Hepatology

Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.

NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.

“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”

To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.

Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.

At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.

But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.

“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.

Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.

“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.

Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.

“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”

The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.

SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.

Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.

NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.

“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”

To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.

Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.

At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.

But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.

“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.

Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.

“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.

Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.

“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”

The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.

SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.

Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.

NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.

“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”

To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.

Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.

At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.

But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.

“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.

Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.

“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.

Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.

“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”

The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.

SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

Noninvasive fibrosis scores, which are widely used to predict advanced fibrosis in people with nonalcoholic fatty liver disease (NAFLD), do not do a good job of picking up advanced fibrosis in patients with underlying diabetes, according to a new study.

Advanced fibrosis is associated with an increased risk of cirrhosis, end-stage liver disease, and liver failure. Underlying diabetes is a risk factor for both advanced fibrosis and death in patients with NAFLD.

While liver biopsy remains the gold standard for detecting advanced fibrosis, high costs and risks limit its use. Noninvasive scores such as the AST/ALT ratio; AST to platelet ratio index (APRI); fibrosis-4 (FIB-4) index; and NAFLD fibrosis score (NFS) have gained popularity in recent years, as they offer the compelling advantage of using easily and cheaply attained clinical and laboratory measures to assess likelihood of disease.

But their accuracy has come into question, particularly for people with diabetes.

In research published in the Journal of Clinical Gastroenterology, Amandeep Singh, MD, and colleagues at the Cleveland Clinic looked at their center’s records for 1,157 patients with type 2 diabetes (65% women, 88% white, 85% with obesity) who had undergone a liver biopsy for suspected advanced fibrosis between 2000 and 2015. Biopsy results revealed that a third of the cohort (32%) was positive for advanced fibrosis.

The investigators then pulled patients’ laboratory results for AST, ALT, cholesterol, triglycerides, fasting glucose, hemoglobin A_1c, bilirubin, albumin, platelet count, alkaline phosphatase, albumin, and lipid levels, all collected within a year of biopsy. After plugging these into the algorithms of four different scoring systems for advanced fibrosis, they compared results with results from the biopsies.

The scores of AST/ALT greater than 1.4, APRI of at least 1.5, NFS greater than 0.676, and FIB-4 index greater than 2.67 had high specificities of 84%, 97%, 70%, and 93%, respectively, but sensitivities of only 27%, 17%, 64%, and 44%. Even when the cutoff measures were tightened, the scoring systems still missed a lot of disease. This suggests, Dr. Singh and colleagues wrote, that “the presence of diabetes could decrease the predictive value of these scores to detect advanced disease in NAFLD patients.” Reliable noninvasive biomarkers are “urgently needed” for this patient population.

In an interview, Dr. Singh advised that clinicians continue to use current noninvasive scores in patients with diabetes – preferably the NFS – “until we have a better scoring system.” If clinicians suspect advanced fibrosis based on lab tests and clinical data, then “liver biopsy should be considered,” he said.

The investigators described among the limitations of their study its retrospective, single-center design, with patients who were mostly white and from one geographic region.

Dr. Singh and colleagues reported no conflicts of interest or outside funding for their study.

[email protected]

SOURCE: Singh A et al. J Clin Gastroenterol. 2020 Mar 11. doi: 10.1097/MCG.0000000000001339.

In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).

Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.

The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.

For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.

Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.

The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.

Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”

“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.

AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.

People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).

In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.

Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.

As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.

[email protected]

In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).

Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.

The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.

For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.

Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.

The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.

Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”

“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.

AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.

People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).

In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.

Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.

As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.

[email protected]

In liver transplant recipients or patients with autoimmune hepatitis on immunosuppressive therapy, acute cellular rejection or disease flare should not be presumed in the face of active coronavirus disease 2019 (COVID-19), according to the American Association for the Study of Liver Diseases (AASLD).

Signs that would normally be interpreted as flare or rejection need to be considered more cautiously now because the virus attacks the liver, and elevated aspartate aminotransferase, alanine aminotransferase, and slightly elevated bilirubin are common, ranging from a prevalence of 14% to 53% in COVID-19 patients. Acute liver injury is possible, especially in more severe cases, the group said.

The advice comes from a recently released document from AASLD, called “Clinical Insights for Hepatology and Liver Transplant Providers During the Covid-19 Pandemic,” to help hepatologists and liver transplant providers negotiate the pandemic, according to the latest data. It’s a far-ranging work that contains a lot of now familiar steps for providers to take to protect themselves and patients from the virus, but also much advice specific to liver medicine.

For instance, the group said it’s important to keep in mind that experimental treatments for the infection, including statins, remdesivir, and tocilizumab, can be hepatotoxic. Abnormal liver biochemistries are not a contraindication, but liver biochemistries need to be followed regularly in COVID-19 patients, especially those treated with remdesivir or tocilizumab, regardless of baseline values.

Also, lopinavir/ritonavir is a potent inhibitor of cytochrome P450 enzymes involved with calcineurin inhibitor metabolism, so if it’s used, AASLD said to reduce tacrolimus dosages to 1/20–1/50 of baseline.

The group cautioned against anticipatory adjustments to immunosuppressive drugs or dosages in patients without COVID-19, but if immunosuppressed liver disease patients do get the infection, prednisone doses should be reduced but kept above 10 mg/day to avoid adrenal insufficiency. In the setting of lymphopenia, fever, or worsening COVID-19 pneumonia, it advised reduction of azathioprine and mycophenolate dosages and reduction of, but not stopping, calcineurin inhibitors.

Liver transplants should not be postponed. However, to minimize exposure to the hospital environment, AASLD advised to “consider evaluating only patients with HCC [hepatocellular carcinoma] or those patients with severe disease and high MELD [model for end-stage liver disease] scores who are likely to benefit from immediate liver transplant.”

“An argument that has been put forward to justify deferring some transplants is concern about immunosuppressing patients during the COVID-19 pandemic,” the group said, but “data suggest the innate immune response may be the main driver for pulmonary injury due to COVID-19 and [that] immunosuppression may be protective. ... Posttransplant immunosuppression was not a risk factor for mortality associated with” the severe acute respiratory syndrome pandemic in 2003-2004 or the ongoing Middle East respiratory syndrome pandemic, both also caused by coronaviruses.

AASLD advised against reducing immunosuppression or stopping mycophenolate for asymptomatic patients after transplant, but COVID-19 prevention measures should be emphasized, including frequent hand washing and staying away from large crowds.

People who test positive for COVID-19 are ineligible for organ donation. Bronchoalveolar lavage is the most sensitive test (93%), followed by nasal swabs (63%) and pharyngeal swabs (32%).

In general, the group said elective procedures should be postponed, but urgent ones, such as biliary surgery and transjugular intrahepatic portosystemic shunts for bleeding varices, in addition to liver transplants, should not.

Also, HCC patients “should not wait until the pandemic abates to undergo [surveillance] imaging because the prospective duration of the pandemic is unknown. ... An arbitrary delay of 2 months is reasonable” for imaging based on patient and facility circumstances, but otherwise, “proceed with HCC treatments rather than delaying them due to the pandemic,” the group said.

As for who to bring into the office for an initial consult, “consider seeing in person only new adult and pediatric patients with urgent issues and clinically significant liver disease (e.g., jaundice, elevated ALT or AST above 500 U/L, recent onset of hepatic decompensation),” AASLD said.

[email protected]

Current risk factors used to screen for hepatitis C should be updated, according to study results of 106,842 pregnant women who underwent screening.

Courtesy NIH

“Because risk-factor screening has obvious limitations, universal screening in pregnancy has been suggested to allow for linkage to postpartum care and identification of children for future testing and treatment,” wrote Mona Prasad, DO, of Ohio State University, Columbus, and colleagues.

In a study published in Obstetrics & Gynecology, the researchers reviewed data from women with singleton pregnancies presenting for prenatal care prior to 23 weeks’ gestation during 2012-2015. Of these, 254 tested positive for the hepatitis C virus (HCV) antibody, for a seroprevalence rate of 2.4 cases per 1,000 women.

The researchers conducted a case-control analysis of 131 women who tested positive and 251 controls to identify HCV infection risk factors based on interviews and chart reviews. They found that risk factors significantly associated with positive HCV antibodies included injection drug use (adjusted odds ratio, 22.9), a history of blood transfusion (aOR, 3.7), having an HCV-infected partner (aOR, 6.3), having had more than three sexual partners (aOR, 5.3), and smoking during pregnancy (aOR, 2.4).

In an unadjusted analysis, the researchers confirmed two of the risk factors currently recommended by the Centers for Disease Control and Prevention for screening for HCV: injection drug use and being born to a mother with HCV infection, but not dialysis, organ transplantation, or HIV infection.

“Our results demonstrate that current risk factors could be contemporized,” Dr. Prasad and colleagues noted. “The currently accepted risk factors such as exposure to clotting factors, dialysis, and organ transplants are unlikely to be found. A thorough assessment of injection drug use history, smoking, transfusions, number of sexual partners, and partners with HCV infection is more sensitive in an obstetric population.”

The study findings were limited by several factors including possible selection bias and inclusion of only 65% of eligible women who were HCV positive, as well as a lack of screening data from 2016 to the present, which may not reflect the impact of the recent opioid epidemic, the researchers noted. However, the results were strengthened by the large sample size, and the generalizability of the study population.

“Our results regarding prevalence rates and risk factors of HCV antibody among pregnant women in the United States will be valuable to policymakers as they weigh the costs and benefits of universal screening,” Dr. Prasad and associates concluded.

Although universal screening has the potential to be more cost effective, given the small population of pregnant women eligible for treatment and lack of an available treatment, “the rationale is weaker for unique universal HCV screening recommendations for pregnant women,” they said.

By contrast, Sammy Saab, MD, MPH, of the University of California, Los Angeles; Ravina Kullar, PharmD, MPH, of Gilead Sciences, Foster City, Calif.; and Prabhu Gounder, MD, MPH, of the Los Angeles Department of Public Health, wrote an accompanying commentary in favor of universal HCV screening for pregnant women, in part because of the increase in HCV in the younger population overall.

“For many women of reproductive age, pregnancy is one of their few points of contact with their health care provider; therefore, pregnancy could provide a crucial time for targeting this population,” they noted.

Risk-based screening is of limited effectiveness because patients are not identified by way of current screening tools or they decline to reveal risk factors that providers might miss, the editorialists said. Pregnancy has not been shown to affect the accuracy of HCV tests, and identifying infections in mothers allows for screening in children as well.

“The perinatal hepatitis B virus infection program, which has been implemented in several state and local public health departments, could serve as an example for how to conduct surveillance for mothers with HCV infection and to ensure that HCV-exposed children receive appropriate follow-up testing and linkage to care,” the editorialists concluded.

