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Tenofovir disoproxil treated HBV with fewer future HCCs
VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.
This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).
However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).
Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.
At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).
The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.
During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.
In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.
As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.
Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb.
SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.
VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.
This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).
However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).
Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.
At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).
The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.
During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.
In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.
As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.
Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb.
SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.
VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.
This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).
However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).
Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.
At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).
The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.
During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.
In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.
As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.
Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb.
SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.
REPORTING FROM ILC 2019
Three-drug regimen shows promise for refractory primary biliary cholangitis
VIENNA –
In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.
Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.
Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).
The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.
The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).
Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.
Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).
SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.
Clinicians in Europe already use this triple therapy in appropriate patients. Bezafibrate is cheap, it has been used since the 1970s to lower triglyceride levels, and it is generally safe. Following the report of results from the BEZURSO trial in 2018, guidelines changed to accept the option of adding a fibrate to ursodeoxycholic acid and obeticholic acid.
Thomas Berg, MD, is professor and head of hepatology at University Hospital in Leipzig, Germany. He has received personal fees and research support from several companies including Intercept, the company that markets obeticholic acid (Ocaliva). He made these comments in an interview.
Clinicians in Europe already use this triple therapy in appropriate patients. Bezafibrate is cheap, it has been used since the 1970s to lower triglyceride levels, and it is generally safe. Following the report of results from the BEZURSO trial in 2018, guidelines changed to accept the option of adding a fibrate to ursodeoxycholic acid and obeticholic acid.
Thomas Berg, MD, is professor and head of hepatology at University Hospital in Leipzig, Germany. He has received personal fees and research support from several companies including Intercept, the company that markets obeticholic acid (Ocaliva). He made these comments in an interview.
Clinicians in Europe already use this triple therapy in appropriate patients. Bezafibrate is cheap, it has been used since the 1970s to lower triglyceride levels, and it is generally safe. Following the report of results from the BEZURSO trial in 2018, guidelines changed to accept the option of adding a fibrate to ursodeoxycholic acid and obeticholic acid.
Thomas Berg, MD, is professor and head of hepatology at University Hospital in Leipzig, Germany. He has received personal fees and research support from several companies including Intercept, the company that markets obeticholic acid (Ocaliva). He made these comments in an interview.
VIENNA –
In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.
Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.
Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).
The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.
The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).
Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.
Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).
SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.
VIENNA –
In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.
Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.
Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).
The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.
The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).
Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.
Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).
SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.
REPORTING FROM ILC 2019
HCC linked to mitochondrial damage, iron accumulation from HCV
according to an extensive literature review.
Although the mechanisms underlying the hepatocellular carcinoma development are not fully understood, it is known that oxidative stress exists to a greater degree in hepatitis C virus (HCV) infection, compared with other inflammatory liver diseases. Such stress has been proposed as a major mechanism of liver injury in patients with chronic HCV, the authors reported in Free Radical Biology and Medicine.
Patients with HCV have significant hepatocellular mitochondrial alterations, and iron accumulation is also a well-known characteristic in patients with chronic HCV. Such alterations in mitochondria and iron accumulation are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction, according to the review.
“The greatest concern is whether mitochondrial damage and iron metabolic dysregulation persist even after HCV eradication and to what extent such pathological conditions affect the development of HCC. Determining the molecular signaling that underlies the mitophagy induced by iron depletion is another topic of interest and is expected to lead to potential therapeutic approaches for multiple diseases,” the researchers concluded.
Support was from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development. The authors reported no disclosures.
SOURCE: Keisuke H et al. Free Radic Biol Med. 2019;133:193-9.
according to an extensive literature review.
Although the mechanisms underlying the hepatocellular carcinoma development are not fully understood, it is known that oxidative stress exists to a greater degree in hepatitis C virus (HCV) infection, compared with other inflammatory liver diseases. Such stress has been proposed as a major mechanism of liver injury in patients with chronic HCV, the authors reported in Free Radical Biology and Medicine.
Patients with HCV have significant hepatocellular mitochondrial alterations, and iron accumulation is also a well-known characteristic in patients with chronic HCV. Such alterations in mitochondria and iron accumulation are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction, according to the review.
“The greatest concern is whether mitochondrial damage and iron metabolic dysregulation persist even after HCV eradication and to what extent such pathological conditions affect the development of HCC. Determining the molecular signaling that underlies the mitophagy induced by iron depletion is another topic of interest and is expected to lead to potential therapeutic approaches for multiple diseases,” the researchers concluded.
Support was from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development. The authors reported no disclosures.
SOURCE: Keisuke H et al. Free Radic Biol Med. 2019;133:193-9.
according to an extensive literature review.
Although the mechanisms underlying the hepatocellular carcinoma development are not fully understood, it is known that oxidative stress exists to a greater degree in hepatitis C virus (HCV) infection, compared with other inflammatory liver diseases. Such stress has been proposed as a major mechanism of liver injury in patients with chronic HCV, the authors reported in Free Radical Biology and Medicine.
Patients with HCV have significant hepatocellular mitochondrial alterations, and iron accumulation is also a well-known characteristic in patients with chronic HCV. Such alterations in mitochondria and iron accumulation are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction, according to the review.
“The greatest concern is whether mitochondrial damage and iron metabolic dysregulation persist even after HCV eradication and to what extent such pathological conditions affect the development of HCC. Determining the molecular signaling that underlies the mitophagy induced by iron depletion is another topic of interest and is expected to lead to potential therapeutic approaches for multiple diseases,” the researchers concluded.
Support was from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development. The authors reported no disclosures.
SOURCE: Keisuke H et al. Free Radic Biol Med. 2019;133:193-9.
FROM FREE RADICAL BIOLOGY AND MEDICINE
Blunted cardiac reserve strongly predicts incident hepatorenal syndrome
VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.
The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.
The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.
The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.
Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.
Dr. Koshy had no disclosures.
SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.
Cardiovascular abnormalities develop in patients with advanced chronic liver disease to produce a hyperdynamic systemic circulation with splanchnic vasodilation, decreased systemic vascular resistance, and increased cardiac output (J Hepatol. 2018;69[4]:958-60). The term cirrhotic cardiomyopathy has also been used for the changes of systolic dysfunction with impaired cardiac contractile response to stress and altered diastolic relaxation that develops in patients with cirrhosis (J Hepatol. 2010;53[1]:179-90).
