The American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA) and International Antiviral Society-USA (IAS-USA) yesterday announced the first new hepatitis C treatment guidelines to include next-generation direct-acting antiviral agents recently approved by the US Food and Drug Administration (FDA). The guidance, available on the newly launched website HCVguidelines.org, will be updated frequently to reflect emerging data.
The advent of direct-acting antivirals has revolutionised 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.
"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," said AASLD panel co-chair Donald Jensen during a media teleconference on Tuesday 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 types of providers who will be called on to treat the growing number of people 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.
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 FDA-approved indications. Furthermore, it provides recommendations for special patient populations – including people with HIV and hepatitis C co-infection, patients with kidney failure, people with decompensated liver cirrhosis and liver transplant recipients – that have not yet have been extensively studied.
"FDA only will approve drugs that have gone through rigorous testing," said IAS-USA panel co-chair Michael Saag. "We cannot run a phase 3 trial on every possible [drug] combination or every possible patient population."
Recommendations for initial therapy
Recommendations for initial therapy for people with hepatitis C virus (HCV) who have decided to start treatment include the following:
- For initial treatment of genotype 1 hepatitis C, the panel recommends the recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi) plus weight-based ribavirin and pegylated interferon for 12 weeks, regardless of HCV subtype 1a or 1b.
- An alternative is the HCV protease inhibitor simeprevir (Olysio) for 12 weeks plus pegylated interferon and ribavirin for 24 weeks for people with genotype 1b or those with 1a who do not carry the Q80K resistance mutation.
- For people with genotype 1 who cannot take interferon, the panel recommends sofosbuvir plus simeprevir, with or without ribavirin, for 12 weeks. This off-label regimen has not been through 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 people with liver cirrhosis.
- For people with easier-to-treat HCV genotype 2, the panel recommends first-line treatment using sofosbuvir plus weight-based ribavirin for 12 weeks.
- For people with HCV genotype 3, the recommendation is sofosbuvir plus weight-based ribavirin for 24 weeks, with an alternative of sofosbuvir plus ribavirin plus pegylated interferon for 12 weeks.
- For people with HCV genotype 4 – which 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.
Treatment recommendations for previous non-responders
Recommendations for re-treating people who did not respond to prior interferon-based therapy include:
- For re-treatment of people with HCV genotype 1, 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 to 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 alternative of 24 weeks of sofosbuvir plus ribavirin alone for those who cannot take interferon.
Recommendations for people with HIV/HCV co-infection
Recommendations for people with HIV/HCV co-infection include:
- For co-infection with HCV genotype 1 – either treatment-naive or prior relapsers – the panel recommends sofosbuvir, weight-based ribavirin plus pegylated interferon for 12 weeks.
- For people with HIV/HCV co-infection who are unwilling or unable to take interferon, alternatives include sofosbuvir plus ribavirin alone for 24 weeks. Another option is sofosbuvir plus simeprevir, with or without ribavirin, but simeprevir can interact with several HIV drugs.
- The panel's recommendations for people with HIV/HCV co-infection 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. They also advise against regimens containing the first-generation HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivo), which can improve cure rates compared to interferon/ribavirin alone but come with added side-effects and potential for drug interactions.
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? Given the difficulty and suboptimal cure rates of interferon-based therapy, traditionally treatment has only been recommended for people with hepatitis C who have progressive liver disease, as determined by liver biopsy or non-invasive methods such as FibroScan.
With the advent of more effective and better-tolerated direct-acting antivirals, 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 in 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 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." In countries with single-payer health systems like the United Kingdom, however, cost is one of the factors taken into account.
European advocates have expressed concern that patients may be required to start with less effective and poorly tolerated interferon-based regimens due to their lower cost.
"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," said Henry Masur of the US 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."