The study was supported in part by multiple grants from the National Institute of Child Health and Human Development. Dr. Prasad disclosed funding from Ohio State University and from Gilead. Coauthors had links with pharmaceutical companies, associations, and organizations – most unrelated to this study. The editorialists had no financial conflicts to disclose.

SOURCES: Prasad M et al. Obstet Gynecol. 2020;135:778-88; Saab S et al. Obstet Gynecol. 2020;135:773-7.

Current risk factors used to screen for hepatitis C should be updated, according to study results of 106,842 pregnant women who underwent screening.

Courtesy NIH

“Because risk-factor screening has obvious limitations, universal screening in pregnancy has been suggested to allow for linkage to postpartum care and identification of children for future testing and treatment,” wrote Mona Prasad, DO, of Ohio State University, Columbus, and colleagues.

In a study published in Obstetrics & Gynecology, the researchers reviewed data from women with singleton pregnancies presenting for prenatal care prior to 23 weeks’ gestation during 2012-2015. Of these, 254 tested positive for the hepatitis C virus (HCV) antibody, for a seroprevalence rate of 2.4 cases per 1,000 women.

The researchers conducted a case-control analysis of 131 women who tested positive and 251 controls to identify HCV infection risk factors based on interviews and chart reviews. They found that risk factors significantly associated with positive HCV antibodies included injection drug use (adjusted odds ratio, 22.9), a history of blood transfusion (aOR, 3.7), having an HCV-infected partner (aOR, 6.3), having had more than three sexual partners (aOR, 5.3), and smoking during pregnancy (aOR, 2.4).

In an unadjusted analysis, the researchers confirmed two of the risk factors currently recommended by the Centers for Disease Control and Prevention for screening for HCV: injection drug use and being born to a mother with HCV infection, but not dialysis, organ transplantation, or HIV infection.

“Our results demonstrate that current risk factors could be contemporized,” Dr. Prasad and colleagues noted. “The currently accepted risk factors such as exposure to clotting factors, dialysis, and organ transplants are unlikely to be found. A thorough assessment of injection drug use history, smoking, transfusions, number of sexual partners, and partners with HCV infection is more sensitive in an obstetric population.”

The study findings were limited by several factors including possible selection bias and inclusion of only 65% of eligible women who were HCV positive, as well as a lack of screening data from 2016 to the present, which may not reflect the impact of the recent opioid epidemic, the researchers noted. However, the results were strengthened by the large sample size, and the generalizability of the study population.

“Our results regarding prevalence rates and risk factors of HCV antibody among pregnant women in the United States will be valuable to policymakers as they weigh the costs and benefits of universal screening,” Dr. Prasad and associates concluded.

Although universal screening has the potential to be more cost effective, given the small population of pregnant women eligible for treatment and lack of an available treatment, “the rationale is weaker for unique universal HCV screening recommendations for pregnant women,” they said.

By contrast, Sammy Saab, MD, MPH, of the University of California, Los Angeles; Ravina Kullar, PharmD, MPH, of Gilead Sciences, Foster City, Calif.; and Prabhu Gounder, MD, MPH, of the Los Angeles Department of Public Health, wrote an accompanying commentary in favor of universal HCV screening for pregnant women, in part because of the increase in HCV in the younger population overall.

“For many women of reproductive age, pregnancy is one of their few points of contact with their health care provider; therefore, pregnancy could provide a crucial time for targeting this population,” they noted.

Risk-based screening is of limited effectiveness because patients are not identified by way of current screening tools or they decline to reveal risk factors that providers might miss, the editorialists said. Pregnancy has not been shown to affect the accuracy of HCV tests, and identifying infections in mothers allows for screening in children as well.

“The perinatal hepatitis B virus infection program, which has been implemented in several state and local public health departments, could serve as an example for how to conduct surveillance for mothers with HCV infection and to ensure that HCV-exposed children receive appropriate follow-up testing and linkage to care,” the editorialists concluded.

The study was supported in part by multiple grants from the National Institute of Child Health and Human Development. Dr. Prasad disclosed funding from Ohio State University and from Gilead. Coauthors had links with pharmaceutical companies, associations, and organizations – most unrelated to this study. The editorialists had no financial conflicts to disclose.

SOURCES: Prasad M et al. Obstet Gynecol. 2020;135:778-88; Saab S et al. Obstet Gynecol. 2020;135:773-7.

Current risk factors used to screen for hepatitis C should be updated, according to study results of 106,842 pregnant women who underwent screening.

Courtesy NIH

“Because risk-factor screening has obvious limitations, universal screening in pregnancy has been suggested to allow for linkage to postpartum care and identification of children for future testing and treatment,” wrote Mona Prasad, DO, of Ohio State University, Columbus, and colleagues.

In a study published in Obstetrics & Gynecology, the researchers reviewed data from women with singleton pregnancies presenting for prenatal care prior to 23 weeks’ gestation during 2012-2015. Of these, 254 tested positive for the hepatitis C virus (HCV) antibody, for a seroprevalence rate of 2.4 cases per 1,000 women.

The researchers conducted a case-control analysis of 131 women who tested positive and 251 controls to identify HCV infection risk factors based on interviews and chart reviews. They found that risk factors significantly associated with positive HCV antibodies included injection drug use (adjusted odds ratio, 22.9), a history of blood transfusion (aOR, 3.7), having an HCV-infected partner (aOR, 6.3), having had more than three sexual partners (aOR, 5.3), and smoking during pregnancy (aOR, 2.4).

In an unadjusted analysis, the researchers confirmed two of the risk factors currently recommended by the Centers for Disease Control and Prevention for screening for HCV: injection drug use and being born to a mother with HCV infection, but not dialysis, organ transplantation, or HIV infection.

“Our results demonstrate that current risk factors could be contemporized,” Dr. Prasad and colleagues noted. “The currently accepted risk factors such as exposure to clotting factors, dialysis, and organ transplants are unlikely to be found. A thorough assessment of injection drug use history, smoking, transfusions, number of sexual partners, and partners with HCV infection is more sensitive in an obstetric population.”

The study findings were limited by several factors including possible selection bias and inclusion of only 65% of eligible women who were HCV positive, as well as a lack of screening data from 2016 to the present, which may not reflect the impact of the recent opioid epidemic, the researchers noted. However, the results were strengthened by the large sample size, and the generalizability of the study population.

“Our results regarding prevalence rates and risk factors of HCV antibody among pregnant women in the United States will be valuable to policymakers as they weigh the costs and benefits of universal screening,” Dr. Prasad and associates concluded.

Although universal screening has the potential to be more cost effective, given the small population of pregnant women eligible for treatment and lack of an available treatment, “the rationale is weaker for unique universal HCV screening recommendations for pregnant women,” they said.

By contrast, Sammy Saab, MD, MPH, of the University of California, Los Angeles; Ravina Kullar, PharmD, MPH, of Gilead Sciences, Foster City, Calif.; and Prabhu Gounder, MD, MPH, of the Los Angeles Department of Public Health, wrote an accompanying commentary in favor of universal HCV screening for pregnant women, in part because of the increase in HCV in the younger population overall.

“For many women of reproductive age, pregnancy is one of their few points of contact with their health care provider; therefore, pregnancy could provide a crucial time for targeting this population,” they noted.

Risk-based screening is of limited effectiveness because patients are not identified by way of current screening tools or they decline to reveal risk factors that providers might miss, the editorialists said. Pregnancy has not been shown to affect the accuracy of HCV tests, and identifying infections in mothers allows for screening in children as well.

“The perinatal hepatitis B virus infection program, which has been implemented in several state and local public health departments, could serve as an example for how to conduct surveillance for mothers with HCV infection and to ensure that HCV-exposed children receive appropriate follow-up testing and linkage to care,” the editorialists concluded.

The study was supported in part by multiple grants from the National Institute of Child Health and Human Development. Dr. Prasad disclosed funding from Ohio State University and from Gilead. Coauthors had links with pharmaceutical companies, associations, and organizations – most unrelated to this study. The editorialists had no financial conflicts to disclose.

SOURCES: Prasad M et al. Obstet Gynecol. 2020;135:778-88; Saab S et al. Obstet Gynecol. 2020;135:773-7.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

For patients with nonalcoholic steatohepatitis (NASH) with cirrhosis and portal hypertension, belapectin therapy was safe but did not significantly improve fibrosis or hepatic venous pressure gradient, compared with placebo, according to the results of a multicenter phase 2b study.

After 52 weeks of infusions, the change in hepatic venous pressure gradient did not significantly differ between the 2-mg/kg group (–0.28 mm Hg) and the placebo group (0.10 mm Hg) or between the 8-mg/kg group (–0.25 mm Hg) and the placebo group (P = .1 for both comparisons). Belapectin also did not significantly improve fibrosis, nonalcoholic fatty liver disease activity score, or the frequency of various complications of cirrhosis. “However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce hepatic venous pressure gradient and development of varices,” wrote Naga Chalasani, MD, of Indiana University in Indianapolis and his associates. The findings were published in Gastroenterology.

NASH leads to portal hypertension, variceal bleeding, ascites with bacterial peritonitis, hepatic encephalopathy, and liver-related death and is a leading reason for liver transplantation among women and men. Galectin-3, which is primarily secreted by macrophages, is elevated in patients with NASH and has been linked to the pathophysiology of liver fibrosis in mice. Belapectin (GR-MD-02), a complex carbohydrate that targets and disrupts galectin-3, has been found to reduce liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies.

For this double-blind trial, the researchers randomly assigned 162 patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient at least 6 mm Hg) to receive biweekly infusions of belapectin 2 mg/kg (54 patients), belapectin 8 mg/kg (54 patients), or placebo (54 patients). Patients were treated for 52 weeks. The primary endpoint was change from baseline in hepatic venous pressure gradient.

In a post-hoc analysis of the 81 patients who had no esophageal varices at baseline, 2 mg/kg belapectin was associated with an average 1.61-mm Hg reduction in hepatic venous pressure gradient from baseline (P = .02) and with a reduction in the development of new varices (P = .03).These effects did not extend to subgroups of patients with varices at baseline, clinically significant portal hypertension, or mild portal hypertension. Moreover, 2 mg/kg belapectin did not improve fibrosis, and the higher dose of belapectin (8 mg/kg) met neither the primary endpoint nor the secondary endpoints in the overall cohort or in subgroup analyses. In the subgroup with no varices at baseline, Galectin Technologies is proceeding to initiating a phase 3 clinical trial.

“Interestingly and somewhat unexpectedly, belapectin was associated with an improvement in hepatocyte ballooning,” which “is considered fundamental to the pathogenesis of disease progression in nonalcoholic steatohepatitis,” the researchers wrote. “The significance of such improvement in hepatocyte ballooning in the absence of improvement of other histological components, especially inflammation, is unknown.”

