Will Pass

BOSTON – ED-based screening is a feasible method of detecting hepatitis C virus (HCV) in high-risk populations, but linkage to care remains low, according to investigators.

Will Pass/MDedge News

An HCV screening program involving three Seattle hospitals and more than 4,000 patients showed that linkage to care was lowest among patients who were younger, homeless, or used injection drugs, reported lead author Charles S. Landis, MD, PhD, of the University of Washington, Seattle.

“In the U.S., rates of acute HCV infections are increasing in younger patients and in areas disproportionally affected by the opiate epidemic,” Dr. Landis said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In order to achieve a goal of elimination, HCV screening, appropriate linkage to care, and treatment will need to be directed toward younger, marginalized, and underserved populations.”

Dr. Landis explained that EDs are suitable for HCV screening because users of emergency services are disproportionately affected by HCV, compared with patients in primary and specialty care settings. Despite this, linkage to care remains historically higher in primary and specialty care settings at approximately 70%, compared with 30% via the ED, Dr. Landis said.

Historically, EDs have been resistant to HCV screening programs, Dr. Landis said, but with the model used in the present study, which relied upon a full-time staff member in each ED who was employed by the infectious disease or hepatology department, no ED resources were needed.

Participants were willing adults who had reliable contact information. Patients were excluded if they were non–English speaking, incarcerated, enrolled or expected to enroll in another clinical study which excludes coenrollment, planned to move out of the region in the next 6 months, admitted to the ED with an acute life-threatening illness, or admitted to the ED for sexual assault. The program had three objectives: Screening, linkage to care, and treatment, all of which were coordinated by the aforementioned case manager.

To date, 4,182 patients have been screened, 936 have been enrolled, 95 have tested positive for HCV RNA, 32 have been linked with care, and 19 have been treated.

“So you can see, a lot of squeeze for a just a little bit of juice here,” Dr. Landis said, referring to the relatively low number of treated patients, compared with how many were screened.

The prevalence of HCV infection based on RNA testing was 2%, though one hospital had a rate of 5%. “This [prevalence] compares to, but is maybe slightly less than, the prevalence seen in others studies based in the emergency department,” Dr. Landis said. “The thought is, not all emergency departments are equal in terms of the patient population that they serve.”

Data analysis showed that the overall linkage to care was 36%. “This is still suboptimal, from my perspective,” Dr. Landis said, “but it does compare with several other ED-based studies.”

A closer look at the data showed that linkage was not uniform across the population. Among patients with homes, linkage to care was 59%, compared with 20% for patients who were homeless (P = .02).

“Ultimately, we need to tailor our approaches for linking homeless patients differently than patients who are not homeless,” Dr. Landis said.

Patients who reported no injection-drug use had a linkage to care of 50%, which was numerically higher than the rate of 20% among users of injection drugs; this difference was not statistically significant, which Dr. Landis attributed to insufficient population size. Similarly, younger patients showed numerical trends toward lower linkage to care.

“Future work will attempt to optimize linkage to care strategies based on patient demographic factors, such as active injection drug use or homelessness,” Dr. Landis said.

During discussion, a conference attendee from the United States expressed skepticism of the program’s merits.

“I may be a glass-half-empty person, but is it worth all this effort?” the attendee asked. “In all honesty, you treated a few dozen [patients] for 180,000 visits [per year]. I’m really not sure it’s worth those efforts, and I’m wondering if those efforts could be placed in different areas, especially for a higher yield.”

“Point well taken,” Dr. Landis said. “I think that was the purpose of the study, to see if the emergency department is a place to screen and link patients to care, and we’re trying to optimize that. Remember, there were 4,000 patients, but for many of those, it took literally a minute to screen them.”

An attendee from Australia offered a slightly more positive take on the findings, followed by a suggestion to improve linkage in marginalized populations.

“I’m not sure I’d be pessimistic,” the attendee said. “I think you ought to be commended for getting that number of people to link, because it is very difficult when we are looking at linking people from a hospital-based setting who actually live in the community and suffer from homelessness and mental health issues and incarceration and a whole range of other things. ... Maybe we need to change our idea of having these centralized silos where people are referred, and go out into the community, much like [tuberculosis] clinics used to do, and track people down.”

