ribavirin showing in all groups — previously treated, treatment-naive, cirrhotics — very high cure rates better than 95% with a minimum of side effects and a short duration of only 12 weeks of treatment in the SAPPHIRE-II study. [The regimen] was very well tolerated, very effective and very exciting.

Bruce R. Bacon

We also saw at this meeting and at EASL the presentation of the ION-2 study looking at the combination of sofosbuvir and ledipasvir coformulated into a single pill for either 8 or 12 weeks and showing high cure rates above 95% in all groups, except cirrhotics, previously treated patients whose cure rates are not as high with 12 weeks of therapy. For treatment-naive patients with mild disease, 8 weeks [of treatment] seems  to be an effective treatment duration. I’m not sure how that’s actually going to play out, whether we really will only treat patients for 8 weeks or not, but it shows where we are pushing the bar and trying to get out of the envelope to reduce duration of therapy even further. These medicines were well tolerated without any significant side effects.

Douglas T. Dieterich, MD

I presented data at DDW on faldaprevir from a meta-analysis of the four phase 3 STARTVerso trials, and the results included the HIV-infected trial. Faldaprevir (Boehringer Ingelheim) is a protease inhibitor, a one-pill-once-a-day regimen with relatively few side effects. It is a second-wave protease inhibitor used with pegylated interferon and ribavirin. The pooled analysis included four studies in the phase 3 program: STARTVerso 1, 2, 3 and 4. STARTVerso 1 and 2 were conducted in treatment-naive patients looking at 24 vs. 48 weeks of treatment at 120 mg or 240 mg, STARTVerso 3 was in previously treated patients and STARTVerso 4 was in HIV-coinfected patients.

Douglas T. Dieterich

A meta-analysis was performed of all of the factors that were statistically associated in a logistic regression analysis with SVR12. The most surprising finding was that HIV was associated with a much-increased rate of SVR, with an OR of 1.68. That was equivalent to other statistically significant factors like HCV genotype 1a vs. 1b, fibrosis score of 0-2 vs. 3-4, and viral loads of <800,000 IU/mL vs. >800,000 IU/mL. Really interesting was that the demographics of the coinfected patients predicted a much poorer response than monoinfected patients; there were more blacks, more cirrhotics and fewer patients who had the IL28B CC genotype than the monoinfected trials. There was a subanalysis that removed the patients in the coinfected trial who were taking boosted atazanavir (Reyataz, Bristol-Myers Squibb) with ritonavir or Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate, Bristol-Myers Squibb and Gilead) or efavirenz-containing regimens because those patients weren’t randomized, they were allocated to their particular dosage groups. Even when we removed those patients, the OR was still statistically significant.

Overall, in conclusion, there was no difference in dosage, 120 mg vs. 240 mg, of faldaprevir and being HIV-positive was a significant positive predictor of SVR. The only hypothesis we can think of to explain this is that adherence in the HIV patients is better. This represents a reinforcement of previously published data in Clinical Infectious Diseases that showed the same thing, as well as our real-life data from Mount Sinai. This is very encouraging news for HIV patients coinfected with HCV: Response rates are as good as, or better than, those who are not infected with HIV.

Nancy S. Reau, MD

Nancy S. Reau

DDW is a natural time for societies to come together and release impactful data or exchange best practices. This year’s meeting was a wonderful recap of the rapid evolution in HCV therapy. With the next wave of therapy, HCV treatment is going to become much easier and shorter in duration. Baseline characteristics and traditional special populations are becoming less important. There aren’t as many special populations for HCV treatment anymore.

Ira M. Jacobson, MD, presented an oral abstract on the association between sofosbuvir-based regimens and high SVR rates across genotypes and among patients with multiple negative baseline predictive factors. The research group performed univariate and multivariate regression analyses on 868 treatment-naive patients with HCV and looked only at groups that received what is now considered standard of care. [The study included patients with genotype 1 who received sofosbuvir with pegylated interferon alfa plus ribavirin for 12 weeks, patients with genotype 2 who received sofosbuvir with ribavirin for 12 weeks and patients with genotype 3 who received sofosbuvir with ribavirin for 24 weeks.] The data showed that in order to really lower efficacy consistently, you needed to have at least four baseline negative predictors; anything less than that and efficacy was still incredibly high. [The six negative predictors associated with relapse among patients included: male gender, weight of at least 75 kg, IL28B non-cc genotype, cirrhosis, baseline HCV RNA ≥800,000 IU/mL and previous treatment failure. Ninety percent or more of patients in all genotypes still achieved SVR when they had three or fewer negative predictors. SVR rates declined among patients with five or more negative predictors.] These results show that traditional markers of failure are really losing importance.

Also of interest, although not HCV-related, was an abstract presented looking at mortality in fatty liver disease, which showed that lean people with fatty liver disease had a higher rate of mortality. This suggests that not all fatty liver is the same. If a patient is thin and has fatty liver disease, it is probably a very different condition than if he or she has metabolic syndrome and is obese. I think we have traditionally felt that fatty liver disease was a catch-all, and this is the first time it is suggested that maybe the trajectory of diseases are not the same.

Paul J. Pockros, MD

The most important news coming out of DDW this year were the recaps of data presented at EASL, such as that from the ION and SAPPHIRE programs. In short, the cure rates were more than 95% for both the Gilead and AbbVie regimens, and they are all-oral, well-tolerated and we can often give them without ribavirin. However, there are nuances. When you look carefully at the data, it looks like treatment-naive patients without cirrhosis will be able to be treated with the Gilead regimen for 8 weeks, but those with cirrhosis may need 12 weeks of treatment. It remains to be seen whether patients who have previously failed treatment and have cirrhosis are better off getting 24 weeks. It will be an interesting aspect of the labeling from the FDA to see what they do about that. It is very clear in looking at the AbbVie regimen in patients with HCV genotype 1a, that cirrhotics and null-responders do better with 24 weeks of treatment. My guess is that it will be differential labeling of the drugs for different populations.

Paul J. Pockros

Our research presented during a poster session by Kendall Van Keuren-Jensen, PhD, aimed to profile and compare circulating microRNA patterns among patients with chronic HCV and fibrosis stage 0-2 vs. 3-4 prior to antiviral therapy. We studied serum samples from 83 patients with chronic HCV from Scripps Clinic and Mayo Clinic Arizona. The goal of the study was to use microRNAs from serum and tissue to determine whether it would correlate with the degree of fibrosis. We came up with an algorithm that would predict fibrosis from serum samples. We detected 11 differentially expressed circulating microRNAs after multiple testing, and established a pattern that separated patients with fibrosis 0-2 vs. 3-4. These findings suggest that we may be able to establish a circulating microRNA pattern to identify patients with more advanced stages of fibrosis. This is another effort to come up with a way to predict fibrosis without sticking a needle in the liver.