Galectin Therapeutics provided funding. Dr. Chalasani disclosed grant support from Galectin Therapeutics and relevant consulting relationships with NuSirt, AbbVie, Afimmune (DS Biopharma), and several other pharmaceutical companies. Sixteen coinvestigators also disclosed relationships with pharmaceutical companies, of whom eight disclosed consulting relationships, received research funding, or were employed by Galectin.

SOURCE: Chalasani N et al. Gastroenterology. 2019 Dec 5. doi: 10.1053/j.gastro.2019.11.296.

*This story was updated on 3/18/2020.

Adults aged 18-79 years should be screened for hepatitis C virus infection, according to an updated grade B recommendation from the U.S. Preventive Services Task Force.

Cases of acute hepatitis C virus (HCV) infection have spiked in the last decade, in part because of increased use of injection drugs and in part because of better surveillance, Douglas K. Owens, MD, of Stanford (Calif.) University, and colleagues wrote in the recommendation statement published in JAMA.

The recommendation applies to all asymptomatic adults aged 18-79 years without known liver disease, and expands on the 2013 recommendation to screen adults born between 1945 and 1965. The grade B designation means that the task force concluded with moderate certainty that HCV screening for adults aged 18-79 years had “substantial net benefit.”

The recommendations are based on an evidence report including 8 randomized, controlled trials, 48 other treatment studies, and 33 cohort studies published through February 2019 for a total of 179,230 individuals.

The screening is a one-time procedure for most adults, according to the task force, but clinicians should periodically screen individuals at increased risk, such as those with a past or current history of injection drug use. In addition, clinicians should consider screening individuals at increased risk who are above or below the recommended age range.

Although the task force identified no direct evidence on the benefit of screening for HCV infection in asymptomatic adults, a notable finding was that the newer direct-acting antiviral (DAA) regimens are sufficiently effective to support the expanded screening recommendation, they said. However, clinicians should inform patients that screening is voluntary and conducted only with the patient’s knowledge. Clinicians should educate patients about hepatitis C and give them an opportunity to ask questions and to make a decision about screening, according to the task force.

In the evidence report, a total of 49 studies including 10,181 individuals showed DAA treatment associated with pooled sustained virologic response rates greater than 95% across all virus genotypes, and a short-term serious adverse event rate of 1.9%. In addition, sustained virologic response following an antiviral therapy was associated with a reduction in risk of all-cause mortality (pooled hazard ratio 0.40) and of hepatocellular carcinoma (pooled HR 0.29) compared with cases of no sustained virologic response.

The evidence report findings were limited by several factors, including the relatively small number of randomized trials involving current DAA treatments, limited data on baseline symptoms, limited data on adolescents, and limited evidence on potential long-term harms of DAA therapy, noted Richard Chou, MD, of Oregon Health & Science University, Portland, and colleagues. However, new pooled evidence “indicates that SVR rates with currently recommended all-oral DAA regimens are substantially higher (more than 95%) than with interferon-based therapies evaluated in the prior review (68%-78%),” they said.

Several editorials were published concurrently with the recommendation.

In an editorial published in JAMA, Camilla S. Graham, MD, of Harvard Medical School, Boston, and Stacey Trooskin, MD, of the University of Pennsylvania, Philadelphia, wrote that the new recommendation reflects changes in hepatitis C virus management.

“With the approvals of sofosbuvir and simeprevir in 2013, patients with hepatitis C, a chronic viral illness associated with the deaths of more U.S. patients than the next 60 reportable infectious diseases combined, including HIV and tuberculosis, could expect a greater than 90% rate of achieving sustained virologic response (SVR, defined as undetectable HCV levels 12 weeks or longer after treatment completion, which is consistent with virologic cure of HCV infection) following 12 weeks of treatment,” they said.

These medications are effective but expensive; however, the combination of the availability of generic medications and the ongoing opioid epidemic in the United States are important contributors to the expanded recommendations, which “are welcome,” and may help meeting WHO 2030 targets for reducing new HCV infections, they said.

Dr. Graham disclosed personal fees from UpToDate. Dr. Trooskin disclosed grants from Gilead Sciences and personal fees from Merck, AbbVie, and Gilead Sciences.

In an editorial published in JAMA Internal Medicine, Jennifer C. Price, MD, and Danielle Brandman, MD, both of the University of California, San Francisco, wrote that “the advancements in HCV diagnosis and treatment have been extraordinary,” but that the new recommendation does not go far enough. “Implementation of HCV screening and linkage to treatment requires large-scale coordinated efforts, innovation, and resources. For example, point-of-care HCV RNA testing would enable scale-up of HCV screening and confirmatory testing among individuals at greatest risk of HCV infection,” they said. “Additionally, barriers remain between diagnosis and treatment, such as access to a health care provider who can treat HCV and authorization to receive affordable DAAs,” they noted. “Although the USPSTF HCV screening recommendation is a step forward for controlling HCV infection in the U.S., it will take a coordinated and funded effort to ensure that the anticipated benefits are realized,” they concluded.

Dr. Price disclosed research funding from Gilead Sciences and Merck. Dr. Brandman disclosed research funding from Gilead Sciences, Pfizer, Conatus, Allergan, and Grifols, as well as personal fees from Alnylam.

In an editorial published in JAMA Network Open, Eli S. Rosenberg, PhD, of the University at Albany (N.Y.) School of Public Health, and Joshua A. Barocas, MD, of Boston University, emphasized the need to change the stigma surrounding HCV infection in the United States.

“Given the changing epidemiology of HCV infection, new public health priorities, advancements in treatment, and unmet diagnostic needs, it is wise to periodically reevaluate screening recommendations to ensure that they are maximally addressing these areas and patients’ individual needs,” they said. “The Affordable Care Act requires private insurers and Medicaid to cover preventive services recommended by the USPSTF with a grade of A or B with no cost sharing (i.e., no deductible or copayment),” they noted. Although the new recommendation for one-time screening will likely identify more cases, improve outcomes, and reduce deaths, the editorialists cautioned that “one-time screening should not be interpreted like catch-up vaccinations, whereby we immunize someone at any age for hepatitis B virus, for example, and they are then immunized for the remainder of their life,” and that reassessments are needed, especially for younger adults.

In addition, they emphasized the need to reduce the stigma surrounding HCV and allow for recommendations based on risk, rather than age. “We have forced the USPSTF to adopt age-based screening recommendations because we, as a society, have created a culture in which we have stigmatized these behaviors and we, as practitioners, have proven to be inadequate at eliciting HCV risk behaviors,” they said. “Our responsibility as a society and practice community is to address structural and individual factors that limit our ability to most precisely address the needs of our patients and truly move toward HCV elimination,” they concluded.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The task force researchers had no financial conflicts to disclose.

SOURCES: Owens DK et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2020.1123; Chou R et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.20788; Graham CS, Trooskin S. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.22313; Price JC and Brandman D. JAMA Intern Med. 2020 Mar 2. doi: 10.1001/jamainternmed.2019.7334; Rosenberg ES, Barocas JA. JAMA Network Open. 2020 Mar 2. doi: 10.1001/jamanetworkopen.2020.0538.

Adults aged 18-79 years should be screened for hepatitis C virus infection, according to an updated grade B recommendation from the U.S. Preventive Services Task Force.

Cases of acute hepatitis C virus (HCV) infection have spiked in the last decade, in part because of increased use of injection drugs and in part because of better surveillance, Douglas K. Owens, MD, of Stanford (Calif.) University, and colleagues wrote in the recommendation statement published in JAMA.

The recommendation applies to all asymptomatic adults aged 18-79 years without known liver disease, and expands on the 2013 recommendation to screen adults born between 1945 and 1965. The grade B designation means that the task force concluded with moderate certainty that HCV screening for adults aged 18-79 years had “substantial net benefit.”

The recommendations are based on an evidence report including 8 randomized, controlled trials, 48 other treatment studies, and 33 cohort studies published through February 2019 for a total of 179,230 individuals.

The screening is a one-time procedure for most adults, according to the task force, but clinicians should periodically screen individuals at increased risk, such as those with a past or current history of injection drug use. In addition, clinicians should consider screening individuals at increased risk who are above or below the recommended age range.

Although the task force identified no direct evidence on the benefit of screening for HCV infection in asymptomatic adults, a notable finding was that the newer direct-acting antiviral (DAA) regimens are sufficiently effective to support the expanded screening recommendation, they said. However, clinicians should inform patients that screening is voluntary and conducted only with the patient’s knowledge. Clinicians should educate patients about hepatitis C and give them an opportunity to ask questions and to make a decision about screening, according to the task force.

In the evidence report, a total of 49 studies including 10,181 individuals showed DAA treatment associated with pooled sustained virologic response rates greater than 95% across all virus genotypes, and a short-term serious adverse event rate of 1.9%. In addition, sustained virologic response following an antiviral therapy was associated with a reduction in risk of all-cause mortality (pooled hazard ratio 0.40) and of hepatocellular carcinoma (pooled HR 0.29) compared with cases of no sustained virologic response.

The evidence report findings were limited by several factors, including the relatively small number of randomized trials involving current DAA treatments, limited data on baseline symptoms, limited data on adolescents, and limited evidence on potential long-term harms of DAA therapy, noted Richard Chou, MD, of Oregon Health & Science University, Portland, and colleagues. However, new pooled evidence “indicates that SVR rates with currently recommended all-oral DAA regimens are substantially higher (more than 95%) than with interferon-based therapies evaluated in the prior review (68%-78%),” they said.

Several editorials were published concurrently with the recommendation.

In an editorial published in JAMA, Camilla S. Graham, MD, of Harvard Medical School, Boston, and Stacey Trooskin, MD, of the University of Pennsylvania, Philadelphia, wrote that the new recommendation reflects changes in hepatitis C virus management.

“With the approvals of sofosbuvir and simeprevir in 2013, patients with hepatitis C, a chronic viral illness associated with the deaths of more U.S. patients than the next 60 reportable infectious diseases combined, including HIV and tuberculosis, could expect a greater than 90% rate of achieving sustained virologic response (SVR, defined as undetectable HCV levels 12 weeks or longer after treatment completion, which is consistent with virologic cure of HCV infection) following 12 weeks of treatment,” they said.

These medications are effective but expensive; however, the combination of the availability of generic medications and the ongoing opioid epidemic in the United States are important contributors to the expanded recommendations, which “are welcome,” and may help meeting WHO 2030 targets for reducing new HCV infections, they said.

Dr. Graham disclosed personal fees from UpToDate. Dr. Trooskin disclosed grants from Gilead Sciences and personal fees from Merck, AbbVie, and Gilead Sciences.

