AASLD

BOSTON – Lack of health literacy, lack of routine, and being a nonnative speaker of English were predictors of treatment nonadherence in one-quarter of adults with hepatitis B virus in Australia, according to a study.

“Clinicians don’t know this is happening. We overlook it. Because it’s just one tablet a day, we think it’s quite easy, but when I took up this project, I completely underestimated the complexity of adherence and how many different factors can play into why a patient does or doesn’t adhere,” Suzanne Sheppard-Law, RN, MPH, PhD, a senior research fellow at the University of Technology Sydney, said in an interview about her prize-winning poster presentation at this year’s annual meeting of the American Association for the Study of Liver Diseases.

Wavebreakmedia Ltd/Thinkstock

BOSTON – Lack of health literacy, lack of routine, and being a nonnative speaker of English were predictors of treatment nonadherence in one-quarter of adults with hepatitis B virus in Australia, according to a study.

“Clinicians don’t know this is happening. We overlook it. Because it’s just one tablet a day, we think it’s quite easy, but when I took up this project, I completely underestimated the complexity of adherence and how many different factors can play into why a patient does or doesn’t adhere,” Suzanne Sheppard-Law, RN, MPH, PhD, a senior research fellow at the University of Technology Sydney, said in an interview about her prize-winning poster presentation at this year’s annual meeting of the American Association for the Study of Liver Diseases.

Wavebreakmedia Ltd/Thinkstock

BOSTON – Lack of health literacy, lack of routine, and being a nonnative speaker of English were predictors of treatment nonadherence in one-quarter of adults with hepatitis B virus in Australia, according to a study.

“Clinicians don’t know this is happening. We overlook it. Because it’s just one tablet a day, we think it’s quite easy, but when I took up this project, I completely underestimated the complexity of adherence and how many different factors can play into why a patient does or doesn’t adhere,” Suzanne Sheppard-Law, RN, MPH, PhD, a senior research fellow at the University of Technology Sydney, said in an interview about her prize-winning poster presentation at this year’s annual meeting of the American Association for the Study of Liver Diseases.

Wavebreakmedia Ltd/Thinkstock

BOSTON – Oral zinc supplementation was associated with maintenance of liver function and suppression of hepatocellular carcinoma in a retrospective cohort study of 267 patients with chronic liver disease.

Additional analyses revealed stepwise inverse relationships between serum zinc levels and rates of de novo liver failure, hepatocellular carcinoma, and death, Atsushi Hosui, MD, PhD, said at the annual meeting of the American Association for the Study of Liver Diseases. No patients stopped zinc therapy because of adverse events, and there were no serious adverse events, although some patients experienced nausea, which can occur with zinc supplementation, noted Dr. Hosui of Osaka-Rosai Hospital, Japan.

ilkab/Thinkstock

BOSTON – Oral zinc supplementation was associated with maintenance of liver function and suppression of hepatocellular carcinoma in a retrospective cohort study of 267 patients with chronic liver disease.

Additional analyses revealed stepwise inverse relationships between serum zinc levels and rates of de novo liver failure, hepatocellular carcinoma, and death, Atsushi Hosui, MD, PhD, said at the annual meeting of the American Association for the Study of Liver Diseases. No patients stopped zinc therapy because of adverse events, and there were no serious adverse events, although some patients experienced nausea, which can occur with zinc supplementation, noted Dr. Hosui of Osaka-Rosai Hospital, Japan.

ilkab/Thinkstock

BOSTON – Oral zinc supplementation was associated with maintenance of liver function and suppression of hepatocellular carcinoma in a retrospective cohort study of 267 patients with chronic liver disease.

Additional analyses revealed stepwise inverse relationships between serum zinc levels and rates of de novo liver failure, hepatocellular carcinoma, and death, Atsushi Hosui, MD, PhD, said at the annual meeting of the American Association for the Study of Liver Diseases. No patients stopped zinc therapy because of adverse events, and there were no serious adverse events, although some patients experienced nausea, which can occur with zinc supplementation, noted Dr. Hosui of Osaka-Rosai Hospital, Japan.

ilkab/Thinkstock

BOSTON – Obeticholic acid resulted in a significant reduction of a biomarker for liver fibrosis in patients with primary biliary cholangitis, according to a retrospective analysis of clinical trial data. In addition, patients taking obeticholic acid had a mean reduction in liver stiffness as measured by transient elastography.

Gideon Hirschfield, MD, PhD, presented the re-analysis of clinical trial data at the annual meeting of the American Association for the Study of Liver Diseases.

POISE was a phase III randomized, double-blind, placebo-controlled study of obeticholic acid for patients with primary biliary cholangitis (PBC). The clinical trial’s primary composite endpoint was an alkaline phosphatase level less than 1.67 times the upper limit of normal, with at least a 15% reduction in alkaline phosphatase and normal serum bilirubin.

The cohort of POISE patients on obeticholic acid met this biochemical surrogate endpoint, resulting in approval of the farnesoid X receptor agonist for treatment of PBC as an add-on to ursodeoxycholic acid (UDCA), or for patients who cannot tolerate UDCA.

However, transient elastography and the aspartate transaminase (AST) to platelet ratio index (APRI) have both been used to assess fibrosis in PBC, and have been found to predict clinical outcomes in PBC. These measures have the advantage of being noninvasive methods to measure the quality of liver tissue.

Dr. Hirschfield, a transplant hepatologist at the institute of immunology and immunotherapy at the University of Birmingham, England, and his coinvestigators reevaluated data from the POISE trial. They determined that APRI dropped significantly over 12 months of obeticholic acid treatment compared to placebo (P less than .01 for each of the two dosing arms of the POISE trial). Patients who switched to 5-10 mg of obeticholic acid daily from placebo during an open-label extension of POISE also had significant reductions in APRI scores (P less than .05); the reduction for placebo-switchers on a fixed 10-mg dose during the open-label study was not significant

Liver stiffness, as measured by transient elastography, was reduced for both arms of the POISE study at 12 months, but increased for those in the placebo arm. “Fewer patients receiving obeticholic acid 10 mg progressed” to a level associated with histological cirrhosis, “and patients receiving obeticholic acid showed an improvement in liver stiffness,” said Dr. Hirschfield.

Pruritis is a feature of PBC, and worsening pruritis can be a side effect of deoxycholic acid. However, the worsening is often transitory, so patients should be encouraged to try to stay the course, said Dr. Hirschfield. Managing patient expectations; sharing improved biomarkers; and considering the addition of a bile acid sequestrant or rifampicin, or reducing the obeticholic acid dose are all strategies to consider when caring for PBC patients, said Dr. Hirschfield.

Clinical trials to assess the safety and efficacy of obeticholic acid for individuals with nonalcoholic fatty liver disease and steatohepatitis are underway.

Dr. Hirschfield discussed his findings in a video interview.

koakes@frontlinemedcom.com
On Twitter @karioakes

BOSTON – Obeticholic acid resulted in a significant reduction of a biomarker for liver fibrosis in patients with primary biliary cholangitis, according to a retrospective analysis of clinical trial data. In addition, patients taking obeticholic acid had a mean reduction in liver stiffness as measured by transient elastography.

Gideon Hirschfield, MD, PhD, presented the re-analysis of clinical trial data at the annual meeting of the American Association for the Study of Liver Diseases.

POISE was a phase III randomized, double-blind, placebo-controlled study of obeticholic acid for patients with primary biliary cholangitis (PBC). The clinical trial’s primary composite endpoint was an alkaline phosphatase level less than 1.67 times the upper limit of normal, with at least a 15% reduction in alkaline phosphatase and normal serum bilirubin.

The cohort of POISE patients on obeticholic acid met this biochemical surrogate endpoint, resulting in approval of the farnesoid X receptor agonist for treatment of PBC as an add-on to ursodeoxycholic acid (UDCA), or for patients who cannot tolerate UDCA.

However, transient elastography and the aspartate transaminase (AST) to platelet ratio index (APRI) have both been used to assess fibrosis in PBC, and have been found to predict clinical outcomes in PBC. These measures have the advantage of being noninvasive methods to measure the quality of liver tissue.