In this study by Dr. Koshy and colleagues, the inability to increase cardiac output during dobutamine stress echo (DSE) was associated with a greater subsequent risk for hepatorenal syndrome (J Hepatol. 2019;70:e56).
All patients in the study were undergoing pretransplant liver evaluation. Those who developed hepatorenal syndrome (HRS) in follow-up had a higher mean cardiac output with a reduction of the increase in cardiac output that follows dobutamine administration when compared with those who did not develop HRS. A multivariate analysis that adjusted for age, gender, MELD score, and Child-Pugh score found that “impaired contractile response was the strongest predictor of hepatorenal syndrome” as defined by a less than 22% increase in cardiac output following dobutamine. Overall, 40% of those with impaired contractile reserve developed hepatorenal syndrome, compared with 25% of those with normal contractile reserve following dobutamine (P = .006). It is of interest that cirrhotic patients with HRS at the time of initial dobutamine stress echo had a 25% higher average cardiac output than those without HRS. Patients who subsequently developed hepatorenal syndrome also had higher average cardiac output at initial evaluation than those who did not.
This study continues to raise important questions about the role of cardiovascular dysfunction and the risk of hepatorenal syndrome. Additional studies seem warranted to evaluate progression of cardiac changes and dobutamine response throughout follow-up of end-stage liver disease patients, including at the development of hepatorenal syndrome. Studies of HRS patients with specific associations such as sepsis, spontaneous bacterial peritonitis, and gastrointestinal bleeding may also provide information on the role of systolic and diastolic dysfunction during such events.
This article also draws attention to “concerns about using nonselective beta-blocker drugs in patients with cirrhosis.” Current data indicate that nonselective beta-blockers reduce all-cause mortality and the risk of first variceal hemorrhage in patients with advanced liver disease (Hepatology. 2019;69[4]:1657-75). Until we have studies that reveal a clear association between beta-blockers and development of hepatorenal syndrome, I will continue to recommend the use of beta-blockers in cirrhotic patients at risk for first variceal hemorrhage.
Rowen K. Zetterman, MD, is dean emeritus of the Creighton University School of Medicine in Omaha, Neb. He serves as the Associate Vice Chancellor for Academic Affairs and the Associate Vice Chancellor for Planning at the University of Nebraska Medical Center in Omaha. Dr. Zetterman, a gastroenterologist and hepatologist, is also a member of the editorial advisory board of Internal Medicine News.
Cardiovascular abnormalities develop in patients with advanced chronic liver disease to produce a hyperdynamic systemic circulation with splanchnic vasodilation, decreased systemic vascular resistance, and increased cardiac output (J Hepatol. 2018;69[4]:958-60). The term cirrhotic cardiomyopathy has also been used for the changes of systolic dysfunction with impaired cardiac contractile response to stress and altered diastolic relaxation that develops in patients with cirrhosis (J Hepatol. 2010;53[1]:179-90).
In this study by Dr. Koshy and colleagues, the inability to increase cardiac output during dobutamine stress echo (DSE) was associated with a greater subsequent risk for hepatorenal syndrome (J Hepatol. 2019;70:e56).
All patients in the study were undergoing pretransplant liver evaluation. Those who developed hepatorenal syndrome (HRS) in follow-up had a higher mean cardiac output with a reduction of the increase in cardiac output that follows dobutamine administration when compared with those who did not develop HRS. A multivariate analysis that adjusted for age, gender, MELD score, and Child-Pugh score found that “impaired contractile response was the strongest predictor of hepatorenal syndrome” as defined by a less than 22% increase in cardiac output following dobutamine. Overall, 40% of those with impaired contractile reserve developed hepatorenal syndrome, compared with 25% of those with normal contractile reserve following dobutamine (P = .006). It is of interest that cirrhotic patients with HRS at the time of initial dobutamine stress echo had a 25% higher average cardiac output than those without HRS. Patients who subsequently developed hepatorenal syndrome also had higher average cardiac output at initial evaluation than those who did not.
This study continues to raise important questions about the role of cardiovascular dysfunction and the risk of hepatorenal syndrome. Additional studies seem warranted to evaluate progression of cardiac changes and dobutamine response throughout follow-up of end-stage liver disease patients, including at the development of hepatorenal syndrome. Studies of HRS patients with specific associations such as sepsis, spontaneous bacterial peritonitis, and gastrointestinal bleeding may also provide information on the role of systolic and diastolic dysfunction during such events.
This article also draws attention to “concerns about using nonselective beta-blocker drugs in patients with cirrhosis.” Current data indicate that nonselective beta-blockers reduce all-cause mortality and the risk of first variceal hemorrhage in patients with advanced liver disease (Hepatology. 2019;69[4]:1657-75). Until we have studies that reveal a clear association between beta-blockers and development of hepatorenal syndrome, I will continue to recommend the use of beta-blockers in cirrhotic patients at risk for first variceal hemorrhage.
Rowen K. Zetterman, MD, is dean emeritus of the Creighton University School of Medicine in Omaha, Neb. He serves as the Associate Vice Chancellor for Academic Affairs and the Associate Vice Chancellor for Planning at the University of Nebraska Medical Center in Omaha. Dr. Zetterman, a gastroenterologist and hepatologist, is also a member of the editorial advisory board of Internal Medicine News.
Cardiovascular abnormalities develop in patients with advanced chronic liver disease to produce a hyperdynamic systemic circulation with splanchnic vasodilation, decreased systemic vascular resistance, and increased cardiac output (J Hepatol. 2018;69[4]:958-60). The term cirrhotic cardiomyopathy has also been used for the changes of systolic dysfunction with impaired cardiac contractile response to stress and altered diastolic relaxation that develops in patients with cirrhosis (J Hepatol. 2010;53[1]:179-90).
In this study by Dr. Koshy and colleagues, the inability to increase cardiac output during dobutamine stress echo (DSE) was associated with a greater subsequent risk for hepatorenal syndrome (J Hepatol. 2019;70:e56).