In an editorial published in JAMA Internal Medicine, Jennifer C. Price, MD, and Danielle Brandman, MD, both of the University of California, San Francisco, wrote that “the advancements in HCV diagnosis and treatment have been extraordinary,” but that the new recommendation does not go far enough. “Implementation of HCV screening and linkage to treatment requires large-scale coordinated efforts, innovation, and resources. For example, point-of-care HCV RNA testing would enable scale-up of HCV screening and confirmatory testing among individuals at greatest risk of HCV infection,” they said. “Additionally, barriers remain between diagnosis and treatment, such as access to a health care provider who can treat HCV and authorization to receive affordable DAAs,” they noted. “Although the USPSTF HCV screening recommendation is a step forward for controlling HCV infection in the U.S., it will take a coordinated and funded effort to ensure that the anticipated benefits are realized,” they concluded.

Dr. Price disclosed research funding from Gilead Sciences and Merck. Dr. Brandman disclosed research funding from Gilead Sciences, Pfizer, Conatus, Allergan, and Grifols, as well as personal fees from Alnylam.

In an editorial published in JAMA Network Open, Eli S. Rosenberg, PhD, of the University at Albany (N.Y.) School of Public Health, and Joshua A. Barocas, MD, of Boston University, emphasized the need to change the stigma surrounding HCV infection in the United States.

“Given the changing epidemiology of HCV infection, new public health priorities, advancements in treatment, and unmet diagnostic needs, it is wise to periodically reevaluate screening recommendations to ensure that they are maximally addressing these areas and patients’ individual needs,” they said. “The Affordable Care Act requires private insurers and Medicaid to cover preventive services recommended by the USPSTF with a grade of A or B with no cost sharing (i.e., no deductible or copayment),” they noted. Although the new recommendation for one-time screening will likely identify more cases, improve outcomes, and reduce deaths, the editorialists cautioned that “one-time screening should not be interpreted like catch-up vaccinations, whereby we immunize someone at any age for hepatitis B virus, for example, and they are then immunized for the remainder of their life,” and that reassessments are needed, especially for younger adults.

In addition, they emphasized the need to reduce the stigma surrounding HCV and allow for recommendations based on risk, rather than age. “We have forced the USPSTF to adopt age-based screening recommendations because we, as a society, have created a culture in which we have stigmatized these behaviors and we, as practitioners, have proven to be inadequate at eliciting HCV risk behaviors,” they said. “Our responsibility as a society and practice community is to address structural and individual factors that limit our ability to most precisely address the needs of our patients and truly move toward HCV elimination,” they concluded.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The task force researchers had no financial conflicts to disclose.

SOURCES: Owens DK et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2020.1123; Chou R et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.20788; Graham CS, Trooskin S. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.22313; Price JC and Brandman D. JAMA Intern Med. 2020 Mar 2. doi: 10.1001/jamainternmed.2019.7334; Rosenberg ES, Barocas JA. JAMA Network Open. 2020 Mar 2. doi: 10.1001/jamanetworkopen.2020.0538.

Adults aged 18-79 years should be screened for hepatitis C virus infection, according to an updated grade B recommendation from the U.S. Preventive Services Task Force.

Cases of acute hepatitis C virus (HCV) infection have spiked in the last decade, in part because of increased use of injection drugs and in part because of better surveillance, Douglas K. Owens, MD, of Stanford (Calif.) University, and colleagues wrote in the recommendation statement published in JAMA.

The recommendation applies to all asymptomatic adults aged 18-79 years without known liver disease, and expands on the 2013 recommendation to screen adults born between 1945 and 1965. The grade B designation means that the task force concluded with moderate certainty that HCV screening for adults aged 18-79 years had “substantial net benefit.”

The recommendations are based on an evidence report including 8 randomized, controlled trials, 48 other treatment studies, and 33 cohort studies published through February 2019 for a total of 179,230 individuals.

The screening is a one-time procedure for most adults, according to the task force, but clinicians should periodically screen individuals at increased risk, such as those with a past or current history of injection drug use. In addition, clinicians should consider screening individuals at increased risk who are above or below the recommended age range.

Although the task force identified no direct evidence on the benefit of screening for HCV infection in asymptomatic adults, a notable finding was that the newer direct-acting antiviral (DAA) regimens are sufficiently effective to support the expanded screening recommendation, they said. However, clinicians should inform patients that screening is voluntary and conducted only with the patient’s knowledge. Clinicians should educate patients about hepatitis C and give them an opportunity to ask questions and to make a decision about screening, according to the task force.

In the evidence report, a total of 49 studies including 10,181 individuals showed DAA treatment associated with pooled sustained virologic response rates greater than 95% across all virus genotypes, and a short-term serious adverse event rate of 1.9%. In addition, sustained virologic response following an antiviral therapy was associated with a reduction in risk of all-cause mortality (pooled hazard ratio 0.40) and of hepatocellular carcinoma (pooled HR 0.29) compared with cases of no sustained virologic response.

The evidence report findings were limited by several factors, including the relatively small number of randomized trials involving current DAA treatments, limited data on baseline symptoms, limited data on adolescents, and limited evidence on potential long-term harms of DAA therapy, noted Richard Chou, MD, of Oregon Health & Science University, Portland, and colleagues. However, new pooled evidence “indicates that SVR rates with currently recommended all-oral DAA regimens are substantially higher (more than 95%) than with interferon-based therapies evaluated in the prior review (68%-78%),” they said.

Several editorials were published concurrently with the recommendation.

In an editorial published in JAMA, Camilla S. Graham, MD, of Harvard Medical School, Boston, and Stacey Trooskin, MD, of the University of Pennsylvania, Philadelphia, wrote that the new recommendation reflects changes in hepatitis C virus management.

“With the approvals of sofosbuvir and simeprevir in 2013, patients with hepatitis C, a chronic viral illness associated with the deaths of more U.S. patients than the next 60 reportable infectious diseases combined, including HIV and tuberculosis, could expect a greater than 90% rate of achieving sustained virologic response (SVR, defined as undetectable HCV levels 12 weeks or longer after treatment completion, which is consistent with virologic cure of HCV infection) following 12 weeks of treatment,” they said.

These medications are effective but expensive; however, the combination of the availability of generic medications and the ongoing opioid epidemic in the United States are important contributors to the expanded recommendations, which “are welcome,” and may help meeting WHO 2030 targets for reducing new HCV infections, they said.

Dr. Graham disclosed personal fees from UpToDate. Dr. Trooskin disclosed grants from Gilead Sciences and personal fees from Merck, AbbVie, and Gilead Sciences.

In an editorial published in JAMA Internal Medicine, Jennifer C. Price, MD, and Danielle Brandman, MD, both of the University of California, San Francisco, wrote that “the advancements in HCV diagnosis and treatment have been extraordinary,” but that the new recommendation does not go far enough. “Implementation of HCV screening and linkage to treatment requires large-scale coordinated efforts, innovation, and resources. For example, point-of-care HCV RNA testing would enable scale-up of HCV screening and confirmatory testing among individuals at greatest risk of HCV infection,” they said. “Additionally, barriers remain between diagnosis and treatment, such as access to a health care provider who can treat HCV and authorization to receive affordable DAAs,” they noted. “Although the USPSTF HCV screening recommendation is a step forward for controlling HCV infection in the U.S., it will take a coordinated and funded effort to ensure that the anticipated benefits are realized,” they concluded.

Dr. Price disclosed research funding from Gilead Sciences and Merck. Dr. Brandman disclosed research funding from Gilead Sciences, Pfizer, Conatus, Allergan, and Grifols, as well as personal fees from Alnylam.

In an editorial published in JAMA Network Open, Eli S. Rosenberg, PhD, of the University at Albany (N.Y.) School of Public Health, and Joshua A. Barocas, MD, of Boston University, emphasized the need to change the stigma surrounding HCV infection in the United States.

“Given the changing epidemiology of HCV infection, new public health priorities, advancements in treatment, and unmet diagnostic needs, it is wise to periodically reevaluate screening recommendations to ensure that they are maximally addressing these areas and patients’ individual needs,” they said. “The Affordable Care Act requires private insurers and Medicaid to cover preventive services recommended by the USPSTF with a grade of A or B with no cost sharing (i.e., no deductible or copayment),” they noted. Although the new recommendation for one-time screening will likely identify more cases, improve outcomes, and reduce deaths, the editorialists cautioned that “one-time screening should not be interpreted like catch-up vaccinations, whereby we immunize someone at any age for hepatitis B virus, for example, and they are then immunized for the remainder of their life,” and that reassessments are needed, especially for younger adults.

In addition, they emphasized the need to reduce the stigma surrounding HCV and allow for recommendations based on risk, rather than age. “We have forced the USPSTF to adopt age-based screening recommendations because we, as a society, have created a culture in which we have stigmatized these behaviors and we, as practitioners, have proven to be inadequate at eliciting HCV risk behaviors,” they said. “Our responsibility as a society and practice community is to address structural and individual factors that limit our ability to most precisely address the needs of our patients and truly move toward HCV elimination,” they concluded.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The task force researchers had no financial conflicts to disclose.

SOURCES: Owens DK et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2020.1123; Chou R et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.20788; Graham CS, Trooskin S. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.22313; Price JC and Brandman D. JAMA Intern Med. 2020 Mar 2. doi: 10.1001/jamainternmed.2019.7334; Rosenberg ES, Barocas JA. JAMA Network Open. 2020 Mar 2. doi: 10.1001/jamanetworkopen.2020.0538.

LAS VEGAS – Between 2010 and 2017, the proportion of newly diagnosed cases of acute hepatitis C virus infection rose threefold, driven largely by the concomitant opioid epidemic.

Doug Brunk/MDedge News

That makes efforts to screen, diagnose, and cure high-risk populations more important than ever, Stevan A. Gonzalez, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association.

About 70% of HCV cases are related to injection drug use,” said Dr. Gonzalez, medical director of liver transplantation at the Baylor Simmons Transplant Institute at the Baylor Scott & White All Saints Medical Center in Fort Worth, Tex. “This is affecting whites as much as blacks and Hispanics, females as much as males, and in nonurban areas as much as in urban areas.”

Data from the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration indicate that during 2004-2014, the number of acute HCV cases among those aged 18-29 years increased 400%, and the use of injection opioids rose 600%.

At the same time, the number of HCV cases among those aged 30-39 years increased 325%, and the use of injection opioids rose 83%.

“We’re starting to see a pattern overlapping between HCV exposure and opioid injection,” Dr. Gonzalez said. Other high-risk populations include homeless and incarcerated individuals.

More than 70 million people worldwide have chronic HCV infection, Dr. Gonzalez noted, with possibly as many as 5 million cases in the United States. It remains the nation’s most common blood-borne infection.

Chronic disease develops in up to 85% of people who are exposed, infection is asymptomatic, and HCV remains one of the leading indications for liver transplantation and causes of liver cancer.

From a geographic standpoint, the prevalence of HCV in young adults is eclipsing that of Baby Boomers in several states in the Appalachian region and in Northeast, which have long been trouble spots for opioid use disorder (Gastroenterol. 2018 May;154[6]:1850-1).

