The Take Home

The Liver Meeting 2014

Every year at The Liver Meeting, an international group of experts convene to discuss the latest evidence in hepatology, methods to improve clinical care, identify advances in the treatment of liver disease to further the scope of research and eventually apply knowledge that will improve the outcomes of post-transplant patients

HCV Next had the opportunity to sit down with leading experts in the field while onsite at The Liver Meeting. They each provided insight into the data presented and how it will impact care of patients with HCV. Among These included Co-Chief Medical Editor, Ira M. Jacobson, MD, chief of the division of gastroenterology and hepatology and Vincent Astor distinguished professor of medicine at the Joan Sanford I. Weill Cornell Medical College, attending physician at New York-Presbyterian Hospital Cornell Campus and medical director of The Center for the Study of Hepatitis C; and Stevan A. Gonzalez, MD, MS, attending physician in the division of hepatology at the Annette C. and Harold C. Simmons Transplant Institute, Baylor All Saints Medical Center, Fort Worth, and Baylor University Medical Center, Dallas.

Ira M. Jacobson, MD

An interesting theme that’s emerged at this meeting is a resurgence of the potential role of ribavirin.

We had already established that, when administered with a drug regimen not containing a nucleotide polymerase inhibitor, ribavirin would be needed for genotype 1a patients. On the other hand, the recently FDA-approved one-pill combination of ledipasvir and sofosbuvir (Harvoni, Gilead Sciences) is indicated without ribavirin for 12-24 weeks, the latter duration in treatment-experienced cirrhotic patients (8 weeks may be considered in treatment-naïve noncirrhotics with a baseline HCV RNA level of <6 million IU/ml).

Liver Meeting Banner 

But two presentations by Marc Bourliére, MD, at The Liver Meeting 2014 have resurrected interest in the potential for the addition of ribavirin to ledpasvir/sofosbuvir in treatment-experienced cirrhotics to shorten duration of treatment to 12 weeks. The first was a study of more than 150 patients who had failed response to a protease inhibitor. In a comparison of 12 weeks of ledipasvir/sofosbuvir/ribavirin to ledipasvir/sofosbuvir alone for 24 weeks, SVR12 rates were 96% and 97%, respectively. The results of this trial were incorporated into an integrated analysis of several trials which showed SVR rates in treatment-experienced cirrhotics of 90% with 12 weeks of ledipasvir/sofosbuvir, but 96% of those who also received ribavirin for the same duration. SVR occurred in 98% to 100% of those who received 24 weeks of treatment without or with ribavirin, respectively.

Ira M. Jacobson

Ira M. Jacobson

Another study signaling the utility of adding ribavirin to sofosbuvir and ledipasvir was that presented by Steven L. Flamm, MD, showing gratifyingly high rates of SVR and tolerability of this triple regimen for either 12 or 24 weeks in decompensated cirrhotics with Child-Pugh B and C disease.

So we’re seeing this potential paradigm shift, back toward at least the option of using ribavirin in particularly challenging populations who need that extra boost to get rid of all the virus and prevent the emergence of resistance. For now, however, the indicated regimen for treatment-experienced compensated cirrhotics remains 24 weeks of sofosbuvir and ledipasvir.

Another big story from this meeting, currently associated with the C-SWIFT study, is that 4 weeks may be overreaching in terms of a duration of therapy that enables us to cure the majority of our patients.

Merck sponsored the study, which showed a “mere” 38.7% cure rate in treatment-naive non-cirrhotics with 4 weeks of a very potent fixed-dose regimen of three excellent drugs representing different classes: grazoprevir (Merck & Co.), elbasvir (Merck & Co.) and sofosbuvir (Gilead Sciences). SVR increased to 86.7% at 6 weeks.

Perhaps shortening duration of therapy when you can do so well with 8 to 12 weeks should no longer be considered the next “quantum leap,” which a lot of us thought it would be. Other companies have yet to report out their data with ultra-short durations, but I think this has shifted our goal. We need to concentrate on curing every last patient, with whatever duration it takes, rather than shortening the duration for its own sake, as economically desirable as that is.

Additionally, genotype 3 continues to be a challenge, but there are a lot of new data coming out that are promising, although they don’t spell the end of the story.

The ALLY-3 study saw 152 patients, 101 of whom were treatment-naive, with genotype 3 treated with daclatasvir (Bristol-Myers Squibb) and sofosbuvir (Sovaldi, Gilead Sciences). Patients in the naive group experienced an SVR12 of 90%, while those in the experienced group reached 86% SVR12.

