Paul E. Sax, MD; David L. Thomas, MD, MPH

Disclosures

March 24, 2014

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Hepatitis C: A Disease That Straddles 2 Worlds

Paul E. Sax, MD: Hi. This is Dr. Paul Sax from Brigham and Women's Hospital and Harvard Medical School. Today we have a very special guest, Dr. David Thomas, Chief of Infectious Diseases and Professor of Medicine at Johns Hopkins University. Our topic will be hepatitis C virus (HCV) infection.

Dave, why don't we start by talking about the new guidelines[1] that were issued at the beginning of 2014. Why the new guidelines? What are the key messages, and what can we expect going forward?

David L. Thomas, MD, MPH: That's a great question, Paul. The reason for new guidelines is that we anticipate a season in HCV when there will be a string of new developments, in particular the approval of new antiviral therapies for HCV infection. The pace of drug development made the old process -- developing guidelines over a year and a half and having various stages of approval by every vested entity, followed by the publication of those guidelines in a peer-reviewed journal -- very impractical and not likely to be helpful, and it guaranteed that they would always be months, if not years, out of date.

That inevitability led a number of individuals from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) to partner with the International Antiviral Society to develop guidance that would be available right when you need it, yet enabling the guidance to be updated using the Web so that it would be current -- which is really the way that medicine is practiced nowadays anyway.

Dr. Sax: It's an interesting collaboration and it brings up something that I have always found very interesting about HCV, which is that it straddles 2 worlds, sometimes more in one world than the other. Those are the worlds of the gastroenterologists and the infectious disease specialists. How did the process go for the 2 groups together?

Dr. Thomas: Historically, the AASLD has provided the most authoritative guidelines for HCV management. That was logical, because even before the virus was discovered, it was known to be a liver disease primarily because individuals would have persistently elevated liver enzyme levels and eventually would develop cirrhosis. So, historically, the liver societies have embraced the condition, and after the discovery of the virus, that didn't change substantially. But all along, some infectious disease specialists were interested in HCV, of course, because it is a viral infection and they wanted to participate in the care of patients. So it was inevitable that there would be a partnership like this.

It actually went amazingly well. The AASLD recognized that, because of our experience with HIV, the IDSA (and infectious disease specialists in general) had some experience with rapid development of new therapies and the use of online guidelines, such as what we use for antiretroviral agents. So it was a natural partnership for a society that historically had the authoritative information on HCV to partner with another society with a vested interest that also had experience with rapid updates for antiviral therapies.

Dr. Sax: That makes a lot of sense. One thing that you have probably noticed, because you have been interested in HCV for a long time (but many infectious disease doctors are coming to relatively recently), is that the infectious disease clinicians, especially those who manage HIV, take to this very readily for the reasons that you describe.

Dr. Thomas: It has been very interesting. There has been a rapid -- especially in the last year -- uptick in interest in treating HCV. It's expanding quickly, especially among HIV providers. That's logical. Previously there was a bit of an impasse on the use of interferon. Infectious disease specialists often weren't trained in using interferon and felt uncomfortable with it, and also questioned to some extent the risk-benefit ratio for the patients. But that has changed with the use of direct-acting antiviral agents with which we are extremely comfortable and experienced.

Recommending a Not-Yet Approved Regimen

Dr. Sax: If I could put you on the spot: What aspect of the guidelines would you say -- and I mean you personally, because I know you can't speak on behalf of the guidelines -- was the riskiest and most important recommendation that you made?

Dr. Thomas: The most interesting aspect of the guidance that was initially put on the Website at the end of January is the recommendation to use simeprevir and sofosbuvir for the treatment of genotype 1 hepatitis C infection in persons who are intolerant to interferon. The reason that I mention that particular recommendation is that these 2 drugs were not approved by the US Food and Drug Administration (FDA) to be used together. However, each drug has had substantial preclinical and clinical testing to be used with interferon and ribavirin. We had presented (but not published) data[2] in 167 patients on the efficacy of that combination with or without ribavirin. So that brought an interesting element into the recommendations -- in particular, what we would do with the fact that the FDA hadn't yet had a chance to fully consider phase 3 data for this combination. But we had extremely compelling data that had been presented publicly, on 167 patients treated with this combination, and in one of the most difficult-to-treat and important patient groups. So I found that one to be very interesting.

Dr. Sax: Yes, I would completely agree. When the 2 drugs were approved, I was able to poll some readership of the Massachusetts Medical Society blog that I write and ask what readers thought was the recommended treatment for genotype 1 patients. Most chose that exact combination. So, clearly we are heading toward an interferon-free future, and we are already there, so this is a very difficult question to answer. (That's why I get to ask the questions and you are Chief of Infectious Diseases at Johns Hopkins.) What would you say is the next wave of drugs, and how are they going to be used? You don't have to state agents specifically, but feel free to just talk about trends.

Dr. Thomas: There are additional regimens that have completed phase 3 testing and are under consideration by the FDA. We are anticipating that we will have interferon-sparing regimens for genotype 1 HCV that are fully vetted and approved for that indication. Those should be available in 6 months or so, so that is easy to answer and quite exciting. Right now, we already have FDA-approved, interferon-sparing treatments for genotype 2 and genotype 3 HCV infection, but with most patients in the United States having genotype 1 (and especially in some locations such as Baltimore, where more than 85% of HCV is genotype 1), there is substantial interest in a fully vetted FDA-approved genotype 1 interferon-sparing regimen. That is exciting in the near term.

