Editorial

International Liver Congress Offers Continued HCV insight, progress

Sitting among the sessions at the International Liver Congress in Amsterdam, I had the distinct feeling that we are reaching an end to the era of revolutionary change in hepatitis C, but there remained impressive data, engaging debates and ongoing research given to us to better serve our patients. For those of us long involved in this field, we rejoice with our patients, often on a daily basis, and we intend to remain heavily engaged in addressing the remaining issues even as we heed the clarion call to immerse ourselves ever more deeply in the attempts to conquer other prevalent liver diseases.

Ira M. Jacobson, MD

Ira M. Jacobson

Latest Regimens

We saw continued evidence that glecaprevir/pibrentasvir (G/P, AbbVie) is effective in harder-to-treat patient populations. There were increasing data in diverse populations for a regimen that will probably be available this year.

In one study, presented by Xavier Forns, MD, a cohort of 146 patients with HCV genotypes 1, 2, 4, 5 or 6 and compensated cirrhosis — a third of which also had resistance variants — achieved 99% SVR12 with 12 weeks of G/P. The lone relapse was a patient with genotype 1a, Forns said.

Studies presented by Stan Pol, MD, and Fred Poordad, MD, showed very high rates of efficacy of G/P in HCV patients with chronic kidney disease and in treatment-experienced patients.

In a Late Breaker study presented by Nancy Reau, MD, of 80 liver transplant recipients and 20 renal transplant recipients treated for 12 weeks, the overall SVR12 rate was 99%. There was one potentially drug-related adverse event, but overall the regimen seems safe and effective in transplant patients.

In a larger study presented by Graham Foster, MD, on G/P in patients with genotype 3, there were 233 patients treated for 12 weeks, 115 patients treated with sofosbuvir (Sovaldi, Gilead) and daclatasvir (Daklinza, Bristol-Myers Squibb) 12 weeks, and then a third, additional arm that included 157 patients treated with G/P for 8 weeks.

Results indicated a 95% SVR12 rate for either 8 or 12 weeks of the study regimen, and 97% for sofosbuvir/daclatasvir. Foster explained the patient cohorts reflected his ongoing practice with a younger age than many clinical trials and no exclusion of drug users.

In a study of 153 patients with HIV and HCV coinfection presented by Jürgen K. Rockstroh, MD, a cumulative SVR rate of 98% by intent to treat analysis was observed in noncirrhotics and cirrhotics treated for 8 and 12 weeks, respectively.

The impending approval of G/P, I expect, will be a slight game changer because it will be a very solid 8-week regimen for genotype 1 noncirrhotics and it is an excellent regimen for renal failure. For patients with a history of DAA failure, we have seen promising results in a preliminary report last year and further data to follow.

Also, we saw the still-prominent ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) regimen show excellent efficacy in lesser-reported populations such as young pediatric patients and HBV/HCV coinfected patients. In reports from the Veterans Affairs database, we saw more than 95% efficacy in a real-world cohort treated with grazoprevir/elbasvir (Zepatier, Merck), as well as in the VA database on patients with renal failure taking this regimen.

HCC After DAAs

The HCC recurrence issue continues to be a hot controversy at the meeting this year, with experts arguing both sides of the coin.

Of note, Maria Reig, MD, updated her data set from last year’s EASL meeting and showed 31.2% of her cohort to have had a recurrence of HCC after starting DAA therapy. Looking at the group of patients who started HCV treatment within 4 months after complete response to HCC treatment, their rate of recurrence was higher, at 45%, she said, while 30% developed recurrence within the first 6 months.

Reig also maintained her argument that these recurrences are more aggressive and incur a faster tumor evolution.

But Gregory Dore, MD, argued that recurrence is overall common and the apparent increase in HCC occurrence after DAA therapy is merely a side effect of treating an older population with much shorter regimens.

Before adjustment, Dore’s analysis appeared to represent a threefold increase in HCC occurrence with DAAs (1.14 per 100 person-years vs. 3.09 per 100 person-years), but the adjusted analysis changed that picture.

Adjusting for age and follow-up, HCC occurrence between the interferon-treated and DAA-treated groups (9.21 per 100 person-years vs. 12.14 per 100 person-years) became much more equitable.

In the meta-regression adjusted analysis, Dore showed that DAA therapy was not associated with a higher occurrence of HCC (RR = 0.7; 95% CI, 0.2-2.6) or recurrence of HCC (RR = 1.4; 95% CI, 0.5-4.1).

Dore explained that the shorter duration of DAA therapy and, subsequently, follow-up adds to the appearance of higher HCC incidence. With longer treatment periods when using interferon, incidences seen while on-treatment would not be considered occurrences in a post-SVR analysis.

Solomon Owusu Sekyere, MD, also presented data showing DAA therapy significantly decreased HCC-specific CD8+ T-cell response at the end of therapy and through follow-up. This, he said, warrants close observation of patients after DAA therapy because this indicates different soluble inflammatory marker concentrations in this group.