All patients in the study were undergoing pretransplant liver evaluation. Those who developed hepatorenal syndrome (HRS) in follow-up had a higher mean cardiac output with a reduction of the increase in cardiac output that follows dobutamine administration when compared with those who did not develop HRS. A multivariate analysis that adjusted for age, gender, MELD score, and Child-Pugh score found that “impaired contractile response was the strongest predictor of hepatorenal syndrome” as defined by a less than 22% increase in cardiac output following dobutamine. Overall, 40% of those with impaired contractile reserve developed hepatorenal syndrome, compared with 25% of those with normal contractile reserve following dobutamine (P = .006). It is of interest that cirrhotic patients with HRS at the time of initial dobutamine stress echo had a 25% higher average cardiac output than those without HRS. Patients who subsequently developed hepatorenal syndrome also had higher average cardiac output at initial evaluation than those who did not.
This study continues to raise important questions about the role of cardiovascular dysfunction and the risk of hepatorenal syndrome. Additional studies seem warranted to evaluate progression of cardiac changes and dobutamine response throughout follow-up of end-stage liver disease patients, including at the development of hepatorenal syndrome. Studies of HRS patients with specific associations such as sepsis, spontaneous bacterial peritonitis, and gastrointestinal bleeding may also provide information on the role of systolic and diastolic dysfunction during such events.
This article also draws attention to “concerns about using nonselective beta-blocker drugs in patients with cirrhosis.” Current data indicate that nonselective beta-blockers reduce all-cause mortality and the risk of first variceal hemorrhage in patients with advanced liver disease (Hepatology. 2019;69[4]:1657-75). Until we have studies that reveal a clear association between beta-blockers and development of hepatorenal syndrome, I will continue to recommend the use of beta-blockers in cirrhotic patients at risk for first variceal hemorrhage.
Rowen K. Zetterman, MD, is dean emeritus of the Creighton University School of Medicine in Omaha, Neb. He serves as the Associate Vice Chancellor for Academic Affairs and the Associate Vice Chancellor for Planning at the University of Nebraska Medical Center in Omaha. Dr. Zetterman, a gastroenterologist and hepatologist, is also a member of the editorial advisory board of Internal Medicine News.
VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.
The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.
The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.
The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.
Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.
Dr. Koshy had no disclosures.
SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.
VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.
The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.
The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.
The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.
Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.
Dr. Koshy had no disclosures.
SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.
REPORTING FROM ILC 2019
MicroRNA-375 may be key to fibrolamellar carcinoma
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Liver steatosis common in English young adults
VIENNA – The prevalence of liver steatosis among unselected English young adults was 21% in a study of just over 4,000 people. The prevalence of apparent liver fibrosis was 2.4%, and among the 21% with steatosis, nearly half – 10% of the studied cohort – had severe, S3 steatosis.
The prevalence of steatosis, a marker of nonalcoholic fatty liver disease (NAFLD), seemed to be linked with obesity. Among the 79% of the study group who had no steatosis the obesity prevalence was 6%, compared with a 26% prevalence among those with S1 steatosis, a 33% obesity rate among those with S2 steatosis, and a 57% obesity prevalence among those with S3 steatosis, Kushala Abeysekera, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
He and his associates determined these prevalence rates in a population that excluded people who reported consuming what was deemed “excessive” alcohol use.
Another notable finding was that 1,874 of the same people had undergone ultrasound assessment for NAFLD when they were 18 years old, and that assessment found a prevalence of 2.5% (J Clin Endocrinol Metab. 2014 March;99[3]:e410-7), which meant that during the subsequent 6 years prevalence of NAFLD jumped nearly 900%.
Both the 2014 report and the current study used people who had been enrolled in the Avon Longitudinal Study of Parents and Children, a prospective population-based study that began by recruiting a cohort of more than 14,000 pregnant women during 1991-1992, and then followed the more than 13,000 children who resulted from those pregnancies. The study reported by Dr. Abeysekera focused on 4,021 of these children – now young adults – who responded to an invitation to participate in this follow-up, a number that then reduced to 3,600 with informative transient elastography results that quantified fibrosis, and 3,768 with valid Controlled Attenuated Parameter scores from elastography that reflected steatosis extent. Transient elastography is a noninvasive method of measuring liver stiffness using ultrasound and an elastic shear wave (Clin Mol Hepatol. 2012 June;18[2]:163-73).
“To the best of my knowledge, this is the only study that has assessed NAFLD in young adults using transient elastography,” said Dr. Abeysekera, an epidemiologist at the University of Bristol (England).
After subtracting from the study cohort people with excessive alcohol use, the study had transient elastography data from 3,277 24-year-olds that could calculate steatosis severity, and data from 3,128 that could quantify fibrosis.
The analysis also showed a statistically significant link between sex and the presence and severity of steatosis. Among women, 18% had steatosis, including 7% with S3 steatosis, defined as involving at least two-thirds of the liver. Among men, 26% had some degree of steatosis and 14% had the most severe form.
The presence of more severe liver fibrosis also showed a strong link to obesity. The eight people identified with F4 fibrosis (with cirrhosis) had a median body mass index of 32 kg/m2, compared with a median body mass index of 25 kg/m2 or less among those either without fibrosis or with a milder form of F1, F2, or F3 fibrosis.
Dr. Abeysekera reported no disclosures.
VIENNA – The prevalence of liver steatosis among unselected English young adults was 21% in a study of just over 4,000 people. The prevalence of apparent liver fibrosis was 2.4%, and among the 21% with steatosis, nearly half – 10% of the studied cohort – had severe, S3 steatosis.
The prevalence of steatosis, a marker of nonalcoholic fatty liver disease (NAFLD), seemed to be linked with obesity. Among the 79% of the study group who had no steatosis the obesity prevalence was 6%, compared with a 26% prevalence among those with S1 steatosis, a 33% obesity rate among those with S2 steatosis, and a 57% obesity prevalence among those with S3 steatosis, Kushala Abeysekera, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
He and his associates determined these prevalence rates in a population that excluded people who reported consuming what was deemed “excessive” alcohol use.
Another notable finding was that 1,874 of the same people had undergone ultrasound assessment for NAFLD when they were 18 years old, and that assessment found a prevalence of 2.5% (J Clin Endocrinol Metab. 2014 March;99[3]:e410-7), which meant that during the subsequent 6 years prevalence of NAFLD jumped nearly 900%.
