Liver Disease

BOSTON – Exposure to heavy metals from natural and man-made sources may contribute to development of autoimmune liver disease, according to a recent U.K. study involving more than 3,500 patients.

Will Pass/MDedge News

Coal mines were particularly implicated, as they accounted for 39% of the risk of developing primary biliary cholangitis (PBC), reported lead author Jessica Dyson, MBBS, of Newcastle (England) University, and colleagues.

“We know that the etiology of autoimmune liver disease remains unclear, but we’re increasingly coming to understand that it’s likely to be a complex interplay between genetic and environmental factors,” Dr. Dyson said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. Showing a map of England, she pointed out how three autoimmune liver diseases – PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) – each have unique clusters of distribution. “This implies that environmental exposure may have a role in disease pathogenesis.”

To investigate this possibility, Dr. Dyson and colleagues used structural equation modeling to look for associations between the above three autoimmune liver diseases, socioeconomic status, and environmental factors. Specific environmental factors included soil concentrations of heavy metals (cadmium, arsenic, lead, manganese, and iron), coal mines, lead mines, quarries, urban areas, traffic, stream pH, and landfills.

The study was conducted in the northeast of England, where migration rates are low, Dr. Dyson said. From this region, the investigators identified patients with PBC (n = 2,150), AIH (n = 963), and PSC (n = 472). Conceptual models were used to examine relationships between covariates and prevalence of disease, with good models exhibiting a root-mean-square error of association less than 0.05 and a 95% covariate significance. After adjusting for population density, comparative fit was used to measure variation within each model.

The best model for PBC revealed the aforementioned link with coal mines, proximity to which accounted for 39% of the pathogenesis of PBC. High levels of cadmium in soil had an interactive role with coal mines, and itself directly contributed 22% of the risk of PBC; however, Dr. Dyson noted that, while many cadmium-rich areas had high rates of PBC, not all did.

“This demonstrates the complexity of causality of disease, and we certainly can’t say that cadmium, in its own right, is a direct cause and effect,” Dr. Dyson said. “But I think [cadmium] certainly potentially is one of the factors at play.”

For AIH, coal mines contributed less (6%), although cadmium still accounted for 22% of variation of disease, as did alkaline areas. Finally, a significant link was found between PSC and regions with high arsenic levels.

“To conclude, our data suggest that heavy metals may be risk factors for autoimmune liver disease,” Dr. Dyson said. “There are a number of exposure routes that may be pertinent to patients, from heavy metals occurring via natural sources, and also via virtue of human activity, such as burning of fossil fuels, heavy-metal production, and pesticides.” Dr. Dyson emphasized this latter route, as some rural areas, where pesticide use is common, had high prevalence rates of autoimmune liver disease.

Dr. Dyson went on to put her findings in context. “Heavy metals are a well-recognized cause of immune dysregulation and epithelial injury and are actually actively transported into the bile, and that may be particularly relevant in terms of cholangiopathies. And this leads us to the possibility of interventions to reduce toxic exposure that may modify risk of disease.”

Looking to the future, Dr. Dyson described plans to build on this research with measurements of heavy metals in tissues, serum, and urine.

The investigators reported no relevant disclosures.

SOURCE: Dyson J et al. The Liver Meeting 2019, Abstract 48.

BOSTON – Exposure to heavy metals from natural and man-made sources may contribute to development of autoimmune liver disease, according to a recent U.K. study involving more than 3,500 patients.

Will Pass/MDedge News

Coal mines were particularly implicated, as they accounted for 39% of the risk of developing primary biliary cholangitis (PBC), reported lead author Jessica Dyson, MBBS, of Newcastle (England) University, and colleagues.

“We know that the etiology of autoimmune liver disease remains unclear, but we’re increasingly coming to understand that it’s likely to be a complex interplay between genetic and environmental factors,” Dr. Dyson said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. Showing a map of England, she pointed out how three autoimmune liver diseases – PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) – each have unique clusters of distribution. “This implies that environmental exposure may have a role in disease pathogenesis.”

To investigate this possibility, Dr. Dyson and colleagues used structural equation modeling to look for associations between the above three autoimmune liver diseases, socioeconomic status, and environmental factors. Specific environmental factors included soil concentrations of heavy metals (cadmium, arsenic, lead, manganese, and iron), coal mines, lead mines, quarries, urban areas, traffic, stream pH, and landfills.

The study was conducted in the northeast of England, where migration rates are low, Dr. Dyson said. From this region, the investigators identified patients with PBC (n = 2,150), AIH (n = 963), and PSC (n = 472). Conceptual models were used to examine relationships between covariates and prevalence of disease, with good models exhibiting a root-mean-square error of association less than 0.05 and a 95% covariate significance. After adjusting for population density, comparative fit was used to measure variation within each model.

The best model for PBC revealed the aforementioned link with coal mines, proximity to which accounted for 39% of the pathogenesis of PBC. High levels of cadmium in soil had an interactive role with coal mines, and itself directly contributed 22% of the risk of PBC; however, Dr. Dyson noted that, while many cadmium-rich areas had high rates of PBC, not all did.

“This demonstrates the complexity of causality of disease, and we certainly can’t say that cadmium, in its own right, is a direct cause and effect,” Dr. Dyson said. “But I think [cadmium] certainly potentially is one of the factors at play.”

For AIH, coal mines contributed less (6%), although cadmium still accounted for 22% of variation of disease, as did alkaline areas. Finally, a significant link was found between PSC and regions with high arsenic levels.

“To conclude, our data suggest that heavy metals may be risk factors for autoimmune liver disease,” Dr. Dyson said. “There are a number of exposure routes that may be pertinent to patients, from heavy metals occurring via natural sources, and also via virtue of human activity, such as burning of fossil fuels, heavy-metal production, and pesticides.” Dr. Dyson emphasized this latter route, as some rural areas, where pesticide use is common, had high prevalence rates of autoimmune liver disease.

Dr. Dyson went on to put her findings in context. “Heavy metals are a well-recognized cause of immune dysregulation and epithelial injury and are actually actively transported into the bile, and that may be particularly relevant in terms of cholangiopathies. And this leads us to the possibility of interventions to reduce toxic exposure that may modify risk of disease.”

Looking to the future, Dr. Dyson described plans to build on this research with measurements of heavy metals in tissues, serum, and urine.

The investigators reported no relevant disclosures.

SOURCE: Dyson J et al. The Liver Meeting 2019, Abstract 48.

BOSTON – Exposure to heavy metals from natural and man-made sources may contribute to development of autoimmune liver disease, according to a recent U.K. study involving more than 3,500 patients.

Will Pass/MDedge News

Coal mines were particularly implicated, as they accounted for 39% of the risk of developing primary biliary cholangitis (PBC), reported lead author Jessica Dyson, MBBS, of Newcastle (England) University, and colleagues.

“We know that the etiology of autoimmune liver disease remains unclear, but we’re increasingly coming to understand that it’s likely to be a complex interplay between genetic and environmental factors,” Dr. Dyson said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. Showing a map of England, she pointed out how three autoimmune liver diseases – PBC, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) – each have unique clusters of distribution. “This implies that environmental exposure may have a role in disease pathogenesis.”

To investigate this possibility, Dr. Dyson and colleagues used structural equation modeling to look for associations between the above three autoimmune liver diseases, socioeconomic status, and environmental factors. Specific environmental factors included soil concentrations of heavy metals (cadmium, arsenic, lead, manganese, and iron), coal mines, lead mines, quarries, urban areas, traffic, stream pH, and landfills.

The study was conducted in the northeast of England, where migration rates are low, Dr. Dyson said. From this region, the investigators identified patients with PBC (n = 2,150), AIH (n = 963), and PSC (n = 472). Conceptual models were used to examine relationships between covariates and prevalence of disease, with good models exhibiting a root-mean-square error of association less than 0.05 and a 95% covariate significance. After adjusting for population density, comparative fit was used to measure variation within each model.

The best model for PBC revealed the aforementioned link with coal mines, proximity to which accounted for 39% of the pathogenesis of PBC. High levels of cadmium in soil had an interactive role with coal mines, and itself directly contributed 22% of the risk of PBC; however, Dr. Dyson noted that, while many cadmium-rich areas had high rates of PBC, not all did.

“This demonstrates the complexity of causality of disease, and we certainly can’t say that cadmium, in its own right, is a direct cause and effect,” Dr. Dyson said. “But I think [cadmium] certainly potentially is one of the factors at play.”

For AIH, coal mines contributed less (6%), although cadmium still accounted for 22% of variation of disease, as did alkaline areas. Finally, a significant link was found between PSC and regions with high arsenic levels.