Dr. Hirschfield, a transplant hepatologist at the institute of immunology and immunotherapy at the University of Birmingham, England, and his coinvestigators reevaluated data from the POISE trial. They determined that APRI dropped significantly over 12 months of obeticholic acid treatment compared to placebo (P less than .01 for each of the two dosing arms of the POISE trial). Patients who switched to 5-10 mg of obeticholic acid daily from placebo during an open-label extension of POISE also had significant reductions in APRI scores (P less than .05); the reduction for placebo-switchers on a fixed 10-mg dose during the open-label study was not significant

Liver stiffness, as measured by transient elastography, was reduced for both arms of the POISE study at 12 months, but increased for those in the placebo arm. “Fewer patients receiving obeticholic acid 10 mg progressed” to a level associated with histological cirrhosis, “and patients receiving obeticholic acid showed an improvement in liver stiffness,” said Dr. Hirschfield.

Pruritis is a feature of PBC, and worsening pruritis can be a side effect of deoxycholic acid. However, the worsening is often transitory, so patients should be encouraged to try to stay the course, said Dr. Hirschfield. Managing patient expectations; sharing improved biomarkers; and considering the addition of a bile acid sequestrant or rifampicin, or reducing the obeticholic acid dose are all strategies to consider when caring for PBC patients, said Dr. Hirschfield.

Clinical trials to assess the safety and efficacy of obeticholic acid for individuals with nonalcoholic fatty liver disease and steatohepatitis are underway.

Dr. Hirschfield discussed his findings in a video interview.

koakes@frontlinemedcom.com
On Twitter @karioakes

BOSTON – Obeticholic acid resulted in a significant reduction of a biomarker for liver fibrosis in patients with primary biliary cholangitis, according to a retrospective analysis of clinical trial data. In addition, patients taking obeticholic acid had a mean reduction in liver stiffness as measured by transient elastography.

Gideon Hirschfield, MD, PhD, presented the re-analysis of clinical trial data at the annual meeting of the American Association for the Study of Liver Diseases.

POISE was a phase III randomized, double-blind, placebo-controlled study of obeticholic acid for patients with primary biliary cholangitis (PBC). The clinical trial’s primary composite endpoint was an alkaline phosphatase level less than 1.67 times the upper limit of normal, with at least a 15% reduction in alkaline phosphatase and normal serum bilirubin.

The cohort of POISE patients on obeticholic acid met this biochemical surrogate endpoint, resulting in approval of the farnesoid X receptor agonist for treatment of PBC as an add-on to ursodeoxycholic acid (UDCA), or for patients who cannot tolerate UDCA.

However, transient elastography and the aspartate transaminase (AST) to platelet ratio index (APRI) have both been used to assess fibrosis in PBC, and have been found to predict clinical outcomes in PBC. These measures have the advantage of being noninvasive methods to measure the quality of liver tissue.

Dr. Hirschfield, a transplant hepatologist at the institute of immunology and immunotherapy at the University of Birmingham, England, and his coinvestigators reevaluated data from the POISE trial. They determined that APRI dropped significantly over 12 months of obeticholic acid treatment compared to placebo (P less than .01 for each of the two dosing arms of the POISE trial). Patients who switched to 5-10 mg of obeticholic acid daily from placebo during an open-label extension of POISE also had significant reductions in APRI scores (P less than .05); the reduction for placebo-switchers on a fixed 10-mg dose during the open-label study was not significant

Liver stiffness, as measured by transient elastography, was reduced for both arms of the POISE study at 12 months, but increased for those in the placebo arm. “Fewer patients receiving obeticholic acid 10 mg progressed” to a level associated with histological cirrhosis, “and patients receiving obeticholic acid showed an improvement in liver stiffness,” said Dr. Hirschfield.

Pruritis is a feature of PBC, and worsening pruritis can be a side effect of deoxycholic acid. However, the worsening is often transitory, so patients should be encouraged to try to stay the course, said Dr. Hirschfield. Managing patient expectations; sharing improved biomarkers; and considering the addition of a bile acid sequestrant or rifampicin, or reducing the obeticholic acid dose are all strategies to consider when caring for PBC patients, said Dr. Hirschfield.

Clinical trials to assess the safety and efficacy of obeticholic acid for individuals with nonalcoholic fatty liver disease and steatohepatitis are underway.

Dr. Hirschfield discussed his findings in a video interview.

koakes@frontlinemedcom.com
On Twitter @karioakes

BOSTON – Direct-acting antiviral therapy does not appear to increase the risk of de novo hepatocellular carcinoma in cirrhotic patients with hepatitis C virus (HCV) infection, according to findings from a prospective cohort study of more than 2,000 patients.

But curing HCV also did not protect patients from hepatocellular carcinoma (HCC), at least during the first 6-12 months after starting treatment, Antonietta Romano, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Clinicians should continue monitoring HCV patients with advanced liver disease, even after they have achieved sustained viral response, she said.

Recent studies had raised concerns about whether direct-acting antivirals (DAA) increase the risk of HCC, said Dr. Romano of the University of Padova (Italy). To clarify the issue, she and her coinvestigators followed 2,279 HCV patients who received approved DAA regimens. Over a median follow-up time of 305 days, 41 patients developed de novo hepatocellular carcinoma, for an incidence of 1.64 cases per 100 patient-years, Dr. Romano said.

“These results indicate that in cirrhotic patients, the incidence of HCC during the first 6-9 months after initiation of direct-acting antiviral therapy is not different from what we expect in untreated patients, according to historical controls,” she added.

Fully 86% of patients had cirrhosis, of which 91% were Child-Pugh A and 9% were Child-Pugh B, indicating more advanced liver disease, Dr. Romano said. Noncirrhotic patients had an HCC rate of 0.23 cases per 100 patient years – less than one-eighth that for cirrhotic patients (1.93 cases per 100 patient-years). Child-Pugh B patients developed 2.9 cases of HCC per 100 patient years, versus 1.6 for Child-Pugh A patients.

These rates resemble those in historical controls, suggesting that stage of liver disease is the crucial predictor of HCC risk – not DAA therapy, Dr. Romano said. Multivariable analyses supported that conclusion, linking HCC to elevated liver enzymes and to thrombocytopenia but not to DAA regimen, gender, age, or HCV genotype, she reported.

Most HCC cases were diagnosed at least 12 weeks after starting therapy, according to Dr. Romano. Half of patients had a single nodular tumor with a typical vascular pattern, but the other half had a more aggressive multifocal infiltrative pattern. The reason for the high proportion of atypical aggressive pattern was unclear, Dr. Romano said. However, DAA therapy causes HCV to abruptly stop replicating in the liver, leading to marked molecular and immunologic changes that might initially cause microscopic tumors to grow faster than before. So while DAA therapy does not increase the overall risk of HCC, it clearly is not protective, she said.

Nearly 70% of patients in this study were male. About 60% had HCV-1 infection, 22% had HCV-2, 19% had HCV-3, and 8% had HCV-4, Dr. Romano said. In all, 28 of 41 patients who developed HCC had achieved sustained virologic response at 12 weeks, while the other 13 had relapsed.

The investigators received no outside funding for this study. Dr. Romano reported ties to Gilead, Abbvie, and Bristol Myers Squibb.

BOSTON – Direct-acting antiviral therapy does not appear to increase the risk of de novo hepatocellular carcinoma in cirrhotic patients with hepatitis C virus (HCV) infection, according to findings from a prospective cohort study of more than 2,000 patients.

But curing HCV also did not protect patients from hepatocellular carcinoma (HCC), at least during the first 6-12 months after starting treatment, Antonietta Romano, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Clinicians should continue monitoring HCV patients with advanced liver disease, even after they have achieved sustained viral response, she said.

Recent studies had raised concerns about whether direct-acting antivirals (DAA) increase the risk of HCC, said Dr. Romano of the University of Padova (Italy). To clarify the issue, she and her coinvestigators followed 2,279 HCV patients who received approved DAA regimens. Over a median follow-up time of 305 days, 41 patients developed de novo hepatocellular carcinoma, for an incidence of 1.64 cases per 100 patient-years, Dr. Romano said.