Both the 2014 report and the current study used people who had been enrolled in the Avon Longitudinal Study of Parents and Children, a prospective population-based study that began by recruiting a cohort of more than 14,000 pregnant women during 1991-1992, and then followed the more than 13,000 children who resulted from those pregnancies. The study reported by Dr. Abeysekera focused on 4,021 of these children – now young adults – who responded to an invitation to participate in this follow-up, a number that then reduced to 3,600 with informative transient elastography results that quantified fibrosis, and 3,768 with valid Controlled Attenuated Parameter scores from elastography that reflected steatosis extent. Transient elastography is a noninvasive method of measuring liver stiffness using ultrasound and an elastic shear wave (Clin Mol Hepatol. 2012 June;18[2]:163-73).
“To the best of my knowledge, this is the only study that has assessed NAFLD in young adults using transient elastography,” said Dr. Abeysekera, an epidemiologist at the University of Bristol (England).
After subtracting from the study cohort people with excessive alcohol use, the study had transient elastography data from 3,277 24-year-olds that could calculate steatosis severity, and data from 3,128 that could quantify fibrosis.
The analysis also showed a statistically significant link between sex and the presence and severity of steatosis. Among women, 18% had steatosis, including 7% with S3 steatosis, defined as involving at least two-thirds of the liver. Among men, 26% had some degree of steatosis and 14% had the most severe form.
The presence of more severe liver fibrosis also showed a strong link to obesity. The eight people identified with F4 fibrosis (with cirrhosis) had a median body mass index of 32 kg/m2, compared with a median body mass index of 25 kg/m2 or less among those either without fibrosis or with a milder form of F1, F2, or F3 fibrosis.
Dr. Abeysekera reported no disclosures.
VIENNA – The prevalence of liver steatosis among unselected English young adults was 21% in a study of just over 4,000 people. The prevalence of apparent liver fibrosis was 2.4%, and among the 21% with steatosis, nearly half – 10% of the studied cohort – had severe, S3 steatosis.
The prevalence of steatosis, a marker of nonalcoholic fatty liver disease (NAFLD), seemed to be linked with obesity. Among the 79% of the study group who had no steatosis the obesity prevalence was 6%, compared with a 26% prevalence among those with S1 steatosis, a 33% obesity rate among those with S2 steatosis, and a 57% obesity prevalence among those with S3 steatosis, Kushala Abeysekera, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.
He and his associates determined these prevalence rates in a population that excluded people who reported consuming what was deemed “excessive” alcohol use.
Another notable finding was that 1,874 of the same people had undergone ultrasound assessment for NAFLD when they were 18 years old, and that assessment found a prevalence of 2.5% (J Clin Endocrinol Metab. 2014 March;99[3]:e410-7), which meant that during the subsequent 6 years prevalence of NAFLD jumped nearly 900%.
Both the 2014 report and the current study used people who had been enrolled in the Avon Longitudinal Study of Parents and Children, a prospective population-based study that began by recruiting a cohort of more than 14,000 pregnant women during 1991-1992, and then followed the more than 13,000 children who resulted from those pregnancies. The study reported by Dr. Abeysekera focused on 4,021 of these children – now young adults – who responded to an invitation to participate in this follow-up, a number that then reduced to 3,600 with informative transient elastography results that quantified fibrosis, and 3,768 with valid Controlled Attenuated Parameter scores from elastography that reflected steatosis extent. Transient elastography is a noninvasive method of measuring liver stiffness using ultrasound and an elastic shear wave (Clin Mol Hepatol. 2012 June;18[2]:163-73).
“To the best of my knowledge, this is the only study that has assessed NAFLD in young adults using transient elastography,” said Dr. Abeysekera, an epidemiologist at the University of Bristol (England).
After subtracting from the study cohort people with excessive alcohol use, the study had transient elastography data from 3,277 24-year-olds that could calculate steatosis severity, and data from 3,128 that could quantify fibrosis.
The analysis also showed a statistically significant link between sex and the presence and severity of steatosis. Among women, 18% had steatosis, including 7% with S3 steatosis, defined as involving at least two-thirds of the liver. Among men, 26% had some degree of steatosis and 14% had the most severe form.
The presence of more severe liver fibrosis also showed a strong link to obesity. The eight people identified with F4 fibrosis (with cirrhosis) had a median body mass index of 32 kg/m2, compared with a median body mass index of 25 kg/m2 or less among those either without fibrosis or with a milder form of F1, F2, or F3 fibrosis.
Dr. Abeysekera reported no disclosures.
REPORTING FROM ILC 2019
Obeticholic acid reversed NASH liver fibrosis in phase 3 trial
VIENNA – making obeticholic acid the first agent proven to improve the course of this disease.
“There is no doubt that with these data we have changed the treatment” of nonalcoholic steatohepatitis (NASH), Zobair M. Younossi, MD, of Inova Fairfax Medical Campus in Falls Church, Va., said at the meeting sponsored by the European Association for the Study of the Liver. “We are at a watershed moment” in NASH treatment, Dr. Younossi added in a video interview.
Until now “we have had no effective treatments for NASH. This is the first success in a phase 3 trial; obeticholic acid looks very promising,” commented Philip N. Newsome, PhD, professor of experimental hepatology at the University of Birmingham (England).
Obeticholic acid (OCA), an agonist of the farnesoid X receptor, already has Food and Drug Administration marketing approval for the indication of primary biliary cholangitis, a much rarer disease than NASH.
The REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment) trial has so far enrolled 931 patients at about 350 sites in 20 countries, including the United States, and followed them during 18 months of treatment, the prespecified time for an interim analysis. The study enrolled adults with biopsy-proven NASH and generally focused on patients with either stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease activity score of at least 4. Enrolled patients averaged about 55 years old, slightly more than half the enrolled patients had type 2 diabetes, and more than half had stage 3 fibrosis.
The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.
For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.
The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.
Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.
Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.
REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.
Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.
REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.
VIENNA – making obeticholic acid the first agent proven to improve the course of this disease.
“There is no doubt that with these data we have changed the treatment” of nonalcoholic steatohepatitis (NASH), Zobair M. Younossi, MD, of Inova Fairfax Medical Campus in Falls Church, Va., said at the meeting sponsored by the European Association for the Study of the Liver. “We are at a watershed moment” in NASH treatment, Dr. Younossi added in a video interview.
Until now “we have had no effective treatments for NASH. This is the first success in a phase 3 trial; obeticholic acid looks very promising,” commented Philip N. Newsome, PhD, professor of experimental hepatology at the University of Birmingham (England).
