Ira M. Jacobson, MD - 3/23/2015 More from this author
The recently updated AASLD/IDSA HCV management guidance recommends the following regimens for treatment-experienced patients with genotype 1 HCV infection who have compensated cirrhosis and who experienced previous treatment failure with peginterferon and ribavirin:
Ledipasvir/sofosbuvir for 24 weeks (rating: class I, level A)
Ledipasvir/sofosbuvir plus ribavirin for 12 weeks (rating: class I, level B)
Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin for 12 weeks if genotype 1b HCV and for 24 weeks if genotype 1a HCV (rating: class I, level A)
Sofosbuvir plus simeprevir with or without ribavirin for 24 weeks (rating: class IIa, level B)
In this ClinicalThought commentary, I focus on considerations for the use of ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis. In an upcoming commentary, Paul Y. Kwo, MD, will have a discussion about the use of ombitasvir/paritaprevir/ritonavir and dasabuvir in this setting.
Multiple Options: How to Choose?
In 2015, we are fortunate to have so many highly effective and tolerable options to consider for our patients, particularly those who have already experienced treatment failure following a challenging course of interferon-based therapy and who are in great need of treatment due to advanced fibrosis or cirrhosis. The key remaining challenge is in selection of therapy. When considering the use of ledipasvir/sofosbuvir, the guidance provides 2 options for this group of patients: a 24-week course without ribavirin or a 12-week course with ribavirin. So what is my approach to this decision for my patients?
Data Supporting Ledipasvir/Sofosbuvir Without Ribavirin for 24 Weeks
The recommendation for the use of a 24-week ribavirin-free regimen is based on data from the ION-2 study, which enrolled previously treated patients with genotype 1 HCV infection, 20% of whom had cirrhosis. The SVR rates in ION-2 were 94% and 96% with 12 weeks of ledipasvir/sofosbuvir, without and with ribavirin, respectively, vs 99% with 24 weeks of ledipasvir/sofosbuvir regardless of the addition of ribavirin. When the investigators analyzed the data, they found that the slight arithmetic difference between 12 and 24 weeks of therapy was driven by the subgroup of patients with cirrhosis who had SVR rates of 86% without ribavirin and 82% with ribavirin when treated for 12 weeks vs 100% with or without ribavirin when treated for 24 weeks. Although each of the 4 groups with cirrhosis included only 22 patients, the data strongly suggested that 24 weeks of therapy was optimal when using ledipasvir/sofosbuvir in treatment-experienced patients with cirrhosis and that ribavirin is not necessary. Therefore, the FDA-approved prescribing information recommends 24 weeks of ledipasvir/sofosbuvir without ribavirin for this group of patients.
Data Supporting Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
One of the most notable stories that emerged at the 2014 AASLD annual meeting was an unexpected resurgence of interest in the use of ribavirin in this setting because of 2 reports suggesting that adding ribavirin to ledipasvir/sofosbuvir for 12 weeks may confer an advantage over ribavirin-free therapy for 12 weeks in treatment-experienced patients with genotype 1 HCV infection and cirrhosis, yielding an SVR rate that approached or even matched the SVR rates conferred by 24 weeks of ledipasvir/sofosbuvir without ribavirin. As the presenter noted from the podium, these data have the potential to create a paradigm shift in how ledipasvir/sofosbuvir is used in this population relatively soon after its approval.
Specifically, the 2 reports in question were from the SIRIUS study by Bourlière and colleagues and an integrated analysis of data from multiple studies. SIRIUS was a well-designed, placebo-controlled study comparing 12 weeks of ledipasvir/sofosbuvir plus ribavirin vs 24 weeks of ledipasvir/sofosbuvir without ribavirin in patients with genotype 1 HCV infection and cirrhosis who experienced previous treatment failure with peginterferon/ribavirin plus telaprevir or boceprevir. The SVR rates were 96% with the 12-week regimen and 97% with the 24-week regimen. This study included 154 cirrhotic patients, a larger number than the 88 patients with cirrhosis enrolled in ION-2.
In the integrated analysis, the same group of investigators evaluated data from 513 patients with cirrhosis—both treatment experienced and treatment naive—across the entire development program for ledipasvir/sofosbuvir, into which the data from the SIRIUS study were incorporated. Among treatment-experienced patients with cirrhosis, the results demonstrated a 90% SVR rate with ledipasvir/sofosbuvir alone for 12 weeks vs 96% with ledipasvir/sofosbuvir plus ribavirin for 12 weeks. The SVR rates with 24 weeks of treatment were 98% and 100% without and with ribavirin, respectively. This sparked much discussion about the potential to conserve resources and reduce costs by administering only 12 weeks of ledipasvir/sofosbuvir plus ribavirin with equivalent results to those achieved with the approved regimen of ledipasvir/sofosbuvir alone for 24 weeks in treatment-experienced patients with cirrhosis. Many hepatologists appeared quite ready to embrace the 12-week regimen with ribavirin as their new standard of practice when using ledipasvir/sofosbuvir in this patient population, whereas others seemed more hesitant to do so.