HBV Recurrence

In an Asian cohort of 111 patients with genotype 1 and 2, the researchers showed that ledipasvir/sofosbuvir produced a 100% SVR12. They said patients did show an increase in HBV DNA, but ALT was not doubled over baseline and no one needed retreatment for their HBV.

The result is not much of a surprise; there is a little bit of HBV reactivation but no serious players or as much concern as was originally thought. As Douglas T. Dieterich, MD, and I wrote in a previous editorial, this is not so much a story as it has been made in certain corners of the lay press over the past few months.

Other Areas of Interest

As we do taper down the revolution in HCV, there was some groundbreaking data shown in other emerging areas of treatment: non-alcoholic steatohepatitis, primary biliary cholangitis and HBV.

At this meeting, we saw that bezafibrate induced an additional biochemical response in patients with PBC, improving pruritus and other markers, when used as a complementary therapy in patients who do not respond to ursodeoxycholic acid. Nearly all markers presented improved with bezafibrate. The rate of liver test normalization was 30% and of alkaline phosphatase normalization over twice as high, accompanied by a 75% decrease in itch score and a 10% reduction in liver stiffness.

Two Late Breakers, which are the tip of the iceberg in terms of the expanding volume of studies and novel agents presented at this meeting, showed significant reductions in liver fat in patients with NASH, offering new glimpses of hope in the epidemic.

Stephen A. Harrison, MD, showed that 80% of patients responded to an engineered variant of human fibroblast growth factor 19, or FGF19, referred to as NGM292 (NGM Bio). In the cohort of 82 with a minimum of 8% absolute liver fat content treated for 12 weeks, 34% achieved normalized liver fat content.

In the same session, Arun Sanyal, MD, showed that BMS-986036 (Bristol-Myers Squibb), a pegylated form of the hormone FGF21 injected subcutaneously, induced a relative reduction of 29% or greater in MRI-PDFF, proving a histologic response in liver fat. More than half of the treated patients saw a similar response and liver stiffness was reduced in more than one-third of the cohort.

Lastly, HBV treatments are emerging — everything from siRNA to capsid inhibitors, nucleic acid polymers, lysine methane inhibitors and more — with a renewed focus on the quest to cure, not only suppress, HBV(the benefits of which cannot be overestimated). I expect HBV therapeutics to be an increasingly dynamic, exciting field in the years to come.

Ira M. Jacobson, MD

HCV Next

Co-Chief Medical Editor

Sitting among the sessions at the International Liver Congress in Amsterdam, I had the distinct feeling that we are reaching an end to the era of revolutionary change in hepatitis C, but there remained impressive data, engaging debates and ongoing research given to us to better serve our patients. For those of us long involved in this field, we rejoice with our patients, often on a daily basis, and we intend to remain heavily engaged in addressing the remaining issues even as we heed the clarion call to immerse ourselves ever more deeply in the attempts to conquer other prevalent liver diseases.

Ira M. Jacobson, MD

Ira M. Jacobson

Latest Regimens

We saw continued evidence that glecaprevir/pibrentasvir (G/P, AbbVie) is effective in harder-to-treat patient populations. There were increasing data in diverse populations for a regimen that will probably be available this year.

In one study, presented by Xavier Forns, MD, a cohort of 146 patients with HCV genotypes 1, 2, 4, 5 or 6 and compensated cirrhosis — a third of which also had resistance variants — achieved 99% SVR12 with 12 weeks of G/P. The lone relapse was a patient with genotype 1a, Forns said.

Studies presented by Stan Pol, MD, and Fred Poordad, MD, showed very high rates of efficacy of G/P in HCV patients with chronic kidney disease and in treatment-experienced patients.

In a Late Breaker study presented by Nancy Reau, MD, of 80 liver transplant recipients and 20 renal transplant recipients treated for 12 weeks, the overall SVR12 rate was 99%. There was one potentially drug-related adverse event, but overall the regimen seems safe and effective in transplant patients.

In a larger study presented by Graham Foster, MD, on G/P in patients with genotype 3, there were 233 patients treated for 12 weeks, 115 patients treated with sofosbuvir (Sovaldi, Gilead) and daclatasvir (Daklinza, Bristol-Myers Squibb) 12 weeks, and then a third, additional arm that included 157 patients treated with G/P for 8 weeks.

Results indicated a 95% SVR12 rate for either 8 or 12 weeks of the study regimen, and 97% for sofosbuvir/daclatasvir. Foster explained the patient cohorts reflected his ongoing practice with a younger age than many clinical trials and no exclusion of drug users.

In a study of 153 patients with HIV and HCV coinfection presented by Jürgen K. Rockstroh, MD, a cumulative SVR rate of 98% by intent to treat analysis was observed in noncirrhotics and cirrhotics treated for 8 and 12 weeks, respectively.