Obeticholic acid (OCA), an agonist of the farnesoid X receptor, already has Food and Drug Administration marketing approval for the indication of primary biliary cholangitis, a much rarer disease than NASH.
The REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment) trial has so far enrolled 931 patients at about 350 sites in 20 countries, including the United States, and followed them during 18 months of treatment, the prespecified time for an interim analysis. The study enrolled adults with biopsy-proven NASH and generally focused on patients with either stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease activity score of at least 4. Enrolled patients averaged about 55 years old, slightly more than half the enrolled patients had type 2 diabetes, and more than half had stage 3 fibrosis.
The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.
For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.
The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.
Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.
Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.
REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.
Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.
REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.
VIENNA – making obeticholic acid the first agent proven to improve the course of this disease.
“There is no doubt that with these data we have changed the treatment” of nonalcoholic steatohepatitis (NASH), Zobair M. Younossi, MD, of Inova Fairfax Medical Campus in Falls Church, Va., said at the meeting sponsored by the European Association for the Study of the Liver. “We are at a watershed moment” in NASH treatment, Dr. Younossi added in a video interview.
Until now “we have had no effective treatments for NASH. This is the first success in a phase 3 trial; obeticholic acid looks very promising,” commented Philip N. Newsome, PhD, professor of experimental hepatology at the University of Birmingham (England).
Obeticholic acid (OCA), an agonist of the farnesoid X receptor, already has Food and Drug Administration marketing approval for the indication of primary biliary cholangitis, a much rarer disease than NASH.
The REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment) trial has so far enrolled 931 patients at about 350 sites in 20 countries, including the United States, and followed them during 18 months of treatment, the prespecified time for an interim analysis. The study enrolled adults with biopsy-proven NASH and generally focused on patients with either stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease activity score of at least 4. Enrolled patients averaged about 55 years old, slightly more than half the enrolled patients had type 2 diabetes, and more than half had stage 3 fibrosis.
The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.
For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.
The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.
Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.
Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.
REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.
Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.
REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.
REPORTING FROM ILC 2019
Research coalition issues plan for curing hepatitis B virus
VIENNA – They hope either to have a cure or to have made substantial progress toward this goal over the next 10 years.
Treatments already are on the market that effectively inhibit hepatitis B replication in infected patients (and an effective preventive vaccine also exists). Still, these treatments are not curative, and for the vast majority of patients treatment must continue indefinitely, while their risk for liver cancer and their virally induced immune system abnormalities remain, Peter A. Revill, PhD, said during a press briefing that introduced a strategy for hepatitis B virus (HBV) cure development from the International Coalition to Eliminate HBV. Concurrently with the briefing session, the strategy appeared in an article published online (Lancet Gastroenterol Hepatol. 2019 Apr 10. doi: 10.1016/s2468-1253(19)30119-0).
The way forward will likely be a “two-pronged approach or restoring immune responses and targeting the virus,” Dr. Revill, head of molecular virology at the Doherty Institute in Melbourne, said in a video interview.
The new strategy recognizes the huge challenge of devising a treatment that produces a total cure that includes elimination of all traces of viral DNA from patients and for the immediate future focuses on the goal of functional cure. The term functional cure means a sustained period without detectable HBV surface antigen or HBV DNA in a patient’s serum, as well as suppressed virus release. Another feature of a functional cure would be a halt to progression of liver disease, replaced by liver regeneration, said Anna S. Lok, MD, professor of medicine and director of clinical hepatology at the University of Michigan, Ann Arbor, and a member of the strategy-writing group. She and her colleagues who wrote the strategy foresee the need for drug combinations with agents that can hit multiple viral targets as well as agents that restore normal immune function.
Several novel drug classes aimed at new viral targets, such as capsid inhibitors, are in various stages of clinical development, said Fabien Zoulim, MD, head of the gastroenterology and hepatology service at the Red Cross Hospital in Lyon, France, and another member of the writing panel. “We have many drug candidates” that use novel approaches to further restrict viral growth, roughly 50 agents in phase 1 and 2 studies, he said during the press briefing, held during the meeting sponsored by the European Association for the Study of the Liver. The other, immunologic aspect of the two-part cure strategy – restoring the “exhausted” HBV-specific T-cell population and stimulating production of neutralizing antibody to HBV – remains hypothetical right now, however. “It’s a concept that needs development,” Dr. Zoulim said.
A reason members of the coalition are optimistic about eventual prospects for a cure is that currently about 1% of patients on HBV antiviral treatments have a functional cure after relatively brief treatment, and the percentage of cured patients plateaus at about 10% among those who remain on current HBV antiviral drugs for several years. In addition, a substantial fraction of patients spontaneously resolve their HBV infection without any treatment. Experts estimate that more than 1 billion people worldwide have been infected by HBV and then later had their infection clear “naturally,” said Dr. Revill. But the mechanism by which this happens is currently a mystery. “We don’t know how or why” so many infected people are “cured” naturally, Dr. Revill admitted, but it gives him and his colleagues hope that the numbers can expand once more and better treatments for HBV infection are available.
VIENNA – They hope either to have a cure or to have made substantial progress toward this goal over the next 10 years.
Treatments already are on the market that effectively inhibit hepatitis B replication in infected patients (and an effective preventive vaccine also exists). Still, these treatments are not curative, and for the vast majority of patients treatment must continue indefinitely, while their risk for liver cancer and their virally induced immune system abnormalities remain, Peter A. Revill, PhD, said during a press briefing that introduced a strategy for hepatitis B virus (HBV) cure development from the International Coalition to Eliminate HBV. Concurrently with the briefing session, the strategy appeared in an article published online (Lancet Gastroenterol Hepatol. 2019 Apr 10. doi: 10.1016/s2468-1253(19)30119-0).
The way forward will likely be a “two-pronged approach or restoring immune responses and targeting the virus,” Dr. Revill, head of molecular virology at the Doherty Institute in Melbourne, said in a video interview.
The new strategy recognizes the huge challenge of devising a treatment that produces a total cure that includes elimination of all traces of viral DNA from patients and for the immediate future focuses on the goal of functional cure. The term functional cure means a sustained period without detectable HBV surface antigen or HBV DNA in a patient’s serum, as well as suppressed virus release. Another feature of a functional cure would be a halt to progression of liver disease, replaced by liver regeneration, said Anna S. Lok, MD, professor of medicine and director of clinical hepatology at the University of Michigan, Ann Arbor, and a member of the strategy-writing group. She and her colleagues who wrote the strategy foresee the need for drug combinations with agents that can hit multiple viral targets as well as agents that restore normal immune function.