“To conclude, our data suggest that heavy metals may be risk factors for autoimmune liver disease,” Dr. Dyson said. “There are a number of exposure routes that may be pertinent to patients, from heavy metals occurring via natural sources, and also via virtue of human activity, such as burning of fossil fuels, heavy-metal production, and pesticides.” Dr. Dyson emphasized this latter route, as some rural areas, where pesticide use is common, had high prevalence rates of autoimmune liver disease.

Dr. Dyson went on to put her findings in context. “Heavy metals are a well-recognized cause of immune dysregulation and epithelial injury and are actually actively transported into the bile, and that may be particularly relevant in terms of cholangiopathies. And this leads us to the possibility of interventions to reduce toxic exposure that may modify risk of disease.”

Looking to the future, Dr. Dyson described plans to build on this research with measurements of heavy metals in tissues, serum, and urine.

The investigators reported no relevant disclosures.

SOURCE: Dyson J et al. The Liver Meeting 2019, Abstract 48.

BOSTON – Some of the most notable abstracts presented here at the annual meeting of the American Association for the Study of Liver Diseases dealt with key topics including the natural history of hepatitis B virus, novel treatment approaches, and prevention, according to Marc Ghany, MD.

Andrew Bowser/MDedge News

During a special hepatitis debriefing session held on the last day of the conference, Dr. Ghany reviewed his key selections in hepatitis B virus (HBV) research, including the following:
 

Natural history

Steatohepatitis may worsen HBV-related liver injury, according to results of an analysis of liver biopsies from adult patients enrolled in a North American cohort study (Abstract 162). Investigators found that steatohepatitis was associated with a 1.6-fold increased risk of advanced fibrosis.

“For all patients with hepatitis B, I think it’s important to screen and manage metabolic abnormalities to prevent liver disease progression,” said Dr. Ghany, who is with the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.

Risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B was evaluated in two notable studies, Dr. Ghany said, including one that found no difference in risk of HCC development among white patients who received long-term entecavir versus those who received long-term tenofovir (Abstract 454). This stands in contrast to a previous and controversial finding, according to investigators, that HCC incidence was lower in Asian patients treated with tenofovir versus those treated with entecavir.

In the other study, investigators found that dual-antiplatelet therapy (DAPT) was associated with a lower risk of HCC versus aspirin monotherapy in patients with chronic hepatitis B (Abstract 934). Antiplatelet therapy was associated with a near 20% reduction in HCC risk, while DAPT as compared with aspirin monotherapy was linked to a near 30% reduction. “These are very provocative findings,” Dr. Ghany said. “Of course they need to be confirmed, but if so, may open new avenues of HCC chemoprevention.”
 

Novel therapies

Several new and promising drugs are undergoing clinical trials, including JNJ-64530440 (JNJ-0440), a novel class N capsid assembly modulator. In phase 1a data presented here at The Liver Meeting, the treatment was safe, well tolerated, and resulted in potent inhibition of viral replication (Abstract 0089). “We await further studies on its effect on functional cure,” Dr. Ghany told attendees.

Another treatment to watch is GSK3389404 (GSK404), a liver-targeted antisense oligonucleotide; in a phase 2 placebo-controlled study in patients with chronic hepatitis B on stable nucleos(t)ide therapy, this treatment had acceptable safety and produced dose-dependent declines in hepatitis B surface antigen (HBsAg), according to investigators (Abstract 0695). Dr. Ghany said this constitutes “proof of principle” that antisense oligonucleotides can decrease HBsAg levels.

In a phase 2 randomized, placebo-controlled study in virally suppressed adults with chronic hepatitis B, the toll-like receptor 8 (TLR8) agonist GS-9688 was safe and well tolerated, and resulted in dose-dependent pharmacodynamic changes, with 5% of patients experiencing a 1 log₁₀ IU/mL or greater decline in HBsAg levels or an HBsAg loss by week 24 (Abstract 0697). This is a “promising approach” that merits further study, according to Dr. Ghany.
 

Prevention: Vaccination and screening

A trivalent HBV vaccine is superior to monovalent vaccine, according to results from the double-blind, randomized, controlled, phase 3 PROTECT study presented here at the meeting (Abstract LP13). Known as Sci-B-Vac, the mammalian cell-derived trivalent vaccine had higher response rates versus the recombinant monovalent vaccine Engerix-B in difficult-to-vaccinate populations, according to Dr. Ghany.

A separate report based on a national health insurance cohort study in Korea demonstrated that regular follow-up, that is to say, every 3-6 months, significantly reduced liver cancer–related mortality (Abstract 0159). Patients compliant with screening in the study not only had a 44% reduction in risk of death from HCC, but also were more likely to receive curative treatments (23.1% versus 15.1%). “Notwithstanding the limitations or cohort studies, I think these data reinforce the need to screen patients with chronic hepatitis B,” Dr. Ghany said.

He provided no disclosures in his presentation.

BOSTON – Some of the most notable abstracts presented here at the annual meeting of the American Association for the Study of Liver Diseases dealt with key topics including the natural history of hepatitis B virus, novel treatment approaches, and prevention, according to Marc Ghany, MD.

Andrew Bowser/MDedge News

During a special hepatitis debriefing session held on the last day of the conference, Dr. Ghany reviewed his key selections in hepatitis B virus (HBV) research, including the following:
 

Natural history

Steatohepatitis may worsen HBV-related liver injury, according to results of an analysis of liver biopsies from adult patients enrolled in a North American cohort study (Abstract 162). Investigators found that steatohepatitis was associated with a 1.6-fold increased risk of advanced fibrosis.

“For all patients with hepatitis B, I think it’s important to screen and manage metabolic abnormalities to prevent liver disease progression,” said Dr. Ghany, who is with the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.

Risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B was evaluated in two notable studies, Dr. Ghany said, including one that found no difference in risk of HCC development among white patients who received long-term entecavir versus those who received long-term tenofovir (Abstract 454). This stands in contrast to a previous and controversial finding, according to investigators, that HCC incidence was lower in Asian patients treated with tenofovir versus those treated with entecavir.

In the other study, investigators found that dual-antiplatelet therapy (DAPT) was associated with a lower risk of HCC versus aspirin monotherapy in patients with chronic hepatitis B (Abstract 934). Antiplatelet therapy was associated with a near 20% reduction in HCC risk, while DAPT as compared with aspirin monotherapy was linked to a near 30% reduction. “These are very provocative findings,” Dr. Ghany said. “Of course they need to be confirmed, but if so, may open new avenues of HCC chemoprevention.”
 

Novel therapies

Several new and promising drugs are undergoing clinical trials, including JNJ-64530440 (JNJ-0440), a novel class N capsid assembly modulator. In phase 1a data presented here at The Liver Meeting, the treatment was safe, well tolerated, and resulted in potent inhibition of viral replication (Abstract 0089). “We await further studies on its effect on functional cure,” Dr. Ghany told attendees.

Another treatment to watch is GSK3389404 (GSK404), a liver-targeted antisense oligonucleotide; in a phase 2 placebo-controlled study in patients with chronic hepatitis B on stable nucleos(t)ide therapy, this treatment had acceptable safety and produced dose-dependent declines in hepatitis B surface antigen (HBsAg), according to investigators (Abstract 0695). Dr. Ghany said this constitutes “proof of principle” that antisense oligonucleotides can decrease HBsAg levels.

In a phase 2 randomized, placebo-controlled study in virally suppressed adults with chronic hepatitis B, the toll-like receptor 8 (TLR8) agonist GS-9688 was safe and well tolerated, and resulted in dose-dependent pharmacodynamic changes, with 5% of patients experiencing a 1 log₁₀ IU/mL or greater decline in HBsAg levels or an HBsAg loss by week 24 (Abstract 0697). This is a “promising approach” that merits further study, according to Dr. Ghany.
 

Prevention: Vaccination and screening

A trivalent HBV vaccine is superior to monovalent vaccine, according to results from the double-blind, randomized, controlled, phase 3 PROTECT study presented here at the meeting (Abstract LP13). Known as Sci-B-Vac, the mammalian cell-derived trivalent vaccine had higher response rates versus the recombinant monovalent vaccine Engerix-B in difficult-to-vaccinate populations, according to Dr. Ghany.

A separate report based on a national health insurance cohort study in Korea demonstrated that regular follow-up, that is to say, every 3-6 months, significantly reduced liver cancer–related mortality (Abstract 0159). Patients compliant with screening in the study not only had a 44% reduction in risk of death from HCC, but also were more likely to receive curative treatments (23.1% versus 15.1%). “Notwithstanding the limitations or cohort studies, I think these data reinforce the need to screen patients with chronic hepatitis B,” Dr. Ghany said.

