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Early treatment with direct-acting antivirals linked to reduced medical costs in noncirrhotic HCV
SAN FRANCISCO – Patients with noncirrhotic chronic hepatitis C virus (HCV) infection incur high medical costs in the three years following their diagnosis. However, early initiation of oral direct-acting therapies is associated with significant medical cost savings, largely driven by reduced extrahepatic manifestations.
Those are key findings from an analysis of “real-world” claims data that Carol Bao, PhD, presented on behalf of senior author Patrice Cacoub, MD, during a poster session at the annual meeting of the American Association for the Study of Liver Diseases.
“This [study] highlights the importance of treating HCV patients early, especially with active therapies, because that will benefit not only their liver disease but, from a population health perspective, you are lifting the entire health of those patients as well,” Dr. Bao, senior director of health economics and outcomes research at AbbVie, North Chicago, said in an interview.
In an effort to quantify the health care cost savings associated with initiation of direct-acting antiviral (DAA) therapies within 2 years of the first chronic HCV (CHC) diagnosis among noncirrhotic patients in the United States, the researchers drew from Clinformatics Data Mart, a diverse health care database with longitudinal data for more than 15 million lives each year. They collected data between Jan. 1, 2009, and Jan. 31, 2016, and excluded patients followed for less than 6 months before the CHC diagnosis or less than 1 year after the CHC diagnosis, as well as those who received interferon/ribavirin therapy before their first DAA. This yielded a sample of 3,069 adults first diagnosed with CHC on or after 2013.
The index date was defined as the data of the first CHC diagnosis and researchers established two cohorts: 852 patients who initiated DAAs in the 3 years postindex date and 2,217 who did not receive any CHC treatment in the 3 years postindex date.
Outcomes of interest included all-cause and disease-specific medical costs measured yearly up to 3 years post index. These included costs related to CHC management or hepatic complications as well as those related to extrahepatic manifestations (EHMs) such as fatigue, type 2 diabetes, and cardiovascular disease.
Patients in the DAA-treated group were slightly older than those in the untreated group (a median age of 52.6 vs. 50.9 years, respectively; P less than .001) and had a higher proportion of men (65.1% vs. 60.7%; P = .07). They were also diagnosed more recently and had more advanced fibrosis at baseline. In the first 3 years post index, the researchers found that the average medical costs incurred in the DAA-treated and untreated groups were $28,392 and $42,914, respectively. On multivariate regression analyses, total all-cause medical costs were statistically lower across DAA-treated years than across the untreated years: $6,379 per year on average, because of savings related to health care for EHMs ($3,158 per year on average) and diagnoses other than CHC, hepatitis, or EHMs considered in this study ($4,638 per year on average).
When Dr. Bao and her colleagues conducted post hoc exploratory analyses of the $4,638 per year cost differences for diagnoses other than CHC, hepatic, or the EMHs considered, they determined that they appear to be driven by diagnoses related to the circulatory system (especially essential hypertension), respiratory system, blood/immune/endocrine systems, and claims with diagnoses that were not disease specific.
Dr. Bao acknowledged certain limitations of the study, including the potential for errors and omissions associated with claims data and that costs were recorded as charged amounts, which may be different from the amount actually paid. In addition, the fibrosis level could not be inferred for all patients.
AbbVie provided funding for the study, which received a “poster of distinction” award at the meeting. The company employs Dr. Bao and two of the study coauthors.
SAN FRANCISCO – Patients with noncirrhotic chronic hepatitis C virus (HCV) infection incur high medical costs in the three years following their diagnosis. However, early initiation of oral direct-acting therapies is associated with significant medical cost savings, largely driven by reduced extrahepatic manifestations.
Those are key findings from an analysis of “real-world” claims data that Carol Bao, PhD, presented on behalf of senior author Patrice Cacoub, MD, during a poster session at the annual meeting of the American Association for the Study of Liver Diseases.
“This [study] highlights the importance of treating HCV patients early, especially with active therapies, because that will benefit not only their liver disease but, from a population health perspective, you are lifting the entire health of those patients as well,” Dr. Bao, senior director of health economics and outcomes research at AbbVie, North Chicago, said in an interview.
In an effort to quantify the health care cost savings associated with initiation of direct-acting antiviral (DAA) therapies within 2 years of the first chronic HCV (CHC) diagnosis among noncirrhotic patients in the United States, the researchers drew from Clinformatics Data Mart, a diverse health care database with longitudinal data for more than 15 million lives each year. They collected data between Jan. 1, 2009, and Jan. 31, 2016, and excluded patients followed for less than 6 months before the CHC diagnosis or less than 1 year after the CHC diagnosis, as well as those who received interferon/ribavirin therapy before their first DAA. This yielded a sample of 3,069 adults first diagnosed with CHC on or after 2013.
The index date was defined as the data of the first CHC diagnosis and researchers established two cohorts: 852 patients who initiated DAAs in the 3 years postindex date and 2,217 who did not receive any CHC treatment in the 3 years postindex date.
Outcomes of interest included all-cause and disease-specific medical costs measured yearly up to 3 years post index. These included costs related to CHC management or hepatic complications as well as those related to extrahepatic manifestations (EHMs) such as fatigue, type 2 diabetes, and cardiovascular disease.
Patients in the DAA-treated group were slightly older than those in the untreated group (a median age of 52.6 vs. 50.9 years, respectively; P less than .001) and had a higher proportion of men (65.1% vs. 60.7%; P = .07). They were also diagnosed more recently and had more advanced fibrosis at baseline. In the first 3 years post index, the researchers found that the average medical costs incurred in the DAA-treated and untreated groups were $28,392 and $42,914, respectively. On multivariate regression analyses, total all-cause medical costs were statistically lower across DAA-treated years than across the untreated years: $6,379 per year on average, because of savings related to health care for EHMs ($3,158 per year on average) and diagnoses other than CHC, hepatitis, or EHMs considered in this study ($4,638 per year on average).
When Dr. Bao and her colleagues conducted post hoc exploratory analyses of the $4,638 per year cost differences for diagnoses other than CHC, hepatic, or the EMHs considered, they determined that they appear to be driven by diagnoses related to the circulatory system (especially essential hypertension), respiratory system, blood/immune/endocrine systems, and claims with diagnoses that were not disease specific.
Dr. Bao acknowledged certain limitations of the study, including the potential for errors and omissions associated with claims data and that costs were recorded as charged amounts, which may be different from the amount actually paid. In addition, the fibrosis level could not be inferred for all patients.
AbbVie provided funding for the study, which received a “poster of distinction” award at the meeting. The company employs Dr. Bao and two of the study coauthors.
SAN FRANCISCO – Patients with noncirrhotic chronic hepatitis C virus (HCV) infection incur high medical costs in the three years following their diagnosis. However, early initiation of oral direct-acting therapies is associated with significant medical cost savings, largely driven by reduced extrahepatic manifestations.
Those are key findings from an analysis of “real-world” claims data that Carol Bao, PhD, presented on behalf of senior author Patrice Cacoub, MD, during a poster session at the annual meeting of the American Association for the Study of Liver Diseases.
“This [study] highlights the importance of treating HCV patients early, especially with active therapies, because that will benefit not only their liver disease but, from a population health perspective, you are lifting the entire health of those patients as well,” Dr. Bao, senior director of health economics and outcomes research at AbbVie, North Chicago, said in an interview.