Several novel drug classes aimed at new viral targets, such as capsid inhibitors, are in various stages of clinical development, said Fabien Zoulim, MD, head of the gastroenterology and hepatology service at the Red Cross Hospital in Lyon, France, and another member of the writing panel. “We have many drug candidates” that use novel approaches to further restrict viral growth, roughly 50 agents in phase 1 and 2 studies, he said during the press briefing, held during the meeting sponsored by the European Association for the Study of the Liver. The other, immunologic aspect of the two-part cure strategy – restoring the “exhausted” HBV-specific T-cell population and stimulating production of neutralizing antibody to HBV – remains hypothetical right now, however. “It’s a concept that needs development,” Dr. Zoulim said.
A reason members of the coalition are optimistic about eventual prospects for a cure is that currently about 1% of patients on HBV antiviral treatments have a functional cure after relatively brief treatment, and the percentage of cured patients plateaus at about 10% among those who remain on current HBV antiviral drugs for several years. In addition, a substantial fraction of patients spontaneously resolve their HBV infection without any treatment. Experts estimate that more than 1 billion people worldwide have been infected by HBV and then later had their infection clear “naturally,” said Dr. Revill. But the mechanism by which this happens is currently a mystery. “We don’t know how or why” so many infected people are “cured” naturally, Dr. Revill admitted, but it gives him and his colleagues hope that the numbers can expand once more and better treatments for HBV infection are available.
VIENNA – They hope either to have a cure or to have made substantial progress toward this goal over the next 10 years.
Treatments already are on the market that effectively inhibit hepatitis B replication in infected patients (and an effective preventive vaccine also exists). Still, these treatments are not curative, and for the vast majority of patients treatment must continue indefinitely, while their risk for liver cancer and their virally induced immune system abnormalities remain, Peter A. Revill, PhD, said during a press briefing that introduced a strategy for hepatitis B virus (HBV) cure development from the International Coalition to Eliminate HBV. Concurrently with the briefing session, the strategy appeared in an article published online (Lancet Gastroenterol Hepatol. 2019 Apr 10. doi: 10.1016/s2468-1253(19)30119-0).
The way forward will likely be a “two-pronged approach or restoring immune responses and targeting the virus,” Dr. Revill, head of molecular virology at the Doherty Institute in Melbourne, said in a video interview.
The new strategy recognizes the huge challenge of devising a treatment that produces a total cure that includes elimination of all traces of viral DNA from patients and for the immediate future focuses on the goal of functional cure. The term functional cure means a sustained period without detectable HBV surface antigen or HBV DNA in a patient’s serum, as well as suppressed virus release. Another feature of a functional cure would be a halt to progression of liver disease, replaced by liver regeneration, said Anna S. Lok, MD, professor of medicine and director of clinical hepatology at the University of Michigan, Ann Arbor, and a member of the strategy-writing group. She and her colleagues who wrote the strategy foresee the need for drug combinations with agents that can hit multiple viral targets as well as agents that restore normal immune function.
Several novel drug classes aimed at new viral targets, such as capsid inhibitors, are in various stages of clinical development, said Fabien Zoulim, MD, head of the gastroenterology and hepatology service at the Red Cross Hospital in Lyon, France, and another member of the writing panel. “We have many drug candidates” that use novel approaches to further restrict viral growth, roughly 50 agents in phase 1 and 2 studies, he said during the press briefing, held during the meeting sponsored by the European Association for the Study of the Liver. The other, immunologic aspect of the two-part cure strategy – restoring the “exhausted” HBV-specific T-cell population and stimulating production of neutralizing antibody to HBV – remains hypothetical right now, however. “It’s a concept that needs development,” Dr. Zoulim said.
A reason members of the coalition are optimistic about eventual prospects for a cure is that currently about 1% of patients on HBV antiviral treatments have a functional cure after relatively brief treatment, and the percentage of cured patients plateaus at about 10% among those who remain on current HBV antiviral drugs for several years. In addition, a substantial fraction of patients spontaneously resolve their HBV infection without any treatment. Experts estimate that more than 1 billion people worldwide have been infected by HBV and then later had their infection clear “naturally,” said Dr. Revill. But the mechanism by which this happens is currently a mystery. “We don’t know how or why” so many infected people are “cured” naturally, Dr. Revill admitted, but it gives him and his colleagues hope that the numbers can expand once more and better treatments for HBV infection are available.
REPORTING FROM ILC 2019
An HCV-infected population showed gaps in HBV testing, vaccination, and care
Assessment of a large cohort of hepatitis C virus (HCV)–infected patients revealed a high prevalence of current or past hepatitis B virus. However, within this cohort, there were notable gaps in HBV testing, directed care, and vaccination, according to Aaron M. Harris, MD, of the Centers for Disease Control and Prevention.
Dr. Harris and his colleagues abstracted patient-level data from the Grady Health System EHR in August 2016 to create an HCV patient registry. They found that, among 4,224 HCV-infected patients, 3,629 (86%) had test results for the hepatitis B surface antigen (HBsAg), with 43 (1.2%) being HBsAg positive.
“Our results identified a gap in care as a minority of HBsAg-positive patients with HCV coinfection received HBV DNA and/or e-antigen [HBeAg] testing,” the researchers stated.
Overall, only 2,342 (55.4%) patients had test results for all three HBV serologic markers. Among these, 789 (33.7%) were anti-HBc positive only, 678 (28.9%) were anti-HBc/anti-HBs positive, 190 (8.1%) were anti-HBs positive only, and 642 (27.4%) were HBV susceptible. In addition, only 50% of the HBV-susceptible patients received at least one dose of hepatitis B vaccine, according to the report published in Vaccine.
“Strategies are needed to increase hepatitis B testing, linkage to hepatitis B–directed care of HBV/HCV-coinfected patients, and to increase uptake in hepatitis B vaccination for HCV-infected patients within the Grady Health System,” the researchers concluded.
The study was funded by the CDC and the authors reported that they had no conflicts.
SOURCE: Harris AM et al. Vaccine. 2019;37:2188-93.