The study was funded by Gilead. The investigators disclosed additional relationships with HighTide Therapeutics, Intercept, AbbVie, and others.

SOURCE: Landis CS et al. The Liver Meeting 2019, Abstract 168.

BOSTON – ED-based screening is a feasible method of detecting hepatitis C virus (HCV) in high-risk populations, but linkage to care remains low, according to investigators.

Will Pass/MDedge News

An HCV screening program involving three Seattle hospitals and more than 4,000 patients showed that linkage to care was lowest among patients who were younger, homeless, or used injection drugs, reported lead author Charles S. Landis, MD, PhD, of the University of Washington, Seattle.

“In the U.S., rates of acute HCV infections are increasing in younger patients and in areas disproportionally affected by the opiate epidemic,” Dr. Landis said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In order to achieve a goal of elimination, HCV screening, appropriate linkage to care, and treatment will need to be directed toward younger, marginalized, and underserved populations.”

Dr. Landis explained that EDs are suitable for HCV screening because users of emergency services are disproportionately affected by HCV, compared with patients in primary and specialty care settings. Despite this, linkage to care remains historically higher in primary and specialty care settings at approximately 70%, compared with 30% via the ED, Dr. Landis said.

Historically, EDs have been resistant to HCV screening programs, Dr. Landis said, but with the model used in the present study, which relied upon a full-time staff member in each ED who was employed by the infectious disease or hepatology department, no ED resources were needed.

Participants were willing adults who had reliable contact information. Patients were excluded if they were non–English speaking, incarcerated, enrolled or expected to enroll in another clinical study which excludes coenrollment, planned to move out of the region in the next 6 months, admitted to the ED with an acute life-threatening illness, or admitted to the ED for sexual assault. The program had three objectives: Screening, linkage to care, and treatment, all of which were coordinated by the aforementioned case manager.

To date, 4,182 patients have been screened, 936 have been enrolled, 95 have tested positive for HCV RNA, 32 have been linked with care, and 19 have been treated.

“So you can see, a lot of squeeze for a just a little bit of juice here,” Dr. Landis said, referring to the relatively low number of treated patients, compared with how many were screened.

The prevalence of HCV infection based on RNA testing was 2%, though one hospital had a rate of 5%. “This [prevalence] compares to, but is maybe slightly less than, the prevalence seen in others studies based in the emergency department,” Dr. Landis said. “The thought is, not all emergency departments are equal in terms of the patient population that they serve.”

Data analysis showed that the overall linkage to care was 36%. “This is still suboptimal, from my perspective,” Dr. Landis said, “but it does compare with several other ED-based studies.”

A closer look at the data showed that linkage was not uniform across the population. Among patients with homes, linkage to care was 59%, compared with 20% for patients who were homeless (P = .02).

“Ultimately, we need to tailor our approaches for linking homeless patients differently than patients who are not homeless,” Dr. Landis said.

Patients who reported no injection-drug use had a linkage to care of 50%, which was numerically higher than the rate of 20% among users of injection drugs; this difference was not statistically significant, which Dr. Landis attributed to insufficient population size. Similarly, younger patients showed numerical trends toward lower linkage to care.

“Future work will attempt to optimize linkage to care strategies based on patient demographic factors, such as active injection drug use or homelessness,” Dr. Landis said.

During discussion, a conference attendee from the United States expressed skepticism of the program’s merits.

“I may be a glass-half-empty person, but is it worth all this effort?” the attendee asked. “In all honesty, you treated a few dozen [patients] for 180,000 visits [per year]. I’m really not sure it’s worth those efforts, and I’m wondering if those efforts could be placed in different areas, especially for a higher yield.”

“Point well taken,” Dr. Landis said. “I think that was the purpose of the study, to see if the emergency department is a place to screen and link patients to care, and we’re trying to optimize that. Remember, there were 4,000 patients, but for many of those, it took literally a minute to screen them.”

An attendee from Australia offered a slightly more positive take on the findings, followed by a suggestion to improve linkage in marginalized populations.

“I’m not sure I’d be pessimistic,” the attendee said. “I think you ought to be commended for getting that number of people to link, because it is very difficult when we are looking at linking people from a hospital-based setting who actually live in the community and suffer from homelessness and mental health issues and incarceration and a whole range of other things. ... Maybe we need to change our idea of having these centralized silos where people are referred, and go out into the community, much like [tuberculosis] clinics used to do, and track people down.”