In an effort to quantify the health care cost savings associated with initiation of direct-acting antiviral (DAA) therapies within 2 years of the first chronic HCV (CHC) diagnosis among noncirrhotic patients in the United States, the researchers drew from Clinformatics Data Mart, a diverse health care database with longitudinal data for more than 15 million lives each year. They collected data between Jan. 1, 2009, and Jan. 31, 2016, and excluded patients followed for less than 6 months before the CHC diagnosis or less than 1 year after the CHC diagnosis, as well as those who received interferon/ribavirin therapy before their first DAA. This yielded a sample of 3,069 adults first diagnosed with CHC on or after 2013.
The index date was defined as the data of the first CHC diagnosis and researchers established two cohorts: 852 patients who initiated DAAs in the 3 years postindex date and 2,217 who did not receive any CHC treatment in the 3 years postindex date.
Outcomes of interest included all-cause and disease-specific medical costs measured yearly up to 3 years post index. These included costs related to CHC management or hepatic complications as well as those related to extrahepatic manifestations (EHMs) such as fatigue, type 2 diabetes, and cardiovascular disease.
Patients in the DAA-treated group were slightly older than those in the untreated group (a median age of 52.6 vs. 50.9 years, respectively; P less than .001) and had a higher proportion of men (65.1% vs. 60.7%; P = .07). They were also diagnosed more recently and had more advanced fibrosis at baseline. In the first 3 years post index, the researchers found that the average medical costs incurred in the DAA-treated and untreated groups were $28,392 and $42,914, respectively. On multivariate regression analyses, total all-cause medical costs were statistically lower across DAA-treated years than across the untreated years: $6,379 per year on average, because of savings related to health care for EHMs ($3,158 per year on average) and diagnoses other than CHC, hepatitis, or EHMs considered in this study ($4,638 per year on average).
When Dr. Bao and her colleagues conducted post hoc exploratory analyses of the $4,638 per year cost differences for diagnoses other than CHC, hepatic, or the EMHs considered, they determined that they appear to be driven by diagnoses related to the circulatory system (especially essential hypertension), respiratory system, blood/immune/endocrine systems, and claims with diagnoses that were not disease specific.
Dr. Bao acknowledged certain limitations of the study, including the potential for errors and omissions associated with claims data and that costs were recorded as charged amounts, which may be different from the amount actually paid. In addition, the fibrosis level could not be inferred for all patients.
AbbVie provided funding for the study, which received a “poster of distinction” award at the meeting. The company employs Dr. Bao and two of the study coauthors.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: Noncirrhotic chronic hepatitis C patients incur high medical costs after their first diagnosis if left untreated.
Major finding: In the first 3 years post index, the average medical costs incurred in the direct-acting antiviral–treated and untreated groups were $28,392 and $42,914, respectively.
Study details: A database sample of 3,069 adults first diagnosed with chronic hepatitis C in or after 2013.
Disclosures: AbbVie provided funding for the study. The company employs Dr. Bao and two of the study coauthors.
Normothermic machine perfusion found to salvage fatty livers for transplantation
SAN FRANCISCO – results from a small trial showed.
“This is important in the context of liver transplantation, because fatty livers do very badly when their time is blunted,” study coauthor Carlo Ceresa, MBChB, MRCS, said during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases. “They’re susceptible to ischemia reperfusion injury, and as a result, a large number are discarded. In the U.S., it’s estimated that around 6,000 steatotic livers are discarded each year. In the U.K., the picture is very similar. Because up to 20% of patients die on the waiting list for liver transplant, we need to try to identify methods to use more marginal organs. Unfortunately, with the obesity epidemic and obesity being a risk factor for NAFLD [nonalcoholic fatty liver disease], we find more fatty livers in the donor pool, and we aren’t able to use them. Identifying methods to salvage these livers for transplantation [is] of great importance.”
NMP maintains the liver in a fully functioning state ex situ and provides oxygen and nutrition at 37° C, said Dr. Ceresa, who is a clinical research fellow with the Medical Research Council and a PhD candidate at the University of Oxford, England. In an effort to evaluate the impact of NMP and defatting adjuncts on human steatotic livers, he and his colleagues perfused 18 discarded human steatotic livers on a normothermic, blood-based circuit for 48 hours. Of these, six were perfused by normothermic machine perfusion alone (group 1), while six were perfused by NMP plus apheresis filtration, which removes lipoproteins (group 2). “The hypothesis here was that we could mechanically remove the fat that the liver releases,” he said. The remaining six livers were perfused with NMP, lipid apheresis filtration, and defatting agents including
The livers in group 1 “did pretty badly,” Dr. Ceresa said. “Their function wasn’t great and within 48 hours deteriorated, and there was a slight increase in liver fat. That’s probably attributable to de novo lipogenesis.” However, the livers in groups 2 and 3 demonstrated a significant reduction in circulating triglycerides and in perfusate total cholesterol by 48 hours, compared with those in group 1. The researchers also observed an increase in median fatty acid oxidation as measured by 3-hydroxybutyrate among the livers in group 3, compared with those in groups 1 and 2. In addition, the livers in group 3 were the only ones to show a mean reduction in tissue triglyceride level.
Dr. Ceresa described the findings as “exciting, because we have a captive organ we can manipulate, which could then result in a successful transplantation,” he said. “You also get to test drive and get an objective assessment of the organ’s function before you transplant it, so the result may be more predictable. It gives us a very useful model to study NAFLD.”
The next step, he said, is to plan a clinical trial to determine if clinical outcomes can be improved through these ex situ interventions on steatotic livers.
Dr. Ceresa reported having no financial disclosures.
Source: Hepatology 2018;68[S1], Abstract 3.
SAN FRANCISCO – results from a small trial showed.
“This is important in the context of liver transplantation, because fatty livers do very badly when their time is blunted,” study coauthor Carlo Ceresa, MBChB, MRCS, said during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases. “They’re susceptible to ischemia reperfusion injury, and as a result, a large number are discarded. In the U.S., it’s estimated that around 6,000 steatotic livers are discarded each year. In the U.K., the picture is very similar. Because up to 20% of patients die on the waiting list for liver transplant, we need to try to identify methods to use more marginal organs. Unfortunately, with the obesity epidemic and obesity being a risk factor for NAFLD [nonalcoholic fatty liver disease], we find more fatty livers in the donor pool, and we aren’t able to use them. Identifying methods to salvage these livers for transplantation [is] of great importance.”
NMP maintains the liver in a fully functioning state ex situ and provides oxygen and nutrition at 37° C, said Dr. Ceresa, who is a clinical research fellow with the Medical Research Council and a PhD candidate at the University of Oxford, England. In an effort to evaluate the impact of NMP and defatting adjuncts on human steatotic livers, he and his colleagues perfused 18 discarded human steatotic livers on a normothermic, blood-based circuit for 48 hours. Of these, six were perfused by normothermic machine perfusion alone (group 1), while six were perfused by NMP plus apheresis filtration, which removes lipoproteins (group 2). “The hypothesis here was that we could mechanically remove the fat that the liver releases,” he said. The remaining six livers were perfused with NMP, lipid apheresis filtration, and defatting agents including
The livers in group 1 “did pretty badly,” Dr. Ceresa said. “Their function wasn’t great and within 48 hours deteriorated, and there was a slight increase in liver fat. That’s probably attributable to de novo lipogenesis.” However, the livers in groups 2 and 3 demonstrated a significant reduction in circulating triglycerides and in perfusate total cholesterol by 48 hours, compared with those in group 1. The researchers also observed an increase in median fatty acid oxidation as measured by 3-hydroxybutyrate among the livers in group 3, compared with those in groups 1 and 2. In addition, the livers in group 3 were the only ones to show a mean reduction in tissue triglyceride level.