Assessment of a large cohort of hepatitis C virus (HCV)–infected patients revealed a high prevalence of current or past hepatitis B virus. However, within this cohort, there were notable gaps in HBV testing, directed care, and vaccination, according to Aaron M. Harris, MD, of the Centers for Disease Control and Prevention.
Dr. Harris and his colleagues abstracted patient-level data from the Grady Health System EHR in August 2016 to create an HCV patient registry. They found that, among 4,224 HCV-infected patients, 3,629 (86%) had test results for the hepatitis B surface antigen (HBsAg), with 43 (1.2%) being HBsAg positive.
“Our results identified a gap in care as a minority of HBsAg-positive patients with HCV coinfection received HBV DNA and/or e-antigen [HBeAg] testing,” the researchers stated.
Overall, only 2,342 (55.4%) patients had test results for all three HBV serologic markers. Among these, 789 (33.7%) were anti-HBc positive only, 678 (28.9%) were anti-HBc/anti-HBs positive, 190 (8.1%) were anti-HBs positive only, and 642 (27.4%) were HBV susceptible. In addition, only 50% of the HBV-susceptible patients received at least one dose of hepatitis B vaccine, according to the report published in Vaccine.
“Strategies are needed to increase hepatitis B testing, linkage to hepatitis B–directed care of HBV/HCV-coinfected patients, and to increase uptake in hepatitis B vaccination for HCV-infected patients within the Grady Health System,” the researchers concluded.
The study was funded by the CDC and the authors reported that they had no conflicts.
SOURCE: Harris AM et al. Vaccine. 2019;37:2188-93.
Assessment of a large cohort of hepatitis C virus (HCV)–infected patients revealed a high prevalence of current or past hepatitis B virus. However, within this cohort, there were notable gaps in HBV testing, directed care, and vaccination, according to Aaron M. Harris, MD, of the Centers for Disease Control and Prevention.
Dr. Harris and his colleagues abstracted patient-level data from the Grady Health System EHR in August 2016 to create an HCV patient registry. They found that, among 4,224 HCV-infected patients, 3,629 (86%) had test results for the hepatitis B surface antigen (HBsAg), with 43 (1.2%) being HBsAg positive.
“Our results identified a gap in care as a minority of HBsAg-positive patients with HCV coinfection received HBV DNA and/or e-antigen [HBeAg] testing,” the researchers stated.
Overall, only 2,342 (55.4%) patients had test results for all three HBV serologic markers. Among these, 789 (33.7%) were anti-HBc positive only, 678 (28.9%) were anti-HBc/anti-HBs positive, 190 (8.1%) were anti-HBs positive only, and 642 (27.4%) were HBV susceptible. In addition, only 50% of the HBV-susceptible patients received at least one dose of hepatitis B vaccine, according to the report published in Vaccine.
“Strategies are needed to increase hepatitis B testing, linkage to hepatitis B–directed care of HBV/HCV-coinfected patients, and to increase uptake in hepatitis B vaccination for HCV-infected patients within the Grady Health System,” the researchers concluded.
The study was funded by the CDC and the authors reported that they had no conflicts.
SOURCE: Harris AM et al. Vaccine. 2019;37:2188-93.
FROM VACCINE
Future of NASH care means multiple targets, multiple providers, expert says
PHILADELPHIA – While current treatment options are limited for patients with nonalcoholic steatohepatitis (NASH), a number of potential agents in clinical trials, Zobair M. Younossi, MD, MPH, said here at the 6th annual Digestive Diseases: New Advances conference.
With agents currently available and those to come, the future will be focused on long-term management of NASH as a chronic disease in specialized centers, according to Dr. Younossi, chairman in the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System, both in Falls Church, Va.
“We are not going to be able to cure NASH – we need to manage it,” Dr. Younossi said in a podium presentation. “NASH will be managed like type 2 diabetes. It’s not going to be treated like hepatitis C.”
Current treatment options are limited, with no Food and Drug Administration–approved options, and just two agents, vitamin E and pioglitazone, supported by guidance from the American Association for the Study of Liver Diseases (AASLD), Dr. Younossi said.
Public health interventions are needed to address the obesity and type 2 diabetes that are “the root of this disease,” Dr. Younossi said at the meeting, which was jointly provided by Rutgers and Global Academy for Medical Education.
Current AASLD guidance is based on studies suggesting that weight loss in the 3%-5% range may improve steatosis, and a 7%-10% weight loss can improve most histologic features of NASH, including fibrosis.
“The problem is that this is very hard to achieve,” Dr. Younossi said, adding that it is also hard to maintain. In a 2011 meta-analysis of clinical trials for reduction in nonalcoholic fatty liver disease, only a small minority of patients were able to maintain weight loss.
Bariatric surgery may be “very effective” for weight loss in the right patients, with some trials showing a proportion of patients maintaining improvement at 5-year follow-up, he said.
Exercise alone might prevent or reduce steatosis, but its effects on other aspects of liver histology, such as fibrosis, remain unknown, Dr. Younossi said.
Pioglitazone improves liver histology in patients with biopsy-proven NASH, although the benefits and risks, including potential adverse effects such as bone loss, diastolic dysfunction, or weight gain, should be discussed with each individual patient, he said.
Dr. Younossi highlighted randomized phase 3 trials for several agents that could figure into the treatment paradigm of NASH in the future by targeting different promoters of NASH and fibrosis progression. One of those was elafibranor, which targets the PPAR alpha/gamma pathways and is being evaluated versus placebo in NASH patients in the phase 3 RESOLVE-IT study. In a post hoc analysis of a previous randomized trial, the treatment resolved NASH without fibrosis worsening.
Other agents being evaluated in phase 3 trials include the CCR2/CCR5 receptor blocker cenicriviroc, the FXR agonist obeticholic acid, and the ASK-1 inhibitor selonsertib, Dr. Younossi said.
Optimal NASH care in the future may be based on targeting multiple such pathways, with patients increasingly treated at specialized centers that incorporate not only hepatologists, but also diabetes experts, dietitians, and exercise specialists.
“My own belief is that you have to treat this in the long term and also in a multidisciplinary sort of approach,” he said.
Dr. Younossi indicated that he is a consultant for Gilead, Intercept, Bristol-Myers Squibb, Novo Nordisk, Viking, Terms, Shionogi, AbbVie, Merck, and Novartis.
Global Academy and this news organization are owned by the same parent company.