The study was funded by Gilead. The investigators disclosed additional relationships with HighTide Therapeutics, Intercept, AbbVie, and others.

SOURCE: Landis CS et al. The Liver Meeting 2019, Abstract 168.

BOSTON – ED-based screening is a feasible method of detecting hepatitis C virus (HCV) in high-risk populations, but linkage to care remains low, according to investigators.

Will Pass/MDedge News

An HCV screening program involving three Seattle hospitals and more than 4,000 patients showed that linkage to care was lowest among patients who were younger, homeless, or used injection drugs, reported lead author Charles S. Landis, MD, PhD, of the University of Washington, Seattle.

“In the U.S., rates of acute HCV infections are increasing in younger patients and in areas disproportionally affected by the opiate epidemic,” Dr. Landis said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In order to achieve a goal of elimination, HCV screening, appropriate linkage to care, and treatment will need to be directed toward younger, marginalized, and underserved populations.”

Dr. Landis explained that EDs are suitable for HCV screening because users of emergency services are disproportionately affected by HCV, compared with patients in primary and specialty care settings. Despite this, linkage to care remains historically higher in primary and specialty care settings at approximately 70%, compared with 30% via the ED, Dr. Landis said.

Historically, EDs have been resistant to HCV screening programs, Dr. Landis said, but with the model used in the present study, which relied upon a full-time staff member in each ED who was employed by the infectious disease or hepatology department, no ED resources were needed.

Participants were willing adults who had reliable contact information. Patients were excluded if they were non–English speaking, incarcerated, enrolled or expected to enroll in another clinical study which excludes coenrollment, planned to move out of the region in the next 6 months, admitted to the ED with an acute life-threatening illness, or admitted to the ED for sexual assault. The program had three objectives: Screening, linkage to care, and treatment, all of which were coordinated by the aforementioned case manager.

To date, 4,182 patients have been screened, 936 have been enrolled, 95 have tested positive for HCV RNA, 32 have been linked with care, and 19 have been treated.

“So you can see, a lot of squeeze for a just a little bit of juice here,” Dr. Landis said, referring to the relatively low number of treated patients, compared with how many were screened.

The prevalence of HCV infection based on RNA testing was 2%, though one hospital had a rate of 5%. “This [prevalence] compares to, but is maybe slightly less than, the prevalence seen in others studies based in the emergency department,” Dr. Landis said. “The thought is, not all emergency departments are equal in terms of the patient population that they serve.”

Data analysis showed that the overall linkage to care was 36%. “This is still suboptimal, from my perspective,” Dr. Landis said, “but it does compare with several other ED-based studies.”

A closer look at the data showed that linkage was not uniform across the population. Among patients with homes, linkage to care was 59%, compared with 20% for patients who were homeless (P = .02).

“Ultimately, we need to tailor our approaches for linking homeless patients differently than patients who are not homeless,” Dr. Landis said.

Patients who reported no injection-drug use had a linkage to care of 50%, which was numerically higher than the rate of 20% among users of injection drugs; this difference was not statistically significant, which Dr. Landis attributed to insufficient population size. Similarly, younger patients showed numerical trends toward lower linkage to care.

“Future work will attempt to optimize linkage to care strategies based on patient demographic factors, such as active injection drug use or homelessness,” Dr. Landis said.

During discussion, a conference attendee from the United States expressed skepticism of the program’s merits.

“I may be a glass-half-empty person, but is it worth all this effort?” the attendee asked. “In all honesty, you treated a few dozen [patients] for 180,000 visits [per year]. I’m really not sure it’s worth those efforts, and I’m wondering if those efforts could be placed in different areas, especially for a higher yield.”

“Point well taken,” Dr. Landis said. “I think that was the purpose of the study, to see if the emergency department is a place to screen and link patients to care, and we’re trying to optimize that. Remember, there were 4,000 patients, but for many of those, it took literally a minute to screen them.”

An attendee from Australia offered a slightly more positive take on the findings, followed by a suggestion to improve linkage in marginalized populations.