“These results indicate that in cirrhotic patients, the incidence of HCC during the first 6-9 months after initiation of direct-acting antiviral therapy is not different from what we expect in untreated patients, according to historical controls,” she added.

Fully 86% of patients had cirrhosis, of which 91% were Child-Pugh A and 9% were Child-Pugh B, indicating more advanced liver disease, Dr. Romano said. Noncirrhotic patients had an HCC rate of 0.23 cases per 100 patient years – less than one-eighth that for cirrhotic patients (1.93 cases per 100 patient-years). Child-Pugh B patients developed 2.9 cases of HCC per 100 patient years, versus 1.6 for Child-Pugh A patients.

These rates resemble those in historical controls, suggesting that stage of liver disease is the crucial predictor of HCC risk – not DAA therapy, Dr. Romano said. Multivariable analyses supported that conclusion, linking HCC to elevated liver enzymes and to thrombocytopenia but not to DAA regimen, gender, age, or HCV genotype, she reported.

Most HCC cases were diagnosed at least 12 weeks after starting therapy, according to Dr. Romano. Half of patients had a single nodular tumor with a typical vascular pattern, but the other half had a more aggressive multifocal infiltrative pattern. The reason for the high proportion of atypical aggressive pattern was unclear, Dr. Romano said. However, DAA therapy causes HCV to abruptly stop replicating in the liver, leading to marked molecular and immunologic changes that might initially cause microscopic tumors to grow faster than before. So while DAA therapy does not increase the overall risk of HCC, it clearly is not protective, she said.

Nearly 70% of patients in this study were male. About 60% had HCV-1 infection, 22% had HCV-2, 19% had HCV-3, and 8% had HCV-4, Dr. Romano said. In all, 28 of 41 patients who developed HCC had achieved sustained virologic response at 12 weeks, while the other 13 had relapsed.

The investigators received no outside funding for this study. Dr. Romano reported ties to Gilead, Abbvie, and Bristol Myers Squibb.

BOSTON – Direct-acting antiviral therapy does not appear to increase the risk of de novo hepatocellular carcinoma in cirrhotic patients with hepatitis C virus (HCV) infection, according to findings from a prospective cohort study of more than 2,000 patients.

But curing HCV also did not protect patients from hepatocellular carcinoma (HCC), at least during the first 6-12 months after starting treatment, Antonietta Romano, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Clinicians should continue monitoring HCV patients with advanced liver disease, even after they have achieved sustained viral response, she said.

Recent studies had raised concerns about whether direct-acting antivirals (DAA) increase the risk of HCC, said Dr. Romano of the University of Padova (Italy). To clarify the issue, she and her coinvestigators followed 2,279 HCV patients who received approved DAA regimens. Over a median follow-up time of 305 days, 41 patients developed de novo hepatocellular carcinoma, for an incidence of 1.64 cases per 100 patient-years, Dr. Romano said.

“These results indicate that in cirrhotic patients, the incidence of HCC during the first 6-9 months after initiation of direct-acting antiviral therapy is not different from what we expect in untreated patients, according to historical controls,” she added.

Fully 86% of patients had cirrhosis, of which 91% were Child-Pugh A and 9% were Child-Pugh B, indicating more advanced liver disease, Dr. Romano said. Noncirrhotic patients had an HCC rate of 0.23 cases per 100 patient years – less than one-eighth that for cirrhotic patients (1.93 cases per 100 patient-years). Child-Pugh B patients developed 2.9 cases of HCC per 100 patient years, versus 1.6 for Child-Pugh A patients.

These rates resemble those in historical controls, suggesting that stage of liver disease is the crucial predictor of HCC risk – not DAA therapy, Dr. Romano said. Multivariable analyses supported that conclusion, linking HCC to elevated liver enzymes and to thrombocytopenia but not to DAA regimen, gender, age, or HCV genotype, she reported.

Most HCC cases were diagnosed at least 12 weeks after starting therapy, according to Dr. Romano. Half of patients had a single nodular tumor with a typical vascular pattern, but the other half had a more aggressive multifocal infiltrative pattern. The reason for the high proportion of atypical aggressive pattern was unclear, Dr. Romano said. However, DAA therapy causes HCV to abruptly stop replicating in the liver, leading to marked molecular and immunologic changes that might initially cause microscopic tumors to grow faster than before. So while DAA therapy does not increase the overall risk of HCC, it clearly is not protective, she said.

Nearly 70% of patients in this study were male. About 60% had HCV-1 infection, 22% had HCV-2, 19% had HCV-3, and 8% had HCV-4, Dr. Romano said. In all, 28 of 41 patients who developed HCC had achieved sustained virologic response at 12 weeks, while the other 13 had relapsed.

The investigators received no outside funding for this study. Dr. Romano reported ties to Gilead, Abbvie, and Bristol Myers Squibb.

BOSTON – A new scoring system fared better than the Milan criteria in predicting risk for recurrent hepatocellular carcinoma after liver transplant.

The scoring system combines an assessment of the number and size of tumors on the explanted liver with serum alpha-fetoprotein (AFP) score and the presence of microvascular invasion to assign a numeric risk score to patients who have received liver transplant for hepatocellular carcinoma (HCC).

The risk estimation tool showed good model estimation, with a C statistic of 0.82 (95% confidence interval, 0.77-0.86), according to Neil Mehta, MD, who presented the study validating the risk estimation tool at the annual meeting of the American Association for the Study of Liver Diseases. The C statistic is a measure of goodness of fit, with values closer to 1 indicating better fit.

In a paper published simultaneously in JAMA Oncology, Dr. Mehta and his collaborators said that the tool had “superior recurrence risk classification, compared with explant Milan criteria (net reclassification index, 0.40; P = 0.001) in the study’s validation cohort” (JAMA Oncol. 2016 Nov 13. doi: 10:1001/jamaoncol2016/5116).

Under the Milan criteria, patients with HCC are eligible for liver transplant if there are no extrahepatic manifestations and no vascular invasion. One lesion must be smaller than 5 cm, and up to three lesions smaller than 3 cm are permitted.

Dr. Mehta, a gastroenterologist and transplant hepatologist at the University of California, San Francisco, worked with colleagues to narrow down a long list of factors that in previous studies had been associated with HCC recurrence. The final Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score uses just three factors that multivariable analysis found were most highly predictive of HCC recurrence after liver transplant.

The three factors are microvascular invasion; AFP at the time of liver transplant; and the sum of the largest viable tumor diameter plus the number of viable tumors, assessed at the time of explant.

This last factor uses pathology examination, rather than radiology results, to assess tumor number, size, and viability. If a tumor is found to be completely necrotic, for example, it is not included when counting tumors for this component of the RETREAT score.

To develop the scoring system, Dr. Mehta and his coauthors enrolled adult patients with HCC who had liver transplant at three centers, each with a different wait time for transplant – short, medium, or long. Patients in the development cohort (n=721) had Model for End-Stage Liver Disease (MELD) score exception, and patients always met Milan criteria on imaging.

The validation cohort (n=340) had the same inclusion and exclusion criteria, but differed in several significant ways from the development cohort, with more young people, men, and individuals with hepatitis B or alcohol abuse. Individuals in the validation cohort were less likely to have received locoregional therapy (LRT) before liver transplant, but were more likely to have had a single tumor. They had more microvascular invasion, more tumors that were poorly differentiated, and more tumor staging beyond Milan criteria on explant.

The primary outcome measures for the study were overall survival and 5-year post–liver transplant HCC recurrence.

In developing the RETREAT scoring system, investigators used the final multivariable model coefficients to produce a “simplified point scale reflecting the relative impact of model covariables,” Dr. Mehta and his coauthors wrote.

RETREAT scoring ranges from 0 to 8; in the studied patients, the most common score was 1. Any microvascular invasion is assigned a point value of 2. The sum of the largest viable tumor diameter – in centimeters – plus the number of viable tumors is divided into four categories. If there are no tumors, the score is 0. For a sum of 1.1-4.9, the score is 1; a sum of 5.0-9.9 is assigned a score of 2, and a sum or 10 or greater is assigned a score of 3.