He provided no disclosures in his presentation.

BOSTON – Some of the most notable abstracts presented here at the annual meeting of the American Association for the Study of Liver Diseases dealt with key topics including the natural history of hepatitis B virus, novel treatment approaches, and prevention, according to Marc Ghany, MD.

Andrew Bowser/MDedge News

During a special hepatitis debriefing session held on the last day of the conference, Dr. Ghany reviewed his key selections in hepatitis B virus (HBV) research, including the following:
 

Natural history

Steatohepatitis may worsen HBV-related liver injury, according to results of an analysis of liver biopsies from adult patients enrolled in a North American cohort study (Abstract 162). Investigators found that steatohepatitis was associated with a 1.6-fold increased risk of advanced fibrosis.

“For all patients with hepatitis B, I think it’s important to screen and manage metabolic abnormalities to prevent liver disease progression,” said Dr. Ghany, who is with the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.

Risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B was evaluated in two notable studies, Dr. Ghany said, including one that found no difference in risk of HCC development among white patients who received long-term entecavir versus those who received long-term tenofovir (Abstract 454). This stands in contrast to a previous and controversial finding, according to investigators, that HCC incidence was lower in Asian patients treated with tenofovir versus those treated with entecavir.

In the other study, investigators found that dual-antiplatelet therapy (DAPT) was associated with a lower risk of HCC versus aspirin monotherapy in patients with chronic hepatitis B (Abstract 934). Antiplatelet therapy was associated with a near 20% reduction in HCC risk, while DAPT as compared with aspirin monotherapy was linked to a near 30% reduction. “These are very provocative findings,” Dr. Ghany said. “Of course they need to be confirmed, but if so, may open new avenues of HCC chemoprevention.”
 

Novel therapies

Several new and promising drugs are undergoing clinical trials, including JNJ-64530440 (JNJ-0440), a novel class N capsid assembly modulator. In phase 1a data presented here at The Liver Meeting, the treatment was safe, well tolerated, and resulted in potent inhibition of viral replication (Abstract 0089). “We await further studies on its effect on functional cure,” Dr. Ghany told attendees.

Another treatment to watch is GSK3389404 (GSK404), a liver-targeted antisense oligonucleotide; in a phase 2 placebo-controlled study in patients with chronic hepatitis B on stable nucleos(t)ide therapy, this treatment had acceptable safety and produced dose-dependent declines in hepatitis B surface antigen (HBsAg), according to investigators (Abstract 0695). Dr. Ghany said this constitutes “proof of principle” that antisense oligonucleotides can decrease HBsAg levels.

In a phase 2 randomized, placebo-controlled study in virally suppressed adults with chronic hepatitis B, the toll-like receptor 8 (TLR8) agonist GS-9688 was safe and well tolerated, and resulted in dose-dependent pharmacodynamic changes, with 5% of patients experiencing a 1 log₁₀ IU/mL or greater decline in HBsAg levels or an HBsAg loss by week 24 (Abstract 0697). This is a “promising approach” that merits further study, according to Dr. Ghany.
 

Prevention: Vaccination and screening

A trivalent HBV vaccine is superior to monovalent vaccine, according to results from the double-blind, randomized, controlled, phase 3 PROTECT study presented here at the meeting (Abstract LP13). Known as Sci-B-Vac, the mammalian cell-derived trivalent vaccine had higher response rates versus the recombinant monovalent vaccine Engerix-B in difficult-to-vaccinate populations, according to Dr. Ghany.

A separate report based on a national health insurance cohort study in Korea demonstrated that regular follow-up, that is to say, every 3-6 months, significantly reduced liver cancer–related mortality (Abstract 0159). Patients compliant with screening in the study not only had a 44% reduction in risk of death from HCC, but also were more likely to receive curative treatments (23.1% versus 15.1%). “Notwithstanding the limitations or cohort studies, I think these data reinforce the need to screen patients with chronic hepatitis B,” Dr. Ghany said.

He provided no disclosures in his presentation.

BOSTON – For patients with hepatitis C virus infection who achieve sustained virologic response to interferon-free therapy, changes in hepatic venous pressure gradient (HVPG) predict clinical benefit, according to investigators.

Will Pass/MDedge News

This finding will allow investigators to use HVPG as a surrogate endpoint for etiologic therapies, which could accelerate future research, reported lead author Mattias Mandorfer, MD, PhD, of the Medical University of Vienna and colleagues.

“Sustained virologic response to interferon-free therapies ameliorates portal hypertension,” Dr. Mandorfer said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “[Previous research has shown that] nearly two-thirds of patients with pretreatment clinically significant portal hypertension had an HVPG decrease above or equal to 10%, which denotes a clinically meaningful change according to current recommendations. However, evidence is limited to studies evaluating the impact of HVPG response to nonselective beta-blockers, and nonselective beta-blockers have a completely different mode of action than etiological therapies. Accordingly, it is unclear whether a decrease in HVPG after the cure of hepatitis C translates into the same clinical benefit.”

To find out, the investigators enrolled 90 patients with hepatitis C virus who had an elevated HVPG of 6 mm Hg or higher prior to sustained virologic response. Before and after interferon-free therapy, patients underwent paired HVPG measurement. In addition, to evaluate noninvasive methods of HVPG assessment, transient elastography and von Willebrand factor to platelet count ratio testing were performed.

Analysis showed that HVPG measurements after, but not before, interferon-free therapy predicted liver decompensation. Specifically, HVPG was associated with an 18% increased risk of hepatic decompensation per mm Hg. After 3 years, 40.1% of patients with posttherapy HVPG measurements of 16 mm Hg or more developed hepatic decompensation, an event that occurred in none of the patients with a posttherapy HVPG of 9 mm Hg or less. Among patients who had a baseline HVPG of 10 mm Hg or more, which is considered a clinically significant level of portal hypertension, a decrease in HVPG of least 10% after therapy was associated with a similar level of protection against decompensation, compared with those who had no such decrease (2.5% vs. 31.8%).

While the two noninvasive methods (transient elastography and von Willebrand factor to platelet count ratio) were able to detect clinically significant portal hypertension (at least 10 mm Hg), they were not accurate enough to detect the protective 10% drop in HVPG.

“These results support the concept of applying HVPG as a surrogate endpoint for interventions that primarily aim at decreasing intrahepatic resistance (e.g., etiological therapies),” the investigators concluded in their abstract.

Jaime Bosch, MD, PhD, of the University of Barcelona provided some expert insight into the findings.

“The significance of the work is very important,” Dr. Bosch said in a public comment. “This provides, for the first time, firm evidence that HVPG can be taken as a surrogate endpoint ... for studies involving portal hypertension and cirrhosis in general.”

In an interview, Dr. Bosch elaborated on this statement. “The problem is, it takes a long time to get rid of cirrhosis [after sustained virologic response], and meanwhile, as long as portal hypertension remains, there is a risk for decompensation, so the patients cannot be said to be cured. They are cured of the infection, of the consequences of the infection, but it may take 10 years or more [to resolve cirrhosis], so the patient needs clinical surveillance and treatment after curing the cause of the disease.

“An academic consequence of these findings is that they’ve proved that decreasing HVPG by means of achieving sustained virologic response is followed by an improvement in prognosis. ... And when you can influence prognosis, and the influence in prognosis is reflected by a measurement independent from the way that we achieve this effect on the measurement, it means that this measurement is robust and now has to be used as a surrogate marker of resolution of cirrhosis.”

The study was funded by the Medical Scientific Fund of the city of Vienna. The investigators disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead, and others.

SOURCE: Mandorfer M et al. The Liver Meeting 2019, Abstract 146.

BOSTON – For patients with hepatitis C virus infection who achieve sustained virologic response to interferon-free therapy, changes in hepatic venous pressure gradient (HVPG) predict clinical benefit, according to investigators.

Will Pass/MDedge News

This finding will allow investigators to use HVPG as a surrogate endpoint for etiologic therapies, which could accelerate future research, reported lead author Mattias Mandorfer, MD, PhD, of the Medical University of Vienna and colleagues.

“Sustained virologic response to interferon-free therapies ameliorates portal hypertension,” Dr. Mandorfer said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “[Previous research has shown that] nearly two-thirds of patients with pretreatment clinically significant portal hypertension had an HVPG decrease above or equal to 10%, which denotes a clinically meaningful change according to current recommendations. However, evidence is limited to studies evaluating the impact of HVPG response to nonselective beta-blockers, and nonselective beta-blockers have a completely different mode of action than etiological therapies. Accordingly, it is unclear whether a decrease in HVPG after the cure of hepatitis C translates into the same clinical benefit.”