Concerns With Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
My opinion, cost differences aside, is based on the data from the integrated analysis showing an SVR rate of 96% with 12 weeks of ledipasvir/sofosbuvir plus ribavirin vs 98% to 100% with 24 weeks of ledipasvir/sofosbuvir with or without ribavirin. Even if not statistically significant, this may represent a trend that could result in treatment failure for a small number of patients who receive the 12-week ribavirin-containing regimen vs the 24-week ribavirin-free regimen.
The second concern I have is that all the evidence accumulated to date, including all the data on ledipasvir/sofosbuvir from the ION studies (ION-1 and -3 in treatment-naive and ION-2 in treatment-experienced patients) and the real-world data on sofosbuvir-based regimens from the TRIO and HCV-TARGET databases, has failed to provide a hint that adding ribavirin confers an incremental benefit in the efficacy of sofosbuvir-based therapy. Clinicians who are proposing to immediately start using 12 weeks of ledipasvir/sofosbuvir plus ribavirin in treatment-experienced patients with cirrhosis are accepting the idea that ribavirin adds benefit, despite the absence of any other signal across the entire development program or real-world studies and based only on the SIRIUS study and the recent integrated analysis. I find myself reluctant to deviate from what is still the FDA-approved regimen for ledipasvir/sofosbuvir based on that analysis alone. When considering that ribavirin is a relatively weak antiviral agent by itself, with a mechanism of action in combination with either interferon or direct-acting antivirals that is still entirely unclear, I am intuitively hesitant to conclude that adding ribavirin to a 12-week ledipasvir/sofosbuvir regimen can confer the same benefit as continuing 2 potent, well-tolerated direct-acting antiviral agents for 12 additional weeks. It is worth noting that the AASLD/IDSA guidance indicates the lower level of evidence to support the 12-week regimen vs the 24-week regimen by assigning level B, (data derived from a single randomized trial, nonrandomized studies, or equivalent) to the 12-week recommendation and level A data derived from multiple randomized clinical trials, meta-analyses, or equivalent) to the 24-week recommendation.
The Case for Ledipasvir/Sofosbuvir Without Ribavirin for 24 Weeks
In my practice, we follow the FDA-approved prescribing information for ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis, which indicates 24 weeks of treatment without ribavirin. In addition to an element of residual uncertainty about whether a 12-week regimen with ribavirin is every bit as effective as 24 weeks without ribavirin, there are considerations of tolerability relevant to ribavirin. Although ribavirin is admittedly better tolerated when not coadministered with interferon, particularly regarding anemia, the fact remains that it can cause anemia with 5% to 10% of patients experiencing declines in hemoglobin to < 10 g/dL, which may be problematic in patients such as those with cardiac or pulmonary disease, baseline anemia, or elderly patients. Ribavirin is also a category X drug that mandates strict birth control throughout the duration of therapy, as well as for 6 months thereafter due to potential teratogenicity. Other adverse effects of ribavirin, such as insomnia, pruritus, and nausea, may make 12 weeks of a ribavirin-containing regimen less well tolerated than 24 weeks of therapy with ledipasvir/sofosbuvir alone.
Of course, both regimens represent revolutionary development for the better in the treatment of hepatitis C. However, despite the inclusion of the 12-week, ribavirin-containing ledipasvir/sofosbuvir regimen in the revised AASLD/IDSA guidance, my personal preference when using ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis is to avoid ribavirin and administer treatment for 24 weeks, as long as I can obtain access to this regimen for my patients. Admittedly, 12 weeks of ledipasvir and sofosbuvir with ribavirin appear to also be a highly effective option.
When I Would Choose Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
Are there any instances in which I would choose the 12-week course of ledipasvir/sofosbuvir plus ribavirin over the 24-week course of ledipasvir/sofosbuvir alone? Yes—in patients for whom there are anticipated adherence challenges or economic barriers. In these cases, I have a dialogue with my patients to ensure they understand that we are making a decision with potential medical implications, particularly regarding tolerability, on the basis of economic concerns. They should be counseled as to the potential adverse effects, such as anemia and teratogenicity.
Your Thoughts?
I am interested to hear your thoughts. How will you be using ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis?