By the end of treatment, 99% of patients in the previously untreated arm and 100% of those in the treatment-experienced arm had undetectable HCV RNA. However, cirrhosis had a significant impact with an overall SVR12 rate of 63% among patients with cirrhosis, compared with 96% for those without cirrhosis.

In the ELECTRON 2 study, presented at The Liver Meeting, pangenotypic NS5A inhibitor GS-5816 (Gilead Sciences) as part of treatment regimens with sofosbuvir (Sovaldi, Gilead Sciences) with or without ribavirin for treatment-naive noncirrhotic patients with genotype 3.

SVR12 rates were 100% among 27 patients who received sofosbuvir plus GS-5816 25 mg without ribavirin; 88% among 24 patients who received sofosbuvir plus GS-5816 25 mg with ribavirin (including the only two relapsers in the study); 96% among 27 patients who received sofosbuvir plus GS-5816 100 mg without ribavirin; and 100% among 26 patients who received sofosbuvir plus GS-5816 100 mg with ribavirin.

Lastly, this meeting showcased quality-of-life. Studies by Younossi and colleagues continue to demonstrate improvement in patient-reported outcomes in virologically cured patients treated with DAA therapy.

A paper that had held particular fascination was presented by Nezam Afdhal, MD, of the Beth Israel Deaconess Medical Center in Boston, on MR spectroscopy of the brain. Afdhal and colleagues evaluated 14 patients randomized to sofosbuvir-ledipasvir combination treatment or that plus ribavirin. Their results suggest improved neuronal function in patients after attainment of SVR, although ribavirin appeared to have an adverse impact on brain function and may have delayed neuronal recovery.

The findings vindicate long-harbored suspicions and prior evidence that HCV infection impairs central nervous system function and that quantifiable improvements can be documented following sustained viral clearance. This has profound implications for the argument that DAA-based HCV therapy should be offered even to patients with mild liver fibrosis.

Stevan A. Gonzalez, MD, MS

The data presented at The Liver Meeting pointed to impressive real-world experiences with the new treatment regimens.

Both the TRIO Network and HCV Target enrolled more than 1,000 patients each and presented better-than-anticipated results.

A key point to take from these studies is that the efficacy remains very high in the real world as it was demonstrated previously in clinical trials. This may be attributed to the improved tolerability and adherence associated with interferon-free regimens. These studies reported only minimal early discontinuations or serious adverse events.

Additionally, the role of ribavirin appears to be diminishing, particularly in the sofosbuvir and simeprevir combination, in which the addition of ribavirin did not make a difference. However, other data presented during the meeting involving combination sofosbuvir-ledipasvir suggested that an exception to this may apply to those with more advanced disease who failed prior treatment and in post-transplant recurrence.

Stevan Gonzalez

Stevan A. Gonzalez

In the HCV TARGET study, data were presented involving post-transplant patients with recurrent HCV. The majority of genotype 1 patients were treated with sofosbuvir and simeprevir (Olysio, Janssen). Data presented on 68 post-transplant patients who completed this regimen noted an SVR4 of 91%.

The post-transplant population has a lot to gain from achieving a cure because recurrence of hepatitis C is universal in all transplant recipients. And they are historically a difficult population to treat because they’re more susceptible to adverse events and poor tolerability of interferon-based regimens. The availability of highly effective oral regimens with a lower side effect profile and low potential for drug interactions with immunosuppressive medications will have a huge impact.

In patients who are post-transplant, achievement of an SVR opens the door for them to maintain good allograft function of their transplanted liver for the long term.

Putting this all together, these studies are demonstrating that the direct-acting antivirals really are having an impact beyond the clinical trials in a real-world setting.

This is important because clinical trials tend to have restricted populations, leading to a debate about whether clinical trials reflect what happens in the real world.

To me, these were very important consortia that will have the ability to produce large-scale data involving various populations and different direct-acting antiviral regimens. It’s exciting to see that we’re achieving high efficacy rates even in the real-world setting where historically we have always seen a decrease in response rates usually as a consequence of decreased adherence to therapy in clinical practice, increased severity of liver disease associated with populations not included in clinical trials, or concerns for adverse events.

Disclosure: Gonzalez reports participating on the speakers’ bureau and advisory board of Gilead Sciences. Jacobson reports no relevant disclosures.