Dr. Ceresa described the findings as “exciting, because we have a captive organ we can manipulate, which could then result in a successful transplantation,” he said. “You also get to test drive and get an objective assessment of the organ’s function before you transplant it, so the result may be more predictable. It gives us a very useful model to study NAFLD.”
The next step, he said, is to plan a clinical trial to determine if clinical outcomes can be improved through these ex situ interventions on steatotic livers.
Dr. Ceresa reported having no financial disclosures.
Source: Hepatology 2018;68[S1], Abstract 3.
SAN FRANCISCO – results from a small trial showed.
“This is important in the context of liver transplantation, because fatty livers do very badly when their time is blunted,” study coauthor Carlo Ceresa, MBChB, MRCS, said during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases. “They’re susceptible to ischemia reperfusion injury, and as a result, a large number are discarded. In the U.S., it’s estimated that around 6,000 steatotic livers are discarded each year. In the U.K., the picture is very similar. Because up to 20% of patients die on the waiting list for liver transplant, we need to try to identify methods to use more marginal organs. Unfortunately, with the obesity epidemic and obesity being a risk factor for NAFLD [nonalcoholic fatty liver disease], we find more fatty livers in the donor pool, and we aren’t able to use them. Identifying methods to salvage these livers for transplantation [is] of great importance.”
NMP maintains the liver in a fully functioning state ex situ and provides oxygen and nutrition at 37° C, said Dr. Ceresa, who is a clinical research fellow with the Medical Research Council and a PhD candidate at the University of Oxford, England. In an effort to evaluate the impact of NMP and defatting adjuncts on human steatotic livers, he and his colleagues perfused 18 discarded human steatotic livers on a normothermic, blood-based circuit for 48 hours. Of these, six were perfused by normothermic machine perfusion alone (group 1), while six were perfused by NMP plus apheresis filtration, which removes lipoproteins (group 2). “The hypothesis here was that we could mechanically remove the fat that the liver releases,” he said. The remaining six livers were perfused with NMP, lipid apheresis filtration, and defatting agents including
The livers in group 1 “did pretty badly,” Dr. Ceresa said. “Their function wasn’t great and within 48 hours deteriorated, and there was a slight increase in liver fat. That’s probably attributable to de novo lipogenesis.” However, the livers in groups 2 and 3 demonstrated a significant reduction in circulating triglycerides and in perfusate total cholesterol by 48 hours, compared with those in group 1. The researchers also observed an increase in median fatty acid oxidation as measured by 3-hydroxybutyrate among the livers in group 3, compared with those in groups 1 and 2. In addition, the livers in group 3 were the only ones to show a mean reduction in tissue triglyceride level.
Dr. Ceresa described the findings as “exciting, because we have a captive organ we can manipulate, which could then result in a successful transplantation,” he said. “You also get to test drive and get an objective assessment of the organ’s function before you transplant it, so the result may be more predictable. It gives us a very useful model to study NAFLD.”
The next step, he said, is to plan a clinical trial to determine if clinical outcomes can be improved through these ex situ interventions on steatotic livers.
Dr. Ceresa reported having no financial disclosures.
Source: Hepatology 2018;68[S1], Abstract 3.
AT THE LIVER MEETING 2018
Key clinical point: The addition of apheresis filtration and defatting agents to normothermic machine perfusion led to significant improvements in liver function.
Major finding: Livers which received apheresis filtration and defatting agents fared better than those that did not.
Study details: An analysis of 18 discarded human steatotic livers that were perfused on a normothermic, blood-based circuit for 48 hours.
Disclosures: Dr. Ceresa reported having no financial disclosures.
Source: Hepatology 2018;68[S1], Abstract 3.
Skin rashes often accompany drug-induced liver injury
SAN FRANCISCO – More than a quarter of drug-induced liver injury (DILI) cases also involve skin reactions, most often drug rash with eosinophilia and system symptoms (DRESS) syndrome. These dual cases of DILI and drug-induced skin injury (DISI) underscore the need for hepatologists to pay attention to dermatologic conditions and emphasize the need for the two specialties to work together.
The findings suggest that DISI/DILI comorbidity is not uncommon, and may hint at underlying mechanisms that could be used to tailor treatment, according to Harshad Devarbhavi, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. “My message was that people should work more and see if there’s any type of genotype or HLA [human leukocyte antigen] that produces this reaction. It’s a multisystem disease. It doesn’t belong to dermatologists, it’s a domain that also belongs to hepatologists,” said Dr. Devarbhavi, who is a hepatology fellow at St. John’s Medical College in Bangalore, India.
DISI is more common than DILI, and may or may not be caused by an immune response. The two conditions were previously known to co-occur, but it is rarely reported because dermatologists and hepatologists report findings in different journals.
The researchers defined DILI as a fivefold or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT); a threefold or greater increase with symptoms, including cutaneous reactions; any elevation of AST, ALT, or alkaline phosphatase (ALP) accompanying a bilirubin increase of 2 mg/dL or more; or a twofold or higher increase in ALP combined with a cutaneous reaction.
They analyzed 921 DILI patients from a single registry in India, who were seen between 1997 and April 2018. All patients with skin reactions were seen by dermatologists and competing causes were excluded. A total of 28% of patients with DILI also had DISI, 13% of whom were also HIV positive; 56% developed jaundice. The mean age of patients with DILI/DISI was 35 years, compared with 42 years in DILI only patients (P = .001) and the mean duration of drug therapy was 42 days, compared with 89 days (P = .002). Twelve percent of DILI/DISI patients died, which was lower than the 17% mortality in those with DILI alone.
Of the DILI/DISI patients, 59% experienced DRESS, and 19% had Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Six percent of patients with DRESS died, as did 22% of those with SJS/TEN. Mortality was 16% among those with other skin manifestations. Eighteen percent of those with jaundice died, compared with 3% of those without jaundice.
Thirty patients with DILI/DISI died; 37% (11) of them had SJS/TEN, compared with 17% of survivors (P = .01). DRESS was more common in survivors (62% vs. 33%; P = .02).
Of DILI/DISI and SJS/TEN cases, 75% were associated with four drug classes: antiepileptic drugs, dapsone, antiretroviral therapies, and leflunomide.
“The liver is the biggest internal organ in the body, and skin is the largest external organ, so there is some correlation between the two, but people haven’t looked at it. People should come together and see why some drugs produce both these injuries. I think there is some mechanistic information in these drugs,” said Dr. Devarbhavi.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
SAN FRANCISCO – More than a quarter of drug-induced liver injury (DILI) cases also involve skin reactions, most often drug rash with eosinophilia and system symptoms (DRESS) syndrome. These dual cases of DILI and drug-induced skin injury (DISI) underscore the need for hepatologists to pay attention to dermatologic conditions and emphasize the need for the two specialties to work together.