To find out, the investigators enrolled 90 patients with hepatitis C virus who had an elevated HVPG of 6 mm Hg or higher prior to sustained virologic response. Before and after interferon-free therapy, patients underwent paired HVPG measurement. In addition, to evaluate noninvasive methods of HVPG assessment, transient elastography and von Willebrand factor to platelet count ratio testing were performed.

Analysis showed that HVPG measurements after, but not before, interferon-free therapy predicted liver decompensation. Specifically, HVPG was associated with an 18% increased risk of hepatic decompensation per mm Hg. After 3 years, 40.1% of patients with posttherapy HVPG measurements of 16 mm Hg or more developed hepatic decompensation, an event that occurred in none of the patients with a posttherapy HVPG of 9 mm Hg or less. Among patients who had a baseline HVPG of 10 mm Hg or more, which is considered a clinically significant level of portal hypertension, a decrease in HVPG of least 10% after therapy was associated with a similar level of protection against decompensation, compared with those who had no such decrease (2.5% vs. 31.8%).

While the two noninvasive methods (transient elastography and von Willebrand factor to platelet count ratio) were able to detect clinically significant portal hypertension (at least 10 mm Hg), they were not accurate enough to detect the protective 10% drop in HVPG.

“These results support the concept of applying HVPG as a surrogate endpoint for interventions that primarily aim at decreasing intrahepatic resistance (e.g., etiological therapies),” the investigators concluded in their abstract.

Jaime Bosch, MD, PhD, of the University of Barcelona provided some expert insight into the findings.

“The significance of the work is very important,” Dr. Bosch said in a public comment. “This provides, for the first time, firm evidence that HVPG can be taken as a surrogate endpoint ... for studies involving portal hypertension and cirrhosis in general.”

In an interview, Dr. Bosch elaborated on this statement. “The problem is, it takes a long time to get rid of cirrhosis [after sustained virologic response], and meanwhile, as long as portal hypertension remains, there is a risk for decompensation, so the patients cannot be said to be cured. They are cured of the infection, of the consequences of the infection, but it may take 10 years or more [to resolve cirrhosis], so the patient needs clinical surveillance and treatment after curing the cause of the disease.

“An academic consequence of these findings is that they’ve proved that decreasing HVPG by means of achieving sustained virologic response is followed by an improvement in prognosis. ... And when you can influence prognosis, and the influence in prognosis is reflected by a measurement independent from the way that we achieve this effect on the measurement, it means that this measurement is robust and now has to be used as a surrogate marker of resolution of cirrhosis.”

The study was funded by the Medical Scientific Fund of the city of Vienna. The investigators disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead, and others.

SOURCE: Mandorfer M et al. The Liver Meeting 2019, Abstract 146.

BOSTON – For patients with hepatitis C virus infection who achieve sustained virologic response to interferon-free therapy, changes in hepatic venous pressure gradient (HVPG) predict clinical benefit, according to investigators.

Will Pass/MDedge News

This finding will allow investigators to use HVPG as a surrogate endpoint for etiologic therapies, which could accelerate future research, reported lead author Mattias Mandorfer, MD, PhD, of the Medical University of Vienna and colleagues.

“Sustained virologic response to interferon-free therapies ameliorates portal hypertension,” Dr. Mandorfer said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “[Previous research has shown that] nearly two-thirds of patients with pretreatment clinically significant portal hypertension had an HVPG decrease above or equal to 10%, which denotes a clinically meaningful change according to current recommendations. However, evidence is limited to studies evaluating the impact of HVPG response to nonselective beta-blockers, and nonselective beta-blockers have a completely different mode of action than etiological therapies. Accordingly, it is unclear whether a decrease in HVPG after the cure of hepatitis C translates into the same clinical benefit.”

To find out, the investigators enrolled 90 patients with hepatitis C virus who had an elevated HVPG of 6 mm Hg or higher prior to sustained virologic response. Before and after interferon-free therapy, patients underwent paired HVPG measurement. In addition, to evaluate noninvasive methods of HVPG assessment, transient elastography and von Willebrand factor to platelet count ratio testing were performed.

Analysis showed that HVPG measurements after, but not before, interferon-free therapy predicted liver decompensation. Specifically, HVPG was associated with an 18% increased risk of hepatic decompensation per mm Hg. After 3 years, 40.1% of patients with posttherapy HVPG measurements of 16 mm Hg or more developed hepatic decompensation, an event that occurred in none of the patients with a posttherapy HVPG of 9 mm Hg or less. Among patients who had a baseline HVPG of 10 mm Hg or more, which is considered a clinically significant level of portal hypertension, a decrease in HVPG of least 10% after therapy was associated with a similar level of protection against decompensation, compared with those who had no such decrease (2.5% vs. 31.8%).

While the two noninvasive methods (transient elastography and von Willebrand factor to platelet count ratio) were able to detect clinically significant portal hypertension (at least 10 mm Hg), they were not accurate enough to detect the protective 10% drop in HVPG.

“These results support the concept of applying HVPG as a surrogate endpoint for interventions that primarily aim at decreasing intrahepatic resistance (e.g., etiological therapies),” the investigators concluded in their abstract.

Jaime Bosch, MD, PhD, of the University of Barcelona provided some expert insight into the findings.

“The significance of the work is very important,” Dr. Bosch said in a public comment. “This provides, for the first time, firm evidence that HVPG can be taken as a surrogate endpoint ... for studies involving portal hypertension and cirrhosis in general.”

In an interview, Dr. Bosch elaborated on this statement. “The problem is, it takes a long time to get rid of cirrhosis [after sustained virologic response], and meanwhile, as long as portal hypertension remains, there is a risk for decompensation, so the patients cannot be said to be cured. They are cured of the infection, of the consequences of the infection, but it may take 10 years or more [to resolve cirrhosis], so the patient needs clinical surveillance and treatment after curing the cause of the disease.

“An academic consequence of these findings is that they’ve proved that decreasing HVPG by means of achieving sustained virologic response is followed by an improvement in prognosis. ... And when you can influence prognosis, and the influence in prognosis is reflected by a measurement independent from the way that we achieve this effect on the measurement, it means that this measurement is robust and now has to be used as a surrogate marker of resolution of cirrhosis.”

The study was funded by the Medical Scientific Fund of the city of Vienna. The investigators disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead, and others.

SOURCE: Mandorfer M et al. The Liver Meeting 2019, Abstract 146.

BOSTON – Children who have recurrence of primary sclerosing cholangitis after liver transplant tend to be younger and have more rapidly progressive disease, based on an international retrospective analysis.

Will Pass/MDedge News

Within 5 years of transplant, the probability of primary sclerosing cholangitis (PSC) recurrence in pediatric patients is 26%, reported lead author Mercedes Martinez, MD, of Columbia University, New York, and colleagues.

“The aim of our study was to identify risk factors for primary sclerosing cholangitis recurrence following transplant,” Dr. Martinez said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. This may be the largest pediatric study evaluating recurrent PSC to date, she added.

The investigators drew data from 35 centers around the world via the Pediatric PSC Consortium database. Recurrence was defined by cholestatic biochemistry with nonanastomotic biliary strictures and beading of bile ducts on cholangiography. Recurrences caused by hepatic artery thrombosis or chronic rejection were excluded, as were any cases that recurred within 6 months of transplant.

The final analysis included 149 patients with a median age at diagnosis and liver transplant of 12 years and 15.4 years, respectively. Of these, 31 patients had recurrence after a median of 3.3 years. A closer look at the data showed that recurrence was linked with younger median age at time of transplant (13.2 vs. 16.2 years). In cases of recurrence, PSC was generally more aggressive prior to transplant, with a shorter interval between diagnosis and transplant (1.6 vs. 4.1 years), higher total bilirubin (7.8 vs. 3.8 mg/dL), and higher ALT (118 vs. 62 U/L). Furthermore, almost half of the patients (45%) who had recurrence also had pretransplant autoimmune hepatitis overlap, compared with approximately one-quarter of the patients (27%) who did not have recurrence, although this trend was not statistically significant (P = .06).

Recurrent PSC was also associated with poorer outcomes; almost half of those with recurrence (48%) were relisted for liver transplant, developed portal hypertension, or died within 2 years of diagnosis. Mean rejection rates were higher in recurrent versus nonrecurrent cases (3 vs. 1); recurrent cases also had shorter time until rejection (3 vs. 6 months) and greater prevalence of rejection that was refractory to steroids (23% vs. 12%). Moreover, a significantly greater proportion of patients with recurrence had Epstein-Barr viremia (41% vs. 21%).

Dr. Martinez noted that ongoing therapy involving mammalian target of rapamycin inhibition was associated with lower rates of recurrence and suggested that this deserves further investigation; however, owing to small population size, she urged a cautious interpretation of this finding.