Every year at The Liver Meeting, an international group of experts convene to discuss the latest evidence in hepatology, methods to improve clinical care, identify advances in the treatment of liver disease to further the scope of research and eventually apply knowledge that will improve the outcomes of post-transplant patients

HCV Next had the opportunity to sit down with leading experts in the field while onsite at The Liver Meeting. They each provided insight into the data presented and how it will impact care of patients with HCV. Among These included Co-Chief Medical Editor, Ira M. Jacobson, MD, chief of the division of gastroenterology and hepatology and Vincent Astor distinguished professor of medicine at the Joan Sanford I. Weill Cornell Medical College, attending physician at New York-Presbyterian Hospital Cornell Campus and medical director of The Center for the Study of Hepatitis C; and Stevan A. Gonzalez, MD, MS, attending physician in the division of hepatology at the Annette C. and Harold C. Simmons Transplant Institute, Baylor All Saints Medical Center, Fort Worth, and Baylor University Medical Center, Dallas.

Ira M. Jacobson, MD

An interesting theme that’s emerged at this meeting is a resurgence of the potential role of ribavirin.

We had already established that, when administered with a drug regimen not containing a nucleotide polymerase inhibitor, ribavirin would be needed for genotype 1a patients. On the other hand, the recently FDA-approved one-pill combination of ledipasvir and sofosbuvir (Harvoni, Gilead Sciences) is indicated without ribavirin for 12-24 weeks, the latter duration in treatment-experienced cirrhotic patients (8 weeks may be considered in treatment-naïve noncirrhotics with a baseline HCV RNA level of <6 million IU/ml).

Liver Meeting Banner 

But two presentations by Marc Bourliére, MD, at The Liver Meeting 2014 have resurrected interest in the potential for the addition of ribavirin to ledpasvir/sofosbuvir in treatment-experienced cirrhotics to shorten duration of treatment to 12 weeks. The first was a study of more than 150 patients who had failed response to a protease inhibitor. In a comparison of 12 weeks of ledipasvir/sofosbuvir/ribavirin to ledipasvir/sofosbuvir alone for 24 weeks, SVR12 rates were 96% and 97%, respectively. The results of this trial were incorporated into an integrated analysis of several trials which showed SVR rates in treatment-experienced cirrhotics of 90% with 12 weeks of ledipasvir/sofosbuvir, but 96% of those who also received ribavirin for the same duration. SVR occurred in 98% to 100% of those who received 24 weeks of treatment without or with ribavirin, respectively.

Ira M. Jacobson

Ira M. Jacobson

Another study signaling the utility of adding ribavirin to sofosbuvir and ledipasvir was that presented by Steven L. Flamm, MD, showing gratifyingly high rates of SVR and tolerability of this triple regimen for either 12 or 24 weeks in decompensated cirrhotics with Child-Pugh B and C disease.

So we’re seeing this potential paradigm shift, back toward at least the option of using ribavirin in particularly challenging populations who need that extra boost to get rid of all the virus and prevent the emergence of resistance. For now, however, the indicated regimen for treatment-experienced compensated cirrhotics remains 24 weeks of sofosbuvir and ledipasvir.

Another big story from this meeting, currently associated with the C-SWIFT study, is that 4 weeks may be overreaching in terms of a duration of therapy that enables us to cure the majority of our patients.

Merck sponsored the study, which showed a “mere” 38.7% cure rate in treatment-naive non-cirrhotics with 4 weeks of a very potent fixed-dose regimen of three excellent drugs representing different classes: grazoprevir (Merck & Co.), elbasvir (Merck & Co.) and sofosbuvir (Gilead Sciences). SVR increased to 86.7% at 6 weeks.

Perhaps shortening duration of therapy when you can do so well with 8 to 12 weeks should no longer be considered the next “quantum leap,” which a lot of us thought it would be. Other companies have yet to report out their data with ultra-short durations, but I think this has shifted our goal. We need to concentrate on curing every last patient, with whatever duration it takes, rather than shortening the duration for its own sake, as economically desirable as that is.

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Additionally, genotype 3 continues to be a challenge, but there are a lot of new data coming out that are promising, although they don’t spell the end of the story.

The ALLY-3 study saw 152 patients, 101 of whom were treatment-naive, with genotype 3 treated with daclatasvir (Bristol-Myers Squibb) and sofosbuvir (Sovaldi, Gilead Sciences). Patients in the naive group experienced an SVR12 of 90%, while those in the experienced group reached 86% SVR12.