Topics: HCV - Treatment, Fibrosis and Cirrhosis - Treatment
The recently updated AASLD/IDSA HCV management guidance recommends the following regimens for treatment-experienced patients with genotype 1 HCV infection who have compensated cirrhosis and who experienced previous treatment failure with peginterferon and ribavirin:
Ledipasvir/sofosbuvir for 24 weeks (rating: class I, level A)
Ledipasvir/sofosbuvir plus ribavirin for 12 weeks (rating: class I, level B)
Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin for 12 weeks if genotype 1b HCV and for 24 weeks if genotype 1a HCV (rating: class I, level A)
Sofosbuvir plus simeprevir with or without ribavirin for 24 weeks (rating: class IIa, level B)
In this ClinicalThought commentary, I focus on considerations for the use of ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis. In an upcoming commentary, Paul Y. Kwo, MD, will have a discussion about the use of ombitasvir/paritaprevir/ritonavir and dasabuvir in this setting.
Multiple Options: How to Choose?
In 2015, we are fortunate to have so many highly effective and tolerable options to consider for our patients, particularly those who have already experienced treatment failure following a challenging course of interferon-based therapy and who are in great need of treatment due to advanced fibrosis or cirrhosis. The key remaining challenge is in selection of therapy. When considering the use of ledipasvir/sofosbuvir, the guidance provides 2 options for this group of patients: a 24-week course without ribavirin or a 12-week course with ribavirin. So what is my approach to this decision for my patients?
Data Supporting Ledipasvir/Sofosbuvir Without Ribavirin for 24 Weeks
The recommendation for the use of a 24-week ribavirin-free regimen is based on data from the ION-2 study, which enrolled previously treated patients with genotype 1 HCV infection, 20% of whom had cirrhosis. The SVR rates in ION-2 were 94% and 96% with 12 weeks of ledipasvir/sofosbuvir, without and with ribavirin, respectively, vs 99% with 24 weeks of ledipasvir/sofosbuvir regardless of the addition of ribavirin. When the investigators analyzed the data, they found that the slight arithmetic difference between 12 and 24 weeks of therapy was driven by the subgroup of patients with cirrhosis who had SVR rates of 86% without ribavirin and 82% with ribavirin when treated for 12 weeks vs 100% with or without ribavirin when treated for 24 weeks. Although each of the 4 groups with cirrhosis included only 22 patients, the data strongly suggested that 24 weeks of therapy was optimal when using ledipasvir/sofosbuvir in treatment-experienced patients with cirrhosis and that ribavirin is not necessary. Therefore, the FDA-approved prescribing information recommends 24 weeks of ledipasvir/sofosbuvir without ribavirin for this group of patients.
Data Supporting Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
One of the most notable stories that emerged at the 2014 AASLD annual meeting was an unexpected resurgence of interest in the use of ribavirin in this setting because of 2 reports suggesting that adding ribavirin to ledipasvir/sofosbuvir for 12 weeks may confer an advantage over ribavirin-free therapy for 12 weeks in treatment-experienced patients with genotype 1 HCV infection and cirrhosis, yielding an SVR rate that approached or even matched the SVR rates conferred by 24 weeks of ledipasvir/sofosbuvir without ribavirin. As the presenter noted from the podium, these data have the potential to create a paradigm shift in how ledipasvir/sofosbuvir is used in this population relatively soon after its approval.
Specifically, the 2 reports in question were from the SIRIUS study by Bourlière and colleagues and an integrated analysis of data from multiple studies. SIRIUS was a well-designed, placebo-controlled study comparing 12 weeks of ledipasvir/sofosbuvir plus ribavirin vs 24 weeks of ledipasvir/sofosbuvir without ribavirin in patients with genotype 1 HCV infection and cirrhosis who experienced previous treatment failure with peginterferon/ribavirin plus telaprevir or boceprevir. The SVR rates were 96% with the 12-week regimen and 97% with the 24-week regimen. This study included 154 cirrhotic patients, a larger number than the 88 patients with cirrhosis enrolled in ION-2.
In the integrated analysis, the same group of investigators evaluated data from 513 patients with cirrhosis—both treatment experienced and treatment naive—across the entire development program for ledipasvir/sofosbuvir, into which the data from the SIRIUS study were incorporated. Among treatment-experienced patients with cirrhosis, the results demonstrated a 90% SVR rate with ledipasvir/sofosbuvir alone for 12 weeks vs 96% with ledipasvir/sofosbuvir plus ribavirin for 12 weeks. The SVR rates with 24 weeks of treatment were 98% and 100% without and with ribavirin, respectively. This sparked much discussion about the potential to conserve resources and reduce costs by administering only 12 weeks of ledipasvir/sofosbuvir plus ribavirin with equivalent results to those achieved with the approved regimen of ledipasvir/sofosbuvir alone for 24 weeks in treatment-experienced patients with cirrhosis. Many hepatologists appeared quite ready to embrace the 12-week regimen with ribavirin as their new standard of practice when using ledipasvir/sofosbuvir in this patient population, whereas others seemed more hesitant to do so.