Serum AFP at the time of liver transplant (measured in ng/mL) is given a score of 0 if the value is less than 20. AFP of 20-99 is assigned a score of 1, values of 100-999 a score of 2, and 1,000 or greater a score of 3.

“Predicted risk of 1- and 5-year HCC recurrence rose with each point scored such that a patient with a RETREAT score of 5 or higher … had a predicted 1- and 5-year recurrence risk of 39.3 (95% CI, 25.5%-50.5%) and 75.2% (95% CI, 56.7%-85.8%), respectively,” the researchers wrote.

Dr. Mehta and his coauthors emphasized that the RETREAT scoring system represents an effort to strike a balance between including clinically meaningful variables to predict HCC recurrence and retaining simplicity and ease of use.

The researchers suggested guidelines for post–liver transplant HCC recurrence surveillance based on RETREAT scoring. They recommend no follow-up for a score of 0; surveillance scans and AFP monitoring every 6 months for 2 years for a score of 1-3, and every 6 months for 5 years for a score of 4. RETREAT scores of 5 or higher warrant surveillance every 3-4 months for 2 years, followed by every 6 months through year 5.

This surveillance stratification, they said, should help control costs while retaining a vigilant approach for those most at risk of recurrence. This approach is currently in use at University of California, San Francisco.

Study limitations included some missing information on AFP levels in the development cohort, and a small number of missing histologic tumor grading in both cohorts. In order to address limitations in the retrospective design of the present study, Dr. Mehta and his coauthors are planning another multicenter study to evaluate RETREAT as a surveillance tool and confirm its prognostic value.

The authors reported no conflicts of interest. The study was funded by the Biostatistics Core of the UCSF Liver Center.

koakes@frontlinemedcom.com

On Twitter @karioakes

BOSTON – A new scoring system fared better than the Milan criteria in predicting risk for recurrent hepatocellular carcinoma after liver transplant.

The scoring system combines an assessment of the number and size of tumors on the explanted liver with serum alpha-fetoprotein (AFP) score and the presence of microvascular invasion to assign a numeric risk score to patients who have received liver transplant for hepatocellular carcinoma (HCC).

The risk estimation tool showed good model estimation, with a C statistic of 0.82 (95% confidence interval, 0.77-0.86), according to Neil Mehta, MD, who presented the study validating the risk estimation tool at the annual meeting of the American Association for the Study of Liver Diseases. The C statistic is a measure of goodness of fit, with values closer to 1 indicating better fit.

In a paper published simultaneously in JAMA Oncology, Dr. Mehta and his collaborators said that the tool had “superior recurrence risk classification, compared with explant Milan criteria (net reclassification index, 0.40; P = 0.001) in the study’s validation cohort” (JAMA Oncol. 2016 Nov 13. doi: 10:1001/jamaoncol2016/5116).

Under the Milan criteria, patients with HCC are eligible for liver transplant if there are no extrahepatic manifestations and no vascular invasion. One lesion must be smaller than 5 cm, and up to three lesions smaller than 3 cm are permitted.

Dr. Mehta, a gastroenterologist and transplant hepatologist at the University of California, San Francisco, worked with colleagues to narrow down a long list of factors that in previous studies had been associated with HCC recurrence. The final Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score uses just three factors that multivariable analysis found were most highly predictive of HCC recurrence after liver transplant.

The three factors are microvascular invasion; AFP at the time of liver transplant; and the sum of the largest viable tumor diameter plus the number of viable tumors, assessed at the time of explant.

This last factor uses pathology examination, rather than radiology results, to assess tumor number, size, and viability. If a tumor is found to be completely necrotic, for example, it is not included when counting tumors for this component of the RETREAT score.

To develop the scoring system, Dr. Mehta and his coauthors enrolled adult patients with HCC who had liver transplant at three centers, each with a different wait time for transplant – short, medium, or long. Patients in the development cohort (n=721) had Model for End-Stage Liver Disease (MELD) score exception, and patients always met Milan criteria on imaging.

The validation cohort (n=340) had the same inclusion and exclusion criteria, but differed in several significant ways from the development cohort, with more young people, men, and individuals with hepatitis B or alcohol abuse. Individuals in the validation cohort were less likely to have received locoregional therapy (LRT) before liver transplant, but were more likely to have had a single tumor. They had more microvascular invasion, more tumors that were poorly differentiated, and more tumor staging beyond Milan criteria on explant.

The primary outcome measures for the study were overall survival and 5-year post–liver transplant HCC recurrence.

In developing the RETREAT scoring system, investigators used the final multivariable model coefficients to produce a “simplified point scale reflecting the relative impact of model covariables,” Dr. Mehta and his coauthors wrote.

RETREAT scoring ranges from 0 to 8; in the studied patients, the most common score was 1. Any microvascular invasion is assigned a point value of 2. The sum of the largest viable tumor diameter – in centimeters – plus the number of viable tumors is divided into four categories. If there are no tumors, the score is 0. For a sum of 1.1-4.9, the score is 1; a sum of 5.0-9.9 is assigned a score of 2, and a sum or 10 or greater is assigned a score of 3.

Serum AFP at the time of liver transplant (measured in ng/mL) is given a score of 0 if the value is less than 20. AFP of 20-99 is assigned a score of 1, values of 100-999 a score of 2, and 1,000 or greater a score of 3.

“Predicted risk of 1- and 5-year HCC recurrence rose with each point scored such that a patient with a RETREAT score of 5 or higher … had a predicted 1- and 5-year recurrence risk of 39.3 (95% CI, 25.5%-50.5%) and 75.2% (95% CI, 56.7%-85.8%), respectively,” the researchers wrote.

Dr. Mehta and his coauthors emphasized that the RETREAT scoring system represents an effort to strike a balance between including clinically meaningful variables to predict HCC recurrence and retaining simplicity and ease of use.

The researchers suggested guidelines for post–liver transplant HCC recurrence surveillance based on RETREAT scoring. They recommend no follow-up for a score of 0; surveillance scans and AFP monitoring every 6 months for 2 years for a score of 1-3, and every 6 months for 5 years for a score of 4. RETREAT scores of 5 or higher warrant surveillance every 3-4 months for 2 years, followed by every 6 months through year 5.

This surveillance stratification, they said, should help control costs while retaining a vigilant approach for those most at risk of recurrence. This approach is currently in use at University of California, San Francisco.

Study limitations included some missing information on AFP levels in the development cohort, and a small number of missing histologic tumor grading in both cohorts. In order to address limitations in the retrospective design of the present study, Dr. Mehta and his coauthors are planning another multicenter study to evaluate RETREAT as a surveillance tool and confirm its prognostic value.

The authors reported no conflicts of interest. The study was funded by the Biostatistics Core of the UCSF Liver Center.

koakes@frontlinemedcom.com

On Twitter @karioakes

BOSTON – A new scoring system fared better than the Milan criteria in predicting risk for recurrent hepatocellular carcinoma after liver transplant.

The scoring system combines an assessment of the number and size of tumors on the explanted liver with serum alpha-fetoprotein (AFP) score and the presence of microvascular invasion to assign a numeric risk score to patients who have received liver transplant for hepatocellular carcinoma (HCC).

The risk estimation tool showed good model estimation, with a C statistic of 0.82 (95% confidence interval, 0.77-0.86), according to Neil Mehta, MD, who presented the study validating the risk estimation tool at the annual meeting of the American Association for the Study of Liver Diseases. The C statistic is a measure of goodness of fit, with values closer to 1 indicating better fit.

In a paper published simultaneously in JAMA Oncology, Dr. Mehta and his collaborators said that the tool had “superior recurrence risk classification, compared with explant Milan criteria (net reclassification index, 0.40; P = 0.001) in the study’s validation cohort” (JAMA Oncol. 2016 Nov 13. doi: 10:1001/jamaoncol2016/5116).

Under the Milan criteria, patients with HCC are eligible for liver transplant if there are no extrahepatic manifestations and no vascular invasion. One lesion must be smaller than 5 cm, and up to three lesions smaller than 3 cm are permitted.

Dr. Mehta, a gastroenterologist and transplant hepatologist at the University of California, San Francisco, worked with colleagues to narrow down a long list of factors that in previous studies had been associated with HCC recurrence. The final Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score uses just three factors that multivariable analysis found were most highly predictive of HCC recurrence after liver transplant.