The findings suggest that DISI/DILI comorbidity is not uncommon, and may hint at underlying mechanisms that could be used to tailor treatment, according to Harshad Devarbhavi, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. “My message was that people should work more and see if there’s any type of genotype or HLA [human leukocyte antigen] that produces this reaction. It’s a multisystem disease. It doesn’t belong to dermatologists, it’s a domain that also belongs to hepatologists,” said Dr. Devarbhavi, who is a hepatology fellow at St. John’s Medical College in Bangalore, India.
DISI is more common than DILI, and may or may not be caused by an immune response. The two conditions were previously known to co-occur, but it is rarely reported because dermatologists and hepatologists report findings in different journals.
The researchers defined DILI as a fivefold or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT); a threefold or greater increase with symptoms, including cutaneous reactions; any elevation of AST, ALT, or alkaline phosphatase (ALP) accompanying a bilirubin increase of 2 mg/dL or more; or a twofold or higher increase in ALP combined with a cutaneous reaction.
They analyzed 921 DILI patients from a single registry in India, who were seen between 1997 and April 2018. All patients with skin reactions were seen by dermatologists and competing causes were excluded. A total of 28% of patients with DILI also had DISI, 13% of whom were also HIV positive; 56% developed jaundice. The mean age of patients with DILI/DISI was 35 years, compared with 42 years in DILI only patients (P = .001) and the mean duration of drug therapy was 42 days, compared with 89 days (P = .002). Twelve percent of DILI/DISI patients died, which was lower than the 17% mortality in those with DILI alone.
Of the DILI/DISI patients, 59% experienced DRESS, and 19% had Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Six percent of patients with DRESS died, as did 22% of those with SJS/TEN. Mortality was 16% among those with other skin manifestations. Eighteen percent of those with jaundice died, compared with 3% of those without jaundice.
Thirty patients with DILI/DISI died; 37% (11) of them had SJS/TEN, compared with 17% of survivors (P = .01). DRESS was more common in survivors (62% vs. 33%; P = .02).
Of DILI/DISI and SJS/TEN cases, 75% were associated with four drug classes: antiepileptic drugs, dapsone, antiretroviral therapies, and leflunomide.
“The liver is the biggest internal organ in the body, and skin is the largest external organ, so there is some correlation between the two, but people haven’t looked at it. People should come together and see why some drugs produce both these injuries. I think there is some mechanistic information in these drugs,” said Dr. Devarbhavi.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
SAN FRANCISCO – More than a quarter of drug-induced liver injury (DILI) cases also involve skin reactions, most often drug rash with eosinophilia and system symptoms (DRESS) syndrome. These dual cases of DILI and drug-induced skin injury (DISI) underscore the need for hepatologists to pay attention to dermatologic conditions and emphasize the need for the two specialties to work together.
The findings suggest that DISI/DILI comorbidity is not uncommon, and may hint at underlying mechanisms that could be used to tailor treatment, according to Harshad Devarbhavi, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. “My message was that people should work more and see if there’s any type of genotype or HLA [human leukocyte antigen] that produces this reaction. It’s a multisystem disease. It doesn’t belong to dermatologists, it’s a domain that also belongs to hepatologists,” said Dr. Devarbhavi, who is a hepatology fellow at St. John’s Medical College in Bangalore, India.
DISI is more common than DILI, and may or may not be caused by an immune response. The two conditions were previously known to co-occur, but it is rarely reported because dermatologists and hepatologists report findings in different journals.
The researchers defined DILI as a fivefold or greater increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT); a threefold or greater increase with symptoms, including cutaneous reactions; any elevation of AST, ALT, or alkaline phosphatase (ALP) accompanying a bilirubin increase of 2 mg/dL or more; or a twofold or higher increase in ALP combined with a cutaneous reaction.
They analyzed 921 DILI patients from a single registry in India, who were seen between 1997 and April 2018. All patients with skin reactions were seen by dermatologists and competing causes were excluded. A total of 28% of patients with DILI also had DISI, 13% of whom were also HIV positive; 56% developed jaundice. The mean age of patients with DILI/DISI was 35 years, compared with 42 years in DILI only patients (P = .001) and the mean duration of drug therapy was 42 days, compared with 89 days (P = .002). Twelve percent of DILI/DISI patients died, which was lower than the 17% mortality in those with DILI alone.
Of the DILI/DISI patients, 59% experienced DRESS, and 19% had Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Six percent of patients with DRESS died, as did 22% of those with SJS/TEN. Mortality was 16% among those with other skin manifestations. Eighteen percent of those with jaundice died, compared with 3% of those without jaundice.
Thirty patients with DILI/DISI died; 37% (11) of them had SJS/TEN, compared with 17% of survivors (P = .01). DRESS was more common in survivors (62% vs. 33%; P = .02).
Of DILI/DISI and SJS/TEN cases, 75% were associated with four drug classes: antiepileptic drugs, dapsone, antiretroviral therapies, and leflunomide.
“The liver is the biggest internal organ in the body, and skin is the largest external organ, so there is some correlation between the two, but people haven’t looked at it. People should come together and see why some drugs produce both these injuries. I think there is some mechanistic information in these drugs,” said Dr. Devarbhavi.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: Researchers hope the findings will shed light on the mechanism of injury.
Major finding: 28% of patients with DILI also had a skin rash.
Study details: Retrospective analysis of 921 DILI patients.
Disclosures: No source of funding was disclosed. Dr. Devarbhavi disclosed no relevant conflicts.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 37.
Medicaid patients have higher MELD scores at time of liver transplantation
SAN FRANCISCO – Despite implementation of the Model for End Stage Liver Disease score to prioritize liver transplantation, .
“It can be difficult for patients with Medicaid to access liver transplantation,” lead study author Ann Robinson, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “These patients may be living in underserved areas with limited resources.”
In an effort to evaluate insurance-specific disparities in severity of liver disease at the time of liver transplantation wait-list registration and at the time of liver transplantation, Dr. Robinson and her colleagues retrospectively evaluated the 2005-2016 United Network for Organ Sharing/Organ Procurement and Transplant Network liver transplant registry. They used multivariate linear regression models to make insurance-specific comparisons of MELD scores at wait-list registration and at liver transplantation, which included adjustments for age, sex, year, etiology of liver disease, body mass index, ascites, hepatocellular carcinoma (HCC), and hepatic encephalopathy.
Dr. Robinson, who is a third-year internal medicine resident at Highland Hospital, Oakland, Calif., reported findings from 88,542 liver transplantation wait-list registrants with a mean age of 56 years. Their overall mean MELD score was 17.4 at wait-list registration and 22.6 at time of liver transplantation. The greatest mean MELD score at the time of wait-list registration was observed in Medicaid patients (18.4, compared with 17.2 among Veterans Affairs patients, 17 among Medicare patients, and 17 among privately/commercially insured patients; P less than .01). Meanwhile, the greatest mean MELD score at the time of liver transplantation was observed in Medicaid patients (23.5, compared with 21.4 among VA patients, 21.3 among privately/commercially insured patients, and 21.1 among Medicare patients; P less than .01).