PHILADELPHIA – While current treatment options are limited for patients with nonalcoholic steatohepatitis (NASH), a number of potential agents in clinical trials, Zobair M. Younossi, MD, MPH, said here at the 6th annual Digestive Diseases: New Advances conference.
With agents currently available and those to come, the future will be focused on long-term management of NASH as a chronic disease in specialized centers, according to Dr. Younossi, chairman in the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System, both in Falls Church, Va.
“We are not going to be able to cure NASH – we need to manage it,” Dr. Younossi said in a podium presentation. “NASH will be managed like type 2 diabetes. It’s not going to be treated like hepatitis C.”
Current treatment options are limited, with no Food and Drug Administration–approved options, and just two agents, vitamin E and pioglitazone, supported by guidance from the American Association for the Study of Liver Diseases (AASLD), Dr. Younossi said.
Public health interventions are needed to address the obesity and type 2 diabetes that are “the root of this disease,” Dr. Younossi said at the meeting, which was jointly provided by Rutgers and Global Academy for Medical Education.
Current AASLD guidance is based on studies suggesting that weight loss in the 3%-5% range may improve steatosis, and a 7%-10% weight loss can improve most histologic features of NASH, including fibrosis.
“The problem is that this is very hard to achieve,” Dr. Younossi said, adding that it is also hard to maintain. In a 2011 meta-analysis of clinical trials for reduction in nonalcoholic fatty liver disease, only a small minority of patients were able to maintain weight loss.
Bariatric surgery may be “very effective” for weight loss in the right patients, with some trials showing a proportion of patients maintaining improvement at 5-year follow-up, he said.
Exercise alone might prevent or reduce steatosis, but its effects on other aspects of liver histology, such as fibrosis, remain unknown, Dr. Younossi said.
Pioglitazone improves liver histology in patients with biopsy-proven NASH, although the benefits and risks, including potential adverse effects such as bone loss, diastolic dysfunction, or weight gain, should be discussed with each individual patient, he said.
Dr. Younossi highlighted randomized phase 3 trials for several agents that could figure into the treatment paradigm of NASH in the future by targeting different promoters of NASH and fibrosis progression. One of those was elafibranor, which targets the PPAR alpha/gamma pathways and is being evaluated versus placebo in NASH patients in the phase 3 RESOLVE-IT study. In a post hoc analysis of a previous randomized trial, the treatment resolved NASH without fibrosis worsening.
Other agents being evaluated in phase 3 trials include the CCR2/CCR5 receptor blocker cenicriviroc, the FXR agonist obeticholic acid, and the ASK-1 inhibitor selonsertib, Dr. Younossi said.
Optimal NASH care in the future may be based on targeting multiple such pathways, with patients increasingly treated at specialized centers that incorporate not only hepatologists, but also diabetes experts, dietitians, and exercise specialists.
“My own belief is that you have to treat this in the long term and also in a multidisciplinary sort of approach,” he said.
Dr. Younossi indicated that he is a consultant for Gilead, Intercept, Bristol-Myers Squibb, Novo Nordisk, Viking, Terms, Shionogi, AbbVie, Merck, and Novartis.
Global Academy and this news organization are owned by the same parent company.
PHILADELPHIA – While current treatment options are limited for patients with nonalcoholic steatohepatitis (NASH), a number of potential agents in clinical trials, Zobair M. Younossi, MD, MPH, said here at the 6th annual Digestive Diseases: New Advances conference.
With agents currently available and those to come, the future will be focused on long-term management of NASH as a chronic disease in specialized centers, according to Dr. Younossi, chairman in the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System, both in Falls Church, Va.
“We are not going to be able to cure NASH – we need to manage it,” Dr. Younossi said in a podium presentation. “NASH will be managed like type 2 diabetes. It’s not going to be treated like hepatitis C.”
Current treatment options are limited, with no Food and Drug Administration–approved options, and just two agents, vitamin E and pioglitazone, supported by guidance from the American Association for the Study of Liver Diseases (AASLD), Dr. Younossi said.
Public health interventions are needed to address the obesity and type 2 diabetes that are “the root of this disease,” Dr. Younossi said at the meeting, which was jointly provided by Rutgers and Global Academy for Medical Education.
Current AASLD guidance is based on studies suggesting that weight loss in the 3%-5% range may improve steatosis, and a 7%-10% weight loss can improve most histologic features of NASH, including fibrosis.
“The problem is that this is very hard to achieve,” Dr. Younossi said, adding that it is also hard to maintain. In a 2011 meta-analysis of clinical trials for reduction in nonalcoholic fatty liver disease, only a small minority of patients were able to maintain weight loss.
Bariatric surgery may be “very effective” for weight loss in the right patients, with some trials showing a proportion of patients maintaining improvement at 5-year follow-up, he said.
Exercise alone might prevent or reduce steatosis, but its effects on other aspects of liver histology, such as fibrosis, remain unknown, Dr. Younossi said.
Pioglitazone improves liver histology in patients with biopsy-proven NASH, although the benefits and risks, including potential adverse effects such as bone loss, diastolic dysfunction, or weight gain, should be discussed with each individual patient, he said.
Dr. Younossi highlighted randomized phase 3 trials for several agents that could figure into the treatment paradigm of NASH in the future by targeting different promoters of NASH and fibrosis progression. One of those was elafibranor, which targets the PPAR alpha/gamma pathways and is being evaluated versus placebo in NASH patients in the phase 3 RESOLVE-IT study. In a post hoc analysis of a previous randomized trial, the treatment resolved NASH without fibrosis worsening.
Other agents being evaluated in phase 3 trials include the CCR2/CCR5 receptor blocker cenicriviroc, the FXR agonist obeticholic acid, and the ASK-1 inhibitor selonsertib, Dr. Younossi said.
Optimal NASH care in the future may be based on targeting multiple such pathways, with patients increasingly treated at specialized centers that incorporate not only hepatologists, but also diabetes experts, dietitians, and exercise specialists.
“My own belief is that you have to treat this in the long term and also in a multidisciplinary sort of approach,” he said.
Dr. Younossi indicated that he is a consultant for Gilead, Intercept, Bristol-Myers Squibb, Novo Nordisk, Viking, Terms, Shionogi, AbbVie, Merck, and Novartis.
Global Academy and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM DIGESTIVE DISEASES: NEW ADVANCES