Surprising exposure risk

The primary risk of transmission is through contaminated blood and the exposure through needles.

“It really doesn’t matter whether it’s a needle that has a small amount of dead space where a little bit of blood can remain or needles that have a larger amount of blood,” Dr. Gonzalez said.

“I’ve had patients who come to me and say, ‘I can’t believe I have HCV. It’s impossible. I always use my own needles. They’re always brand new; I’ve never shared with anybody,’” he continued.

“This is where education and awareness is so critical, because it’s not just the needles,” Dr. Gonzalez explained. “HCV can survive on inanimate objects. For example, on a tabletop surface or a water container, HCV can remain viable up to 3 weeks. In a syringe, 2 months. For that reason, HCV can also be transmitted through crack pipes and nasal drug use, where the prevalence can be up to 35%.”

The duration of a person’s HCV infection drives the transmission.

“That’s important to think about, because people who have chronic hepatitis C are infectious until they’re treated,” Dr. Gonzalez said. “If they don’t know that they have hepatitis C, they continue to transmit the virus to others.”

One study found that half of people living with HCV are unaware of their infection (PLoS One. 2014 Jul 2;9[7]:e101554). According to Dr. Gonzalez, forthcoming guidelines from the U.S. Preventive Services Task Force are expected to recommend a one-time screening for HCV infection in all adults aged 18-79 years, a Grade B recommendation. “That’s a big deal,” he said. (The draft recommendations are available here.)

HCV infection disproportionately affects individuals in correctional institutions. In fact, an estimated one in three inmates in the United States has chronic HCV.

“This is sort of a forgotten population with a lot of substance use and mental illness,” Dr. Gonzalez said. “Injection drug use in that setting is the most common risk factor: It’s about 60% in terms of the risk of transmission within correctional settings. HCV-associated liver disease has now surpassed HIV as a cause of death within correctional settings.”
 

Weighing treatment options

The most common oral regimens for chronic HCV include sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. They achieve cure in 93%-100% of cases.

“HCV can be cured; it can be eradicated from the body long term,” Dr. Gonzalez said. “The choice of regimen, treatment duration, and use of ribavirin depends on the presence/absence of cirrhosis, prior treatment experience, and the genotype.”

All six forms of the HCV genotype can be treated with oral medication, he added, and methadone, bupropion, and naloxone are safe to use during therapy.

Reinfection following HCV treatment occurs infrequently. Dr. Gonzalez cited a randomized, controlled trial presented as an abstract at the 2018 annual meeting of the American Association for the Study of Liver Diseases. That study’s researchers found that – among 199 patients on opioid-replacement therapy who were receiving direct-acting antiviral therapy, in whom greater than 50% were actively using drugs – the rate of reinfection at 3 years was 1.8 reinfections/100 person-years.

“That’s lower than people expect,” Dr. Gonzalez said.
 

How to boost screening

Electronic health record systems can be used as an important tool to increase HCV screening in health care settings.

In 2017, researchers published an analysis of three randomized trials carried out at three separate primary care settings to improve screening for HCV: repeated mailings, an EHR best practice alert (BPA), and patient solicitation (Hepatology 2017 Jan;65[1]:44-53). They evaluated HCV antibody testing, diagnosis, and costs for each of the interventions, compared with standard-of-care testing.

The investigators found that the BPA intervention had the lowest incremental cost per completed test – $24 with fixed start-up costs, including technical design and development of the BPA system; $3 without fixed start-up costs. The BPA intervention also had the lowest incremental cost per new case identified.

Other efforts to expand access to screening and treatment are underway.

In 2019, Louisiana health officials negotiated a one-time fee for unlimited access for 5 years to sofosbuvir/velpatasvir (Epclusa) to treat the estimated 30,000 patients on Louisiana Medicaid and in that state’s department of corrections who have HCV.

“The goal is 90% cure; the burden is on the state health department to screen, diagnose, and dispense medication,” Dr. Gonzalez said.

Also in 2019, the state of Washington used an open bidding process to negotiate access to glecaprevir/pibrentasvir (Mavyret) for the state’s Medicaid population who have HCV.

“Those states are setting the pace,” Dr. Gonzalez said. “They are showing examples of how we can start implementing a process to treat these vulnerable populations.”

Meanwhile, the World Health Organization set a goal of eliminating viral hepatitis as a major public health threat by 2030.

“That sounds ambitious, but I think it’s possible,” Dr. Gonzalez said. “It’s important to address these high-risk populations: the incarcerated, people who use drugs, and the homeless, because those are the groups that have a high prevalence of HCV – mainly through injection drug use.

“If we don’t address that population, and we only target the general population, we’re going to have a continual source of transmission,” Dr. Gonzalez warned. “In that case, we would never be able to achieve elimination.”

Dr. Gonzalez disclosed that he is a member of the speakers bureau for AbbVie and Salix.

[email protected]

LAS VEGAS – Between 2010 and 2017, the proportion of newly diagnosed cases of acute hepatitis C virus infection rose threefold, driven largely by the concomitant opioid epidemic.

Doug Brunk/MDedge News

That makes efforts to screen, diagnose, and cure high-risk populations more important than ever, Stevan A. Gonzalez, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association.

About 70% of HCV cases are related to injection drug use,” said Dr. Gonzalez, medical director of liver transplantation at the Baylor Simmons Transplant Institute at the Baylor Scott & White All Saints Medical Center in Fort Worth, Tex. “This is affecting whites as much as blacks and Hispanics, females as much as males, and in nonurban areas as much as in urban areas.”

Data from the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration indicate that during 2004-2014, the number of acute HCV cases among those aged 18-29 years increased 400%, and the use of injection opioids rose 600%.

At the same time, the number of HCV cases among those aged 30-39 years increased 325%, and the use of injection opioids rose 83%.

“We’re starting to see a pattern overlapping between HCV exposure and opioid injection,” Dr. Gonzalez said. Other high-risk populations include homeless and incarcerated individuals.

More than 70 million people worldwide have chronic HCV infection, Dr. Gonzalez noted, with possibly as many as 5 million cases in the United States. It remains the nation’s most common blood-borne infection.

Chronic disease develops in up to 85% of people who are exposed, infection is asymptomatic, and HCV remains one of the leading indications for liver transplantation and causes of liver cancer.

From a geographic standpoint, the prevalence of HCV in young adults is eclipsing that of Baby Boomers in several states in the Appalachian region and in Northeast, which have long been trouble spots for opioid use disorder (Gastroenterol. 2018 May;154[6]:1850-1).

Surprising exposure risk

The primary risk of transmission is through contaminated blood and the exposure through needles.

“It really doesn’t matter whether it’s a needle that has a small amount of dead space where a little bit of blood can remain or needles that have a larger amount of blood,” Dr. Gonzalez said.

“I’ve had patients who come to me and say, ‘I can’t believe I have HCV. It’s impossible. I always use my own needles. They’re always brand new; I’ve never shared with anybody,’” he continued.

“This is where education and awareness is so critical, because it’s not just the needles,” Dr. Gonzalez explained. “HCV can survive on inanimate objects. For example, on a tabletop surface or a water container, HCV can remain viable up to 3 weeks. In a syringe, 2 months. For that reason, HCV can also be transmitted through crack pipes and nasal drug use, where the prevalence can be up to 35%.”

The duration of a person’s HCV infection drives the transmission.

“That’s important to think about, because people who have chronic hepatitis C are infectious until they’re treated,” Dr. Gonzalez said. “If they don’t know that they have hepatitis C, they continue to transmit the virus to others.”

One study found that half of people living with HCV are unaware of their infection (PLoS One. 2014 Jul 2;9[7]:e101554). According to Dr. Gonzalez, forthcoming guidelines from the U.S. Preventive Services Task Force are expected to recommend a one-time screening for HCV infection in all adults aged 18-79 years, a Grade B recommendation. “That’s a big deal,” he said. (The draft recommendations are available here.)

HCV infection disproportionately affects individuals in correctional institutions. In fact, an estimated one in three inmates in the United States has chronic HCV.

“This is sort of a forgotten population with a lot of substance use and mental illness,” Dr. Gonzalez said. “Injection drug use in that setting is the most common risk factor: It’s about 60% in terms of the risk of transmission within correctional settings. HCV-associated liver disease has now surpassed HIV as a cause of death within correctional settings.”
 

Weighing treatment options

The most common oral regimens for chronic HCV include sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. They achieve cure in 93%-100% of cases.

“HCV can be cured; it can be eradicated from the body long term,” Dr. Gonzalez said. “The choice of regimen, treatment duration, and use of ribavirin depends on the presence/absence of cirrhosis, prior treatment experience, and the genotype.”

All six forms of the HCV genotype can be treated with oral medication, he added, and methadone, bupropion, and naloxone are safe to use during therapy.

Reinfection following HCV treatment occurs infrequently. Dr. Gonzalez cited a randomized, controlled trial presented as an abstract at the 2018 annual meeting of the American Association for the Study of Liver Diseases. That study’s researchers found that – among 199 patients on opioid-replacement therapy who were receiving direct-acting antiviral therapy, in whom greater than 50% were actively using drugs – the rate of reinfection at 3 years was 1.8 reinfections/100 person-years.

“That’s lower than people expect,” Dr. Gonzalez said.
 

How to boost screening

Electronic health record systems can be used as an important tool to increase HCV screening in health care settings.

In 2017, researchers published an analysis of three randomized trials carried out at three separate primary care settings to improve screening for HCV: repeated mailings, an EHR best practice alert (BPA), and patient solicitation (Hepatology 2017 Jan;65[1]:44-53). They evaluated HCV antibody testing, diagnosis, and costs for each of the interventions, compared with standard-of-care testing.

The investigators found that the BPA intervention had the lowest incremental cost per completed test – $24 with fixed start-up costs, including technical design and development of the BPA system; $3 without fixed start-up costs. The BPA intervention also had the lowest incremental cost per new case identified.

Other efforts to expand access to screening and treatment are underway.

In 2019, Louisiana health officials negotiated a one-time fee for unlimited access for 5 years to sofosbuvir/velpatasvir (Epclusa) to treat the estimated 30,000 patients on Louisiana Medicaid and in that state’s department of corrections who have HCV.

“The goal is 90% cure; the burden is on the state health department to screen, diagnose, and dispense medication,” Dr. Gonzalez said.

Also in 2019, the state of Washington used an open bidding process to negotiate access to glecaprevir/pibrentasvir (Mavyret) for the state’s Medicaid population who have HCV.

“Those states are setting the pace,” Dr. Gonzalez said. “They are showing examples of how we can start implementing a process to treat these vulnerable populations.”

Meanwhile, the World Health Organization set a goal of eliminating viral hepatitis as a major public health threat by 2030.