Multivariate regression analysis revealed that, among patients without hepatocellular carcinoma, those with coverage other than private or commercial insurance had significantly higher MELD scores at wait-list registration (P less than .01). Specifically, the odds ratio was highest for VA patients (odds ratio, 2.59), followed by those covered by Medicaid (OR, 2.45), and Medicare (OR, 1.86). Similar trends were observed in hepatocellular carcinoma patients, with the highest biological MELD score at wait-list seen in those covered by Medicaid.
On regression analysis, while Medicaid patients with hepatocellular carcinoma had significantly higher biological MELD scores at time of liver transplantation, compared with those with private/commercial insurance (Medicaid OR, 2.06; P less than .05), no differences were observed among patients without hepatocellular carcinoma.
Dr. Robinson reported having no financial disclosures.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 464.
SAN FRANCISCO – Despite implementation of the Model for End Stage Liver Disease score to prioritize liver transplantation, .
“It can be difficult for patients with Medicaid to access liver transplantation,” lead study author Ann Robinson, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “These patients may be living in underserved areas with limited resources.”
In an effort to evaluate insurance-specific disparities in severity of liver disease at the time of liver transplantation wait-list registration and at the time of liver transplantation, Dr. Robinson and her colleagues retrospectively evaluated the 2005-2016 United Network for Organ Sharing/Organ Procurement and Transplant Network liver transplant registry. They used multivariate linear regression models to make insurance-specific comparisons of MELD scores at wait-list registration and at liver transplantation, which included adjustments for age, sex, year, etiology of liver disease, body mass index, ascites, hepatocellular carcinoma (HCC), and hepatic encephalopathy.
Dr. Robinson, who is a third-year internal medicine resident at Highland Hospital, Oakland, Calif., reported findings from 88,542 liver transplantation wait-list registrants with a mean age of 56 years. Their overall mean MELD score was 17.4 at wait-list registration and 22.6 at time of liver transplantation. The greatest mean MELD score at the time of wait-list registration was observed in Medicaid patients (18.4, compared with 17.2 among Veterans Affairs patients, 17 among Medicare patients, and 17 among privately/commercially insured patients; P less than .01). Meanwhile, the greatest mean MELD score at the time of liver transplantation was observed in Medicaid patients (23.5, compared with 21.4 among VA patients, 21.3 among privately/commercially insured patients, and 21.1 among Medicare patients; P less than .01).
Multivariate regression analysis revealed that, among patients without hepatocellular carcinoma, those with coverage other than private or commercial insurance had significantly higher MELD scores at wait-list registration (P less than .01). Specifically, the odds ratio was highest for VA patients (odds ratio, 2.59), followed by those covered by Medicaid (OR, 2.45), and Medicare (OR, 1.86). Similar trends were observed in hepatocellular carcinoma patients, with the highest biological MELD score at wait-list seen in those covered by Medicaid.
On regression analysis, while Medicaid patients with hepatocellular carcinoma had significantly higher biological MELD scores at time of liver transplantation, compared with those with private/commercial insurance (Medicaid OR, 2.06; P less than .05), no differences were observed among patients without hepatocellular carcinoma.
Dr. Robinson reported having no financial disclosures.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 464.
SAN FRANCISCO – Despite implementation of the Model for End Stage Liver Disease score to prioritize liver transplantation, .
“It can be difficult for patients with Medicaid to access liver transplantation,” lead study author Ann Robinson, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “These patients may be living in underserved areas with limited resources.”
In an effort to evaluate insurance-specific disparities in severity of liver disease at the time of liver transplantation wait-list registration and at the time of liver transplantation, Dr. Robinson and her colleagues retrospectively evaluated the 2005-2016 United Network for Organ Sharing/Organ Procurement and Transplant Network liver transplant registry. They used multivariate linear regression models to make insurance-specific comparisons of MELD scores at wait-list registration and at liver transplantation, which included adjustments for age, sex, year, etiology of liver disease, body mass index, ascites, hepatocellular carcinoma (HCC), and hepatic encephalopathy.
Dr. Robinson, who is a third-year internal medicine resident at Highland Hospital, Oakland, Calif., reported findings from 88,542 liver transplantation wait-list registrants with a mean age of 56 years. Their overall mean MELD score was 17.4 at wait-list registration and 22.6 at time of liver transplantation. The greatest mean MELD score at the time of wait-list registration was observed in Medicaid patients (18.4, compared with 17.2 among Veterans Affairs patients, 17 among Medicare patients, and 17 among privately/commercially insured patients; P less than .01). Meanwhile, the greatest mean MELD score at the time of liver transplantation was observed in Medicaid patients (23.5, compared with 21.4 among VA patients, 21.3 among privately/commercially insured patients, and 21.1 among Medicare patients; P less than .01).
Multivariate regression analysis revealed that, among patients without hepatocellular carcinoma, those with coverage other than private or commercial insurance had significantly higher MELD scores at wait-list registration (P less than .01). Specifically, the odds ratio was highest for VA patients (odds ratio, 2.59), followed by those covered by Medicaid (OR, 2.45), and Medicare (OR, 1.86). Similar trends were observed in hepatocellular carcinoma patients, with the highest biological MELD score at wait-list seen in those covered by Medicaid.
On regression analysis, while Medicaid patients with hepatocellular carcinoma had significantly higher biological MELD scores at time of liver transplantation, compared with those with private/commercial insurance (Medicaid OR, 2.06; P less than .05), no differences were observed among patients without hepatocellular carcinoma.
Dr. Robinson reported having no financial disclosures.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 464.
AT THE LIVER MEETING 2018
Key clinical point: Significant insurance-specific disparities in MELD scores at time of wait-list registration were observed among patients with and without hepatocellular carcinoma.
Major finding: Among patients without hepatocellular carcinoma, those with Medicaid coverage were 2.45 times more likely to have higher MELD scores at wait-list registration, compared with those covered by commercial or private insurance (P less than .01).
Study details: A retrospective analysis of 88,542 liver transplantation wait-list registrants.
Disclosures: Dr. Robinson reported having no disclosures.
Source: Hepatology 2018 Oct 1;68[S1], Abstract 464.
The Liver Meeting 2018: Hepatitis B novel therapies debrief – key abstracts
SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.
“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.
An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.
Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.
One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.
Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.
Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.
A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.
Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.
Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.
Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.
Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.
Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.
SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.
“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.
An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.
Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.
One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.
Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.
Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.
A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.
Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.
Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.
Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.
Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.
Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.
SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.
“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.
An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.
Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.
One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.
Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.
Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.
A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.
Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.
Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.
Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.
Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.
Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.
REPORTING FROM THE LIVER MEETING 2018
Routine markers predicted histologic response to obeticholic acid in NASH
Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.
In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.
A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”
NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).
In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.
The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.
Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.
The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.
SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.
Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.
In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.
A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”
NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).
In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.
The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.
Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.
The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.
SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.
Routine clinical and laboratory markers predicted histologic response to obeticholic acid therapy among patients with nonalcoholic steatohepatitis (NASH), investigators reported in Gastroenterology.
In a secondary analysis of data from the FLINT trial, histologic response at treatment week 24 correlated significantly with baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides 154 mg/dL or less, baseline international normalized ratio no greater than 1, baseline aspartate aminotransferase (AST) level no greater than 49 U/L, and at least a 17-U/L decrease from baseline in alanine aminotransferase (ALT) level.
