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The Liver Meeting 2016 debrief – key abstracts
BOSTON – Amid a plethora of quality research, several abstracts stood out at the annual meeting of the American Association for the Study of Liver Diseases, Arun J. Sanyal, MD, said during the final debrief.
He focused first on nonalcoholic fatty liver disease (NAFLD), which has lacked rigorous studies of disease evolution. Consequently, “current therapeutic development is based on small retrospective data sets with heterogenous populations,” Dr. Sanyal said. Therefore, he and his associates correlated serial biopsies with clinical data (abstract 37). The results confirmed the waxing and waning nature of NAFLD and linked regressing or progressive fibrosis to several factors, including NAFLD Disease Activity score (NAS). NAFLD and nonalcoholic steatohepatitis (NASH) are “not two different diseases, it’s the same disease,” Dr. Sanyal said. “Establishing disease activity as a driver of disease progression is highly relevant for development of noninvasive biomarkers, and also gives us a foundation for the development of clinical trials in this space.”
Several studies of NASH biomarkers yielded notable results at the meeting. In the largest study to date of circulating microRNAs as markers of NASH, (LB2) the miRNAs 34a, 122a, and 200a distinguished patients with and without NAS scores of at least 4 and at least stage 2 fibrosis with areas under the receiver operating characteristic curve (AUROC) between 0.59 and 0.80. “MicroRNAs appear promising, but likely need to be combined with additional biomarkers,” Dr. Sanyal said.
He also noted a study (abstract 40) in which metabolomics of liquid biopsies comprehensively evaluated NAFLD, including fibrosis stage, with AUROCs up to 0.95. Metabolomics “holds promise as a diagnostic tool that can be operationalized for point-of-care testing,” he said.
When it comes to NAFLD, hepatologists “often struggle with what to tell our patients about alcohol,” Dr. Sanyal said. To help clarify the issue, abstract 31 compared NAFLD patients who did or did not report habitually consuming up to two drinks a day in formal prospective questionnaires. After adjustment for baseline histology, abstainers and modest drinkers did not differ on any measure of histologic change, except that abstainers had a greater decrease in steatosis on follow-up biopsy. These findings negate several retrospective studies by suggesting that alcohol consumption does not positively affect the trajectory of NAFLD, Dr. Sanyal concluded.
Many new compounds for treating NASH are in early development, he noted. Among those further along the pipeline, the immunomodulator and CCR2/CCR5 inhibitor cenicriviroc (CVC) missed its primary endpoint (improved NAS and no worsening of fibrosis) but was associated with significantly improved fibrosis without worsening of NASH in the phase 2b CENTAUR study (LB1).
“We also saw highly promising evidence for the effects of ASK1 [apoptosis signal regulating kinase] inhibition on hepatic fibrosis and disease activity in NASH,” Dr. Sanyal added. In a randomized phase II trial (LB3), the ASK1 inhibitor GS-4997 was associated with significant improvement in fibrosis without worsening of NASH when given in combination with simtuzumab, and also improved liver stiffness and magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF). “These very promising and exciting results need confirmation in more advanced, placebo-controlled trials,” Dr. Sanyal said.
Studies of alcohol use disorders of the liver confirmed that prednisolone has marginal benefits, that the benefits of steroids in general are offset by sepsis, and that pentoxifylline produced no mortality benefit, Dr. Sanyal noted. In studies of primary biliary cirrhosis, the farnesoid-X receptor agonist obeticholic acid (OCA), which was approved by the Food and Drug Administration in 2016, was associated with significantly improved AST to Platelet Ratio Index (APRI) and liver stiffness measures by transient elastography at doses of 10 mg or titrated from 5 mg to 10 mg, with or without ursodeoxycholic acid (abstract 209). In another study, patients with PBC who received norUDCA, a side chain–shortened version of UDCA, experienced decreases in serum ALP levels that were dose dependent and differed significantly from trends in the placebo group (abstract 210).
In another study, the investigational ileal bile acid transporter inhibitor GSK2330672 was associated with significant reductions in itch, compared with placebo, and with lower serum bile acids among pruritic PBC patients (abstract 205). Treatment was associated with diarrhea, but it was usually mild and transient.
Dr. Sanyal concluded by reviewing several studies of cirrhosis and hepatic encephalopathy. In a prospective randomized controlled trial (abstract 247), lactulose with albumin significantly outperformed lactulose monotherapy for reversing hepatic encephalopathy, reducing hospital stays, and preventing mortality, especially sepsis-related death.
In another multicenter, 24-week, phase IV open-label study (abstract 248), 25% of patients experienced breakthrough hepatic encephalopathy when treated with rifaximin monotherapy, compared with only 14% of patients who received both rifaximin and lactulose.
Finally, in a phase II trial (abstract 2064), rifaximin immediate-release (40 mg) significantly outperformed placebo in terms of cirrhosis-related mortality, hospitalizations for cirrhosis, and breakthrough hepatic encephalopathy. The takeaways? “Use albumin with lactulose for acute hepatic encephalopathy,” Dr. Sanyal said. “Rifaximin with lactulose is better than rifaximin alone for secondary prophylaxis, and rifaximin immediate-release may decrease the need for hospitalization and the first bout of hepatic encephalopathy.”
The Liver Meeting next convenes October 20-24, 2017, in Washington, D.C.
Dr. Sanyal disclosed ties to Genfit, NewCo, Akarna, Elsevier, UptoDate, Novartis, Pfizer, Lilly, Astra Zeneca, and a number of other companies.
BOSTON – Amid a plethora of quality research, several abstracts stood out at the annual meeting of the American Association for the Study of Liver Diseases, Arun J. Sanyal, MD, said during the final debrief.
He focused first on nonalcoholic fatty liver disease (NAFLD), which has lacked rigorous studies of disease evolution. Consequently, “current therapeutic development is based on small retrospective data sets with heterogenous populations,” Dr. Sanyal said. Therefore, he and his associates correlated serial biopsies with clinical data (abstract 37). The results confirmed the waxing and waning nature of NAFLD and linked regressing or progressive fibrosis to several factors, including NAFLD Disease Activity score (NAS). NAFLD and nonalcoholic steatohepatitis (NASH) are “not two different diseases, it’s the same disease,” Dr. Sanyal said. “Establishing disease activity as a driver of disease progression is highly relevant for development of noninvasive biomarkers, and also gives us a foundation for the development of clinical trials in this space.”
Several studies of NASH biomarkers yielded notable results at the meeting. In the largest study to date of circulating microRNAs as markers of NASH, (LB2) the miRNAs 34a, 122a, and 200a distinguished patients with and without NAS scores of at least 4 and at least stage 2 fibrosis with areas under the receiver operating characteristic curve (AUROC) between 0.59 and 0.80. “MicroRNAs appear promising, but likely need to be combined with additional biomarkers,” Dr. Sanyal said.
He also noted a study (abstract 40) in which metabolomics of liquid biopsies comprehensively evaluated NAFLD, including fibrosis stage, with AUROCs up to 0.95. Metabolomics “holds promise as a diagnostic tool that can be operationalized for point-of-care testing,” he said.
When it comes to NAFLD, hepatologists “often struggle with what to tell our patients about alcohol,” Dr. Sanyal said. To help clarify the issue, abstract 31 compared NAFLD patients who did or did not report habitually consuming up to two drinks a day in formal prospective questionnaires. After adjustment for baseline histology, abstainers and modest drinkers did not differ on any measure of histologic change, except that abstainers had a greater decrease in steatosis on follow-up biopsy. These findings negate several retrospective studies by suggesting that alcohol consumption does not positively affect the trajectory of NAFLD, Dr. Sanyal concluded.
Many new compounds for treating NASH are in early development, he noted. Among those further along the pipeline, the immunomodulator and CCR2/CCR5 inhibitor cenicriviroc (CVC) missed its primary endpoint (improved NAS and no worsening of fibrosis) but was associated with significantly improved fibrosis without worsening of NASH in the phase 2b CENTAUR study (LB1).
“We also saw highly promising evidence for the effects of ASK1 [apoptosis signal regulating kinase] inhibition on hepatic fibrosis and disease activity in NASH,” Dr. Sanyal added. In a randomized phase II trial (LB3), the ASK1 inhibitor GS-4997 was associated with significant improvement in fibrosis without worsening of NASH when given in combination with simtuzumab, and also improved liver stiffness and magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF). “These very promising and exciting results need confirmation in more advanced, placebo-controlled trials,” Dr. Sanyal said.