The three factors are microvascular invasion; AFP at the time of liver transplant; and the sum of the largest viable tumor diameter plus the number of viable tumors, assessed at the time of explant.

This last factor uses pathology examination, rather than radiology results, to assess tumor number, size, and viability. If a tumor is found to be completely necrotic, for example, it is not included when counting tumors for this component of the RETREAT score.

To develop the scoring system, Dr. Mehta and his coauthors enrolled adult patients with HCC who had liver transplant at three centers, each with a different wait time for transplant – short, medium, or long. Patients in the development cohort (n=721) had Model for End-Stage Liver Disease (MELD) score exception, and patients always met Milan criteria on imaging.

The validation cohort (n=340) had the same inclusion and exclusion criteria, but differed in several significant ways from the development cohort, with more young people, men, and individuals with hepatitis B or alcohol abuse. Individuals in the validation cohort were less likely to have received locoregional therapy (LRT) before liver transplant, but were more likely to have had a single tumor. They had more microvascular invasion, more tumors that were poorly differentiated, and more tumor staging beyond Milan criteria on explant.

The primary outcome measures for the study were overall survival and 5-year post–liver transplant HCC recurrence.

In developing the RETREAT scoring system, investigators used the final multivariable model coefficients to produce a “simplified point scale reflecting the relative impact of model covariables,” Dr. Mehta and his coauthors wrote.

RETREAT scoring ranges from 0 to 8; in the studied patients, the most common score was 1. Any microvascular invasion is assigned a point value of 2. The sum of the largest viable tumor diameter – in centimeters – plus the number of viable tumors is divided into four categories. If there are no tumors, the score is 0. For a sum of 1.1-4.9, the score is 1; a sum of 5.0-9.9 is assigned a score of 2, and a sum or 10 or greater is assigned a score of 3.

Serum AFP at the time of liver transplant (measured in ng/mL) is given a score of 0 if the value is less than 20. AFP of 20-99 is assigned a score of 1, values of 100-999 a score of 2, and 1,000 or greater a score of 3.

“Predicted risk of 1- and 5-year HCC recurrence rose with each point scored such that a patient with a RETREAT score of 5 or higher … had a predicted 1- and 5-year recurrence risk of 39.3 (95% CI, 25.5%-50.5%) and 75.2% (95% CI, 56.7%-85.8%), respectively,” the researchers wrote.

Dr. Mehta and his coauthors emphasized that the RETREAT scoring system represents an effort to strike a balance between including clinically meaningful variables to predict HCC recurrence and retaining simplicity and ease of use.

The researchers suggested guidelines for post–liver transplant HCC recurrence surveillance based on RETREAT scoring. They recommend no follow-up for a score of 0; surveillance scans and AFP monitoring every 6 months for 2 years for a score of 1-3, and every 6 months for 5 years for a score of 4. RETREAT scores of 5 or higher warrant surveillance every 3-4 months for 2 years, followed by every 6 months through year 5.

This surveillance stratification, they said, should help control costs while retaining a vigilant approach for those most at risk of recurrence. This approach is currently in use at University of California, San Francisco.

Study limitations included some missing information on AFP levels in the development cohort, and a small number of missing histologic tumor grading in both cohorts. In order to address limitations in the retrospective design of the present study, Dr. Mehta and his coauthors are planning another multicenter study to evaluate RETREAT as a surveillance tool and confirm its prognostic value.

The authors reported no conflicts of interest. The study was funded by the Biostatistics Core of the UCSF Liver Center.

koakes@frontlinemedcom.com

On Twitter @karioakes

BOSTON – A novel therapeutic approach to nonalcoholic steatohepatitis could one day mean sufferers of this severe form of nonalcoholic fatty liver disease have an alternative to transplantation.

Preclinical findings from a study using mesenchymal stem cells adapted from unsuitable organs for transplant have shown promise in suppressing inflammation in nonalcoholic steatohepatitis (NASH).

Eraxion/thinkstockphotos.com

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

BOSTON – A novel therapeutic approach to nonalcoholic steatohepatitis could one day mean sufferers of this severe form of nonalcoholic fatty liver disease have an alternative to transplantation.

Preclinical findings from a study using mesenchymal stem cells adapted from unsuitable organs for transplant have shown promise in suppressing inflammation in nonalcoholic steatohepatitis (NASH).

Eraxion/thinkstockphotos.com

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

BOSTON – A novel therapeutic approach to nonalcoholic steatohepatitis could one day mean sufferers of this severe form of nonalcoholic fatty liver disease have an alternative to transplantation.

Preclinical findings from a study using mesenchymal stem cells adapted from unsuitable organs for transplant have shown promise in suppressing inflammation in nonalcoholic steatohepatitis (NASH).

Eraxion/thinkstockphotos.com

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

decade3d/thinkstockphotos.com

Cenicriviroc, an oral chemokine receptor CCR/5 antagonist, was well tolerated, although it did not best placebo across all study endpoints, according to results of a 1-year phase IIb study released in an abstract in advance of the annual meeting of the American Association for the Study of Liver Diseases.

A correlation between treatment benefit and disease severity was reported by Arun J. Sanyal, MD, of Virginia Commonwealth University in Richmond, and coworkers, however.

In the 2-year, multinational, phase IIb, double-blind CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) study, 289 adults with chronic liver disease were randomly assigned to either 150 mg cenicriviroc (CVC) once daily or to placebo. At baseline, study participants had either histologically defined nonalcoholic steatohepatitis, a nonalcoholic fatty liver disease score (NAS) of 4 or greater, or liver fibrosis between stages 1 and 3. Just over half of the cohort were women, 72% had metabolic syndrome, and 53% had diabetes. Three-quarters had an NAS score of 5 or higher, and 67% had fibrosis between stages 2 and 3. The mean body mass index across the study was 34 kg/m².

At 1 year, liver biopsy showed that 16% of the CVC group had achieved at least a 2-point improvement in NAS, 3% less than controls (P = .519). Resolution of steatohepatitis with no worsening of fibrosis was higher in the study arm, compared with controls: 8% vs. 6% (P = .494). A significant difference was seen in members of the study arm who had advanced disease characteristics at baseline, compared with controls, by at least one stage in fibrosis improvement, with no worsening of steatohepatitis (P = .023). Across the study, improvement in fibrosis by two stages was seen in eight patients given CVC and in three controls. Progression to cirrhosis occurred in two members of the study arm and in five controls.

Adverse treatment-related events were similar across the study. The most commonly reported were fatigue (2.8%) and diarrhea (2.1%) in the study arm and headache (3.5%) in controls.

Most of the researchers associated with this study have industry relationships, including Brian L. Wiens, PhD, Pamela Vig, PhD, Star Seyedkazemi, PharmD, and Eric Lefebvre, MD, all of whom are employed by study sponsor, Tobira Therapeutics.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

decade3d/thinkstockphotos.com

Cenicriviroc, an oral chemokine receptor CCR/5 antagonist, was well tolerated, although it did not best placebo across all study endpoints, according to results of a 1-year phase IIb study released in an abstract in advance of the annual meeting of the American Association for the Study of Liver Diseases.

A correlation between treatment benefit and disease severity was reported by Arun J. Sanyal, MD, of Virginia Commonwealth University in Richmond, and coworkers, however.

In the 2-year, multinational, phase IIb, double-blind CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) study, 289 adults with chronic liver disease were randomly assigned to either 150 mg cenicriviroc (CVC) once daily or to placebo. At baseline, study participants had either histologically defined nonalcoholic steatohepatitis, a nonalcoholic fatty liver disease score (NAS) of 4 or greater, or liver fibrosis between stages 1 and 3. Just over half of the cohort were women, 72% had metabolic syndrome, and 53% had diabetes. Three-quarters had an NAS score of 5 or higher, and 67% had fibrosis between stages 2 and 3. The mean body mass index across the study was 34 kg/m².