A stepwise logistic regression model including these variables and receipt of obeticholic acid distinguished histologic responders from nonresponders with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval, 0.77-0.89; P less than .0001). These parameters “are readily available clinical and biochemical characteristics that are routinely available to clinicians and may be applied to daily practice,” wrote Rohit Loomba, MD, of the University of California, San Diego, with his associates. They may show “that the patients most likely to achieve histologic response are those with higher disease activity, but still with largely conserved liver function, allowing for potential healing or improvement.”
NASH is expected to become the leading reason for liver transplantation in the next few decades. Several treatments can induce histologic hepatic improvement, but none are approved for NASH. Obeticholic acid (Ocaliva) is a selective agonist of the farsenoid X receptor ligand and is indicated for treating primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA).
In the 72-week, multicenter, randomized, double-blind FLINT trial, noncirrhotic adults with biopsy-confirmed NASH received once-daily obeticholic acid (25 mg) or placebo. Blinded pathologists interpreted biopsies. The primary endpoint (improvement in liver histology) was met in the interim analysis, so the researchers stopped collecting final liver biopsies.
The secondary analysis included all patients with baseline and final biopsies, including 73 histologic responders and 127 nonresponders. “[The] trends for each of the selected predictors was the same when comparing histologic responders to nonresponders, regardless of treatment group (obeticholic acid versus placebo),” the researchers wrote. The predictors are biologically feasible, the researchers contended – for example, high baseline NAS would be more susceptible to significant improvement, while lower baseline triglyceride levels might reflect a liver that “is less burdened by triglyceride secretion” and, therefore, might have greater capacity to heal. Both AST and ALT “are metrics of liver injury,” and lower baseline AST, in combination with greater reduction in ALT at week 24, probably reflected “AST and ALT levels that are closer to normal,” they added.
Nonetheless, the researchers acknowledged several possible sources of bias. Trial participants were recruited from tertiary care settings and had complete biopsy data, which might not reflect the overall NASH population. Overfitting also could have biased the model because the number of variables assessed approached the number of events being predicted. Furthermore, the model assessed no treatment other than obeticholic acid. “A more robust model could potentially be developed if multiple pharmacological interventions could be considered simultaneously,” the researchers noted. The ongoing phase 3 REGENERATE trial aims to confirm the benefit of obeticholic acid in patients with NASH, they added. Topline results are expected in October 2022.
The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.
SOURCE: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.
FROM GASTROENTEROLOGY
Key clinical point: Routine clinical and laboratory parameters were significant correlates of histologic response to obeticholic acid therapy in patients with nonalcoholic steatohepatitis.
Major finding: Significant predictors included baseline nonalcoholic fatty liver disease activity score (NAS) greater than 5, baseline triglycerides up to 154 mg/dL, baseline international normalized ratio up to 1, baseline aspartate aminotransferase up to 49 U/L, and at least a 17-U/L decrease in alanine aminotransferase at week 24.
Study details: Secondary analysis of data from 200 patients with nonalcoholic steatohepatitis in the randomized, double-blind FLINT trial.
Disclosures: The FLINT trial was funded by Intercept Pharmaceuticals and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Loomba cochaired the FLINT trial protocol writing committee, is on the steering committee of the ongoing REGENERATE trial, and has received research funding from Intercept Pharmaceuticals, which developed and markets obeticholic acid. Several other coinvestigators reported ties to Intercept and to other pharmaceutical companies.
Source: Loomba R et al. Gastroenterology. 2018 Sep 14. doi: 10.1053/j.gastro.2018.09.021.
Hep C–infected livers are safe for transplant
SAN FRANCISCO – A new analysis shows that hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality. The work confirms that readily available direct-acting antiviral therapy can protect organ recipients and open a source of organs that is typically overlooked.
The work should encourage both physicians and patients to take a closer look at hepatitis C–infected organs, especially for sicker patients, according to Sonali Paul, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Disease 2018.
“A lot of people have an ethical issue with it because we’re actively transplanting a virus into someone. We’re giving someone a disease. My take on it is that we give people Epstein Barr virus or cytomegalovirus all the time – we just [provide] prophylaxis against it, and we don’t even bat an eye. Hepatitis C can be devastating, but we have totally effective treatments for it,” said Dr. Paul, who is an assistant professor of medicine at the University of Chicago.
She cited one colleague at the University of Chicago who several years ago transplanted an organ that had been passed over 700 times, though times have changed since then. “I think people more and more are doing this practice because we know it’s so successful,” said Dr. Paul.
It’s also cost effective. Another study, presented during the same session by Jag Chhatwal, PhD, assistant professor at Harvard Medical School, Boston, showed that accepting a hepatitis C–positive liver is cost effective in patients with Model for End-Stage Liver Disease (MELD) scores ranging from 22 to 40.
“I think we’re going to find across all organ systems, if we can transplant patients rather than keep them on dialysis or keep them on wait lists, it’s got to be cost effective, especially if you think of the health care–associated costs – like a heart transplant patient waiting on the list in the ICU. That’s a huge health care cost,” said Dr. Paul.
Dr. Paul’s team performed an analysis of the Scientific Registry of Transplant Recipients, including single organ transplants from deceased donors, during 2014-2018. Over that period, the number of transplants from hepatitis C–positive donors to hepatitis C–positive recipients rose from 8 in 2014 to 269, and the number of transplants from hepatitis C–positive donors to hepatitis C–negative recipients rose from 0 to 46.
The researchers compared trends from hepatitis C–negative donors with hepatitis C–negative recipients (n = 11,270), negative donors with positive recipients (n = 4,748), positive donors with negative recipients (n = 87), and positive donors with positive recipients (n = 753). Donor status had no effect on graft survival times at 1 or 2 years, with values ranging from 92.6% (negative to negative) to 94.3% (positive to positive) at 1 year and between 85.7% (positive to negative) and 89.7% (positive to positive) at 2 years.
“For someone who has a MELD score of over 20, who has a declining quality of life and really can’t do anything, I think this is a great opportunity. And most patients are absolutely willing to take these organs. We haven’t had many people say no, especially if they feel poorly,” said Dr. Paul.
She also underscored the importance of ensuring that the patient is informed of the status of the donor liver and the need to complete treatment: “The patient has to know what’s happening, and the hospital has to have a safety net if the insurance doesn’t pay for hepatitis C treatment.”
SOURCE: AASLD 2018, Abstract 0249.
SAN FRANCISCO – A new analysis shows that hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality. The work confirms that readily available direct-acting antiviral therapy can protect organ recipients and open a source of organs that is typically overlooked.
The work should encourage both physicians and patients to take a closer look at hepatitis C–infected organs, especially for sicker patients, according to Sonali Paul, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Disease 2018.
“A lot of people have an ethical issue with it because we’re actively transplanting a virus into someone. We’re giving someone a disease. My take on it is that we give people Epstein Barr virus or cytomegalovirus all the time – we just [provide] prophylaxis against it, and we don’t even bat an eye. Hepatitis C can be devastating, but we have totally effective treatments for it,” said Dr. Paul, who is an assistant professor of medicine at the University of Chicago.
She cited one colleague at the University of Chicago who several years ago transplanted an organ that had been passed over 700 times, though times have changed since then. “I think people more and more are doing this practice because we know it’s so successful,” said Dr. Paul.