Studies of alcohol use disorders of the liver confirmed that prednisolone has marginal benefits, that the benefits of steroids in general are offset by sepsis, and that pentoxifylline produced no mortality benefit, Dr. Sanyal noted. In studies of primary biliary cirrhosis, the farnesoid-X receptor agonist obeticholic acid (OCA), which was approved by the Food and Drug Administration in 2016, was associated with significantly improved AST to Platelet Ratio Index (APRI) and liver stiffness measures by transient elastography at doses of 10 mg or titrated from 5 mg to 10 mg, with or without ursodeoxycholic acid (abstract 209). In another study, patients with PBC who received norUDCA, a side chain–shortened version of UDCA, experienced decreases in serum ALP levels that were dose dependent and differed significantly from trends in the placebo group (abstract 210).
In another study, the investigational ileal bile acid transporter inhibitor GSK2330672 was associated with significant reductions in itch, compared with placebo, and with lower serum bile acids among pruritic PBC patients (abstract 205). Treatment was associated with diarrhea, but it was usually mild and transient.
Dr. Sanyal concluded by reviewing several studies of cirrhosis and hepatic encephalopathy. In a prospective randomized controlled trial (abstract 247), lactulose with albumin significantly outperformed lactulose monotherapy for reversing hepatic encephalopathy, reducing hospital stays, and preventing mortality, especially sepsis-related death.
In another multicenter, 24-week, phase IV open-label study (abstract 248), 25% of patients experienced breakthrough hepatic encephalopathy when treated with rifaximin monotherapy, compared with only 14% of patients who received both rifaximin and lactulose.
Finally, in a phase II trial (abstract 2064), rifaximin immediate-release (40 mg) significantly outperformed placebo in terms of cirrhosis-related mortality, hospitalizations for cirrhosis, and breakthrough hepatic encephalopathy. The takeaways? “Use albumin with lactulose for acute hepatic encephalopathy,” Dr. Sanyal said. “Rifaximin with lactulose is better than rifaximin alone for secondary prophylaxis, and rifaximin immediate-release may decrease the need for hospitalization and the first bout of hepatic encephalopathy.”
The Liver Meeting next convenes October 20-24, 2017, in Washington, D.C.
Dr. Sanyal disclosed ties to Genfit, NewCo, Akarna, Elsevier, UptoDate, Novartis, Pfizer, Lilly, Astra Zeneca, and a number of other companies.
BOSTON – Amid a plethora of quality research, several abstracts stood out at the annual meeting of the American Association for the Study of Liver Diseases, Arun J. Sanyal, MD, said during the final debrief.
He focused first on nonalcoholic fatty liver disease (NAFLD), which has lacked rigorous studies of disease evolution. Consequently, “current therapeutic development is based on small retrospective data sets with heterogenous populations,” Dr. Sanyal said. Therefore, he and his associates correlated serial biopsies with clinical data (abstract 37). The results confirmed the waxing and waning nature of NAFLD and linked regressing or progressive fibrosis to several factors, including NAFLD Disease Activity score (NAS). NAFLD and nonalcoholic steatohepatitis (NASH) are “not two different diseases, it’s the same disease,” Dr. Sanyal said. “Establishing disease activity as a driver of disease progression is highly relevant for development of noninvasive biomarkers, and also gives us a foundation for the development of clinical trials in this space.”
Several studies of NASH biomarkers yielded notable results at the meeting. In the largest study to date of circulating microRNAs as markers of NASH, (LB2) the miRNAs 34a, 122a, and 200a distinguished patients with and without NAS scores of at least 4 and at least stage 2 fibrosis with areas under the receiver operating characteristic curve (AUROC) between 0.59 and 0.80. “MicroRNAs appear promising, but likely need to be combined with additional biomarkers,” Dr. Sanyal said.
He also noted a study (abstract 40) in which metabolomics of liquid biopsies comprehensively evaluated NAFLD, including fibrosis stage, with AUROCs up to 0.95. Metabolomics “holds promise as a diagnostic tool that can be operationalized for point-of-care testing,” he said.
When it comes to NAFLD, hepatologists “often struggle with what to tell our patients about alcohol,” Dr. Sanyal said. To help clarify the issue, abstract 31 compared NAFLD patients who did or did not report habitually consuming up to two drinks a day in formal prospective questionnaires. After adjustment for baseline histology, abstainers and modest drinkers did not differ on any measure of histologic change, except that abstainers had a greater decrease in steatosis on follow-up biopsy. These findings negate several retrospective studies by suggesting that alcohol consumption does not positively affect the trajectory of NAFLD, Dr. Sanyal concluded.
Many new compounds for treating NASH are in early development, he noted. Among those further along the pipeline, the immunomodulator and CCR2/CCR5 inhibitor cenicriviroc (CVC) missed its primary endpoint (improved NAS and no worsening of fibrosis) but was associated with significantly improved fibrosis without worsening of NASH in the phase 2b CENTAUR study (LB1).
“We also saw highly promising evidence for the effects of ASK1 [apoptosis signal regulating kinase] inhibition on hepatic fibrosis and disease activity in NASH,” Dr. Sanyal added. In a randomized phase II trial (LB3), the ASK1 inhibitor GS-4997 was associated with significant improvement in fibrosis without worsening of NASH when given in combination with simtuzumab, and also improved liver stiffness and magnetic resonance imaging–estimated proton density fat fraction (MRI-PDFF). “These very promising and exciting results need confirmation in more advanced, placebo-controlled trials,” Dr. Sanyal said.
Studies of alcohol use disorders of the liver confirmed that prednisolone has marginal benefits, that the benefits of steroids in general are offset by sepsis, and that pentoxifylline produced no mortality benefit, Dr. Sanyal noted. In studies of primary biliary cirrhosis, the farnesoid-X receptor agonist obeticholic acid (OCA), which was approved by the Food and Drug Administration in 2016, was associated with significantly improved AST to Platelet Ratio Index (APRI) and liver stiffness measures by transient elastography at doses of 10 mg or titrated from 5 mg to 10 mg, with or without ursodeoxycholic acid (abstract 209). In another study, patients with PBC who received norUDCA, a side chain–shortened version of UDCA, experienced decreases in serum ALP levels that were dose dependent and differed significantly from trends in the placebo group (abstract 210).
In another study, the investigational ileal bile acid transporter inhibitor GSK2330672 was associated with significant reductions in itch, compared with placebo, and with lower serum bile acids among pruritic PBC patients (abstract 205). Treatment was associated with diarrhea, but it was usually mild and transient.
Dr. Sanyal concluded by reviewing several studies of cirrhosis and hepatic encephalopathy. In a prospective randomized controlled trial (abstract 247), lactulose with albumin significantly outperformed lactulose monotherapy for reversing hepatic encephalopathy, reducing hospital stays, and preventing mortality, especially sepsis-related death.
In another multicenter, 24-week, phase IV open-label study (abstract 248), 25% of patients experienced breakthrough hepatic encephalopathy when treated with rifaximin monotherapy, compared with only 14% of patients who received both rifaximin and lactulose.
Finally, in a phase II trial (abstract 2064), rifaximin immediate-release (40 mg) significantly outperformed placebo in terms of cirrhosis-related mortality, hospitalizations for cirrhosis, and breakthrough hepatic encephalopathy. The takeaways? “Use albumin with lactulose for acute hepatic encephalopathy,” Dr. Sanyal said. “Rifaximin with lactulose is better than rifaximin alone for secondary prophylaxis, and rifaximin immediate-release may decrease the need for hospitalization and the first bout of hepatic encephalopathy.”
The Liver Meeting next convenes October 20-24, 2017, in Washington, D.C.
Dr. Sanyal disclosed ties to Genfit, NewCo, Akarna, Elsevier, UptoDate, Novartis, Pfizer, Lilly, Astra Zeneca, and a number of other companies.
AT THE LIVER MEETING 2016
HCV patients with early-stage hepatocellular carcinoma can achieve SVR
BOSTON – Among patients with hepatocellular carcinoma (HCC), rates of sustained viral response (SVR) to direct-acting regimens for hepatitis C virus were 79% for genotype 1, 69% for genotype 2, and 47% for genotype 3 infections, reported George N. Ioannou, MD.