“We have to do prospective research,” Dr. Martinez said, emphasizing that tissue immunophenotyping was needed, as a better understanding of underlying immune processes and disease subtypes may open doors to more effective therapies.

The investigators disclosed relationships with Gilead, Merck, Novartis, and others.

SOURCE: Martinez M et al. The Liver Meeting 2019, Abstract 44.

BOSTON – Children who have recurrence of primary sclerosing cholangitis after liver transplant tend to be younger and have more rapidly progressive disease, based on an international retrospective analysis.

Will Pass/MDedge News

Within 5 years of transplant, the probability of primary sclerosing cholangitis (PSC) recurrence in pediatric patients is 26%, reported lead author Mercedes Martinez, MD, of Columbia University, New York, and colleagues.

“The aim of our study was to identify risk factors for primary sclerosing cholangitis recurrence following transplant,” Dr. Martinez said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. This may be the largest pediatric study evaluating recurrent PSC to date, she added.

The investigators drew data from 35 centers around the world via the Pediatric PSC Consortium database. Recurrence was defined by cholestatic biochemistry with nonanastomotic biliary strictures and beading of bile ducts on cholangiography. Recurrences caused by hepatic artery thrombosis or chronic rejection were excluded, as were any cases that recurred within 6 months of transplant.

The final analysis included 149 patients with a median age at diagnosis and liver transplant of 12 years and 15.4 years, respectively. Of these, 31 patients had recurrence after a median of 3.3 years. A closer look at the data showed that recurrence was linked with younger median age at time of transplant (13.2 vs. 16.2 years). In cases of recurrence, PSC was generally more aggressive prior to transplant, with a shorter interval between diagnosis and transplant (1.6 vs. 4.1 years), higher total bilirubin (7.8 vs. 3.8 mg/dL), and higher ALT (118 vs. 62 U/L). Furthermore, almost half of the patients (45%) who had recurrence also had pretransplant autoimmune hepatitis overlap, compared with approximately one-quarter of the patients (27%) who did not have recurrence, although this trend was not statistically significant (P = .06).

Recurrent PSC was also associated with poorer outcomes; almost half of those with recurrence (48%) were relisted for liver transplant, developed portal hypertension, or died within 2 years of diagnosis. Mean rejection rates were higher in recurrent versus nonrecurrent cases (3 vs. 1); recurrent cases also had shorter time until rejection (3 vs. 6 months) and greater prevalence of rejection that was refractory to steroids (23% vs. 12%). Moreover, a significantly greater proportion of patients with recurrence had Epstein-Barr viremia (41% vs. 21%).

Dr. Martinez noted that ongoing therapy involving mammalian target of rapamycin inhibition was associated with lower rates of recurrence and suggested that this deserves further investigation; however, owing to small population size, she urged a cautious interpretation of this finding.

“We have to do prospective research,” Dr. Martinez said, emphasizing that tissue immunophenotyping was needed, as a better understanding of underlying immune processes and disease subtypes may open doors to more effective therapies.

The investigators disclosed relationships with Gilead, Merck, Novartis, and others.

SOURCE: Martinez M et al. The Liver Meeting 2019, Abstract 44.

BOSTON – Children who have recurrence of primary sclerosing cholangitis after liver transplant tend to be younger and have more rapidly progressive disease, based on an international retrospective analysis.

Will Pass/MDedge News

Within 5 years of transplant, the probability of primary sclerosing cholangitis (PSC) recurrence in pediatric patients is 26%, reported lead author Mercedes Martinez, MD, of Columbia University, New York, and colleagues.

“The aim of our study was to identify risk factors for primary sclerosing cholangitis recurrence following transplant,” Dr. Martinez said during a presentation at the annual meeting of the American Association for the Study of Liver Diseases. This may be the largest pediatric study evaluating recurrent PSC to date, she added.

The investigators drew data from 35 centers around the world via the Pediatric PSC Consortium database. Recurrence was defined by cholestatic biochemistry with nonanastomotic biliary strictures and beading of bile ducts on cholangiography. Recurrences caused by hepatic artery thrombosis or chronic rejection were excluded, as were any cases that recurred within 6 months of transplant.

The final analysis included 149 patients with a median age at diagnosis and liver transplant of 12 years and 15.4 years, respectively. Of these, 31 patients had recurrence after a median of 3.3 years. A closer look at the data showed that recurrence was linked with younger median age at time of transplant (13.2 vs. 16.2 years). In cases of recurrence, PSC was generally more aggressive prior to transplant, with a shorter interval between diagnosis and transplant (1.6 vs. 4.1 years), higher total bilirubin (7.8 vs. 3.8 mg/dL), and higher ALT (118 vs. 62 U/L). Furthermore, almost half of the patients (45%) who had recurrence also had pretransplant autoimmune hepatitis overlap, compared with approximately one-quarter of the patients (27%) who did not have recurrence, although this trend was not statistically significant (P = .06).

Recurrent PSC was also associated with poorer outcomes; almost half of those with recurrence (48%) were relisted for liver transplant, developed portal hypertension, or died within 2 years of diagnosis. Mean rejection rates were higher in recurrent versus nonrecurrent cases (3 vs. 1); recurrent cases also had shorter time until rejection (3 vs. 6 months) and greater prevalence of rejection that was refractory to steroids (23% vs. 12%). Moreover, a significantly greater proportion of patients with recurrence had Epstein-Barr viremia (41% vs. 21%).

Dr. Martinez noted that ongoing therapy involving mammalian target of rapamycin inhibition was associated with lower rates of recurrence and suggested that this deserves further investigation; however, owing to small population size, she urged a cautious interpretation of this finding.

“We have to do prospective research,” Dr. Martinez said, emphasizing that tissue immunophenotyping was needed, as a better understanding of underlying immune processes and disease subtypes may open doors to more effective therapies.

The investigators disclosed relationships with Gilead, Merck, Novartis, and others.

SOURCE: Martinez M et al. The Liver Meeting 2019, Abstract 44.

BOSTON – Bezafibrate was superior to placebo for ameliorating pruritus in patients with chronic cholestatic liver diseases, investigators reported at the annual meeting of the American Association for the Study of Liver Diseases.

Improvements in itch were reported by four times as many patients treated with the peroxisome proliferator-activated receptor (PPAR) agonist, compared with those treated with placebo, according to results of the FITCH (Fibrates for cholestatic ITCH) trial.

That finding from FITCH is very encouraging for patients with this “vexing” clinical issue, which can be highly distressing and is a common feature of cholestatic liver diseases, said Michael R. Charlton, MBBS, FRCP, director of the Transplant Institute and hepatology chief at the University of Chicago.

“It’s generally a misery-making condition,” Dr. Charlton said in a podium discussion of the FITCH study results at the Liver Meeting 2019. “I had a patient tell me that they felt like the subject of Edvard Munch’s ‘Scream’ painting.”

As of this meeting, bezafibrate should be considered superior to placebo for treatment of pruritus in cholangiopathies and should be “considered as first-line treatment” for pruritus in primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), added Dr. Charlton, who was not involved in the study.

Investigators in FITCH recruited a total of 74 patients – all enrolled in the Netherlands or Spain – with cholestasis-induced pruritus who reported itch with an intensity of least 5 out of 10 on a visual analogue scale (VAS). Of the 70 patients who completed the trial, 44 had PSC, 24 had PBC, and 2 had secondary sclerosing cholangitis. Patients were randomly allocated to receive bezafibrate 400 mg once daily or placebo for 21 days.

The hypothesis was that PPAR agonist treatment would relieve itch by alleviating hepatobiliary inflammation and reducing formation of a biliary itch factor, according to the investigators, led by Elsemieke de Vries, MD, of the department of gastroenterology and hepatology, Amsterdam University Medical Centers.

“Guideline-approved pharmacological strategies show limited efficacy and can provoke serious side effects,” Dr. de Vries and coauthors said in the published abstract on the study.

The primary study endpoint, a 50% reduction in pruritus VAS score, was achieved in 45% of patients in the bezafibrate treatment arm (17 of 38 patients) versus just 11% in the placebo arm (4 of 36 patients; P = .003), according to updated results presented at the meeting.

The mean VAS score, comparable at baseline, was significantly lower in the bezafibrate group vs. the placebo group at day 21 (P < .001), the results showed.

Authors of the FITCH study reported disclosures related to Intercept Pharmaceuticals, Gilead, Takeda, Tillotts, Pliant, and Dr. Falk GmbH.

SOURCE: de Vries E et al. The Liver Meeting 2019. Abstract 13.