The impending approval of G/P, I expect, will be a slight game changer because it will be a very solid 8-week regimen for genotype 1 noncirrhotics and it is an excellent regimen for renal failure. For patients with a history of DAA failure, we have seen promising results in a preliminary report last year and further data to follow.

PAGE BREAK

Also, we saw the still-prominent ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) regimen show excellent efficacy in lesser-reported populations such as young pediatric patients and HBV/HCV coinfected patients. In reports from the Veterans Affairs database, we saw more than 95% efficacy in a real-world cohort treated with grazoprevir/elbasvir (Zepatier, Merck), as well as in the VA database on patients with renal failure taking this regimen.

HCC After DAAs

The HCC recurrence issue continues to be a hot controversy at the meeting this year, with experts arguing both sides of the coin.

Of note, Maria Reig, MD, updated her data set from last year’s EASL meeting and showed 31.2% of her cohort to have had a recurrence of HCC after starting DAA therapy. Looking at the group of patients who started HCV treatment within 4 months after complete response to HCC treatment, their rate of recurrence was higher, at 45%, she said, while 30% developed recurrence within the first 6 months.

Reig also maintained her argument that these recurrences are more aggressive and incur a faster tumor evolution.

But Gregory Dore, MD, argued that recurrence is overall common and the apparent increase in HCC occurrence after DAA therapy is merely a side effect of treating an older population with much shorter regimens.

Before adjustment, Dore’s analysis appeared to represent a threefold increase in HCC occurrence with DAAs (1.14 per 100 person-years vs. 3.09 per 100 person-years), but the adjusted analysis changed that picture.

Adjusting for age and follow-up, HCC occurrence between the interferon-treated and DAA-treated groups (9.21 per 100 person-years vs. 12.14 per 100 person-years) became much more equitable.

In the meta-regression adjusted analysis, Dore showed that DAA therapy was not associated with a higher occurrence of HCC (RR = 0.7; 95% CI, 0.2-2.6) or recurrence of HCC (RR = 1.4; 95% CI, 0.5-4.1).

Dore explained that the shorter duration of DAA therapy and, subsequently, follow-up adds to the appearance of higher HCC incidence. With longer treatment periods when using interferon, incidences seen while on-treatment would not be considered occurrences in a post-SVR analysis.

Solomon Owusu Sekyere, MD, also presented data showing DAA therapy significantly decreased HCC-specific CD8+ T-cell response at the end of therapy and through follow-up. This, he said, warrants close observation of patients after DAA therapy because this indicates different soluble inflammatory marker concentrations in this group.

HBV Recurrence

In an Asian cohort of 111 patients with genotype 1 and 2, the researchers showed that ledipasvir/sofosbuvir produced a 100% SVR12. They said patients did show an increase in HBV DNA, but ALT was not doubled over baseline and no one needed retreatment for their HBV.

PAGE BREAK

The result is not much of a surprise; there is a little bit of HBV reactivation but no serious players or as much concern as was originally thought. As Douglas T. Dieterich, MD, and I wrote in a previous editorial, this is not so much a story as it has been made in certain corners of the lay press over the past few months.

Other Areas of Interest

As we do taper down the revolution in HCV, there was some groundbreaking data shown in other emerging areas of treatment: non-alcoholic steatohepatitis, primary biliary cholangitis and HBV.

At this meeting, we saw that bezafibrate induced an additional biochemical response in patients with PBC, improving pruritus and other markers, when used as a complementary therapy in patients who do not respond to ursodeoxycholic acid. Nearly all markers presented improved with bezafibrate. The rate of liver test normalization was 30% and of alkaline phosphatase normalization over twice as high, accompanied by a 75% decrease in itch score and a 10% reduction in liver stiffness.

Two Late Breakers, which are the tip of the iceberg in terms of the expanding volume of studies and novel agents presented at this meeting, showed significant reductions in liver fat in patients with NASH, offering new glimpses of hope in the epidemic.

Stephen A. Harrison, MD, showed that 80% of patients responded to an engineered variant of human fibroblast growth factor 19, or FGF19, referred to as NGM292 (NGM Bio). In the cohort of 82 with a minimum of 8% absolute liver fat content treated for 12 weeks, 34% achieved normalized liver fat content.

In the same session, Arun Sanyal, MD, showed that BMS-986036 (Bristol-Myers Squibb), a pegylated form of the hormone FGF21 injected subcutaneously, induced a relative reduction of 29% or greater in MRI-PDFF, proving a histologic response in liver fat. More than half of the treated patients saw a similar response and liver stiffness was reduced in more than one-third of the cohort.

Lastly, HBV treatments are emerging — everything from siRNA to capsid inhibitors, nucleic acid polymers, lysine methane inhibitors and more — with a renewed focus on the quest to cure, not only suppress, HBV(the benefits of which cannot be overestimated). I expect HBV therapeutics to be an increasingly dynamic, exciting field in the years to come.

Ira M. Jacobson, MD

HCV Next

Co-Chief Medical Editor