“These rates are lower than in patients who do not have hepatocellular carcinoma [HCC], but are still remarkably high,” Dr. Ioannou said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases. “Antiviral therapy should be considered in patients with early-stage hepatocellular carcinoma, ideally after adequate locoregional treatments.”
The study included Veterans Affairs Health Care System data on 17,487 recipients of direct-acting anti-HCV regimens. When patients did not have HCC, SVR rates were 93% for genotype 1 infection, 87% for genotype 2 (GT2), and 76% for GT3. Among the 624 (3.6%) patients with a history of HCC, 142 underwent antiviral treatment after transplantation and 482 received other types of cancer therapy.
Why HCC is associated with lower SVR in HCV patients remains unclear, Dr. Ioannou noted. Age does not seem to explain the effect, and neither does sex, race, or ethnicity; cirrhosis or decompensated cirrhosis; renal disease; diabetes; HCV viral load; genotype or subgenotype; HCV regimen; or treatment experience, he said.
Dr. Ioannou noted several study limitations. Nine percent of patients lacked data on SVR, and the imputation to correct for this lowered SVR rates by about 1%-2%. The dataset also did not include information on HCC tumor size or number, and the researchers have not yet examined how antiviral therapy affects the likelihood of de novo HCC, recurrent HCC, or progression of cirrhosis and liver dysfunction.
The Veterans Affairs Office of Research and Development sponsored the study. Dr. Ioannou had no disclosures.
BOSTON – Among patients with hepatocellular carcinoma (HCC), rates of sustained viral response (SVR) to direct-acting regimens for hepatitis C virus were 79% for genotype 1, 69% for genotype 2, and 47% for genotype 3 infections, reported George N. Ioannou, MD.
“These rates are lower than in patients who do not have hepatocellular carcinoma [HCC], but are still remarkably high,” Dr. Ioannou said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases. “Antiviral therapy should be considered in patients with early-stage hepatocellular carcinoma, ideally after adequate locoregional treatments.”
The study included Veterans Affairs Health Care System data on 17,487 recipients of direct-acting anti-HCV regimens. When patients did not have HCC, SVR rates were 93% for genotype 1 infection, 87% for genotype 2 (GT2), and 76% for GT3. Among the 624 (3.6%) patients with a history of HCC, 142 underwent antiviral treatment after transplantation and 482 received other types of cancer therapy.
Why HCC is associated with lower SVR in HCV patients remains unclear, Dr. Ioannou noted. Age does not seem to explain the effect, and neither does sex, race, or ethnicity; cirrhosis or decompensated cirrhosis; renal disease; diabetes; HCV viral load; genotype or subgenotype; HCV regimen; or treatment experience, he said.
Dr. Ioannou noted several study limitations. Nine percent of patients lacked data on SVR, and the imputation to correct for this lowered SVR rates by about 1%-2%. The dataset also did not include information on HCC tumor size or number, and the researchers have not yet examined how antiviral therapy affects the likelihood of de novo HCC, recurrent HCC, or progression of cirrhosis and liver dysfunction.
The Veterans Affairs Office of Research and Development sponsored the study. Dr. Ioannou had no disclosures.
BOSTON – Among patients with hepatocellular carcinoma (HCC), rates of sustained viral response (SVR) to direct-acting regimens for hepatitis C virus were 79% for genotype 1, 69% for genotype 2, and 47% for genotype 3 infections, reported George N. Ioannou, MD.
“These rates are lower than in patients who do not have hepatocellular carcinoma [HCC], but are still remarkably high,” Dr. Ioannou said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases. “Antiviral therapy should be considered in patients with early-stage hepatocellular carcinoma, ideally after adequate locoregional treatments.”
The study included Veterans Affairs Health Care System data on 17,487 recipients of direct-acting anti-HCV regimens. When patients did not have HCC, SVR rates were 93% for genotype 1 infection, 87% for genotype 2 (GT2), and 76% for GT3. Among the 624 (3.6%) patients with a history of HCC, 142 underwent antiviral treatment after transplantation and 482 received other types of cancer therapy.
Why HCC is associated with lower SVR in HCV patients remains unclear, Dr. Ioannou noted. Age does not seem to explain the effect, and neither does sex, race, or ethnicity; cirrhosis or decompensated cirrhosis; renal disease; diabetes; HCV viral load; genotype or subgenotype; HCV regimen; or treatment experience, he said.
Dr. Ioannou noted several study limitations. Nine percent of patients lacked data on SVR, and the imputation to correct for this lowered SVR rates by about 1%-2%. The dataset also did not include information on HCC tumor size or number, and the researchers have not yet examined how antiviral therapy affects the likelihood of de novo HCC, recurrent HCC, or progression of cirrhosis and liver dysfunction.
The Veterans Affairs Office of Research and Development sponsored the study. Dr. Ioannou had no disclosures.
AT THE LIVER MEETING
Key clinical point: Consider direct-acting antiviral therapy in HCV-infected patients with early-stage HCC.
Major finding: Rates of sustained viral response were 79% in HCC patients with GT1 HCV infection, 69% in GT2 patients, and 47% in GT3 patients.
Data source: An analysis of Veterans Affairs Health Care System data on 17,487 recipients of direct-acting antiviral regimens, including 624 patients with HCC.
Disclosures: The Veterans Affairs Office of Research and Development sponsored the study.
Metabolomics of liquid biopsies offer a comprehensive look at NAFLD
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
AT THE LIVER MEETING 2016
Key clinical point: Metabolomics of liquid biopsies identified and characterized nonalcoholic fatty liver disease in a proof-of-concept study.
Major finding: Four distinct models diagnosed NAFLD, diagnosed NASH, and characterized the severity of steatosis and fibrosis.
Data source: A multicenter study of 817 patients with biopsy-confirmed NAFLD and 130 biopsy-confirmed controls.
Disclosures: Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
Sofosbuvir/velpatasvir improved patient-reported outcomes, knocked out HCV genotypes 1-6
BOSTON – When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.
Patients with and without cirrhosis also reported meaningful improvements across a variety of outcome measures after successfully completing treatment with Epclusa or sofosbuvir (Harvoni), said Dr. Younossi of Inova Fairfax Hospital in Falls Church, Va. “Although on-treatment patient-reported outcomes improved more with ribavirin-free regimens, post-SVR improvements were similar,” regardless of whether patients had received ribavirin, he reported at the annual meeting of the American Association for the Study of Liver Diseases.
Epclusa without ribavirin led to SVR-12 in 85% of decompensated cirrhotic patients and nearly 99% of noncirrhotic patients of all HCV genotypes, Dr. Younossi reported. For sofosbuvir with ribavirin, rates of SVR-12 were 66% in genotype 3 cirrhotic patients and 95% in cirrhotic patients of other HCV genotypes.
At baseline, cirrhotic patients scored up to 33.5 points worse than noncirrhotics on a universal 100-point scale covering 26 patient-reported domains (P less than .05 for all but 3 domains). Decompensated cirrhotics reported more baseline depression and fatigue than other patients (P less than .002 for each comparison), while patients without cirrhosis were more likely to be treatment naive and employed (both P less than .0001). But after the investigators controlled for these differences, decompensated cirrhotics who received Epclusa reported an additional 5.5-9 points of improvement in treatment-emergent outcomes than those who received sofosbuvir plus ribavirin (P less than .002). Patients with compensated cirrhosis reported 2.3-5 points more improvement in treatment-emergent outcomes on Epclusa than on sofosbuvir plus ribavirin (P less than .05). “Decompensated cirrhotics experienced the best and greatest improvement of patient-reported outcome scores during treatment with sofosbuvir/velpatasvir,” Dr. Younossi said.
Patients who received ribavirin reported similar changes across domains at the end of treatment, regardless of cirrhosis status. Among patients who achieved SVR-12, decompensated cirrhotics reported significantly more improvement 12 weeks later than did patients with less severe liver disease, although both groups showed long-term improvements (5.8 points vs. 4.1 points, P less than .05). Clearly, patients continue to report improvements in various domains as time goes on, “suggesting that all the benefit of cure is not achieved by 12 weeks of follow-up,” said Dr. Younossi.
Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
BOSTON – When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.