By the end of treatment, 99% of patients in the previously untreated arm and 100% of those in the treatment-experienced arm had undetectable HCV RNA. However, cirrhosis had a significant impact with an overall SVR12 rate of 63% among patients with cirrhosis, compared with 96% for those without cirrhosis.

In the ELECTRON 2 study, presented at The Liver Meeting, pangenotypic NS5A inhibitor GS-5816 (Gilead Sciences) as part of treatment regimens with sofosbuvir (Sovaldi, Gilead Sciences) with or without ribavirin for treatment-naive noncirrhotic patients with genotype 3.

SVR12 rates were 100% among 27 patients who received sofosbuvir plus GS-5816 25 mg without ribavirin; 88% among 24 patients who received sofosbuvir plus GS-5816 25 mg with ribavirin (including the only two relapsers in the study); 96% among 27 patients who received sofosbuvir plus GS-5816 100 mg without ribavirin; and 100% among 26 patients who received sofosbuvir plus GS-5816 100 mg with ribavirin.

Lastly, this meeting showcased quality-of-life. Studies by Younossi and colleagues continue to demonstrate improvement in patient-reported outcomes in virologically cured patients treated with DAA therapy.

A paper that had held particular fascination was presented by Nezam Afdhal, MD, of the Beth Israel Deaconess Medical Center in Boston, on MR spectroscopy of the brain. Afdhal and colleagues evaluated 14 patients randomized to sofosbuvir-ledipasvir combination treatment or that plus ribavirin. Their results suggest improved neuronal function in patients after attainment of SVR, although ribavirin appeared to have an adverse impact on brain function and may have delayed neuronal recovery.

The findings vindicate long-harbored suspicions and prior evidence that HCV infection impairs central nervous system function and that quantifiable improvements can be documented following sustained viral clearance. This has profound implications for the argument that DAA-based HCV therapy should be offered even to patients with mild liver fibrosis.

Stevan A. Gonzalez, MD, MS

The data presented at The Liver Meeting pointed to impressive real-world experiences with the new treatment regimens.

Both the TRIO Network and HCV Target enrolled more than 1,000 patients each and presented better-than-anticipated results.

A key point to take from these studies is that the efficacy remains very high in the real world as it was demonstrated previously in clinical trials. This may be attributed to the improved tolerability and adherence associated with interferon-free regimens. These studies reported only minimal early discontinuations or serious adverse events.

Additionally, the role of ribavirin appears to be diminishing, particularly in the sofosbuvir and simeprevir combination, in which the addition of ribavirin did not make a difference. However, other data presented during the meeting involving combination sofosbuvir-ledipasvir suggested that an exception to this may apply to those with more advanced disease who failed prior treatment and in post-transplant recurrence.

Stevan Gonzalez

Stevan A. Gonzalez

In the HCV TARGET study, data were presented involving post-transplant patients with recurrent HCV. The majority of genotype 1 patients were treated with sofosbuvir and simeprevir (Olysio, Janssen). Data presented on 68 post-transplant patients who completed this regimen noted an SVR4 of 91%.

The post-transplant population has a lot to gain from achieving a cure because recurrence of hepatitis C is universal in all transplant recipients. And they are historically a difficult population to treat because they’re more susceptible to adverse events and poor tolerability of interferon-based regimens. The availability of highly effective oral regimens with a lower side effect profile and low potential for drug interactions with immunosuppressive medications will have a huge impact.

In patients who are post-transplant, achievement of an SVR opens the door for them to maintain good allograft function of their transplanted liver for the long term.

Putting this all together, these studies are demonstrating that the direct-acting antivirals really are having an impact beyond the clinical trials in a real-world setting.

This is important because clinical trials tend to have restricted populations, leading to a debate about whether clinical trials reflect what happens in the real world.

To me, these were very important consortia that will have the ability to produce large-scale data involving various populations and different direct-acting antiviral regimens. It’s exciting to see that we’re achieving high efficacy rates even in the real-world setting where historically we have always seen a decrease in response rates usually as a consequence of decreased adherence to therapy in clinical practice, increased severity of liver disease associated with populations not included in clinical trials, or concerns for adverse events.

Disclosure: Gonzalez reports participating on the speakers’ bureau and advisory board of Gilead Sciences. Jacobson reports no relevant disclosures.