At 1 year, liver biopsy showed that 16% of the CVC group had achieved at least a 2-point improvement in NAS, 3% less than controls (P = .519). Resolution of steatohepatitis with no worsening of fibrosis was higher in the study arm, compared with controls: 8% vs. 6% (P = .494). A significant difference was seen in members of the study arm who had advanced disease characteristics at baseline, compared with controls, by at least one stage in fibrosis improvement, with no worsening of steatohepatitis (P = .023). Across the study, improvement in fibrosis by two stages was seen in eight patients given CVC and in three controls. Progression to cirrhosis occurred in two members of the study arm and in five controls.

Adverse treatment-related events were similar across the study. The most commonly reported were fatigue (2.8%) and diarrhea (2.1%) in the study arm and headache (3.5%) in controls.

Most of the researchers associated with this study have industry relationships, including Brian L. Wiens, PhD, Pamela Vig, PhD, Star Seyedkazemi, PharmD, and Eric Lefebvre, MD, all of whom are employed by study sponsor, Tobira Therapeutics.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

decade3d/thinkstockphotos.com

Cenicriviroc, an oral chemokine receptor CCR/5 antagonist, was well tolerated, although it did not best placebo across all study endpoints, according to results of a 1-year phase IIb study released in an abstract in advance of the annual meeting of the American Association for the Study of Liver Diseases.

A correlation between treatment benefit and disease severity was reported by Arun J. Sanyal, MD, of Virginia Commonwealth University in Richmond, and coworkers, however.

In the 2-year, multinational, phase IIb, double-blind CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) study, 289 adults with chronic liver disease were randomly assigned to either 150 mg cenicriviroc (CVC) once daily or to placebo. At baseline, study participants had either histologically defined nonalcoholic steatohepatitis, a nonalcoholic fatty liver disease score (NAS) of 4 or greater, or liver fibrosis between stages 1 and 3. Just over half of the cohort were women, 72% had metabolic syndrome, and 53% had diabetes. Three-quarters had an NAS score of 5 or higher, and 67% had fibrosis between stages 2 and 3. The mean body mass index across the study was 34 kg/m².

At 1 year, liver biopsy showed that 16% of the CVC group had achieved at least a 2-point improvement in NAS, 3% less than controls (P = .519). Resolution of steatohepatitis with no worsening of fibrosis was higher in the study arm, compared with controls: 8% vs. 6% (P = .494). A significant difference was seen in members of the study arm who had advanced disease characteristics at baseline, compared with controls, by at least one stage in fibrosis improvement, with no worsening of steatohepatitis (P = .023). Across the study, improvement in fibrosis by two stages was seen in eight patients given CVC and in three controls. Progression to cirrhosis occurred in two members of the study arm and in five controls.

Adverse treatment-related events were similar across the study. The most commonly reported were fatigue (2.8%) and diarrhea (2.1%) in the study arm and headache (3.5%) in controls.

Most of the researchers associated with this study have industry relationships, including Brian L. Wiens, PhD, Pamela Vig, PhD, Star Seyedkazemi, PharmD, and Eric Lefebvre, MD, all of whom are employed by study sponsor, Tobira Therapeutics.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

The investigational peroxisome proliferator–activated receptor delta agonist MBX-8025 exhibited a “striking anticholestatic effect” without causing pruritus in a phase II trial of 35 patients with primary biliary cholangitis.

But three patients developed grade 3 increases in serum transaminase levels that reversed when they stopped treatment, David Jones, MD, of the University of Newcastle (United Kingdom) and his associates will report at the annual meeting of the American Association of Liver Diseases. The effect seemed dose related, so future studies should explore whether MBX-8025 is effective at lower doses, they concluded in a late-breaking abstract released in advance of the meeting.

Primary biliary cholangitis, an important cause of end-stage liver disease, is initially associated with fatigue and pruritus and often responds inadequately to first-line treatment with ursodeoxycholic acid. MBX-8025 selectively activates the peroxisome proliferator–activated receptor delta, a nuclear receptor that regulates genes involved in lipid storage and transport. In prior studies, MBX-8025 decreased serum alkaline phosphatase (ALP) levels and seemed well tolerated in healthy volunteers and patients with dyslipidemia, the investigators noted.

As a next step, they randomly assigned patients with primary biliary cholangitis whose ALP levels remained at least 1.67 times the upper limit of normal, despite at least 12 months of ursodeoxycholic acid therapy, to receive either placebo or 50 or 200 mg MBX-8026 for 12 weeks. The primary outcome was percent change in ALP levels, which, at baseline, averaged 233 U/L in the placebo group, 312 U/L in the 50 mg group, and 248 U/L in the 200-mg group.

At the end of treatment, ALP levels had dropped by an average of 63% in the 200-mg MBX-8025 group, 53% in the 50-mg group, and 2% in the placebo group (P less than .0001 for each dose effect versus placebo). Percent decreases in gamma-glutamyl transferase averaged 43% for both dose groups and 3% in the placebo group. Median levels of 7-alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, fell by 77% in the 200-mg group and by 55% in the 50-mg group, but rose by 29% in the placebo group. Both the 50-mg and the 200-mg doses yielded statistically similar effects on all three cholestatic markers.

Although MBX-8025 did not appear to cause or worsen pruritus, 3 of the 35 patients developed rapid, asymptomatic, grade 3 increases in serum levels of alanine aminotransferase, the researchers reported. Two patients were taking 200 mg MBX-8025, and one was taking 50 mg. The effect fully reversed after patients stopped treatment, and was not associated with hyperbilirubinemia. Another patient in the 200-mg group stopped treatment because of what the investigators called “a muscle adverse event [that we] considered drug-related.”

The trial was halted halfway through recruitment, having established proof of concept, the investigators concluded. Because MBX-8025 is primarily excreted in bile, and primary biliary cholangitis obstructs bile flow, affected patients might have had more hepatic exposure to the agent than did those in previous trials, and this might explain the new safety signal, they noted.

CymaBay Therapeutics makes MBX-8025 and funded the trial. Dr. Jones disclosed ties to Intercept, GlaxoSmithKline, Novartis, and Falk. Eight coinvestigators disclosed employment with or other ties to CymaBay Therapeutics. The other three coinvestigators had no relevant disclosures.

The investigational peroxisome proliferator–activated receptor delta agonist MBX-8025 exhibited a “striking anticholestatic effect” without causing pruritus in a phase II trial of 35 patients with primary biliary cholangitis.

But three patients developed grade 3 increases in serum transaminase levels that reversed when they stopped treatment, David Jones, MD, of the University of Newcastle (United Kingdom) and his associates will report at the annual meeting of the American Association of Liver Diseases. The effect seemed dose related, so future studies should explore whether MBX-8025 is effective at lower doses, they concluded in a late-breaking abstract released in advance of the meeting.

Primary biliary cholangitis, an important cause of end-stage liver disease, is initially associated with fatigue and pruritus and often responds inadequately to first-line treatment with ursodeoxycholic acid. MBX-8025 selectively activates the peroxisome proliferator–activated receptor delta, a nuclear receptor that regulates genes involved in lipid storage and transport. In prior studies, MBX-8025 decreased serum alkaline phosphatase (ALP) levels and seemed well tolerated in healthy volunteers and patients with dyslipidemia, the investigators noted.

As a next step, they randomly assigned patients with primary biliary cholangitis whose ALP levels remained at least 1.67 times the upper limit of normal, despite at least 12 months of ursodeoxycholic acid therapy, to receive either placebo or 50 or 200 mg MBX-8026 for 12 weeks. The primary outcome was percent change in ALP levels, which, at baseline, averaged 233 U/L in the placebo group, 312 U/L in the 50 mg group, and 248 U/L in the 200-mg group.

At the end of treatment, ALP levels had dropped by an average of 63% in the 200-mg MBX-8025 group, 53% in the 50-mg group, and 2% in the placebo group (P less than .0001 for each dose effect versus placebo). Percent decreases in gamma-glutamyl transferase averaged 43% for both dose groups and 3% in the placebo group. Median levels of 7-alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, fell by 77% in the 200-mg group and by 55% in the 50-mg group, but rose by 29% in the placebo group. Both the 50-mg and the 200-mg doses yielded statistically similar effects on all three cholestatic markers.