Patients with and without cirrhosis also reported meaningful improvements across a variety of outcome measures after successfully completing treatment with Epclusa or sofosbuvir (Harvoni), said Dr. Younossi of Inova Fairfax Hospital in Falls Church, Va. “Although on-treatment patient-reported outcomes improved more with ribavirin-free regimens, post-SVR improvements were similar,” regardless of whether patients had received ribavirin, he reported at the annual meeting of the American Association for the Study of Liver Diseases.
Epclusa without ribavirin led to SVR-12 in 85% of decompensated cirrhotic patients and nearly 99% of noncirrhotic patients of all HCV genotypes, Dr. Younossi reported. For sofosbuvir with ribavirin, rates of SVR-12 were 66% in genotype 3 cirrhotic patients and 95% in cirrhotic patients of other HCV genotypes.
At baseline, cirrhotic patients scored up to 33.5 points worse than noncirrhotics on a universal 100-point scale covering 26 patient-reported domains (P less than .05 for all but 3 domains). Decompensated cirrhotics reported more baseline depression and fatigue than other patients (P less than .002 for each comparison), while patients without cirrhosis were more likely to be treatment naive and employed (both P less than .0001). But after the investigators controlled for these differences, decompensated cirrhotics who received Epclusa reported an additional 5.5-9 points of improvement in treatment-emergent outcomes than those who received sofosbuvir plus ribavirin (P less than .002). Patients with compensated cirrhosis reported 2.3-5 points more improvement in treatment-emergent outcomes on Epclusa than on sofosbuvir plus ribavirin (P less than .05). “Decompensated cirrhotics experienced the best and greatest improvement of patient-reported outcome scores during treatment with sofosbuvir/velpatasvir,” Dr. Younossi said.
Patients who received ribavirin reported similar changes across domains at the end of treatment, regardless of cirrhosis status. Among patients who achieved SVR-12, decompensated cirrhotics reported significantly more improvement 12 weeks later than did patients with less severe liver disease, although both groups showed long-term improvements (5.8 points vs. 4.1 points, P less than .05). Clearly, patients continue to report improvements in various domains as time goes on, “suggesting that all the benefit of cure is not achieved by 12 weeks of follow-up,” said Dr. Younossi.
Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
BOSTON – When given with ribavirin, a fixed-dose combination of sofosbuvir/velpatasvir (Epclusa) achieved a sustained viral response at 12 weeks (SVR-12) in 94% of decompensated cirrhotic patients with hepatitis C virus (HCV) genotypes 1-6 infection, according to Zobair M. Younossi, MD.
Patients with and without cirrhosis also reported meaningful improvements across a variety of outcome measures after successfully completing treatment with Epclusa or sofosbuvir (Harvoni), said Dr. Younossi of Inova Fairfax Hospital in Falls Church, Va. “Although on-treatment patient-reported outcomes improved more with ribavirin-free regimens, post-SVR improvements were similar,” regardless of whether patients had received ribavirin, he reported at the annual meeting of the American Association for the Study of Liver Diseases.
Epclusa without ribavirin led to SVR-12 in 85% of decompensated cirrhotic patients and nearly 99% of noncirrhotic patients of all HCV genotypes, Dr. Younossi reported. For sofosbuvir with ribavirin, rates of SVR-12 were 66% in genotype 3 cirrhotic patients and 95% in cirrhotic patients of other HCV genotypes.
At baseline, cirrhotic patients scored up to 33.5 points worse than noncirrhotics on a universal 100-point scale covering 26 patient-reported domains (P less than .05 for all but 3 domains). Decompensated cirrhotics reported more baseline depression and fatigue than other patients (P less than .002 for each comparison), while patients without cirrhosis were more likely to be treatment naive and employed (both P less than .0001). But after the investigators controlled for these differences, decompensated cirrhotics who received Epclusa reported an additional 5.5-9 points of improvement in treatment-emergent outcomes than those who received sofosbuvir plus ribavirin (P less than .002). Patients with compensated cirrhosis reported 2.3-5 points more improvement in treatment-emergent outcomes on Epclusa than on sofosbuvir plus ribavirin (P less than .05). “Decompensated cirrhotics experienced the best and greatest improvement of patient-reported outcome scores during treatment with sofosbuvir/velpatasvir,” Dr. Younossi said.
Patients who received ribavirin reported similar changes across domains at the end of treatment, regardless of cirrhosis status. Among patients who achieved SVR-12, decompensated cirrhotics reported significantly more improvement 12 weeks later than did patients with less severe liver disease, although both groups showed long-term improvements (5.8 points vs. 4.1 points, P less than .05). Clearly, patients continue to report improvements in various domains as time goes on, “suggesting that all the benefit of cure is not achieved by 12 weeks of follow-up,” said Dr. Younossi.
Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
AT THE LIVER MEETING 2016
Key clinical point: Sofosbuvir/velpatasvir with ribavirin effectively cured most hepatitis C virus–infected patients with decompensated cirrhosis.
Major finding: In all, 94% of patients achieved a sustained viral response at 12 weeks, regardless of HCV genotype.
Data source: The phase III ASTRAL trials involving 1,701 patients with pangenotypic hepatitis C virus infections.
Disclosures: Gilead Sciences makes Epclusa and Harvoni and funded the study. Dr. Younossi reported having no relevant financial conflicts.
NAFLD can regress with weight loss, activity
BOSTON – All phenotypes of nonalcoholic fatty liver disease (NAFLD) can progress or regress even without pharmacologic intervention, according to a prospective longitudinal study of 394 patients.
Weight loss and baseline NAFLD Activity Score predicted resolution of NAFLD, while weight gain and rising serum transaminases predicted progression to nonalcoholic steatohepatitis (NASH), Arun J. Sanyal, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Baseline and subsequent NAFLD Activity Score also was “a strong predictor of fibrosis progression or regression,” as was AST, portal inflammation, and baseline fibrosis stage, said Dr. Sanyal of Virginia Commonwealth University in Richmond, Va.
NAFLD comprises two main phenotypes, fatty liver and steatohepatitis. “The phenotype can change over time, and both phenotypes can be associated with fibrosis,” Dr. Sanyal noted. To better understand trends and clinical correlates for these phenotypes, he and his associates analyzed prospectively collected clinical and biopsy data from the NASH Clinical Research Network of the National Institutes of Diabetes and Digestive and Kidney Diseases. Each patient attended multiple clinic visits and underwent two liver biopsies at least 1 year and usually 4-5 years apart, which were interpreted by a masked central pathology review committee.
At baseline, 75 patients had fatty liver without steatohepatitis, of which only 13% resolved and 44% progressed to borderline or definite steatohepatitis. Similarly, among 74 patients with borderline steatohepatitis at baseline, only 22% regressed to fatty liver disease without steatohepatitis, while 43% progressed to definite steatohepatitis. The remaining 245 patients had definite steatohepatitis at baseline, of which 58% failed to regress at all, 20% regressed to borderline, 11% regressed to fatty liver disease without steatohepatitis, and 11% regressed to normal.
The investigators also performed a multivariable analysis of 197 patients with complete data. After the investigators controlled for serum insulin level, alkaline phosphatase level, NAS, and the presence of metabolic syndrome, each 10-U/L increase in ALT more than doubled the odds of progression from fatty liver without steatohepatitis to NASH (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1; P = .02). The association was even stronger for AST (OR, 3.5; 95% CI, 1.2 to 10.4; P = .03), and each 1-kg gain in body weight increased the odds of progression to NASH by 70% (OR, 1.7; 95% CI, 1.1 to 2.5; P = .01). In contrast, resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
About one in four patients had evidence of fibrosis at baseline, and 44% had at least stage 1 fibrosis at follow-up biopsy. Patients whose NAFLD progressed to a more severe phenotype were much more likely to have evidence of progressive fibrosis than were those whose NAFLD did not progress (OR, 7.2; 95% CI, 2.1 to 21.5; P less than .001), and there was no evidence that time between liver biopsies influenced this relationship. Among patients with definite NASH who had stage 0 fibrosis at baseline, 50% progressed to at least 1 fibrosis stage over the next 6.8 years, and 50% progressed to at least 2 stages over 9.6 years. Patients whose baseline NAFLD Activity Scores were between 1 and 4 were most likely to experience regression of fibrosis, while those with scores between 5 and 8 were more likely to have worsening fibrosis. Patients with severe baseline NAFLD Activity Score component scores for steatosis, lobular inflammation, and ballooning also were significantly more likely to have progressive fibrosis than were those with baseline NAFLD Activity Scores of 0 or 1. Furthermore, increasing NAFLD Activity Score over time predicted fibrosis progression.
