AASLD, IDSA & IAS-USA Announce New Hepatitis C Treatment Guidelines

The American Association for the Study of Liver Diseases (AASLD), the Infectious Diseases Society of America (IDSA), and the International Antiviral Society-USA (IAS-USA) this week announced the first new hepatitis C treatment guidelines that include next-generation direct-acting antiviral agents recently approved by the FDA. The guidance is available on a new website, HCVguidelines.org, that will enable frequent updates to reflect emerging data.

The advent of direct-acting antivirals has revolutionized hepatitis C treatment, but many prospective patients and providers are waiting for all-oral regimens that avoid interferon, which must be injected weekly and can cause debilitating side effects including flu-like symptoms and depression."

Recently approved medications and several others on the horizon promise to cure nearly all treated patients without the many side effects that have plagued past treatment regimens," AASLD panel co-chair Donald Jensen from the University of Chicago said during a Tuesday media teleconference introducing the website and guidelines.

The new guidelines were developed by a panel of 27 liver disease and infectious diseases specialists and a patient advocate. The evidence-based consensus recommendations reflect the latest data on screening, management, and treatment of chronic hepatitis C.

The guidelines are intended for use by both hepatologists and infectious disease doctors who have traditionally treated people with hepatitis C, as well as by other providers -- including primary care physicians -- who will be called on to treat the growing number of patients seeking care due to expanded screening and availability of better treatments.

"We expect the guidelines to be used by practitioners well versed in nuances of antiviral therapy, but also by many who are inexperienced or even new to the field of hepatitis C," said IDSA panel co-chair David Thomas from Johns Hopkins.

Treatment Recommendations

The first iteration of the new guidelines covers testing, linkage to care, and specific treatment recommendations. Panel members noted that the website includes off-label recommendations that go beyond the indications specifically approved by the FDA.

"It is important to keep in mind that FDA only will approve drugs that have gone through rigorous testing," said IAS-USA panel co-chair Michael Saag from the University of Alabama at Birmingham. "We cannot run a Phase 3 trial on every possible [drug] combination or every possible patient population. The website allows experts in the field to look at the emerging data and craft what we feel the evidence supports, [which] may fall short of what is specifically in an FDA-approved package insert."

The website also provides recommendations for specific patient populations -- including HIV/HCV coinfected people, patients with kidney failure, people with decompensated liver cirrhosis, and liver transplant recipients -- some of which have not yet have been extensively studied.

"We tried to approach it as if we were getting a phone call from a practitioner in the community," Saag continued. "We give recommendations based on drugs available on the market. We tried to make it as real-world as possible."

• For initial treatment of people with HCV genotype 1 -- the most common type in the U.S. and the most difficult to treat -- the panel recommends using the HCV polymerase inhibitor sofosbuvir (Sovaldi) plus weight-based ribavirin and pegylated interferon for 12 weeks, regardless of HCV subtype 1a or 1b.
• An alternative regimen is simeprevir for 12 weeks plus ribavirin and interferon for 24 weeks for people with genotype 1b or those with 1a who do not carry the Q80K resistance mutation.
• For genotype 1 patients who cannot take interferon, the panel recommends sofosbuvir plus the HCV protease inhibitor simeprevir (Olysio), with or without ribavirin, again for 12 weeks. This off-label regimen has not been through full Phase 3 testing, but performed very well in the Phase 2 COSMOS trial.
• An alternative for this group is sofosbuvir plus ribavirin for 24 weeks, though the panel noted that it is not as effective as sofosbuvir plus simeprevir, especially for patients with liver cirrhosis.
• For people with easier-to-treat HCV genotype 2, the panel recommends first-time treatment using sofosbuvir plus weight-based ribavirin for 12 weeks.
• For patients with HCV genotype 3, the recommendation is sofosbuvir plus weight-based ribavirin for 24 weeks, with an alterative of sofosbuvir plus ribavirin plus pegylated interferon for 12 weeks.
• For people with HCV genotype 4 -- which is less common in the U.S. and Europe and has not been as extensively studied -- the panel chose sofosbuvir plus weight-based ribavirin and pegylated interferon for 12 weeks, or sofosbuvir plus ribavirin alone for 24 weeks for patients who cannot use interferon. An alternative is simeprevir for 12 weeks plus pegylated interferon/ribavirin for 24-48 weeks.
• For people with HCV genotype 5 or 6 -- about which even less is known -- the recommendation is sofosbuvir plus weight-based ribavirin for 12 weeks, with an alternative of pegylated interferon/ribavirin for 48 weeks.
• For re-treatment of people with HCV genotype 1 who were not cured with prior interferon-based therapy, the panel recommends sofosbuvir plus simeprevir, with or without weight-based ribavirin, for 12 weeks. Alternative regimens combine sofosbuvir or simeprevir with pegylated interferon and ribavirin for 24-48 weeks.
• The panel recommends sofosbuvir plus weight-based ribavirin for 12 or 24 weeks for re-treatment of prior non-responders with genotype 2 or 3, respectively. Again, alternative regimens include pegylated interferon and ribavirin.
• The recommended second-line treatment for HCV genotypes 4, 5, and 6 is sofosbuvir plus weight-based ribavirin and pegylated interferon for 12 weeks, with an alterative of 24 weeks of sofosbuvir plus ribavirin alone for those who cannot take interferon.
• For people with HIV/HCV coinfection with genotype 1 -- either treatment-naive or prior relapsers -- the panel recommends sofosbuvir plus weight-based ribavirin plus pegylated interferon for 12 weeks. For those unwilling or unable to take ribavirin, alternatives include sofosbuvir plus ribavirin alone for 24 weeks. Treatment-naive and treatment-experienced coinfected people may also use sofosbuvir plus simeprevir, with or with ribavirin, with the caveat that simeprevir can interact with several HIV drugs.
• The panel's recommendations for HIV/HCV coinfected people with genotypes 2 or 3 are the same as for those with HCV alone, that is, sofosbuvir plus ribavirin for 12 or 24 weeks, respectively.