Although MBX-8025 did not appear to cause or worsen pruritus, 3 of the 35 patients developed rapid, asymptomatic, grade 3 increases in serum levels of alanine aminotransferase, the researchers reported. Two patients were taking 200 mg MBX-8025, and one was taking 50 mg. The effect fully reversed after patients stopped treatment, and was not associated with hyperbilirubinemia. Another patient in the 200-mg group stopped treatment because of what the investigators called “a muscle adverse event [that we] considered drug-related.”

The trial was halted halfway through recruitment, having established proof of concept, the investigators concluded. Because MBX-8025 is primarily excreted in bile, and primary biliary cholangitis obstructs bile flow, affected patients might have had more hepatic exposure to the agent than did those in previous trials, and this might explain the new safety signal, they noted.

CymaBay Therapeutics makes MBX-8025 and funded the trial. Dr. Jones disclosed ties to Intercept, GlaxoSmithKline, Novartis, and Falk. Eight coinvestigators disclosed employment with or other ties to CymaBay Therapeutics. The other three coinvestigators had no relevant disclosures.

The investigational peroxisome proliferator–activated receptor delta agonist MBX-8025 exhibited a “striking anticholestatic effect” without causing pruritus in a phase II trial of 35 patients with primary biliary cholangitis.

But three patients developed grade 3 increases in serum transaminase levels that reversed when they stopped treatment, David Jones, MD, of the University of Newcastle (United Kingdom) and his associates will report at the annual meeting of the American Association of Liver Diseases. The effect seemed dose related, so future studies should explore whether MBX-8025 is effective at lower doses, they concluded in a late-breaking abstract released in advance of the meeting.

Primary biliary cholangitis, an important cause of end-stage liver disease, is initially associated with fatigue and pruritus and often responds inadequately to first-line treatment with ursodeoxycholic acid. MBX-8025 selectively activates the peroxisome proliferator–activated receptor delta, a nuclear receptor that regulates genes involved in lipid storage and transport. In prior studies, MBX-8025 decreased serum alkaline phosphatase (ALP) levels and seemed well tolerated in healthy volunteers and patients with dyslipidemia, the investigators noted.

As a next step, they randomly assigned patients with primary biliary cholangitis whose ALP levels remained at least 1.67 times the upper limit of normal, despite at least 12 months of ursodeoxycholic acid therapy, to receive either placebo or 50 or 200 mg MBX-8026 for 12 weeks. The primary outcome was percent change in ALP levels, which, at baseline, averaged 233 U/L in the placebo group, 312 U/L in the 50 mg group, and 248 U/L in the 200-mg group.

At the end of treatment, ALP levels had dropped by an average of 63% in the 200-mg MBX-8025 group, 53% in the 50-mg group, and 2% in the placebo group (P less than .0001 for each dose effect versus placebo). Percent decreases in gamma-glutamyl transferase averaged 43% for both dose groups and 3% in the placebo group. Median levels of 7-alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, fell by 77% in the 200-mg group and by 55% in the 50-mg group, but rose by 29% in the placebo group. Both the 50-mg and the 200-mg doses yielded statistically similar effects on all three cholestatic markers.

Although MBX-8025 did not appear to cause or worsen pruritus, 3 of the 35 patients developed rapid, asymptomatic, grade 3 increases in serum levels of alanine aminotransferase, the researchers reported. Two patients were taking 200 mg MBX-8025, and one was taking 50 mg. The effect fully reversed after patients stopped treatment, and was not associated with hyperbilirubinemia. Another patient in the 200-mg group stopped treatment because of what the investigators called “a muscle adverse event [that we] considered drug-related.”

The trial was halted halfway through recruitment, having established proof of concept, the investigators concluded. Because MBX-8025 is primarily excreted in bile, and primary biliary cholangitis obstructs bile flow, affected patients might have had more hepatic exposure to the agent than did those in previous trials, and this might explain the new safety signal, they noted.

CymaBay Therapeutics makes MBX-8025 and funded the trial. Dr. Jones disclosed ties to Intercept, GlaxoSmithKline, Novartis, and Falk. Eight coinvestigators disclosed employment with or other ties to CymaBay Therapeutics. The other three coinvestigators had no relevant disclosures.

BOSTON – An endoscopic procedure that heats and ablates a few centimeters of the surface of the duodenum reduced hepatic transaminases in patients with type 2 diabetes. According to an abstract released in advance of the annual meeting of the American Association for the Study of Liver Diseases , a reduction in transaminases was also seen in a subset of patients who had ultrasonographic evidence of hepatic steatosis.

The meeting presentation will focus on the results of two studies of patients with type 2 diabetes who received duodenal mucosal resurfacing (DMR) to about 9 circumferential cm of their duodenum. The first study, which was a single-site study of 30 patients, was the first human study of DMR. The second study was a multicenter study of 22 patients.

“A single duodenal mucosal resurfacing procedure resulted in a decrease of liver transaminases sustained for 12 months,” Annieke van Baar, an MD-PhD candidate in gastroenterology and hepatology at the Academic University Center, Amsterdam, wrote in the study abstract.

At 6 months after the one-time procedure, the composite cohort of patients in both studies saw a 25% reduction in alanine transaminase, with an absolute reduction of a mean 9.9 plus or minus 22.3 IU/mL. Mean aspartate transaminase also decreased by a mean of 21%, with absolute reduction of a mean 6.1 plus or minus 14.8 IU/mL.

For the subset of 23 patients in the composite cohort who had ultrasound-identified steatosis, AST decreased by 14.4 plus or minus 23 IU/mL at 6 months post procedure; the reduction from baseline was 7.6 plus or minus 9.8 IU/mL at 9 months.

Duodenal mucosal resurfacing, performed endoscopically as a day procedure, has been shown to improve metabolic markers for type 2 diabetes. Though the exact mechanism for improvement is not known, reduction in incretin and other hormonal signaling from the duodenum is thought to increase insulin sensitization.

Patient characteristics were similar in both studies, with a mean age of 52.8 years in the first study and 56.8 in the second. Mean body mass index was 32 kg/m² in both studies. In the first study, mean baseline hemoglobin A_1c (HbA_1c) was 9.7%; HbA_1c was 8.4% in the second study.

Both study groups saw significant reductions in HbA_1c at 6 months post DMR, with reductions of 1.2 plus or minus 1.8% and 0.8 plus or minus 0.9% (P less than .001). Homeostatic model assessment of insulin resistance (HOMA-IR) was reduced after DMR as well, with reductions of 0.9 plus or minus 4, and 2.4 plus or minus 6.8 in the two study groups, though the decrease was not statistically significant.

The transaminase reductions and improved glycemic markers were not accompanied by significant weight loss: Patients lost a mean 1.8 plus or minus 3.6 kg in the first study, and 2.4 plus or minus 3.8 kg in the second study.

“This unique endoscopic intervention deserves further study to ascertain its potential efficacy as a treatment for fatty liver disease,” wrote Ms. van Baar and her coauthors.

The studies were funded by Fractyl Laboratories, the manufacturer of the DMR device. Ms. van Baar had no financial disclosures, but two coauthors reported relationships with Fractyl Laboratories, and another author disclosed relationships with multiple other pharmaceutical companies.

koakes@frontlinemedcom.com

On Twitter @karioakes

BOSTON – An endoscopic procedure that heats and ablates a few centimeters of the surface of the duodenum reduced hepatic transaminases in patients with type 2 diabetes. According to an abstract released in advance of the annual meeting of the American Association for the Study of Liver Diseases , a reduction in transaminases was also seen in a subset of patients who had ultrasonographic evidence of hepatic steatosis.

The meeting presentation will focus on the results of two studies of patients with type 2 diabetes who received duodenal mucosal resurfacing (DMR) to about 9 circumferential cm of their duodenum. The first study, which was a single-site study of 30 patients, was the first human study of DMR. The second study was a multicenter study of 22 patients.

“A single duodenal mucosal resurfacing procedure resulted in a decrease of liver transaminases sustained for 12 months,” Annieke van Baar, an MD-PhD candidate in gastroenterology and hepatology at the Academic University Center, Amsterdam, wrote in the study abstract.