Diabetes did not seem to affect fibrosis progression or regression, Dr. Sanyal noted. However, baseline portal inflammation predicted worsening fibrosis (P less than .01), as did baseline and subsequent elevations in AST (P less than .001), insulin (P = .03), and NAS (P less than 001), and baseline ballooning (P less than .01).
The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to a wide number of drug companies.
BOSTON – All phenotypes of nonalcoholic fatty liver disease (NAFLD) can progress or regress even without pharmacologic intervention, according to a prospective longitudinal study of 394 patients.
Weight loss and baseline NAFLD Activity Score predicted resolution of NAFLD, while weight gain and rising serum transaminases predicted progression to nonalcoholic steatohepatitis (NASH), Arun J. Sanyal, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Baseline and subsequent NAFLD Activity Score also was “a strong predictor of fibrosis progression or regression,” as was AST, portal inflammation, and baseline fibrosis stage, said Dr. Sanyal of Virginia Commonwealth University in Richmond, Va.
NAFLD comprises two main phenotypes, fatty liver and steatohepatitis. “The phenotype can change over time, and both phenotypes can be associated with fibrosis,” Dr. Sanyal noted. To better understand trends and clinical correlates for these phenotypes, he and his associates analyzed prospectively collected clinical and biopsy data from the NASH Clinical Research Network of the National Institutes of Diabetes and Digestive and Kidney Diseases. Each patient attended multiple clinic visits and underwent two liver biopsies at least 1 year and usually 4-5 years apart, which were interpreted by a masked central pathology review committee.
At baseline, 75 patients had fatty liver without steatohepatitis, of which only 13% resolved and 44% progressed to borderline or definite steatohepatitis. Similarly, among 74 patients with borderline steatohepatitis at baseline, only 22% regressed to fatty liver disease without steatohepatitis, while 43% progressed to definite steatohepatitis. The remaining 245 patients had definite steatohepatitis at baseline, of which 58% failed to regress at all, 20% regressed to borderline, 11% regressed to fatty liver disease without steatohepatitis, and 11% regressed to normal.
The investigators also performed a multivariable analysis of 197 patients with complete data. After the investigators controlled for serum insulin level, alkaline phosphatase level, NAS, and the presence of metabolic syndrome, each 10-U/L increase in ALT more than doubled the odds of progression from fatty liver without steatohepatitis to NASH (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1; P = .02). The association was even stronger for AST (OR, 3.5; 95% CI, 1.2 to 10.4; P = .03), and each 1-kg gain in body weight increased the odds of progression to NASH by 70% (OR, 1.7; 95% CI, 1.1 to 2.5; P = .01). In contrast, resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
About one in four patients had evidence of fibrosis at baseline, and 44% had at least stage 1 fibrosis at follow-up biopsy. Patients whose NAFLD progressed to a more severe phenotype were much more likely to have evidence of progressive fibrosis than were those whose NAFLD did not progress (OR, 7.2; 95% CI, 2.1 to 21.5; P less than .001), and there was no evidence that time between liver biopsies influenced this relationship. Among patients with definite NASH who had stage 0 fibrosis at baseline, 50% progressed to at least 1 fibrosis stage over the next 6.8 years, and 50% progressed to at least 2 stages over 9.6 years. Patients whose baseline NAFLD Activity Scores were between 1 and 4 were most likely to experience regression of fibrosis, while those with scores between 5 and 8 were more likely to have worsening fibrosis. Patients with severe baseline NAFLD Activity Score component scores for steatosis, lobular inflammation, and ballooning also were significantly more likely to have progressive fibrosis than were those with baseline NAFLD Activity Scores of 0 or 1. Furthermore, increasing NAFLD Activity Score over time predicted fibrosis progression.
Diabetes did not seem to affect fibrosis progression or regression, Dr. Sanyal noted. However, baseline portal inflammation predicted worsening fibrosis (P less than .01), as did baseline and subsequent elevations in AST (P less than .001), insulin (P = .03), and NAS (P less than 001), and baseline ballooning (P less than .01).
The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to a wide number of drug companies.
BOSTON – All phenotypes of nonalcoholic fatty liver disease (NAFLD) can progress or regress even without pharmacologic intervention, according to a prospective longitudinal study of 394 patients.
Weight loss and baseline NAFLD Activity Score predicted resolution of NAFLD, while weight gain and rising serum transaminases predicted progression to nonalcoholic steatohepatitis (NASH), Arun J. Sanyal, MD, said at the annual meeting of the American Association for the Study of Liver Diseases. Baseline and subsequent NAFLD Activity Score also was “a strong predictor of fibrosis progression or regression,” as was AST, portal inflammation, and baseline fibrosis stage, said Dr. Sanyal of Virginia Commonwealth University in Richmond, Va.
NAFLD comprises two main phenotypes, fatty liver and steatohepatitis. “The phenotype can change over time, and both phenotypes can be associated with fibrosis,” Dr. Sanyal noted. To better understand trends and clinical correlates for these phenotypes, he and his associates analyzed prospectively collected clinical and biopsy data from the NASH Clinical Research Network of the National Institutes of Diabetes and Digestive and Kidney Diseases. Each patient attended multiple clinic visits and underwent two liver biopsies at least 1 year and usually 4-5 years apart, which were interpreted by a masked central pathology review committee.
At baseline, 75 patients had fatty liver without steatohepatitis, of which only 13% resolved and 44% progressed to borderline or definite steatohepatitis. Similarly, among 74 patients with borderline steatohepatitis at baseline, only 22% regressed to fatty liver disease without steatohepatitis, while 43% progressed to definite steatohepatitis. The remaining 245 patients had definite steatohepatitis at baseline, of which 58% failed to regress at all, 20% regressed to borderline, 11% regressed to fatty liver disease without steatohepatitis, and 11% regressed to normal.
The investigators also performed a multivariable analysis of 197 patients with complete data. After the investigators controlled for serum insulin level, alkaline phosphatase level, NAS, and the presence of metabolic syndrome, each 10-U/L increase in ALT more than doubled the odds of progression from fatty liver without steatohepatitis to NASH (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1; P = .02). The association was even stronger for AST (OR, 3.5; 95% CI, 1.2 to 10.4; P = .03), and each 1-kg gain in body weight increased the odds of progression to NASH by 70% (OR, 1.7; 95% CI, 1.1 to 2.5; P = .01). In contrast, resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
About one in four patients had evidence of fibrosis at baseline, and 44% had at least stage 1 fibrosis at follow-up biopsy. Patients whose NAFLD progressed to a more severe phenotype were much more likely to have evidence of progressive fibrosis than were those whose NAFLD did not progress (OR, 7.2; 95% CI, 2.1 to 21.5; P less than .001), and there was no evidence that time between liver biopsies influenced this relationship. Among patients with definite NASH who had stage 0 fibrosis at baseline, 50% progressed to at least 1 fibrosis stage over the next 6.8 years, and 50% progressed to at least 2 stages over 9.6 years. Patients whose baseline NAFLD Activity Scores were between 1 and 4 were most likely to experience regression of fibrosis, while those with scores between 5 and 8 were more likely to have worsening fibrosis. Patients with severe baseline NAFLD Activity Score component scores for steatosis, lobular inflammation, and ballooning also were significantly more likely to have progressive fibrosis than were those with baseline NAFLD Activity Scores of 0 or 1. Furthermore, increasing NAFLD Activity Score over time predicted fibrosis progression.
Diabetes did not seem to affect fibrosis progression or regression, Dr. Sanyal noted. However, baseline portal inflammation predicted worsening fibrosis (P less than .01), as did baseline and subsequent elevations in AST (P less than .001), insulin (P = .03), and NAS (P less than 001), and baseline ballooning (P less than .01).
The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to a wide number of drug companies.
AT THE LIVER MEETING 2016
Key clinical point: Phenotypes of nonalcoholic fatty liver disease can progress or regress over time.
Major finding: Resolution of NAFLD was associated with weight loss (OR per 1 kg, 0.9; P less than .001) and lower baseline NAFLD Activity Score (OR, 0.7; P = .04).