It’s also cost effective. Another study, presented during the same session by Jag Chhatwal, PhD, assistant professor at Harvard Medical School, Boston, showed that accepting a hepatitis C–positive liver is cost effective in patients with Model for End-Stage Liver Disease (MELD) scores ranging from 22 to 40.
“I think we’re going to find across all organ systems, if we can transplant patients rather than keep them on dialysis or keep them on wait lists, it’s got to be cost effective, especially if you think of the health care–associated costs – like a heart transplant patient waiting on the list in the ICU. That’s a huge health care cost,” said Dr. Paul.
Dr. Paul’s team performed an analysis of the Scientific Registry of Transplant Recipients, including single organ transplants from deceased donors, during 2014-2018. Over that period, the number of transplants from hepatitis C–positive donors to hepatitis C–positive recipients rose from 8 in 2014 to 269, and the number of transplants from hepatitis C–positive donors to hepatitis C–negative recipients rose from 0 to 46.
The researchers compared trends from hepatitis C–negative donors with hepatitis C–negative recipients (n = 11,270), negative donors with positive recipients (n = 4,748), positive donors with negative recipients (n = 87), and positive donors with positive recipients (n = 753). Donor status had no effect on graft survival times at 1 or 2 years, with values ranging from 92.6% (negative to negative) to 94.3% (positive to positive) at 1 year and between 85.7% (positive to negative) and 89.7% (positive to positive) at 2 years.
“For someone who has a MELD score of over 20, who has a declining quality of life and really can’t do anything, I think this is a great opportunity. And most patients are absolutely willing to take these organs. We haven’t had many people say no, especially if they feel poorly,” said Dr. Paul.
She also underscored the importance of ensuring that the patient is informed of the status of the donor liver and the need to complete treatment: “The patient has to know what’s happening, and the hospital has to have a safety net if the insurance doesn’t pay for hepatitis C treatment.”
SOURCE: AASLD 2018, Abstract 0249.
SAN FRANCISCO – A new analysis shows that hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality. The work confirms that readily available direct-acting antiviral therapy can protect organ recipients and open a source of organs that is typically overlooked.
The work should encourage both physicians and patients to take a closer look at hepatitis C–infected organs, especially for sicker patients, according to Sonali Paul, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Disease 2018.
“A lot of people have an ethical issue with it because we’re actively transplanting a virus into someone. We’re giving someone a disease. My take on it is that we give people Epstein Barr virus or cytomegalovirus all the time – we just [provide] prophylaxis against it, and we don’t even bat an eye. Hepatitis C can be devastating, but we have totally effective treatments for it,” said Dr. Paul, who is an assistant professor of medicine at the University of Chicago.
She cited one colleague at the University of Chicago who several years ago transplanted an organ that had been passed over 700 times, though times have changed since then. “I think people more and more are doing this practice because we know it’s so successful,” said Dr. Paul.
It’s also cost effective. Another study, presented during the same session by Jag Chhatwal, PhD, assistant professor at Harvard Medical School, Boston, showed that accepting a hepatitis C–positive liver is cost effective in patients with Model for End-Stage Liver Disease (MELD) scores ranging from 22 to 40.
“I think we’re going to find across all organ systems, if we can transplant patients rather than keep them on dialysis or keep them on wait lists, it’s got to be cost effective, especially if you think of the health care–associated costs – like a heart transplant patient waiting on the list in the ICU. That’s a huge health care cost,” said Dr. Paul.
Dr. Paul’s team performed an analysis of the Scientific Registry of Transplant Recipients, including single organ transplants from deceased donors, during 2014-2018. Over that period, the number of transplants from hepatitis C–positive donors to hepatitis C–positive recipients rose from 8 in 2014 to 269, and the number of transplants from hepatitis C–positive donors to hepatitis C–negative recipients rose from 0 to 46.
The researchers compared trends from hepatitis C–negative donors with hepatitis C–negative recipients (n = 11,270), negative donors with positive recipients (n = 4,748), positive donors with negative recipients (n = 87), and positive donors with positive recipients (n = 753). Donor status had no effect on graft survival times at 1 or 2 years, with values ranging from 92.6% (negative to negative) to 94.3% (positive to positive) at 1 year and between 85.7% (positive to negative) and 89.7% (positive to positive) at 2 years.
“For someone who has a MELD score of over 20, who has a declining quality of life and really can’t do anything, I think this is a great opportunity. And most patients are absolutely willing to take these organs. We haven’t had many people say no, especially if they feel poorly,” said Dr. Paul.
She also underscored the importance of ensuring that the patient is informed of the status of the donor liver and the need to complete treatment: “The patient has to know what’s happening, and the hospital has to have a safety net if the insurance doesn’t pay for hepatitis C treatment.”
SOURCE: AASLD 2018, Abstract 0249.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: Use of hepatitis C–positive livers can significantly increase the donor organ pool.
Major finding: Hepatitis C–infected livers can be safely transplanted into recipients with no effect on graft survival, retransplantation, or mortality.
Study details: Retrospective analysis of 16,858 liver transplants.
Disclosures: The study was funded internally. Dr. Paul has no financial disclosures.
Source: AASLD 2018, Abstract 0249.
Risk of cancer in NAFLD is 91% higher than in control subjects
SAN FRANCISCO –
Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”
In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.
The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”
When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”
Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”
Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.
SAN FRANCISCO –
Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”
In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.
The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”
When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”
Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”
Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.
SAN FRANCISCO –
Those are key findings from a community cohort study with up to 21 years of follow-up, which one of the authors, Alina M. Allen, MD, discussed during a press briefing at the annual meeting of the American Association for the Study of Liver Diseases.
“NAFLD is the most common chronic liver disease in the Western world,” said Dr. Allen, a gastroenterologist at the Mayo Clinic, Rochester, Minn. “It affects one in four adults in the U.S. It is related to fat accumulation in the liver in people who are overweight or obese and can lead to cirrhosis and liver-related mortality. However, the most common cause of death in this population is not liver disease but malignancy and cardiovascular disease. There is a paucity of epidemiologic studies of extrahepatic cancer in NAFLD. It is not clear what types of cancers and how much higher their cancer risk is in reference to the general population.”
In an effort to determine the incidence of cancer diagnoses in NALFD, compared with controls, in a U.S. community, Dr. Allen and her colleagues drew from the Rochester Epidemiology Project to evaluate 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects in Olmstead County, Minn., during 1997-2017. The researchers obtained corresponding Surveillance, Epidemiology, and End Results Program (SEER) rates as a quality check and used a regression model to assess the malignancy risk in NAFLD overall and by cancer type, age, sex, and body mass index. They recorded all new diagnoses of cancers that developed in both groups until 2018, for a total possible follow-up of 21 years, and they reported results in incidence rate ratios, a risk estimate similar to hazard ratios.