BOSTON – Bezafibrate was superior to placebo for ameliorating pruritus in patients with chronic cholestatic liver diseases, investigators reported at the annual meeting of the American Association for the Study of Liver Diseases.

Improvements in itch were reported by four times as many patients treated with the peroxisome proliferator-activated receptor (PPAR) agonist, compared with those treated with placebo, according to results of the FITCH (Fibrates for cholestatic ITCH) trial.

That finding from FITCH is very encouraging for patients with this “vexing” clinical issue, which can be highly distressing and is a common feature of cholestatic liver diseases, said Michael R. Charlton, MBBS, FRCP, director of the Transplant Institute and hepatology chief at the University of Chicago.

“It’s generally a misery-making condition,” Dr. Charlton said in a podium discussion of the FITCH study results at the Liver Meeting 2019. “I had a patient tell me that they felt like the subject of Edvard Munch’s ‘Scream’ painting.”

As of this meeting, bezafibrate should be considered superior to placebo for treatment of pruritus in cholangiopathies and should be “considered as first-line treatment” for pruritus in primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), added Dr. Charlton, who was not involved in the study.

Investigators in FITCH recruited a total of 74 patients – all enrolled in the Netherlands or Spain – with cholestasis-induced pruritus who reported itch with an intensity of least 5 out of 10 on a visual analogue scale (VAS). Of the 70 patients who completed the trial, 44 had PSC, 24 had PBC, and 2 had secondary sclerosing cholangitis. Patients were randomly allocated to receive bezafibrate 400 mg once daily or placebo for 21 days.

The hypothesis was that PPAR agonist treatment would relieve itch by alleviating hepatobiliary inflammation and reducing formation of a biliary itch factor, according to the investigators, led by Elsemieke de Vries, MD, of the department of gastroenterology and hepatology, Amsterdam University Medical Centers.

“Guideline-approved pharmacological strategies show limited efficacy and can provoke serious side effects,” Dr. de Vries and coauthors said in the published abstract on the study.

The primary study endpoint, a 50% reduction in pruritus VAS score, was achieved in 45% of patients in the bezafibrate treatment arm (17 of 38 patients) versus just 11% in the placebo arm (4 of 36 patients; P = .003), according to updated results presented at the meeting.

The mean VAS score, comparable at baseline, was significantly lower in the bezafibrate group vs. the placebo group at day 21 (P < .001), the results showed.

Authors of the FITCH study reported disclosures related to Intercept Pharmaceuticals, Gilead, Takeda, Tillotts, Pliant, and Dr. Falk GmbH.

SOURCE: de Vries E et al. The Liver Meeting 2019. Abstract 13.

BOSTON – Bezafibrate was superior to placebo for ameliorating pruritus in patients with chronic cholestatic liver diseases, investigators reported at the annual meeting of the American Association for the Study of Liver Diseases.

Improvements in itch were reported by four times as many patients treated with the peroxisome proliferator-activated receptor (PPAR) agonist, compared with those treated with placebo, according to results of the FITCH (Fibrates for cholestatic ITCH) trial.

That finding from FITCH is very encouraging for patients with this “vexing” clinical issue, which can be highly distressing and is a common feature of cholestatic liver diseases, said Michael R. Charlton, MBBS, FRCP, director of the Transplant Institute and hepatology chief at the University of Chicago.

“It’s generally a misery-making condition,” Dr. Charlton said in a podium discussion of the FITCH study results at the Liver Meeting 2019. “I had a patient tell me that they felt like the subject of Edvard Munch’s ‘Scream’ painting.”

As of this meeting, bezafibrate should be considered superior to placebo for treatment of pruritus in cholangiopathies and should be “considered as first-line treatment” for pruritus in primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), added Dr. Charlton, who was not involved in the study.

Investigators in FITCH recruited a total of 74 patients – all enrolled in the Netherlands or Spain – with cholestasis-induced pruritus who reported itch with an intensity of least 5 out of 10 on a visual analogue scale (VAS). Of the 70 patients who completed the trial, 44 had PSC, 24 had PBC, and 2 had secondary sclerosing cholangitis. Patients were randomly allocated to receive bezafibrate 400 mg once daily or placebo for 21 days.

The hypothesis was that PPAR agonist treatment would relieve itch by alleviating hepatobiliary inflammation and reducing formation of a biliary itch factor, according to the investigators, led by Elsemieke de Vries, MD, of the department of gastroenterology and hepatology, Amsterdam University Medical Centers.

“Guideline-approved pharmacological strategies show limited efficacy and can provoke serious side effects,” Dr. de Vries and coauthors said in the published abstract on the study.

The primary study endpoint, a 50% reduction in pruritus VAS score, was achieved in 45% of patients in the bezafibrate treatment arm (17 of 38 patients) versus just 11% in the placebo arm (4 of 36 patients; P = .003), according to updated results presented at the meeting.

The mean VAS score, comparable at baseline, was significantly lower in the bezafibrate group vs. the placebo group at day 21 (P < .001), the results showed.

Authors of the FITCH study reported disclosures related to Intercept Pharmaceuticals, Gilead, Takeda, Tillotts, Pliant, and Dr. Falk GmbH.

SOURCE: de Vries E et al. The Liver Meeting 2019. Abstract 13.

BOSTON – For almost half of patients with nonalcoholic steatohepatitis (NASH), bariatric surgery does not resolve severe fibrosis, even after significant weight loss and resolution of multiple metabolic comorbidities, according to investigators.

Still, bariatric surgery was highly effective at improving liver histology in patients without severe fibrosis, reported lead author Raluca Pais, MD, of Sorbonne University, Paris, and colleagues.

“There are many targeted agents for NASH at this time, but their response rate is limited to less than 30%,” Dr. Pais said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In very selective patients, bariatric surgery is a very attractive therapeutic option, as it promotes massive weight loss and sustained improvement in metabolic comorbidities, which are concomitant with very high rates of hepatic histological improvement in most but not all patients.” Despite the known benefits of bariatric surgery, histologic outcomes have been minimally studied, Dr. Pais said, which prompted the present trial.

The investigators began by analyzing data from 868 patients with NASH who underwent bariatric surgery with perioperative liver biopsy between 2004 and 2014. Of these patients, 181 had advanced NASH, a diagnosis that was subclassified by severe fibrosis (F3 or F4) or high activity (steatosis, activity, and fibrosis score of 3-4 with F0-2). Out of the 181 patients with advanced NASH, 65 consented to follow-up liver biopsy, which was conducted a mean of 6 years after surgery. Among these patients, 53 had undergone gastric bypass surgery, while 12 had undergone sleeve gastrectomy.

Almost one-third (29%) of the 65 patients who underwent bariatric surgery had normal livers at follow-up biopsy. Among the 35 patients who had severe fibrosis at baseline, slightly more than half (54%) had resolution of severe fibrosis. In contrast, resolution of high activity occurred in almost all affected patients (97%).

While the findings highlighted some of the benefits associated with bariatric surgery, Dr. Pais emphasized the other side of the coin; many patients did not have resolution of severe fibrosis, even years after surgery. Specifically, 45% of patients had persistent severe fibrosis at follow-up biopsy, despite improvements in comorbidities. On average, these patients lost 23% of their baseline body weight, and two-thirds of the group achieved normal ALT and resolution of NASH. Many also had improvements in insulin resistance and nonalcoholic fatty liver disease activity scores. These findings suggest that changes in severe fibrosis occur independently of many other improvements, Dr. Pais said.

Although multiple comorbidities were not correlated with changes in severe fibrosis, several other predictors were identified. Compared with patients who had resolution of severe fibrosis, nonresponders were typically older (56 vs. 49 years), more often had persistent diabetes (79% vs. 50%), and generally had shorter time between surgery and follow-up biopsy (4.2 vs. 7.5 years). Compared with nonresponders, responders were more likely to have undergone gastric bypass surgery (100% vs. 69%), suggesting that this procedure was more effective at resolving severe fibrosis than sleeve gastrectomy.

During the question-and-answer session following the presentation, multiple conference attendees suggested that the title of the study, “Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery,” was unnecessarily negative, when in fact the study offered strong support for bariatric surgery.

“This is wonderful data that shows surgery is very effective,” one attendee said.

“This is really positive data,” said another. “I mean, you’ve got reversal of advanced fibrosis in half of the population by the time you follow up for several years, so I would say this is really, very positive data.”

The investigators disclosed relationships with Allergan, Boehringer Ingelheim, Novo Nordisk, and others.

*This story was updated on November 15, 2019.

SOURCE: Pais R et al. The Liver Meeting 2019, Abstract 66.