For almost all patients, the panel specifically recommends against the old standard of care -- pegylated interferon plus ribavirin alone -- which had to be taken for 48 weeks for genotypes 1 or 4, or for 24 weeks for genotypes 2 or 3. They also advise against regimens containing the first-generation HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek or Incivo), which improve cure rates compared to interferon/ribavirin alone but come with added side effects and potential for drug interactions.

Future Plans

The HCVguidelines.org website does not yet include recommendations about one of the most vexing questions facing people with hepatitis C and their providers: who should start treatment and when.

"That is the next question we're going to deal with," explained Thomas. "The impending availability of new medications made it imperative for us to prioritize providing advice on how to use medicines that had just become available first."

Over years or decades, chronic HCV infection can lead to serious liver damage including cirrhosis and liver cancer, but this occurs at variable rates -- or in some cases not at all -- and it is not possible to predict in advance which patients will progress or when.

Traditionally, given the difficulty and suboptimal cure rates of interferon-based therapy, treatment was only recommended for hepatitis C patients with progressive liver disease, as determined by liver biopsy or less accurate non-invasive methods.

With the advent of more effective and better-tolerated direct-acting antivirals, however, many experts believe that more people are now eligible for treatment. But given the rapid advances in the field, it is often unclear whether to treat someone now with available drugs or to wait for something better.

Many patients have been "warehoused" for the past few years awaiting interferon-free therapy. The first such regimens are now available for people who are unable or unwilling to use interferon, but new and potentially better options are coming down the pipeline, including Gilead Science's sofosbuvir/ledipasvir coformulation, Bristol-Myers Squibb's daclatasvir (a candidate for combination with sofosbuvir), and AbbVie's "3D" combination.

The panel is currently working on recommendations about which patients to treat and when, as well as guidelines for managing acute hepatitis C infection and monitoring of patients during and after treatment.

One issue the panel did not address is the cost of treatment. "The guidelines are not designed to address cost, and we haven’t really taken that into full consideration," said Jensen. "Our recommendations are based on what we think is best for a patient who needs treatment at this time. Obviously this is an important issue that society and the pharmaceutical industry and payers have to wrestle with, but for us this was not a focus of the discussion."

In countries with national health systems, however, cost is one of the factors taken into account when selecting treatments, and European advocates have expressed concern that patients may be required to continue to start with less effective and poorly tolerated interferon-based regimens due to their lower cost.

Wrapping up Tuesday's teleconference, Thomas emphasized the importance of being tested for hepatitis C. "All of the major advances in treatment are insignificant if a person doesn’t even know they are infected," he said. The Centers for Disease Control and Prevention and U.S. Preventive Services Task Force recommend that all Baby Boomers born between 1945 and 1965 should be screened for HCV at least once, as should anyone with known risk factors.

"It's not only about identifying patients, it's linking them to somebody who is willing to treat," added Gary Davis from Baylor University Medical Center. "In the past, many clinicians have looked for excuses not to treat patients. Hopefully these new therapies that are so much better tolerated will allow more patients to be treated. If we don't effectively link them to care, we're not going to make a impact on the future morbidity and mortality of this disease."

"We're all really excited that for the first time we have curative therapies for hepatitis C which are much more effective than what we had before and much easier to tolerate," concluded Henry Masur from the National Institutes of Health. "This is really a revolution, and it's very important that clinicians have access to guidance on how to use these drugs as new trials are quickly done and as new information becomes available."

1/29/14

Sources

HCVguidelines.org. Launched January 29, 2014.

AASLD and IDSA. Online Expert Advice for Clinicians Treating Hepatitis C Now Available at HCVguidelines.org. Press release. January 29, 2014.