Data source: A prospective study of 394 patients with nonalcoholic fatty liver disease.
Disclosures: The investigators reported that the study had no sponsors. Dr. Sanyal disclosed ties to several drug companies.
Tumor boards linked to improved survival in hepatocellular carcinoma
BOSTON – Veterans were about 13% less likely to die within 5 years of hepatocellular carcinoma diagnosis when multidisciplinary tumor boards managed their care than if they did not, according to a large, multicenter observational study.
Seeing a hepatologist or surgeon within 30 days of diagnosis also significantly improved 5-year overall survival, even after controlling for age, race, Charlson-Deyo comorbidity index, Barcelona Clinic Liver Cancer (BCLC) stage, academic center and geographic region of care, and the distance patients lived from the nearest Veterans Affairs transplant center, Marina Serper, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases. “More studies are needed to understand how to best use multidisciplinary tumor boards to improve the care of patients with hepatocellular carcinoma,” she said.
Outcomes data for hepatocellular carcinoma mostly come from clinical trials; transplant centers; and Surveillance, Epidemiology, and End Results-Medicare analyses, noted Dr. Serper of the University of Pennsylvania in Philadelphia.
For a better look at veterans, she and her associates combined administrative, laboratory, and death data with medical chart reviews and information from the Organ Procurement and Transplantation Network’s Standard Transplant Analysis and Research file. The initial cohort included more than 6,800 veterans whose ICD-9CM diagnosis code indicated a malignant hepatic neoplasm. Excluding patients with neoplasms such as cholangiocarcinoma and those managed outside the VA left 3,989 VA patients with hepatocellular carcinoma.
In the multivariable analysis, use of multidisciplinary tumor boards was associated with a statistically significant 13% improvement in 5-year overall survival (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001). Improved survival also was linked with seeing certain specialists within 30 days of diagnosis, including hepatologists (HR, 0.77; P less than .001) and surgeons (HR, 0.72; P less than .001). Consulting with a hepatologist within 30 days of diagnosis, however, did not improve the chances of receiving curative therapy, such as liver transplantation, resection, local ablation, transarterial chemoembolization, or Y-90 radioembolization.
Care also varied substantially geographically and by academic affiliation, Dr. Serper noted. “Treatment of hepatocellular carcinoma is complex, as it depends as much on liver function as it does on tumor staging,” she emphasized. “Studies to improve multidisciplinary approaches for hepatocellular carcinoma in the community are needed to increase rates of curative therapy and improve clinical outcomes.”
Patients in this study averaged 62 years of age at diagnosis, 54% were white, 36% were within Milan criteria, and 45% had a Child-Turcotte-Pugh score of B or higher. Nearly 18% had macrovascular invasion at diagnosis, and 7% had metastatic disease. Nearly two-thirds of patients were BCLC stage A or B at diagnosis, and more than a third had underlying alcohol misuse and chronic hepatitis C virus infection.
The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.
BOSTON – Veterans were about 13% less likely to die within 5 years of hepatocellular carcinoma diagnosis when multidisciplinary tumor boards managed their care than if they did not, according to a large, multicenter observational study.
Seeing a hepatologist or surgeon within 30 days of diagnosis also significantly improved 5-year overall survival, even after controlling for age, race, Charlson-Deyo comorbidity index, Barcelona Clinic Liver Cancer (BCLC) stage, academic center and geographic region of care, and the distance patients lived from the nearest Veterans Affairs transplant center, Marina Serper, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases. “More studies are needed to understand how to best use multidisciplinary tumor boards to improve the care of patients with hepatocellular carcinoma,” she said.
Outcomes data for hepatocellular carcinoma mostly come from clinical trials; transplant centers; and Surveillance, Epidemiology, and End Results-Medicare analyses, noted Dr. Serper of the University of Pennsylvania in Philadelphia.
For a better look at veterans, she and her associates combined administrative, laboratory, and death data with medical chart reviews and information from the Organ Procurement and Transplantation Network’s Standard Transplant Analysis and Research file. The initial cohort included more than 6,800 veterans whose ICD-9CM diagnosis code indicated a malignant hepatic neoplasm. Excluding patients with neoplasms such as cholangiocarcinoma and those managed outside the VA left 3,989 VA patients with hepatocellular carcinoma.
In the multivariable analysis, use of multidisciplinary tumor boards was associated with a statistically significant 13% improvement in 5-year overall survival (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001). Improved survival also was linked with seeing certain specialists within 30 days of diagnosis, including hepatologists (HR, 0.77; P less than .001) and surgeons (HR, 0.72; P less than .001). Consulting with a hepatologist within 30 days of diagnosis, however, did not improve the chances of receiving curative therapy, such as liver transplantation, resection, local ablation, transarterial chemoembolization, or Y-90 radioembolization.
Care also varied substantially geographically and by academic affiliation, Dr. Serper noted. “Treatment of hepatocellular carcinoma is complex, as it depends as much on liver function as it does on tumor staging,” she emphasized. “Studies to improve multidisciplinary approaches for hepatocellular carcinoma in the community are needed to increase rates of curative therapy and improve clinical outcomes.”
Patients in this study averaged 62 years of age at diagnosis, 54% were white, 36% were within Milan criteria, and 45% had a Child-Turcotte-Pugh score of B or higher. Nearly 18% had macrovascular invasion at diagnosis, and 7% had metastatic disease. Nearly two-thirds of patients were BCLC stage A or B at diagnosis, and more than a third had underlying alcohol misuse and chronic hepatitis C virus infection.
The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.
BOSTON – Veterans were about 13% less likely to die within 5 years of hepatocellular carcinoma diagnosis when multidisciplinary tumor boards managed their care than if they did not, according to a large, multicenter observational study.
Seeing a hepatologist or surgeon within 30 days of diagnosis also significantly improved 5-year overall survival, even after controlling for age, race, Charlson-Deyo comorbidity index, Barcelona Clinic Liver Cancer (BCLC) stage, academic center and geographic region of care, and the distance patients lived from the nearest Veterans Affairs transplant center, Marina Serper, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases. “More studies are needed to understand how to best use multidisciplinary tumor boards to improve the care of patients with hepatocellular carcinoma,” she said.
Outcomes data for hepatocellular carcinoma mostly come from clinical trials; transplant centers; and Surveillance, Epidemiology, and End Results-Medicare analyses, noted Dr. Serper of the University of Pennsylvania in Philadelphia.
For a better look at veterans, she and her associates combined administrative, laboratory, and death data with medical chart reviews and information from the Organ Procurement and Transplantation Network’s Standard Transplant Analysis and Research file. The initial cohort included more than 6,800 veterans whose ICD-9CM diagnosis code indicated a malignant hepatic neoplasm. Excluding patients with neoplasms such as cholangiocarcinoma and those managed outside the VA left 3,989 VA patients with hepatocellular carcinoma.
In the multivariable analysis, use of multidisciplinary tumor boards was associated with a statistically significant 13% improvement in 5-year overall survival (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001). Improved survival also was linked with seeing certain specialists within 30 days of diagnosis, including hepatologists (HR, 0.77; P less than .001) and surgeons (HR, 0.72; P less than .001). Consulting with a hepatologist within 30 days of diagnosis, however, did not improve the chances of receiving curative therapy, such as liver transplantation, resection, local ablation, transarterial chemoembolization, or Y-90 radioembolization.
Care also varied substantially geographically and by academic affiliation, Dr. Serper noted. “Treatment of hepatocellular carcinoma is complex, as it depends as much on liver function as it does on tumor staging,” she emphasized. “Studies to improve multidisciplinary approaches for hepatocellular carcinoma in the community are needed to increase rates of curative therapy and improve clinical outcomes.”
Patients in this study averaged 62 years of age at diagnosis, 54% were white, 36% were within Milan criteria, and 45% had a Child-Turcotte-Pugh score of B or higher. Nearly 18% had macrovascular invasion at diagnosis, and 7% had metastatic disease. Nearly two-thirds of patients were BCLC stage A or B at diagnosis, and more than a third had underlying alcohol misuse and chronic hepatitis C virus infection.
The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.
AT THE LIVER MEETING 2016
Key clinical point: The use of multidisciplinary tumor boards was associated with significantly improved overall survival in patients with hepatocellular carcinoma.
Major finding: The risk of death within 5 years dropped by about 13% (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001).