At 6 months after the one-time procedure, the composite cohort of patients in both studies saw a 25% reduction in alanine transaminase, with an absolute reduction of a mean 9.9 plus or minus 22.3 IU/mL. Mean aspartate transaminase also decreased by a mean of 21%, with absolute reduction of a mean 6.1 plus or minus 14.8 IU/mL.

For the subset of 23 patients in the composite cohort who had ultrasound-identified steatosis, AST decreased by 14.4 plus or minus 23 IU/mL at 6 months post procedure; the reduction from baseline was 7.6 plus or minus 9.8 IU/mL at 9 months.

Duodenal mucosal resurfacing, performed endoscopically as a day procedure, has been shown to improve metabolic markers for type 2 diabetes. Though the exact mechanism for improvement is not known, reduction in incretin and other hormonal signaling from the duodenum is thought to increase insulin sensitization.

Patient characteristics were similar in both studies, with a mean age of 52.8 years in the first study and 56.8 in the second. Mean body mass index was 32 kg/m² in both studies. In the first study, mean baseline hemoglobin A_1c (HbA_1c) was 9.7%; HbA_1c was 8.4% in the second study.

Both study groups saw significant reductions in HbA_1c at 6 months post DMR, with reductions of 1.2 plus or minus 1.8% and 0.8 plus or minus 0.9% (P less than .001). Homeostatic model assessment of insulin resistance (HOMA-IR) was reduced after DMR as well, with reductions of 0.9 plus or minus 4, and 2.4 plus or minus 6.8 in the two study groups, though the decrease was not statistically significant.

The transaminase reductions and improved glycemic markers were not accompanied by significant weight loss: Patients lost a mean 1.8 plus or minus 3.6 kg in the first study, and 2.4 plus or minus 3.8 kg in the second study.

“This unique endoscopic intervention deserves further study to ascertain its potential efficacy as a treatment for fatty liver disease,” wrote Ms. van Baar and her coauthors.

The studies were funded by Fractyl Laboratories, the manufacturer of the DMR device. Ms. van Baar had no financial disclosures, but two coauthors reported relationships with Fractyl Laboratories, and another author disclosed relationships with multiple other pharmaceutical companies.

koakes@frontlinemedcom.com

On Twitter @karioakes

BOSTON – An endoscopic procedure that heats and ablates a few centimeters of the surface of the duodenum reduced hepatic transaminases in patients with type 2 diabetes. According to an abstract released in advance of the annual meeting of the American Association for the Study of Liver Diseases , a reduction in transaminases was also seen in a subset of patients who had ultrasonographic evidence of hepatic steatosis.

The meeting presentation will focus on the results of two studies of patients with type 2 diabetes who received duodenal mucosal resurfacing (DMR) to about 9 circumferential cm of their duodenum. The first study, which was a single-site study of 30 patients, was the first human study of DMR. The second study was a multicenter study of 22 patients.

“A single duodenal mucosal resurfacing procedure resulted in a decrease of liver transaminases sustained for 12 months,” Annieke van Baar, an MD-PhD candidate in gastroenterology and hepatology at the Academic University Center, Amsterdam, wrote in the study abstract.

At 6 months after the one-time procedure, the composite cohort of patients in both studies saw a 25% reduction in alanine transaminase, with an absolute reduction of a mean 9.9 plus or minus 22.3 IU/mL. Mean aspartate transaminase also decreased by a mean of 21%, with absolute reduction of a mean 6.1 plus or minus 14.8 IU/mL.

For the subset of 23 patients in the composite cohort who had ultrasound-identified steatosis, AST decreased by 14.4 plus or minus 23 IU/mL at 6 months post procedure; the reduction from baseline was 7.6 plus or minus 9.8 IU/mL at 9 months.

Duodenal mucosal resurfacing, performed endoscopically as a day procedure, has been shown to improve metabolic markers for type 2 diabetes. Though the exact mechanism for improvement is not known, reduction in incretin and other hormonal signaling from the duodenum is thought to increase insulin sensitization.

Patient characteristics were similar in both studies, with a mean age of 52.8 years in the first study and 56.8 in the second. Mean body mass index was 32 kg/m² in both studies. In the first study, mean baseline hemoglobin A_1c (HbA_1c) was 9.7%; HbA_1c was 8.4% in the second study.

Both study groups saw significant reductions in HbA_1c at 6 months post DMR, with reductions of 1.2 plus or minus 1.8% and 0.8 plus or minus 0.9% (P less than .001). Homeostatic model assessment of insulin resistance (HOMA-IR) was reduced after DMR as well, with reductions of 0.9 plus or minus 4, and 2.4 plus or minus 6.8 in the two study groups, though the decrease was not statistically significant.

The transaminase reductions and improved glycemic markers were not accompanied by significant weight loss: Patients lost a mean 1.8 plus or minus 3.6 kg in the first study, and 2.4 plus or minus 3.8 kg in the second study.

“This unique endoscopic intervention deserves further study to ascertain its potential efficacy as a treatment for fatty liver disease,” wrote Ms. van Baar and her coauthors.

The studies were funded by Fractyl Laboratories, the manufacturer of the DMR device. Ms. van Baar had no financial disclosures, but two coauthors reported relationships with Fractyl Laboratories, and another author disclosed relationships with multiple other pharmaceutical companies.

koakes@frontlinemedcom.com

On Twitter @karioakes

The rate of wait-listing for liver transplants for patients with hepatitis C and decompensated cirrhosis has decreased by over 30% since the entry of direct-acting antiviral (DAA) therapy and now equals the wait-list rate for nonalcoholic steatohepatitis, according to an abstract of a study that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

Using the U.S. Scientific Registry of Transplant Recipients (SRTR), Jennifer Flemming, MD, and her coauthors developed a cohort of 47,591 adults who were wait-listed for liver transplant because of HCV or hepatitis B virus infection (HBV), or for nonalcoholic steatohepatitis (NASH).

Dr. Flemming, professor of gastroenterology at Queens University, Kingston, Ont., examined trends in liver transplant wait-listing between 2003 and 2015. The time period was divided into the “interferon era,” from 2003 to 2010, the “protease inhibitor era,” from 2011 to 2013, and the “DAA era,” from 2014 to 2015.

kgtoh/Thinkstock

koakes@frontlinemedcom.com
On Twitter @karioakes

The rate of wait-listing for liver transplants for patients with hepatitis C and decompensated cirrhosis has decreased by over 30% since the entry of direct-acting antiviral (DAA) therapy and now equals the wait-list rate for nonalcoholic steatohepatitis, according to an abstract of a study that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

Using the U.S. Scientific Registry of Transplant Recipients (SRTR), Jennifer Flemming, MD, and her coauthors developed a cohort of 47,591 adults who were wait-listed for liver transplant because of HCV or hepatitis B virus infection (HBV), or for nonalcoholic steatohepatitis (NASH).

Dr. Flemming, professor of gastroenterology at Queens University, Kingston, Ont., examined trends in liver transplant wait-listing between 2003 and 2015. The time period was divided into the “interferon era,” from 2003 to 2010, the “protease inhibitor era,” from 2011 to 2013, and the “DAA era,” from 2014 to 2015.

kgtoh/Thinkstock

koakes@frontlinemedcom.com
On Twitter @karioakes

The rate of wait-listing for liver transplants for patients with hepatitis C and decompensated cirrhosis has decreased by over 30% since the entry of direct-acting antiviral (DAA) therapy and now equals the wait-list rate for nonalcoholic steatohepatitis, according to an abstract of a study that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

Using the U.S. Scientific Registry of Transplant Recipients (SRTR), Jennifer Flemming, MD, and her coauthors developed a cohort of 47,591 adults who were wait-listed for liver transplant because of HCV or hepatitis B virus infection (HBV), or for nonalcoholic steatohepatitis (NASH).

Dr. Flemming, professor of gastroenterology at Queens University, Kingston, Ont., examined trends in liver transplant wait-listing between 2003 and 2015. The time period was divided into the “interferon era,” from 2003 to 2010, the “protease inhibitor era,” from 2011 to 2013, and the “DAA era,” from 2014 to 2015.

kgtoh/Thinkstock

koakes@frontlinemedcom.com
On Twitter @karioakes