Concerns With Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
My opinion, cost differences aside, is based on the data from the integrated analysis showing an SVR rate of 96% with 12 weeks of ledipasvir/sofosbuvir plus ribavirin vs 98% to 100% with 24 weeks of ledipasvir/sofosbuvir with or without ribavirin. Even if not statistically significant, this may represent a trend that could result in treatment failure for a small number of patients who receive the 12-week ribavirin-containing regimen vs the 24-week ribavirin-free regimen.
The second concern I have is that all the evidence accumulated to date, including all the data on ledipasvir/sofosbuvir from the ION studies (ION-1 and -3 in treatment-naive and ION-2 in treatment-experienced patients) and the real-world data on sofosbuvir-based regimens from the TRIO and HCV-TARGET databases, has failed to provide a hint that adding ribavirin confers an incremental benefit in the efficacy of sofosbuvir-based therapy. Clinicians who are proposing to immediately start using 12 weeks of ledipasvir/sofosbuvir plus ribavirin in treatment-experienced patients with cirrhosis are accepting the idea that ribavirin adds benefit, despite the absence of any other signal across the entire development program or real-world studies and based only on the SIRIUS study and the recent integrated analysis. I find myself reluctant to deviate from what is still the FDA-approved regimen for ledipasvir/sofosbuvir based on that analysis alone. When considering that ribavirin is a relatively weak antiviral agent by itself, with a mechanism of action in combination with either interferon or direct-acting antivirals that is still entirely unclear, I am intuitively hesitant to conclude that adding ribavirin to a 12-week ledipasvir/sofosbuvir regimen can confer the same benefit as continuing 2 potent, well-tolerated direct-acting antiviral agents for 12 additional weeks. It is worth noting that the AASLD/IDSA guidance indicates the lower level of evidence to support the 12-week regimen vs the 24-week regimen by assigning level B, (data derived from a single randomized trial, nonrandomized studies, or equivalent) to the 12-week recommendation and level A data derived from multiple randomized clinical trials, meta-analyses, or equivalent) to the 24-week recommendation.
The Case for Ledipasvir/Sofosbuvir Without Ribavirin for 24 Weeks
In my practice, we follow the FDA-approved prescribing information for ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis, which indicates 24 weeks of treatment without ribavirin. In addition to an element of residual uncertainty about whether a 12-week regimen with ribavirin is every bit as effective as 24 weeks without ribavirin, there are considerations of tolerability relevant to ribavirin. Although ribavirin is admittedly better tolerated when not coadministered with interferon, particularly regarding anemia, the fact remains that it can cause anemia with 5% to 10% of patients experiencing declines in hemoglobin to < 10 g/dL, which may be problematic in patients such as those with cardiac or pulmonary disease, baseline anemia, or elderly patients. Ribavirin is also a category X drug that mandates strict birth control throughout the duration of therapy, as well as for 6 months thereafter due to potential teratogenicity. Other adverse effects of ribavirin, such as insomnia, pruritus, and nausea, may make 12 weeks of a ribavirin-containing regimen less well tolerated than 24 weeks of therapy with ledipasvir/sofosbuvir alone.
Of course, both regimens represent revolutionary development for the better in the treatment of hepatitis C. However, despite the inclusion of the 12-week, ribavirin-containing ledipasvir/sofosbuvir regimen in the revised AASLD/IDSA guidance, my personal preference when using ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis is to avoid ribavirin and administer treatment for 24 weeks, as long as I can obtain access to this regimen for my patients. Admittedly, 12 weeks of ledipasvir and sofosbuvir with ribavirin appear to also be a highly effective option.
When I Would Choose Ledipasvir/Sofosbuvir Plus Ribavirin for 12 Weeks
Are there any instances in which I would choose the 12-week course of ledipasvir/sofosbuvir plus ribavirin over the 24-week course of ledipasvir/sofosbuvir alone? Yes—in patients for whom there are anticipated adherence challenges or economic barriers. In these cases, I have a dialogue with my patients to ensure they understand that we are making a decision with potential medical implications, particularly regarding tolerability, on the basis of economic concerns. They should be counseled as to the potential adverse effects, such as anemia and teratogenicity.
Your Thoughts?
I am interested to hear your thoughts. How will you be using ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis?
Topics: HCV - Treatment, Fibrosis and Cirrhosis - Treatment
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Source - Clinical Care Options / Clinical Thought
Thanks for your insight, one area that needs to be addressed is how patients who relapsed from DAA's protocol (failure from 12 weeks Viekara w/Riba) should be treated. With and without Rav's being detected at relapse. Hopefully a very small group but still needing guidance regarding duration and using Riba or not.
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