BOSTON – For almost half of patients with nonalcoholic steatohepatitis (NASH), bariatric surgery does not resolve severe fibrosis, even after significant weight loss and resolution of multiple metabolic comorbidities, according to investigators.

Still, bariatric surgery was highly effective at improving liver histology in patients without severe fibrosis, reported lead author Raluca Pais, MD, of Sorbonne University, Paris, and colleagues.

“There are many targeted agents for NASH at this time, but their response rate is limited to less than 30%,” Dr. Pais said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In very selective patients, bariatric surgery is a very attractive therapeutic option, as it promotes massive weight loss and sustained improvement in metabolic comorbidities, which are concomitant with very high rates of hepatic histological improvement in most but not all patients.” Despite the known benefits of bariatric surgery, histologic outcomes have been minimally studied, Dr. Pais said, which prompted the present trial.

The investigators began by analyzing data from 868 patients with NASH who underwent bariatric surgery with perioperative liver biopsy between 2004 and 2014. Of these patients, 181 had advanced NASH, a diagnosis that was subclassified by severe fibrosis (F3 or F4) or high activity (steatosis, activity, and fibrosis score of 3-4 with F0-2). Out of the 181 patients with advanced NASH, 65 consented to follow-up liver biopsy, which was conducted a mean of 6 years after surgery. Among these patients, 53 had undergone gastric bypass surgery, while 12 had undergone sleeve gastrectomy.

Almost one-third (29%) of the 65 patients who underwent bariatric surgery had normal livers at follow-up biopsy. Among the 35 patients who had severe fibrosis at baseline, slightly more than half (54%) had resolution of severe fibrosis. In contrast, resolution of high activity occurred in almost all affected patients (97%).

While the findings highlighted some of the benefits associated with bariatric surgery, Dr. Pais emphasized the other side of the coin; many patients did not have resolution of severe fibrosis, even years after surgery. Specifically, 45% of patients had persistent severe fibrosis at follow-up biopsy, despite improvements in comorbidities. On average, these patients lost 23% of their baseline body weight, and two-thirds of the group achieved normal ALT and resolution of NASH. Many also had improvements in insulin resistance and nonalcoholic fatty liver disease activity scores. These findings suggest that changes in severe fibrosis occur independently of many other improvements, Dr. Pais said.

Although multiple comorbidities were not correlated with changes in severe fibrosis, several other predictors were identified. Compared with patients who had resolution of severe fibrosis, nonresponders were typically older (56 vs. 49 years), more often had persistent diabetes (79% vs. 50%), and generally had shorter time between surgery and follow-up biopsy (4.2 vs. 7.5 years). Compared with nonresponders, responders were more likely to have undergone gastric bypass surgery (100% vs. 69%), suggesting that this procedure was more effective at resolving severe fibrosis than sleeve gastrectomy.

During the question-and-answer session following the presentation, multiple conference attendees suggested that the title of the study, “Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery,” was unnecessarily negative, when in fact the study offered strong support for bariatric surgery.

“This is wonderful data that shows surgery is very effective,” one attendee said.

“This is really positive data,” said another. “I mean, you’ve got reversal of advanced fibrosis in half of the population by the time you follow up for several years, so I would say this is really, very positive data.”

The investigators disclosed relationships with Allergan, Boehringer Ingelheim, Novo Nordisk, and others.

*This story was updated on November 15, 2019.

SOURCE: Pais R et al. The Liver Meeting 2019, Abstract 66.

BOSTON – For almost half of patients with nonalcoholic steatohepatitis (NASH), bariatric surgery does not resolve severe fibrosis, even after significant weight loss and resolution of multiple metabolic comorbidities, according to investigators.

Still, bariatric surgery was highly effective at improving liver histology in patients without severe fibrosis, reported lead author Raluca Pais, MD, of Sorbonne University, Paris, and colleagues.

“There are many targeted agents for NASH at this time, but their response rate is limited to less than 30%,” Dr. Pais said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In very selective patients, bariatric surgery is a very attractive therapeutic option, as it promotes massive weight loss and sustained improvement in metabolic comorbidities, which are concomitant with very high rates of hepatic histological improvement in most but not all patients.” Despite the known benefits of bariatric surgery, histologic outcomes have been minimally studied, Dr. Pais said, which prompted the present trial.

The investigators began by analyzing data from 868 patients with NASH who underwent bariatric surgery with perioperative liver biopsy between 2004 and 2014. Of these patients, 181 had advanced NASH, a diagnosis that was subclassified by severe fibrosis (F3 or F4) or high activity (steatosis, activity, and fibrosis score of 3-4 with F0-2). Out of the 181 patients with advanced NASH, 65 consented to follow-up liver biopsy, which was conducted a mean of 6 years after surgery. Among these patients, 53 had undergone gastric bypass surgery, while 12 had undergone sleeve gastrectomy.

Almost one-third (29%) of the 65 patients who underwent bariatric surgery had normal livers at follow-up biopsy. Among the 35 patients who had severe fibrosis at baseline, slightly more than half (54%) had resolution of severe fibrosis. In contrast, resolution of high activity occurred in almost all affected patients (97%).

While the findings highlighted some of the benefits associated with bariatric surgery, Dr. Pais emphasized the other side of the coin; many patients did not have resolution of severe fibrosis, even years after surgery. Specifically, 45% of patients had persistent severe fibrosis at follow-up biopsy, despite improvements in comorbidities. On average, these patients lost 23% of their baseline body weight, and two-thirds of the group achieved normal ALT and resolution of NASH. Many also had improvements in insulin resistance and nonalcoholic fatty liver disease activity scores. These findings suggest that changes in severe fibrosis occur independently of many other improvements, Dr. Pais said.

Although multiple comorbidities were not correlated with changes in severe fibrosis, several other predictors were identified. Compared with patients who had resolution of severe fibrosis, nonresponders were typically older (56 vs. 49 years), more often had persistent diabetes (79% vs. 50%), and generally had shorter time between surgery and follow-up biopsy (4.2 vs. 7.5 years). Compared with nonresponders, responders were more likely to have undergone gastric bypass surgery (100% vs. 69%), suggesting that this procedure was more effective at resolving severe fibrosis than sleeve gastrectomy.

During the question-and-answer session following the presentation, multiple conference attendees suggested that the title of the study, “Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery,” was unnecessarily negative, when in fact the study offered strong support for bariatric surgery.

“This is wonderful data that shows surgery is very effective,” one attendee said.

“This is really positive data,” said another. “I mean, you’ve got reversal of advanced fibrosis in half of the population by the time you follow up for several years, so I would say this is really, very positive data.”

The investigators disclosed relationships with Allergan, Boehringer Ingelheim, Novo Nordisk, and others.

*This story was updated on November 15, 2019.

SOURCE: Pais R et al. The Liver Meeting 2019, Abstract 66.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – For patients with nonalcoholic fatty liver disease (NAFLD), leaner may really be meaner, according to a recent French study involving more than 100,000 individuals of the general population.

NAFLD was uncommon among participants with normal bodyweight, but when NAFLD was present, lean patients had almost twice the risk of advanced fibrosis as that of overweight and obese patients, reported principal author Lawrence Serfaty, MD, chief of the department of hepatology at Strasbourg (France) University, who conducted the project with colleagues at the French public research organization, Inserm.

“Normally, NAFLD and [nonalcoholic steatohepatitis (NASH)] are part of metabolic syndrome,” Dr. Serfaty said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “But there are some patients with no metabolic risk factors who are lean and who may have NAFLD.”

To determine the prevalence and characteristics of these patients, the investigators drew data from the CONSTANCES cohort, which is composed of 118,664 members of the general public in France. After excluding those who withdrew consent, had a history of other liver diseases, or reported an excess of alcohol consumption (more than 20 g/day), the analyzed dataset included 102,344 subjects. Among these participants, NAFLD and advanced fibrosis were diagnosed with the Fatty Liver Index (FLI) and the Forns Index (FI), respectively, in which an FLI score greater than 60 indicated NAFLD and an FI score greater than 6.9 indicated advanced fibrosis.

Participants were sorted into three weight categories by body mass index: lean (BMI less than 25 kg/m²), overweight (BMI 25-30), or obese (BMI more than 30). In addition, a variety of other health measures were recorded, including presence of metabolic risk factors, such as diabetes or metabolic syndrome, and elevated alanine transaminase (ALT).

Analysis showed that the prevalence of NAFLD in the general population was 18.2%. Of those diagnosed with NAFLD, 2.6% had advanced fibrosis. As expected, Dr. Serfaty said, NAFLD was much less common among those who were of normal bodyweight, with lean patients accounting for only 1.9% of NAFLD diagnoses. However, when NAFLD was diagnosed in lean patients, it was more often severe. Among lean patients with NAFLD, 4.5% had advanced fibrosis, compared with 2.4% of overweight patients and 2.3% of obese patients.