“That sounds ambitious, but I think it’s possible,” Dr. Gonzalez said. “It’s important to address these high-risk populations: the incarcerated, people who use drugs, and the homeless, because those are the groups that have a high prevalence of HCV – mainly through injection drug use.

“If we don’t address that population, and we only target the general population, we’re going to have a continual source of transmission,” Dr. Gonzalez warned. “In that case, we would never be able to achieve elimination.”

Dr. Gonzalez disclosed that he is a member of the speakers bureau for AbbVie and Salix.

[email protected]

LAS VEGAS – Between 2010 and 2017, the proportion of newly diagnosed cases of acute hepatitis C virus infection rose threefold, driven largely by the concomitant opioid epidemic.

Doug Brunk/MDedge News

That makes efforts to screen, diagnose, and cure high-risk populations more important than ever, Stevan A. Gonzalez, MD, said at an annual psychopharmacology update held by the Nevada Psychiatric Association.

About 70% of HCV cases are related to injection drug use,” said Dr. Gonzalez, medical director of liver transplantation at the Baylor Simmons Transplant Institute at the Baylor Scott & White All Saints Medical Center in Fort Worth, Tex. “This is affecting whites as much as blacks and Hispanics, females as much as males, and in nonurban areas as much as in urban areas.”

Data from the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services Administration indicate that during 2004-2014, the number of acute HCV cases among those aged 18-29 years increased 400%, and the use of injection opioids rose 600%.

At the same time, the number of HCV cases among those aged 30-39 years increased 325%, and the use of injection opioids rose 83%.

“We’re starting to see a pattern overlapping between HCV exposure and opioid injection,” Dr. Gonzalez said. Other high-risk populations include homeless and incarcerated individuals.

More than 70 million people worldwide have chronic HCV infection, Dr. Gonzalez noted, with possibly as many as 5 million cases in the United States. It remains the nation’s most common blood-borne infection.

Chronic disease develops in up to 85% of people who are exposed, infection is asymptomatic, and HCV remains one of the leading indications for liver transplantation and causes of liver cancer.

From a geographic standpoint, the prevalence of HCV in young adults is eclipsing that of Baby Boomers in several states in the Appalachian region and in Northeast, which have long been trouble spots for opioid use disorder (Gastroenterol. 2018 May;154[6]:1850-1).

Surprising exposure risk

The primary risk of transmission is through contaminated blood and the exposure through needles.

“It really doesn’t matter whether it’s a needle that has a small amount of dead space where a little bit of blood can remain or needles that have a larger amount of blood,” Dr. Gonzalez said.

“I’ve had patients who come to me and say, ‘I can’t believe I have HCV. It’s impossible. I always use my own needles. They’re always brand new; I’ve never shared with anybody,’” he continued.

“This is where education and awareness is so critical, because it’s not just the needles,” Dr. Gonzalez explained. “HCV can survive on inanimate objects. For example, on a tabletop surface or a water container, HCV can remain viable up to 3 weeks. In a syringe, 2 months. For that reason, HCV can also be transmitted through crack pipes and nasal drug use, where the prevalence can be up to 35%.”

The duration of a person’s HCV infection drives the transmission.

“That’s important to think about, because people who have chronic hepatitis C are infectious until they’re treated,” Dr. Gonzalez said. “If they don’t know that they have hepatitis C, they continue to transmit the virus to others.”

One study found that half of people living with HCV are unaware of their infection (PLoS One. 2014 Jul 2;9[7]:e101554). According to Dr. Gonzalez, forthcoming guidelines from the U.S. Preventive Services Task Force are expected to recommend a one-time screening for HCV infection in all adults aged 18-79 years, a Grade B recommendation. “That’s a big deal,” he said. (The draft recommendations are available here.)

HCV infection disproportionately affects individuals in correctional institutions. In fact, an estimated one in three inmates in the United States has chronic HCV.

“This is sort of a forgotten population with a lot of substance use and mental illness,” Dr. Gonzalez said. “Injection drug use in that setting is the most common risk factor: It’s about 60% in terms of the risk of transmission within correctional settings. HCV-associated liver disease has now surpassed HIV as a cause of death within correctional settings.”
 

Weighing treatment options

The most common oral regimens for chronic HCV include sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir. They achieve cure in 93%-100% of cases.

“HCV can be cured; it can be eradicated from the body long term,” Dr. Gonzalez said. “The choice of regimen, treatment duration, and use of ribavirin depends on the presence/absence of cirrhosis, prior treatment experience, and the genotype.”

All six forms of the HCV genotype can be treated with oral medication, he added, and methadone, bupropion, and naloxone are safe to use during therapy.

Reinfection following HCV treatment occurs infrequently. Dr. Gonzalez cited a randomized, controlled trial presented as an abstract at the 2018 annual meeting of the American Association for the Study of Liver Diseases. That study’s researchers found that – among 199 patients on opioid-replacement therapy who were receiving direct-acting antiviral therapy, in whom greater than 50% were actively using drugs – the rate of reinfection at 3 years was 1.8 reinfections/100 person-years.

“That’s lower than people expect,” Dr. Gonzalez said.
 

How to boost screening

Electronic health record systems can be used as an important tool to increase HCV screening in health care settings.

In 2017, researchers published an analysis of three randomized trials carried out at three separate primary care settings to improve screening for HCV: repeated mailings, an EHR best practice alert (BPA), and patient solicitation (Hepatology 2017 Jan;65[1]:44-53). They evaluated HCV antibody testing, diagnosis, and costs for each of the interventions, compared with standard-of-care testing.

The investigators found that the BPA intervention had the lowest incremental cost per completed test – $24 with fixed start-up costs, including technical design and development of the BPA system; $3 without fixed start-up costs. The BPA intervention also had the lowest incremental cost per new case identified.

Other efforts to expand access to screening and treatment are underway.

In 2019, Louisiana health officials negotiated a one-time fee for unlimited access for 5 years to sofosbuvir/velpatasvir (Epclusa) to treat the estimated 30,000 patients on Louisiana Medicaid and in that state’s department of corrections who have HCV.

“The goal is 90% cure; the burden is on the state health department to screen, diagnose, and dispense medication,” Dr. Gonzalez said.

Also in 2019, the state of Washington used an open bidding process to negotiate access to glecaprevir/pibrentasvir (Mavyret) for the state’s Medicaid population who have HCV.

“Those states are setting the pace,” Dr. Gonzalez said. “They are showing examples of how we can start implementing a process to treat these vulnerable populations.”

Meanwhile, the World Health Organization set a goal of eliminating viral hepatitis as a major public health threat by 2030.

“That sounds ambitious, but I think it’s possible,” Dr. Gonzalez said. “It’s important to address these high-risk populations: the incarcerated, people who use drugs, and the homeless, because those are the groups that have a high prevalence of HCV – mainly through injection drug use.

“If we don’t address that population, and we only target the general population, we’re going to have a continual source of transmission,” Dr. Gonzalez warned. “In that case, we would never be able to achieve elimination.”

Dr. Gonzalez disclosed that he is a member of the speakers bureau for AbbVie and Salix.

[email protected]

MAUI, HAWAII – Alcohol use and deaths related to alcohol-use disorders are increasing, and young adults might be the group to watch, said Norah Terrault, MD, MPH, professor at the Keck School of Medicine of USC in Los Angeles.

“A lot of young people are drinking large amounts and they don’t know they’re at risk. They may not drink much during the week but then drink 30 drinks on the weekend,” Dr. Terrault told Medscape Medical News.

The largest relative increase in deaths from alcoholic cirrhosis – 10.5% from 2009 to 2016 – was in the 25- to 34-year age group, she reported here at the Gastroenterology Updates IBD Liver Disease Conference 2020.

This highlights the importance of asking for details about alcohol use during primary care visits; not only how much, but also what time of day, for instance, she explained.

Dr. Terrault’s team at Keck is part of the ACCELERATE-AH consortium, a group of 12 transplant centers looking at patterns of alcohol use before and after liver transplantation.

In their retrospective study of 147 consecutive transplant patients from 2006 to 2018, they found that young age, a history of multiple rehab attempts, and overt encephalopathy at time of transplantation were predictors of alcohol use after the procedure.

Corticosteroids remain the only proven therapy for alcoholic hepatitis. “We have not seen a new therapy in this arena in decades,” said Dr. Terrault. “We really have nothing to offer these patients, yet it’s an incredibly common presentation with a high mortality.”
 

More treatment options

The good news is that some phase 2 data look promising for new therapies, she reported.

“Some of them are targeting injury and regeneration primarily. Others are looking at the anti-inflammatory and antifibrotic effects. Some are also looking at how gut permeability and the microbiome are influencing outcomes,” she explained.

Transplantation has become very important for patients who do not respond to current therapy, and selection criteria have evolved over the years to take this into account, she pointed out.

In the early 1980s, alcoholic hepatitis was considered an inappropriate indication for liver transplantation. In the early 2000s, the guidance moved to setting 6 months of alcohol abstinence as a criterion for transplantation. The 6-month rule effectively eliminated patients with severe alcoholic hepatitis, who, by the time they needed a new liver, would not have 6 months to live.

Recently, guidelines have added the option of transplantation for patients with alcoholic hepatitis. The option was always there for people who developed alcohol cirrhosis or liver cancer, but now alcoholic hepatitis is recognized as a potential indication for transplantation, Dr. Terrault explained.

Today, transplant centers are moving away from the 6-month rule for two main reasons, she said. One is that few data support the 6-month time period as the duration that makes a difference.

“There is nothing magical about 6 months vs. 3 months or 12 months,” she said, adding that studies have shown that other factors might be better indicators, such as family support and whether the person is employed.

Second, recent studies have shown that rates of 3-year survival are similar in people who did not abstain at all before the procedure and those who undergo transplantation for other reasons.

The ACCELERATE-AH consortium also found that 70% of patients with severe alcoholic hepatitis remained abstinent up to 3 years after transplantation.

Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant.

The selection process remains complicated and controversial, Dr. Terrault acknowledged.

“Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant,” she said.

And there is concern that because patients with severe alcoholic hepatitis present with severe illness, they get moved to the top of the wait list. The rationale for that, she explained, is that it is done that way in other acute situations.

“We transplant individuals who have an acetaminophen overdose, for example. That’s common in many programs,” she said.

“My issue is that some patients with acute alcoholic hepatitis that have a very high severity score, but some of them, just with abstinence, will get better,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University in New Haven, Conn.

There are cases in which acute alcoholic hepatitis will resolve with abstinence, “and patients can return to an entirely compensated state of cirrhosis, in which they are entirely asymptomatic and they can live,” she told Medscape Medical News.

But it’s hard to know without a control group which patients would have that kind of success with just abstinence, she acknowledged.

Terrault said she agreed, and added that “our tools are not that good,” so determining which patients can be “pulled back from the brink” without transplantation is a challenge.