Data source: A retrospective study of 3,989 Veterans Affairs patients with hepatocellular carcinoma.
Disclosures: The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.
SNP predicts liver cancer in hepatitis C patients regardless of SVR
BOSTON – rs4836493, a single nucleotide polymorphism of the gene encoding chondroitin sulfate synthase-3, significantly predicted hepatocellular carcinoma among patients with HCV even when they achieved sustained virologic response on pegylated interferon, according to a genome-wide association study.
The next step is to determine whether rs4836493 predicts liver cancer after SVR on the new direct-acting antiviral regimens, Basile Njei, MD, MPH, said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Cirrhotic patients face about a 2%-7% annual risk of hepatocellular carcinoma, noted Dr. Njei of Yale University, New Haven, Conn. “Recent studies show that people with HCV may still develop hepatocellular carcinoma even after achieving SVR,” he said.
To look for genetic predictors of this outcome, he and his associates genotyped 958 patients with HCV and advanced hepatic fibrosis from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study. This trial had evaluated long-term, low-dose pegylated interferon therapy (90 mcg per week for 3.5 years) as a means of keeping fibrosis from progressing among HCV patients who had failed peginterferon and ribavirin therapy.
A total of 63% of patients had cirrhosis, and 55 (5.7%) developed biopsy or imaging-confirmed hepatocellular carcinoma over a median of 80 months of follow-up, Dr. Njei said. After the researchers controlled for age, sex, Ishak fibrosis score, and SVR status, rs4836493 predicted hepatocellular carcinoma with a highly significant P value of .000004.
This SNP is located on the CHSY3 gene, which plays a role in the chondroitin polymerization, tissue development, and morphogenesis, according to Dr. Njei. Notably, the gene has been implicated in the biology of colorectal tumors, he added.
Dr. Njei and his associates genotyped patients by using the 610-Quad platform, which contains more than 600,000 SNPs. They double-checked results and conducted more genetic analyses using PLINK 1.9, a free, open-source software program for genome-wide association data. Three-quarters of patients in the study were white, 72% were male, and median age at enrollment was 50 years, he noted.
Linking a single SNP to liver cancer despite SVR is a striking finding, but it is also preliminary, Dr. Njei cautioned. “The SNP identified in our discovery genome-wide association study needs future replication and validation in patients who achieve SVR after receiving the new direct-acting antiviral therapies,” he said.
The National Institutes of Health provided partial funding. Dr. Njei and his coinvestigators had no relevant financial conflicts of interest.
BOSTON – rs4836493, a single nucleotide polymorphism of the gene encoding chondroitin sulfate synthase-3, significantly predicted hepatocellular carcinoma among patients with HCV even when they achieved sustained virologic response on pegylated interferon, according to a genome-wide association study.
The next step is to determine whether rs4836493 predicts liver cancer after SVR on the new direct-acting antiviral regimens, Basile Njei, MD, MPH, said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Cirrhotic patients face about a 2%-7% annual risk of hepatocellular carcinoma, noted Dr. Njei of Yale University, New Haven, Conn. “Recent studies show that people with HCV may still develop hepatocellular carcinoma even after achieving SVR,” he said.
To look for genetic predictors of this outcome, he and his associates genotyped 958 patients with HCV and advanced hepatic fibrosis from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study. This trial had evaluated long-term, low-dose pegylated interferon therapy (90 mcg per week for 3.5 years) as a means of keeping fibrosis from progressing among HCV patients who had failed peginterferon and ribavirin therapy.
A total of 63% of patients had cirrhosis, and 55 (5.7%) developed biopsy or imaging-confirmed hepatocellular carcinoma over a median of 80 months of follow-up, Dr. Njei said. After the researchers controlled for age, sex, Ishak fibrosis score, and SVR status, rs4836493 predicted hepatocellular carcinoma with a highly significant P value of .000004.
This SNP is located on the CHSY3 gene, which plays a role in the chondroitin polymerization, tissue development, and morphogenesis, according to Dr. Njei. Notably, the gene has been implicated in the biology of colorectal tumors, he added.
Dr. Njei and his associates genotyped patients by using the 610-Quad platform, which contains more than 600,000 SNPs. They double-checked results and conducted more genetic analyses using PLINK 1.9, a free, open-source software program for genome-wide association data. Three-quarters of patients in the study were white, 72% were male, and median age at enrollment was 50 years, he noted.
Linking a single SNP to liver cancer despite SVR is a striking finding, but it is also preliminary, Dr. Njei cautioned. “The SNP identified in our discovery genome-wide association study needs future replication and validation in patients who achieve SVR after receiving the new direct-acting antiviral therapies,” he said.
The National Institutes of Health provided partial funding. Dr. Njei and his coinvestigators had no relevant financial conflicts of interest.
BOSTON – rs4836493, a single nucleotide polymorphism of the gene encoding chondroitin sulfate synthase-3, significantly predicted hepatocellular carcinoma among patients with HCV even when they achieved sustained virologic response on pegylated interferon, according to a genome-wide association study.
The next step is to determine whether rs4836493 predicts liver cancer after SVR on the new direct-acting antiviral regimens, Basile Njei, MD, MPH, said during an oral presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Cirrhotic patients face about a 2%-7% annual risk of hepatocellular carcinoma, noted Dr. Njei of Yale University, New Haven, Conn. “Recent studies show that people with HCV may still develop hepatocellular carcinoma even after achieving SVR,” he said.
To look for genetic predictors of this outcome, he and his associates genotyped 958 patients with HCV and advanced hepatic fibrosis from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study. This trial had evaluated long-term, low-dose pegylated interferon therapy (90 mcg per week for 3.5 years) as a means of keeping fibrosis from progressing among HCV patients who had failed peginterferon and ribavirin therapy.
A total of 63% of patients had cirrhosis, and 55 (5.7%) developed biopsy or imaging-confirmed hepatocellular carcinoma over a median of 80 months of follow-up, Dr. Njei said. After the researchers controlled for age, sex, Ishak fibrosis score, and SVR status, rs4836493 predicted hepatocellular carcinoma with a highly significant P value of .000004.
This SNP is located on the CHSY3 gene, which plays a role in the chondroitin polymerization, tissue development, and morphogenesis, according to Dr. Njei. Notably, the gene has been implicated in the biology of colorectal tumors, he added.
Dr. Njei and his associates genotyped patients by using the 610-Quad platform, which contains more than 600,000 SNPs. They double-checked results and conducted more genetic analyses using PLINK 1.9, a free, open-source software program for genome-wide association data. Three-quarters of patients in the study were white, 72% were male, and median age at enrollment was 50 years, he noted.
Linking a single SNP to liver cancer despite SVR is a striking finding, but it is also preliminary, Dr. Njei cautioned. “The SNP identified in our discovery genome-wide association study needs future replication and validation in patients who achieve SVR after receiving the new direct-acting antiviral therapies,” he said.
The National Institutes of Health provided partial funding. Dr. Njei and his coinvestigators had no relevant financial conflicts of interest.
AT THE LIVER MEETING 2016
Key clinical point: A single nucleotide polymorphism of the CHSY3 gene predicted liver cancer in patients who successfully completed treatment for chronic hepatitis C virus infection.
Major finding: After researchers controlled for sustained virologic response and other confounders, the rs4836493 variant predicted hepatocellular carcinoma with a P value of .000004.
Data source: A genome-wide association study of 958 HCV patients with advanced hepatic fibrosis from the HALT-C trial.
Disclosures: The National Institutes of Health provided partial funding. Dr. Njei and his coinvestigators had no relevant financial conflicts of interest.
Study eyed zinc for slowing progression of chronic liver disease
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.
To begin exploring hepatic correlates of zinc supplementation, Dr. Hosui and his associates retrospectively studied 267 patients in Japan with chronic liver diseases between 2006 and 2015. They had a median of 40 months of data for each patient. No patient had hepatocellular carcinoma at baseline. In all, 196 patients received zinc supplementation (average baseline zinc level, 51 mcg/dL), while 71 patients did not (62 mcg/dL). These two groups resembled each other in terms of etiologies of liver disease, but the zinc group was significantly older (73.2 vs. 66.4 years; P less than .0001), had a significantly higher average baseline bilirubin level (1.2 vs. 0.8 mg/dL; P less than .0001), and a significantly lower average platelet concentration and prothrombin time. (P less than .0001).