Dr. Serfaty noted that lean patients with NAFLD tended to have fewer metabolic risk factors, but most had at least one. Lifestyle factors were likely to blame, he said, because lean patients with NAFLD were relatively heavy users of tobacco and alcohol, compared with obese or overweight patients. Cardiovascular disease was also more common among lean patients with NAFLD.

“There are probably other factors [that are different, such as] genetic factors, the microbiome, and maybe the immune system,” Dr. Serfaty said.

While drivers of NAFLD among lean patients remain to be clarified, Dr. Serfaty highlighted the importance of recognizing this unique patient population, and if encountered, not discounting the severity of disease based on a lack of other metabolic risk factors.

“It is very important to know that these patients exist because it is very difficult to identify these patients,” Dr. Serfaty said. “If you have a lean patient with NAFLD, normally you [might] say, it’s not very severe for this patient because he’s lean; but no, [that’s not correct], because maybe he has more advanced fibrosis. So you have to go through and check with other noninvasive markers to be sure that this patient does not have advanced fibrosis.”

Concerning the difficulty of identifying such patients in the first place, Dr. Serfaty suggested that elevated ALT may be the most reliable red flag because this laboratory abnormality occurred in more than half of the lean patients diagnosed with NAFLD, despite no excessive alcohol consumption or prior hepatitis. The investigators disclosed relationships with Gilead, AbbVie, Echosens, and others.

SOURCE: Serfaty L et al. The Liver Meeting 2019, Abstract 1188.

BOSTON – For patients with nonalcoholic fatty liver disease (NAFLD), leaner may really be meaner, according to a recent French study involving more than 100,000 individuals of the general population.

NAFLD was uncommon among participants with normal bodyweight, but when NAFLD was present, lean patients had almost twice the risk of advanced fibrosis as that of overweight and obese patients, reported principal author Lawrence Serfaty, MD, chief of the department of hepatology at Strasbourg (France) University, who conducted the project with colleagues at the French public research organization, Inserm.

“Normally, NAFLD and [nonalcoholic steatohepatitis (NASH)] are part of metabolic syndrome,” Dr. Serfaty said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “But there are some patients with no metabolic risk factors who are lean and who may have NAFLD.”

To determine the prevalence and characteristics of these patients, the investigators drew data from the CONSTANCES cohort, which is composed of 118,664 members of the general public in France. After excluding those who withdrew consent, had a history of other liver diseases, or reported an excess of alcohol consumption (more than 20 g/day), the analyzed dataset included 102,344 subjects. Among these participants, NAFLD and advanced fibrosis were diagnosed with the Fatty Liver Index (FLI) and the Forns Index (FI), respectively, in which an FLI score greater than 60 indicated NAFLD and an FI score greater than 6.9 indicated advanced fibrosis.

Participants were sorted into three weight categories by body mass index: lean (BMI less than 25 kg/m²), overweight (BMI 25-30), or obese (BMI more than 30). In addition, a variety of other health measures were recorded, including presence of metabolic risk factors, such as diabetes or metabolic syndrome, and elevated alanine transaminase (ALT).

Analysis showed that the prevalence of NAFLD in the general population was 18.2%. Of those diagnosed with NAFLD, 2.6% had advanced fibrosis. As expected, Dr. Serfaty said, NAFLD was much less common among those who were of normal bodyweight, with lean patients accounting for only 1.9% of NAFLD diagnoses. However, when NAFLD was diagnosed in lean patients, it was more often severe. Among lean patients with NAFLD, 4.5% had advanced fibrosis, compared with 2.4% of overweight patients and 2.3% of obese patients.

Dr. Serfaty noted that lean patients with NAFLD tended to have fewer metabolic risk factors, but most had at least one. Lifestyle factors were likely to blame, he said, because lean patients with NAFLD were relatively heavy users of tobacco and alcohol, compared with obese or overweight patients. Cardiovascular disease was also more common among lean patients with NAFLD.

“There are probably other factors [that are different, such as] genetic factors, the microbiome, and maybe the immune system,” Dr. Serfaty said.

While drivers of NAFLD among lean patients remain to be clarified, Dr. Serfaty highlighted the importance of recognizing this unique patient population, and if encountered, not discounting the severity of disease based on a lack of other metabolic risk factors.

“It is very important to know that these patients exist because it is very difficult to identify these patients,” Dr. Serfaty said. “If you have a lean patient with NAFLD, normally you [might] say, it’s not very severe for this patient because he’s lean; but no, [that’s not correct], because maybe he has more advanced fibrosis. So you have to go through and check with other noninvasive markers to be sure that this patient does not have advanced fibrosis.”

Concerning the difficulty of identifying such patients in the first place, Dr. Serfaty suggested that elevated ALT may be the most reliable red flag because this laboratory abnormality occurred in more than half of the lean patients diagnosed with NAFLD, despite no excessive alcohol consumption or prior hepatitis. The investigators disclosed relationships with Gilead, AbbVie, Echosens, and others.

SOURCE: Serfaty L et al. The Liver Meeting 2019, Abstract 1188.

BOSTON – For patients with nonalcoholic fatty liver disease (NAFLD), leaner may really be meaner, according to a recent French study involving more than 100,000 individuals of the general population.

NAFLD was uncommon among participants with normal bodyweight, but when NAFLD was present, lean patients had almost twice the risk of advanced fibrosis as that of overweight and obese patients, reported principal author Lawrence Serfaty, MD, chief of the department of hepatology at Strasbourg (France) University, who conducted the project with colleagues at the French public research organization, Inserm.

“Normally, NAFLD and [nonalcoholic steatohepatitis (NASH)] are part of metabolic syndrome,” Dr. Serfaty said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “But there are some patients with no metabolic risk factors who are lean and who may have NAFLD.”

To determine the prevalence and characteristics of these patients, the investigators drew data from the CONSTANCES cohort, which is composed of 118,664 members of the general public in France. After excluding those who withdrew consent, had a history of other liver diseases, or reported an excess of alcohol consumption (more than 20 g/day), the analyzed dataset included 102,344 subjects. Among these participants, NAFLD and advanced fibrosis were diagnosed with the Fatty Liver Index (FLI) and the Forns Index (FI), respectively, in which an FLI score greater than 60 indicated NAFLD and an FI score greater than 6.9 indicated advanced fibrosis.

Participants were sorted into three weight categories by body mass index: lean (BMI less than 25 kg/m²), overweight (BMI 25-30), or obese (BMI more than 30). In addition, a variety of other health measures were recorded, including presence of metabolic risk factors, such as diabetes or metabolic syndrome, and elevated alanine transaminase (ALT).

Analysis showed that the prevalence of NAFLD in the general population was 18.2%. Of those diagnosed with NAFLD, 2.6% had advanced fibrosis. As expected, Dr. Serfaty said, NAFLD was much less common among those who were of normal bodyweight, with lean patients accounting for only 1.9% of NAFLD diagnoses. However, when NAFLD was diagnosed in lean patients, it was more often severe. Among lean patients with NAFLD, 4.5% had advanced fibrosis, compared with 2.4% of overweight patients and 2.3% of obese patients.

Dr. Serfaty noted that lean patients with NAFLD tended to have fewer metabolic risk factors, but most had at least one. Lifestyle factors were likely to blame, he said, because lean patients with NAFLD were relatively heavy users of tobacco and alcohol, compared with obese or overweight patients. Cardiovascular disease was also more common among lean patients with NAFLD.

“There are probably other factors [that are different, such as] genetic factors, the microbiome, and maybe the immune system,” Dr. Serfaty said.

While drivers of NAFLD among lean patients remain to be clarified, Dr. Serfaty highlighted the importance of recognizing this unique patient population, and if encountered, not discounting the severity of disease based on a lack of other metabolic risk factors.

“It is very important to know that these patients exist because it is very difficult to identify these patients,” Dr. Serfaty said. “If you have a lean patient with NAFLD, normally you [might] say, it’s not very severe for this patient because he’s lean; but no, [that’s not correct], because maybe he has more advanced fibrosis. So you have to go through and check with other noninvasive markers to be sure that this patient does not have advanced fibrosis.”

Concerning the difficulty of identifying such patients in the first place, Dr. Serfaty suggested that elevated ALT may be the most reliable red flag because this laboratory abnormality occurred in more than half of the lean patients diagnosed with NAFLD, despite no excessive alcohol consumption or prior hepatitis. The investigators disclosed relationships with Gilead, AbbVie, Echosens, and others.

SOURCE: Serfaty L et al. The Liver Meeting 2019, Abstract 1188.