“There’s still a lot to learn about how we do this, and how we do it well,” she said.

Alcoholic hepatitis as an indication for liver transplantation is rare – less than 1% – but growing.

“This is a potential therapy for your patient who is sick in the ICU with a high severity of disease who has failed steroids. We should call out to see if there’s a transplant program that might be willing to evaluate them,” she said.
 

This article first appeared on Medscape.com.

MAUI, HAWAII – Alcohol use and deaths related to alcohol-use disorders are increasing, and young adults might be the group to watch, said Norah Terrault, MD, MPH, professor at the Keck School of Medicine of USC in Los Angeles.

“A lot of young people are drinking large amounts and they don’t know they’re at risk. They may not drink much during the week but then drink 30 drinks on the weekend,” Dr. Terrault told Medscape Medical News.

The largest relative increase in deaths from alcoholic cirrhosis – 10.5% from 2009 to 2016 – was in the 25- to 34-year age group, she reported here at the Gastroenterology Updates IBD Liver Disease Conference 2020.

This highlights the importance of asking for details about alcohol use during primary care visits; not only how much, but also what time of day, for instance, she explained.

Dr. Terrault’s team at Keck is part of the ACCELERATE-AH consortium, a group of 12 transplant centers looking at patterns of alcohol use before and after liver transplantation.

In their retrospective study of 147 consecutive transplant patients from 2006 to 2018, they found that young age, a history of multiple rehab attempts, and overt encephalopathy at time of transplantation were predictors of alcohol use after the procedure.

Corticosteroids remain the only proven therapy for alcoholic hepatitis. “We have not seen a new therapy in this arena in decades,” said Dr. Terrault. “We really have nothing to offer these patients, yet it’s an incredibly common presentation with a high mortality.”
 

More treatment options

The good news is that some phase 2 data look promising for new therapies, she reported.

“Some of them are targeting injury and regeneration primarily. Others are looking at the anti-inflammatory and antifibrotic effects. Some are also looking at how gut permeability and the microbiome are influencing outcomes,” she explained.

Transplantation has become very important for patients who do not respond to current therapy, and selection criteria have evolved over the years to take this into account, she pointed out.

In the early 1980s, alcoholic hepatitis was considered an inappropriate indication for liver transplantation. In the early 2000s, the guidance moved to setting 6 months of alcohol abstinence as a criterion for transplantation. The 6-month rule effectively eliminated patients with severe alcoholic hepatitis, who, by the time they needed a new liver, would not have 6 months to live.

Recently, guidelines have added the option of transplantation for patients with alcoholic hepatitis. The option was always there for people who developed alcohol cirrhosis or liver cancer, but now alcoholic hepatitis is recognized as a potential indication for transplantation, Dr. Terrault explained.

Today, transplant centers are moving away from the 6-month rule for two main reasons, she said. One is that few data support the 6-month time period as the duration that makes a difference.

“There is nothing magical about 6 months vs. 3 months or 12 months,” she said, adding that studies have shown that other factors might be better indicators, such as family support and whether the person is employed.

Second, recent studies have shown that rates of 3-year survival are similar in people who did not abstain at all before the procedure and those who undergo transplantation for other reasons.

The ACCELERATE-AH consortium also found that 70% of patients with severe alcoholic hepatitis remained abstinent up to 3 years after transplantation.

Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant.

The selection process remains complicated and controversial, Dr. Terrault acknowledged.

“Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant,” she said.

And there is concern that because patients with severe alcoholic hepatitis present with severe illness, they get moved to the top of the wait list. The rationale for that, she explained, is that it is done that way in other acute situations.

“We transplant individuals who have an acetaminophen overdose, for example. That’s common in many programs,” she said.

“My issue is that some patients with acute alcoholic hepatitis that have a very high severity score, but some of them, just with abstinence, will get better,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University in New Haven, Conn.

There are cases in which acute alcoholic hepatitis will resolve with abstinence, “and patients can return to an entirely compensated state of cirrhosis, in which they are entirely asymptomatic and they can live,” she told Medscape Medical News.

But it’s hard to know without a control group which patients would have that kind of success with just abstinence, she acknowledged.

Terrault said she agreed, and added that “our tools are not that good,” so determining which patients can be “pulled back from the brink” without transplantation is a challenge.

“There’s still a lot to learn about how we do this, and how we do it well,” she said.

Alcoholic hepatitis as an indication for liver transplantation is rare – less than 1% – but growing.

“This is a potential therapy for your patient who is sick in the ICU with a high severity of disease who has failed steroids. We should call out to see if there’s a transplant program that might be willing to evaluate them,” she said.
 

This article first appeared on Medscape.com.

MAUI, HAWAII – Alcohol use and deaths related to alcohol-use disorders are increasing, and young adults might be the group to watch, said Norah Terrault, MD, MPH, professor at the Keck School of Medicine of USC in Los Angeles.

“A lot of young people are drinking large amounts and they don’t know they’re at risk. They may not drink much during the week but then drink 30 drinks on the weekend,” Dr. Terrault told Medscape Medical News.

The largest relative increase in deaths from alcoholic cirrhosis – 10.5% from 2009 to 2016 – was in the 25- to 34-year age group, she reported here at the Gastroenterology Updates IBD Liver Disease Conference 2020.

This highlights the importance of asking for details about alcohol use during primary care visits; not only how much, but also what time of day, for instance, she explained.

Dr. Terrault’s team at Keck is part of the ACCELERATE-AH consortium, a group of 12 transplant centers looking at patterns of alcohol use before and after liver transplantation.

In their retrospective study of 147 consecutive transplant patients from 2006 to 2018, they found that young age, a history of multiple rehab attempts, and overt encephalopathy at time of transplantation were predictors of alcohol use after the procedure.

Corticosteroids remain the only proven therapy for alcoholic hepatitis. “We have not seen a new therapy in this arena in decades,” said Dr. Terrault. “We really have nothing to offer these patients, yet it’s an incredibly common presentation with a high mortality.”
 

More treatment options

The good news is that some phase 2 data look promising for new therapies, she reported.

“Some of them are targeting injury and regeneration primarily. Others are looking at the anti-inflammatory and antifibrotic effects. Some are also looking at how gut permeability and the microbiome are influencing outcomes,” she explained.

Transplantation has become very important for patients who do not respond to current therapy, and selection criteria have evolved over the years to take this into account, she pointed out.

In the early 1980s, alcoholic hepatitis was considered an inappropriate indication for liver transplantation. In the early 2000s, the guidance moved to setting 6 months of alcohol abstinence as a criterion for transplantation. The 6-month rule effectively eliminated patients with severe alcoholic hepatitis, who, by the time they needed a new liver, would not have 6 months to live.

Recently, guidelines have added the option of transplantation for patients with alcoholic hepatitis. The option was always there for people who developed alcohol cirrhosis or liver cancer, but now alcoholic hepatitis is recognized as a potential indication for transplantation, Dr. Terrault explained.

Today, transplant centers are moving away from the 6-month rule for two main reasons, she said. One is that few data support the 6-month time period as the duration that makes a difference.

“There is nothing magical about 6 months vs. 3 months or 12 months,” she said, adding that studies have shown that other factors might be better indicators, such as family support and whether the person is employed.

Second, recent studies have shown that rates of 3-year survival are similar in people who did not abstain at all before the procedure and those who undergo transplantation for other reasons.

The ACCELERATE-AH consortium also found that 70% of patients with severe alcoholic hepatitis remained abstinent up to 3 years after transplantation.

Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant.

The selection process remains complicated and controversial, Dr. Terrault acknowledged.

“Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant,” she said.

And there is concern that because patients with severe alcoholic hepatitis present with severe illness, they get moved to the top of the wait list. The rationale for that, she explained, is that it is done that way in other acute situations.

“We transplant individuals who have an acetaminophen overdose, for example. That’s common in many programs,” she said.

“My issue is that some patients with acute alcoholic hepatitis that have a very high severity score, but some of them, just with abstinence, will get better,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University in New Haven, Conn.

There are cases in which acute alcoholic hepatitis will resolve with abstinence, “and patients can return to an entirely compensated state of cirrhosis, in which they are entirely asymptomatic and they can live,” she told Medscape Medical News.

But it’s hard to know without a control group which patients would have that kind of success with just abstinence, she acknowledged.

Terrault said she agreed, and added that “our tools are not that good,” so determining which patients can be “pulled back from the brink” without transplantation is a challenge.

“There’s still a lot to learn about how we do this, and how we do it well,” she said.

Alcoholic hepatitis as an indication for liver transplantation is rare – less than 1% – but growing.

“This is a potential therapy for your patient who is sick in the ICU with a high severity of disease who has failed steroids. We should call out to see if there’s a transplant program that might be willing to evaluate them,” she said.
 

This article first appeared on Medscape.com.

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

M. Alexander Otto/MDedge News

“We are going to have a laundry list of new drugs” that are in the pipeline now. Phase 2 results “look encouraging. You will hear much more about this in the years ahead,” said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn’t clear the HBV surface antigen, which is linked to liver cancer. “Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go,” Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
 

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. “You have a hammer, you want to hit a nail,” Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that “unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients.”

This finding is one reason “we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning” to active disease. “I’m thinking we should really [lower] the age cutoff” to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus “patients feel really good when they know the virus is controlled, and so do physicians,” Dr. Terrault said.
 

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. “This led to a lot of concern that maybe we should be moving all our patients to tenofovir,” she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, “the difference disappeared” (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be “treated many years ago and tended to have more severe [baseline] disease,” Dr. Terrault said.

So “while we see this difference, there’s not enough data yet for us to make a recommendation for our patients to switch from” entecavir to tenofovir. “Until a randomized controlled trial is done, this may remain an issue,” she said.
 

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

“The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates” – perhaps about 40% – “would be well worth the effort,” editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It’s an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn’t be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

[email protected]

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

M. Alexander Otto/MDedge News

“We are going to have a laundry list of new drugs” that are in the pipeline now. Phase 2 results “look encouraging. You will hear much more about this in the years ahead,” said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn’t clear the HBV surface antigen, which is linked to liver cancer. “Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go,” Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
 

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. “You have a hammer, you want to hit a nail,” Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that “unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients.”

This finding is one reason “we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning” to active disease. “I’m thinking we should really [lower] the age cutoff” to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus “patients feel really good when they know the virus is controlled, and so do physicians,” Dr. Terrault said.
 

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. “This led to a lot of concern that maybe we should be moving all our patients to tenofovir,” she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, “the difference disappeared” (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be “treated many years ago and tended to have more severe [baseline] disease,” Dr. Terrault said.

So “while we see this difference, there’s not enough data yet for us to make a recommendation for our patients to switch from” entecavir to tenofovir. “Until a randomized controlled trial is done, this may remain an issue,” she said.
 