“I’m not sure I’d be pessimistic,” the attendee said. “I think you ought to be commended for getting that number of people to link, because it is very difficult when we are looking at linking people from a hospital-based setting who actually live in the community and suffer from homelessness and mental health issues and incarceration and a whole range of other things. ... Maybe we need to change our idea of having these centralized silos where people are referred, and go out into the community, much like [tuberculosis] clinics used to do, and track people down.”

The study was funded by Gilead. The investigators disclosed additional relationships with HighTide Therapeutics, Intercept, AbbVie, and others.

SOURCE: Landis CS et al. The Liver Meeting 2019, Abstract 168.

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

The investigators reported no relevant disclosures.

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

The investigators reported no relevant disclosures.

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

The investigators reported no relevant disclosures.

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.

Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.

Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.

Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.

The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.

SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.

Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.

Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.

Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.

The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.

SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.

Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.

Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.

Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.

The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.

SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.

The Multiple Myeloma Research Foundation (MMRF) recently launched its Direct-to-Patient registry, in what the organization’s leaders are describing as a “disruptive” step toward improving outcomes for patients with multiple myeloma.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The new registry is intended to build upon CoMMpass, a program started 8 years ago that now represents the largest genomic database of any type of cancer. Although CoMMpass includes data from about 1,150 patients with myeloma, it’s not enough information, according to the chief marketing and development officer at the MMRF, Anne Quinn Young.

“For a disease as heterogenous as myeloma is, we need more, particularly because we don’t have all the samples for later-stage disease,” Ms. Quinn Young said in an interview. “And even with the clinical data, given the patient population, both [in terms of] demographics and the nature of the disease, the numbers of patients still living after multiple relapses is rather small.”

In an earlier effort to gather more data, the MMRF first turned to other organizations for help, but this approach fell short because of scarcity of data, and in some cases, unwillingness to share. Steven Labkoff, MD, chief data officer at the MMRF, described this experience in an interview.

The Multiple Myeloma Research Foundation (MMRF) recently launched its Direct-to-Patient registry, in what the organization’s leaders are describing as a “disruptive” step toward improving outcomes for patients with multiple myeloma.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The new registry is intended to build upon CoMMpass, a program started 8 years ago that now represents the largest genomic database of any type of cancer. Although CoMMpass includes data from about 1,150 patients with myeloma, it’s not enough information, according to the chief marketing and development officer at the MMRF, Anne Quinn Young.

“For a disease as heterogenous as myeloma is, we need more, particularly because we don’t have all the samples for later-stage disease,” Ms. Quinn Young said in an interview. “And even with the clinical data, given the patient population, both [in terms of] demographics and the nature of the disease, the numbers of patients still living after multiple relapses is rather small.”

In an earlier effort to gather more data, the MMRF first turned to other organizations for help, but this approach fell short because of scarcity of data, and in some cases, unwillingness to share. Steven Labkoff, MD, chief data officer at the MMRF, described this experience in an interview.

The Multiple Myeloma Research Foundation (MMRF) recently launched its Direct-to-Patient registry, in what the organization’s leaders are describing as a “disruptive” step toward improving outcomes for patients with multiple myeloma.

Peter Anderson/ Pathology Education Informational Resource Digital Library/copyright University of Alabama at Birmingham, Department of Pathology

The new registry is intended to build upon CoMMpass, a program started 8 years ago that now represents the largest genomic database of any type of cancer. Although CoMMpass includes data from about 1,150 patients with myeloma, it’s not enough information, according to the chief marketing and development officer at the MMRF, Anne Quinn Young.

“For a disease as heterogenous as myeloma is, we need more, particularly because we don’t have all the samples for later-stage disease,” Ms. Quinn Young said in an interview. “And even with the clinical data, given the patient population, both [in terms of] demographics and the nature of the disease, the numbers of patients still living after multiple relapses is rather small.”

In an earlier effort to gather more data, the MMRF first turned to other organizations for help, but this approach fell short because of scarcity of data, and in some cases, unwillingness to share. Steven Labkoff, MD, chief data officer at the MMRF, described this experience in an interview.

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

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

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

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

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

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

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

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

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

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

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

*This story was updated on November 15, 2019.

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

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

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

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

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

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

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

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

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

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

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

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

*This story was updated on November 15, 2019.

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

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

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

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

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

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

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

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

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

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

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

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

*This story was updated on November 15, 2019.

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

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

Will Pass/MDedge News

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

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

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

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

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

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

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

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

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

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

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

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.