Dr. Sax: l will mention some of the drugs that are currently being considered. One is a 3-active agent, but 4- or 5-drug regimens are being developed by AbbVie. You are familiar with those. Give me a sense of where you see them fitting in.

Dr. Thomas: That regimen and the medications that Gilead has developed -- a coformulation of 2 medications -- are exciting developments for treatment of genotype 1 infection. On the basis of what we have seen published and presented on those medications, I estimate that they will become very important parts of our formulary and our approach to genotype 1 HCV infection as soon as this fall.

HCV Guidance: An Intentional Work in Progress

Dr. Sax: That's very exciting. Are there any particular parts of the guidelines that you think deserve to be mentioned, perhaps about special populations or the treatment of patients who have previously failed treatment or had no response?

Dr. Thomas: The guidelines are a work in progress, and that is intended. In the initial phase there is guidance on the initial treatment of patients with all HCV genotypes. There is also information on re-treatment for patients with all genotypes. There is information on some special populations, including, for example, HIV-coinfected patients, patients with renal disease, and patients with cirrhosis. It is not so much a cookbook as a strong recommendation to refer patients with more advanced disease to liver specialists for transplantation evaluation. That's the kind of information in the guidance. In addition, there is information on testing, screening, and linkage to care.

What is coming will be information on whom and when to treat. Right now the guidance that is available says that if you are going to treat, this is what you should use to treat the patient. It doesn't actually say which patients should be treated right now and how we would sort that out. That information, which is very important, should be forthcoming in about 3 months. In addition, there should be some new information on the management of patients with acute HCV infection and the critical question of what is the best way to monitor someone while they are on treatment and after treatment. So that is what's coming and what is there already.

HCV News From CROI 2014

Dr. Sax: It is a very dynamic area of both research and clinical practice -- the two of them going in parallel. It's really quite exciting. We just had the Conference on Retroviruses and Opportunistic Infections (CROI) up here in Boston, and I apologize on behalf of our city for the weather that we threw at you. What did you think were the most interesting stories in basic science research or clinical research from CROI related to HCV?

Dr. Thomas: There were many very interesting HCV presentations at CROI. There was additional information on several different interferon sparing-regimens both in patients with HIV and those without HIV. That is exciting, and it was exciting to see the incremental progress in the field. One that stands out was the presentation of the so-called SYNERGY trial.[3] That study was done at the National Institutes of Health, where they tested the hypothesis that therapy could be abbreviated to 6 weeks in patients who were given very potent medications right from the beginning. They were given a nonstructural 5A (NS5A)-acting medication along with a nucleotide inhibitor in all instances, and then patients in 2 arms were given either a protease inhibitor along with that or a nonnucleoside protease inhibitor -- another way of inhibiting the polymerase. The hypothesis was that by acting in multiple steps in the viral life cycle, and doing that quickly, we might be able to abbreviate therapy. There are 20 patients in those 2 arms and then another 20 patients who received what you might consider the standard of care, which was the NS5A drug ledipasvir, along with the nucleotide inhibitor sofosbuvir.

Dr. Sax: It's funny that you would say that's the standard of care.

Dr. Thomas: Yes. It's funny because it's not FDA-approved and it's probably a misuse of the word "standard of care," but it's the gold standard because that medication has gone all the way through phase 3 testing, and we have a real strong sense of what would happen with the use of that medication for 8-12 weeks. That is the control population. What happened was that either 19 or 20 out of the 20 patients had sustained virologic responses in those 6-week arms.

That was very interesting in the sense that we are starting to push the envelope on just how short therapy can be and still be effective -- something that we didn't know beforehand. A year and a half ago, I don't think anyone who was honest would have predicted that we could abbreviate therapy that much and still have a very low relapse rate.

It really brings up a basic science question, which is, why is that? What is it about the RNA template -- the source of new viruses -- that we thought would be stable in a hepatocyte and endure there? Therefore, if you don't kill the cell and that RNA template is allowed to persist, it would form the basis for relapse, which we see even with 6 and 12 months of suppressed viral replication in other contexts. So that information is very interesting, and it starts to shake up our understanding not just of how we approach treatment but also what is going on inside of those cells with this RNA virus.

Dr. Sax: That is very exciting. I thought the coexistence of that study on the same program with some interferon-based regimens was like the most evolved humans and dinosaurs roaming the Earth at the same time. It really did strike a very big contrast.

Dr. Thomas: That's a great metaphor.

Dr. Sax: Is there anything else you want to say before we finish with what we can expect in the future?

Dr. Thomas: The focus of this interview was the Internet-based guidance, which you can find at http://www.hcvguidelines.org/. I would just encourage providers to consider that as a source of information when they have questions about HCV treatment, especially if they are not able to keep up on everything or they are not a really active provider. That is a good place to go to make sure that your treatment is up-to-date and as current as it could possibly be.

Dr. Sax: Thanks very much for your time today. It was very interesting talking with you. Perhaps we will revisit this in 6 months or so and see where things have gone.

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