Despite having multiple indicators of worse liver disease, only 9.5% of zinc recipients developed hepatocellular carcinoma over 3 years, compared with 25% of patients in the control group (P = .005). Rates of liver failure and death were similar between the two groups, but sequential blood tests did indicate worsening liver disease among patients who did not receive zinc – their prothrombin times and branched-chain amino acid to tyrosine ratios steadily dropped over 3 years, while those in zinc recipients did not.
Next, the researchers stratified zinc recipients according to their serum zinc levels 6 months after starting supplementation. Notably, 3-year rates of mortality, liver failure, and death were significantly higher among patients whose zinc levels were lower than in patients who achieved higher serum zinc levels. For example, 3-year mortality rates were 28% among patients whose zinc level was 70-89 mcg/dL, versus 0% among patients whose zinc level was at least 90 mcg/dL (P = .02). Similarly, 3-year rates of liver failure were 3.6% among patients whose zinc level was 50-69 mcg/dL, versus 0% among patients whose serum zinc level was at least 70 mcg/dL (P = .03). Finally, over 3 years, hepatocellular carcinoma was diagnosed in 17% of patients whose zinc level was 50-69 mcg/dL, versus only 3.8% of patients whose zinc level was 70-89 mcg/dL.
“We suggest that oral zinc supplementation is effective for maintaining liver function and suppressing the development of hepatocellular carcinoma,” Dr. Hosui concluded. The data support a target serum zinc level of at least 70 mcg/dL to suppress liver-related events, including hepatocellular carcinoma, he added. The researchers are exploring clinical trials of zinc for these outcomes in Japan.
The investigators did not report funding for this study. They reported having no conflicts of interest.
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.
To begin exploring hepatic correlates of zinc supplementation, Dr. Hosui and his associates retrospectively studied 267 patients in Japan with chronic liver diseases between 2006 and 2015. They had a median of 40 months of data for each patient. No patient had hepatocellular carcinoma at baseline. In all, 196 patients received zinc supplementation (average baseline zinc level, 51 mcg/dL), while 71 patients did not (62 mcg/dL). These two groups resembled each other in terms of etiologies of liver disease, but the zinc group was significantly older (73.2 vs. 66.4 years; P less than .0001), had a significantly higher average baseline bilirubin level (1.2 vs. 0.8 mg/dL; P less than .0001), and a significantly lower average platelet concentration and prothrombin time. (P less than .0001).
Despite having multiple indicators of worse liver disease, only 9.5% of zinc recipients developed hepatocellular carcinoma over 3 years, compared with 25% of patients in the control group (P = .005). Rates of liver failure and death were similar between the two groups, but sequential blood tests did indicate worsening liver disease among patients who did not receive zinc – their prothrombin times and branched-chain amino acid to tyrosine ratios steadily dropped over 3 years, while those in zinc recipients did not.
Next, the researchers stratified zinc recipients according to their serum zinc levels 6 months after starting supplementation. Notably, 3-year rates of mortality, liver failure, and death were significantly higher among patients whose zinc levels were lower than in patients who achieved higher serum zinc levels. For example, 3-year mortality rates were 28% among patients whose zinc level was 70-89 mcg/dL, versus 0% among patients whose zinc level was at least 90 mcg/dL (P = .02). Similarly, 3-year rates of liver failure were 3.6% among patients whose zinc level was 50-69 mcg/dL, versus 0% among patients whose serum zinc level was at least 70 mcg/dL (P = .03). Finally, over 3 years, hepatocellular carcinoma was diagnosed in 17% of patients whose zinc level was 50-69 mcg/dL, versus only 3.8% of patients whose zinc level was 70-89 mcg/dL.
“We suggest that oral zinc supplementation is effective for maintaining liver function and suppressing the development of hepatocellular carcinoma,” Dr. Hosui concluded. The data support a target serum zinc level of at least 70 mcg/dL to suppress liver-related events, including hepatocellular carcinoma, he added. The researchers are exploring clinical trials of zinc for these outcomes in Japan.
The investigators did not report funding for this study. They reported having no conflicts of interest.
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.
To begin exploring hepatic correlates of zinc supplementation, Dr. Hosui and his associates retrospectively studied 267 patients in Japan with chronic liver diseases between 2006 and 2015. They had a median of 40 months of data for each patient. No patient had hepatocellular carcinoma at baseline. In all, 196 patients received zinc supplementation (average baseline zinc level, 51 mcg/dL), while 71 patients did not (62 mcg/dL). These two groups resembled each other in terms of etiologies of liver disease, but the zinc group was significantly older (73.2 vs. 66.4 years; P less than .0001), had a significantly higher average baseline bilirubin level (1.2 vs. 0.8 mg/dL; P less than .0001), and a significantly lower average platelet concentration and prothrombin time. (P less than .0001).
Despite having multiple indicators of worse liver disease, only 9.5% of zinc recipients developed hepatocellular carcinoma over 3 years, compared with 25% of patients in the control group (P = .005). Rates of liver failure and death were similar between the two groups, but sequential blood tests did indicate worsening liver disease among patients who did not receive zinc – their prothrombin times and branched-chain amino acid to tyrosine ratios steadily dropped over 3 years, while those in zinc recipients did not.
Next, the researchers stratified zinc recipients according to their serum zinc levels 6 months after starting supplementation. Notably, 3-year rates of mortality, liver failure, and death were significantly higher among patients whose zinc levels were lower than in patients who achieved higher serum zinc levels. For example, 3-year mortality rates were 28% among patients whose zinc level was 70-89 mcg/dL, versus 0% among patients whose zinc level was at least 90 mcg/dL (P = .02). Similarly, 3-year rates of liver failure were 3.6% among patients whose zinc level was 50-69 mcg/dL, versus 0% among patients whose serum zinc level was at least 70 mcg/dL (P = .03). Finally, over 3 years, hepatocellular carcinoma was diagnosed in 17% of patients whose zinc level was 50-69 mcg/dL, versus only 3.8% of patients whose zinc level was 70-89 mcg/dL.
“We suggest that oral zinc supplementation is effective for maintaining liver function and suppressing the development of hepatocellular carcinoma,” Dr. Hosui concluded. The data support a target serum zinc level of at least 70 mcg/dL to suppress liver-related events, including hepatocellular carcinoma, he added. The researchers are exploring clinical trials of zinc for these outcomes in Japan.
The investigators did not report funding for this study. They reported having no conflicts of interest.
AT THE LIVER MEETING 2016
Key clinical point: Oral zinc sulfate supplementation might help prevent the progression of chronic liver disease and associated hepatocellular carcinoma.
Major finding: Despite having multiple indicators of worse liver disease, only 9.5% of zinc recipients developed hepatocellular carcinoma over 3 years, compared with 25% of patients in the control group (P = .005).
Data source: A retrospective cohort study of 267 patients with chronic liver disease but no hepatocellular carcinoma at baseline.
Disclosures: The investigators did not report funding for this study. They reported having no conflicts of interest.
Study found no link between direct-acting antivirals, hepatocellular carcinoma
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.
AT THE LIVER MEETING
Key clinical point:
Major finding: The overall incidence of de novo hepatocellular carcinoma was 1.64 cases per 100 patient-years during and after treatment, with a median follow-up period of about 305 days.
Data source: A prospective cohort study of 2,279 patients (86% with cirrhosis) who received direct-acting antivirals for HCV.
Disclosures: The investigators received no outside funding for the study. Dr. Romano reported ties to Gilead, Abbvie, and Bristol Myers Squibb.
MBX-8025 yields ‘striking’ efficacy results but new safety signal in primary biliary cholangitis
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.
FROM THE LIVER MEETING 2016
Key clinical point: In patients with primary biliary cholangitis, the investigational agent MBX-8025 was associated with significant decreases in cholestatic markers, but also with grade 3 increases in serum levels of alanine aminotransferase (ALT).
Major finding: At the end of treatment, alkaline phosphatase levels had dropped by 63% and by 53% in the 200-mg and 50-mg groups, respectively, and by 2% in the placebo group (P less than .0001). Three patients developed fully reversible grade 3 ALT increases.
Data source: A 12-week, double-blind, phase II trial of 35 patients with primary biliary cholangitis who had responded inadequately to ursodeoxycholic acid (NCT02609048).
Disclosures: 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 researchers had no relevant disclosures.