The mean age of the study population was 53 years, 53% were female, and the mean follow-up was 8 years with a range from 1 to 21 years. New cancers were identified in 16% of subjects with NALFD and in 12% of control subjects. The overall risk of malignancy was 91% higher in NAFLD subjects, compared with control subjects; there were higher rates in the NAFLD subjects for most types of cancers, but the largest increases were in GI cancers. The greatest malignancy risk was for cancer of the liver (RR, 3.24), followed by cancer of the uterus (RR, 2.39), stomach (RR, 2.34), pancreas (RR, 2.09), and colon (RR, 1.75). “Interestingly, the risk of colon cancer increased only in men but not in women,” Dr. Allen said. “These data provide an important hierarchical overview of the top most important malignancy risks associated with NAFLD that the medical community should be aware of.”
When the researchers looked for differences in age at cancer diagnosis between NAFLD and controls, they found that pancreas cancer occurred at a younger age among subjects with NAFLD. They also observed that colon cancer occurred at a younger age in men with NAFLD, but not in women with the disease. “What was most interesting to us was the assessment of cancer risk in NAFLD versus obesity alone,” Dr. Allen said. “Previous studies from the general population have linked obesity to a higher risk of cancer. Whether the presence of fatty liver disease would impact that risk has not been assessed. We showed that obesity is associated with a higher risk of cancer only in those with NAFLD, not in those without. If validated in independent cohorts, these findings could change our understanding of the relationship between obesity and cancer and the importance of screening for NAFLD – not only to risk-stratify liver disease but also for the risk of extrahepatic malignancy.”
Dr. Allen concluded her presentation by noting that findings from large population-based studies such as the Rochester Epidemiology Project “can offer important epidemiologic data regarding the biggest threats to the health of a community,” she said. “Such data increase awareness, enable appropriate counseling, and could inform screening policies. There is a signal in the fact that the GI cancers are increased [in NAFLD]. It’s an interesting signal that needs to be studied further.”
Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]: Abstract 31.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: The risk of cancer in patients with nonalcoholic fatty liver disease is 91% higher than in control subjects.
Major finding: Among subjects with NAFLD, the greatest malignancy risk was for cancer of the liver (risk ratio, 3.24).
Study details: A cohort study of 4,791 adults diagnosed with NAFLD and 14,432 age- and sex-matched control subjects from the Rochester Epidemiology Project.
Disclosures: Dr. Allen reported having no financial conflicts.
Source: Allen AM. Hepatol. 2018;68[S1]:Abstract 31
Chronic liver disease independently linked to increased risk of falls
SAN FRANCISCO – .
“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”
In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.
The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).
Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).
Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”
Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1], Abstract 756.
SAN FRANCISCO – .
“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”
In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.
The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).
Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).
Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”
Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1], Abstract 756.
SAN FRANCISCO – .
“We have previously known that having cirrhosis, for example, is associated with the risk of falling, but we didn’t have any data from a nationally representative sample,” lead study author Maria Camila Pérez-Matos, MD, said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “What surprised us is that just by having chronic liver disease – any subtype – you’re more likely to fall, and also to have a fracture after you have fallen.”
In an effort to define the association between CLD and fall history and its related injuries, Dr. Pérez-Matos of the division of gastroenterology and hepatology at Beth Israel Deaconess Medical Center, Boston, and her associates examined data from 5,363 subjects aged 60 years and older in the Third National Health and Nutrition Examination Survey, which represents the noninstitutionalized civilian population in the United States. Their outcomes of interest were one or more falls occurring in the previous 12 months and fall-related injuries. The main exposure was definitive CLD, defined by chronic viral hepatitis (hepatitis C RNA or hepatitis B surface antigen), nonalcoholic steatohepatitis (NASH; hepatosteatosis by ultrasound with abnormal transaminases), and alcohol-related liver disease (females consuming more than 7 drinks/week and males consuming 14 drinks/week among, plus having abnormal transaminases). Suspected CLD was defined as having abnormal alanine aminotransferase levels (males greater than 30 IU/L, females greater than 19 IU/L), aspartate aminotransferase levels above 33 IU/L, or alkaline phosphatase levels above 100 IU/L. The researchers used univariate and multivariate logistic regression to examine associations.
The average age of subjects was 70 years, and 59% were female. Of the 5,363 subjects, 340 had definitive CLD. Of these, 234 (69%) had NASH, 85 (25%) had viral hepatitis, and 21 (6%) had alcoholic liver disease. Subjects with definitive CLD were more likely to be female and have diabetes mellitus, a higher body mass index, and physical/functional impairment. Dr. Pérez-Matos and her colleagues found that definitive CLD was associated with a 52% increase in the odds of having a history of falls (odds ratio, 1.52; P = .01). The association remained significant after controlling for age, sex, smoking, race, physical or functional impairment, impaired vision, polypharmacy, and body mass index. The degree of excess falling risk posed by CLD was similar to that of having impaired vision (OR, 1.48; P less than .001).
Of the CLD subtypes, subjects with viral hepatitis had the strongest association with a history of falls (OR, 2.2; P = .001). In addition, definitive CLD was found to have significant association with any physical impairment, even after adjusting for relevant covariates (OR, 1.63; P = .001).
Finally, multivariate logistic regression revealed that both suspected and definitive CLD were associated with injurious falls (OR, 1.40 and OR of 1.67, respectively). “Everyone is interested in preventing falls because of its public health impact, and predictors of falls are relatively limited,” said Elliott B. Tapper, MD, the study’s principal investigator, who is with the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. “Because chronic liver disease is increasingly common, our data is speaking to a hitherto unknown risk factor: one which if you apply it to other data sets might help figure out why more people are falling. The lesson is, there’s something about chronic liver disease; it’s a sign. If it’s fatty liver disease, it’s a sign that diabetes has taken its toll on the body – its nerves and muscles. There’s something about what’s going on in that person that’s worse than it is for other people. We don’t know cause or effect, but the association is strong and deserves further study, particularly when it comes to determining [which patients] in our clinics are at higher risk and making sure they’re doing physical therapy to prevent falls in the future.”
Dr. Tapper disclosed that she has a career development award from the National Institutes of Health. Dr. Pérez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1], Abstract 756.
REPORTING FROM THE LIVER MEETING 2018
Key clinical point: Attention to falls is warranted in chronic liver disease (CLD) patients at all stages of disease.
Major finding: Having definitive CLD was associated with a 52% increase in the odds of having a history of falls (OR 1.52; P = .01).
Study details: A cross-sectional analysis of 5,363 subjects in the Third National Health and Nutrition Examination Survey.
Disclosures: Dr. Tapper disclosed that he has a career development award from the National Institutes of Health. Dr. Perez-Matos reported having no monetary conflicts.
Source: Hepatol. 2018;68[S1]:Abstract 756.
FDA approves pembrolizumab for sorafenib-intolerant HCC patients
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.
Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.
The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.
Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.
Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.
The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.
Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with hepatocellular carcinoma who were previously treated with sorafenib.
Approval was based on results of KEYNOTE-224, a single-arm, open-label, multicenter trial evaluating pembrolizumab in a group of 104 patients with hepatocellular carcinoma who were either intolerant to or had disease progression with sorafenib, according to a company press release.
The objective response rate was 17%, with a complete response rate of 1% and a partial response rate of 16%. In responding patients, 89% had a response duration of at least 6 months, and 56% had a response duration of at least 12 months.
Adverse events were generally similar to those seen in trials of patients with melanoma or non–small cell lung cancer, and included pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and allogeneic hematopoietic stem cell transplantation complications.
“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease. Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib,” Andrew X. Zhu, MD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, said in the press release.