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

“The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates” – perhaps about 40% – “would be well worth the effort,” editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It’s an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn’t be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

[email protected]

MAUI, HAWAII – There might well be a cure for hepatitis B in coming years, just like there is now for hepatitis C, according to Norah Terrault, MD, chief of the division of GI and liver at the University of Southern California, Los Angeles.

M. Alexander Otto/MDedge News

“We are going to have a laundry list of new drugs” that are in the pipeline now. Phase 2 results “look encouraging. You will hear much more about this in the years ahead,” said Dr. Terrault, lead author of the 2018 American Association for the Study of Liver Diseases (AASLD) hepatitis B guidance.

For now, though, the field is largely limited to the nucleoside analogues tenofovir and entecavir. Treatment is often indefinite because, although hepatitis B virus (HBV) e-antigen is cleared, it usually doesn’t clear the HBV surface antigen, which is linked to liver cancer. “Even with e-antigen–negative patients, we feel that indefinite therapy is really the way to go,” Dr. Terrault said at the Gastroenterology Updates, IBD, Liver Disease Conference.

One of the biggest problems with that strategy is what to do when HBV does not seem to be much of a problem for carriers. Such patients are referred to as immune tolerant.
 

A newly recognized cancer risk

Immune tolerant patients tend to be young and have extremely high viral loads but no apparent ill effects, with normal ALT levels, normal histology, and no sign of cirrhosis. Although the AASLD recommends not treating these patients until they are 40 years old, waiting makes people nervous. “You have a hammer, you want to hit a nail,” Dr. Terrault said.

A recent review (Gut. 2018 May;67[5]:945-52) suggests that hitting the nail might be the way to go. South Korean investigators found that 413 untreated immune tolerate patients with a mean age of 38 years had more than twice the risk of liver cancer over 10 years than did almost 1,500 treated patients with active disease.

The study investigators concluded that “unnecessary deaths could be prevented through earlier antiviral intervention in select [immune tolerate] patients.”

This finding is one reason “we [AASLD] are rethinking the mantra of not treating the immune tolerant. There is a group that is transitioning” to active disease. “I’m thinking we should really [lower] the age cutoff” to 30 years, as some other groups [European Association for the Study of the Liver and Asian Pacific Association for the Study of the Liver] have done, plus “patients feel really good when they know the virus is controlled, and so do physicians,” Dr. Terrault said.
 

Entecavir versus tenofovir

Meanwhile, recent studies have raised the question of whether tenofovir is better than entecavir at preventing liver cancer.

A JAMA Oncology (JAMA Oncol. 2019 Jan 1;5[1]:30-6) study of some 25,000 patients in South Korea found a 32% lower risk of liver cancer when they were treated with tenofovir instead of entecavir. “This led to a lot of concern that maybe we should be moving all our patients to tenofovir,” she said.

Another study, a meta-analysis published earlier this year (Hepatol Int. 2020 Jan;14[1]:105-14), confirmed the difference in cancer risk when it combined those findings with other research. After adjustment for potential confounders, including disease stage and length of follow-up, “the difference disappeared” (hazard ration, 0.87; 95% confidence interval, 0.73-1.04), authors of the meta-analysis reported.

Study patients who received entecavir tended to be “treated many years ago and tended to have more severe [baseline] disease,” Dr. Terrault said.

So “while we see this difference, there’s not enough data yet for us to make a recommendation for our patients to switch from” entecavir to tenofovir. “Until a randomized controlled trial is done, this may remain an issue,” she said.
 

A drug holiday?

Dr. Terrault also reviewed research that suggests nucleoside analogue treatment can be stopped in e-antigen–negative patients after at least 3 years.

“The evidence is increasing that a finite NA [nucleoside analogue] treatment approach leads to higher HBsAg [hepatitis B surface antigen] loss rates, compared with the current long-term NA strategy, and can be considered a rational strategy to induce a functional cure in selected HBeAg-negative patients without cirrhosis who are willing to comply with close follow-up monitoring. ... The current observed functional cure rates” – perhaps about 40% – “would be well worth the effort,” editorialists commenting on the research concluded (Hepatology. 2018 Aug;68[2]:397-400).

It’s an interesting idea, Dr. Terrault said, but the virus will flare 8-12 weeks after treatment withdrawal, which is why it shouldn’t be considered in patients with cirrhosis.

Dr. Terrault is a consultant for AbbVie, Merck, Gilead, and other companies and disclosed grants from those companies and others.

[email protected]

Alcohol use is associated with hepatic steatosis, even after exclusion of heavy drinkers. Binge drinking was associated with a particularly high risk. The results are drawn from a retrospective analysis of the Framingham Heart Study and indicate a possible connection between alcohol use and nonalcoholic fatty liver disease (NAFLD). If confirmed prospectively, the results suggest that alcohol use could be a target for prevention and treatment of presumed NAFLD.

The study was led by Michelle Long, MD, of Boston University, and was published in Clinical Gastroenterology and Hepatology.

Previous studies have produced mixed results with respect to alcohol consumption and NAFLD, with some reporting increased risk with alcohol consumption, and some a beneficial effect of moderate alcohol consumption. Most such studies focused on average daily or weekly alcohol intake, without examining individual differences in alcohol use behavior.

The current work included 2,475 participants from the Offspring and Third Generation Cohorts of the multidetector CT (MDCT) substudy of the Framingham Heart Study. The researchers excluded heavy drinkers, defined as those who had more than 21 drinks (men) or 14 drinks (women) per week.

Of the sample, 17.3% had hepatic steatosis as measured by MDCT. The risk of hepatic steatosis increased from 15.3% to 54.3% along increasing categories of alcohol use.

With each standard deviation increase in the number of alcohol drinks per week, the risk of hepatic steatosis increased by 15% (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29). Of subjects with presumed NAFLD, 25.4% were binge drinkers, defined as four or more drinks per day in women and five or more in men.

A pattern of risky weekly drinking – defined as 8 or more drinks for women or 15 or more for men – was associated with a 45% increase in odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98).

An analysis of only current drinkers showed stronger associations between hepatic steatosis and the number of alcoholic drinks per week, risky weekly drinking, and maximum number of drinks in 24 hours.

When the researchers broke down the analysis by beer, wine, or spirit drinkers, they only found a statistically significant association between alcohol consumption and hepatic steatosis in beer drinkers.

The study authors received funding from a range of nonindustry sources. They reported having no relevant financial disclosures.

SOURCE: Long M et al. Clin Gastroenterol Hepatol. 2019 Nov 14. doi: 10.1016/j.cgh.2019.11.022

Alcohol use is associated with hepatic steatosis, even after exclusion of heavy drinkers. Binge drinking was associated with a particularly high risk. The results are drawn from a retrospective analysis of the Framingham Heart Study and indicate a possible connection between alcohol use and nonalcoholic fatty liver disease (NAFLD). If confirmed prospectively, the results suggest that alcohol use could be a target for prevention and treatment of presumed NAFLD.

The study was led by Michelle Long, MD, of Boston University, and was published in Clinical Gastroenterology and Hepatology.

Previous studies have produced mixed results with respect to alcohol consumption and NAFLD, with some reporting increased risk with alcohol consumption, and some a beneficial effect of moderate alcohol consumption. Most such studies focused on average daily or weekly alcohol intake, without examining individual differences in alcohol use behavior.

The current work included 2,475 participants from the Offspring and Third Generation Cohorts of the multidetector CT (MDCT) substudy of the Framingham Heart Study. The researchers excluded heavy drinkers, defined as those who had more than 21 drinks (men) or 14 drinks (women) per week.

Of the sample, 17.3% had hepatic steatosis as measured by MDCT. The risk of hepatic steatosis increased from 15.3% to 54.3% along increasing categories of alcohol use.

With each standard deviation increase in the number of alcohol drinks per week, the risk of hepatic steatosis increased by 15% (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29). Of subjects with presumed NAFLD, 25.4% were binge drinkers, defined as four or more drinks per day in women and five or more in men.

A pattern of risky weekly drinking – defined as 8 or more drinks for women or 15 or more for men – was associated with a 45% increase in odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98).

An analysis of only current drinkers showed stronger associations between hepatic steatosis and the number of alcoholic drinks per week, risky weekly drinking, and maximum number of drinks in 24 hours.

When the researchers broke down the analysis by beer, wine, or spirit drinkers, they only found a statistically significant association between alcohol consumption and hepatic steatosis in beer drinkers.

The study authors received funding from a range of nonindustry sources. They reported having no relevant financial disclosures.

SOURCE: Long M et al. Clin Gastroenterol Hepatol. 2019 Nov 14. doi: 10.1016/j.cgh.2019.11.022

Alcohol use is associated with hepatic steatosis, even after exclusion of heavy drinkers. Binge drinking was associated with a particularly high risk. The results are drawn from a retrospective analysis of the Framingham Heart Study and indicate a possible connection between alcohol use and nonalcoholic fatty liver disease (NAFLD). If confirmed prospectively, the results suggest that alcohol use could be a target for prevention and treatment of presumed NAFLD.

The study was led by Michelle Long, MD, of Boston University, and was published in Clinical Gastroenterology and Hepatology.

Previous studies have produced mixed results with respect to alcohol consumption and NAFLD, with some reporting increased risk with alcohol consumption, and some a beneficial effect of moderate alcohol consumption. Most such studies focused on average daily or weekly alcohol intake, without examining individual differences in alcohol use behavior.

The current work included 2,475 participants from the Offspring and Third Generation Cohorts of the multidetector CT (MDCT) substudy of the Framingham Heart Study. The researchers excluded heavy drinkers, defined as those who had more than 21 drinks (men) or 14 drinks (women) per week.

Of the sample, 17.3% had hepatic steatosis as measured by MDCT. The risk of hepatic steatosis increased from 15.3% to 54.3% along increasing categories of alcohol use.

With each standard deviation increase in the number of alcohol drinks per week, the risk of hepatic steatosis increased by 15% (adjusted odds ratio, 1.15; 95% CI, 1.02-1.29). Of subjects with presumed NAFLD, 25.4% were binge drinkers, defined as four or more drinks per day in women and five or more in men.

A pattern of risky weekly drinking – defined as 8 or more drinks for women or 15 or more for men – was associated with a 45% increase in odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06-1.98).

An analysis of only current drinkers showed stronger associations between hepatic steatosis and the number of alcoholic drinks per week, risky weekly drinking, and maximum number of drinks in 24 hours.

When the researchers broke down the analysis by beer, wine, or spirit drinkers, they only found a statistically significant association between alcohol consumption and hepatic steatosis in beer drinkers.

The study authors received funding from a range of nonindustry sources. They reported having no relevant financial disclosures.

SOURCE: Long M et al. Clin Gastroenterol Hepatol. 2019 Nov 14. doi: 10.1016/j.cgh.2019.11.022