Liver Disease

Changes in a variety of T cells in the liver and visceral adipose tissue play a key role in the pathogenesis of nonalcoholic steatohepatitis, according to the results of a murine study.

Mikhaïl A. Van Herck, of the University of Antwerp (Belgium), and associates fed 8-week old mice a high-fat, high-fructose diet for 20 weeks, and then switched the mice to standard mouse chow for 12 weeks. The high-fat, high-fructose diet induced the metabolic syndrome and nonalcoholic steatohepatitis (NASH), accompanied by shifts in T cells. Interleukin-17–producing (Th17 cells increased in the liver, visceral adipose tissue, and blood, while regulatory T cells decreased in visceral adipose tissue, and cytotoxic T (Tc) cells rose in visceral adipose tissue while dropping in the blood and spleen.

These are “important immune disruptions,” the researchers wrote in Cellular and Molecular Gastroenterology and Hepatology. “In particular, visceral adipose tissue Tc cells are critically involved in NASH pathogenesis, linking adipose tissue inflammation to liver disease.”

After the mice were switched from the high-fat, high-fructose diet to standard mouse chow, their body weight, body fat, and plasma cholesterol significantly decreased and their glucose tolerance and insulin sensitivity improved to resemble the metrics of mice fed standard mouse chow throughout the study. Mice who underwent diet reversal also had significantly decreased liver weight and levels of plasma ALT, compared with mice that remained on the high-fat, high-fructose diet. Diet reversal also improved liver histology (nonalcoholic fatty liver disease activity scores), compared with the high-fat, high-fructose diet, the researchers wrote. “Importantly, the NASH was not significantly different between diet-reversal mice and mice fed the control diet for 32 weeks.”

Genetic tests supported these findings. On multiplex RNA analysis, hepatic expression of Acta2, Col1a1, and Col1a3 reverted to normal with diet reversal, indicating a normalization of hepatic collagen. Hepatic expression of the metabolic genes Ppara, Pparg, and Fgf21 also returned to normal, while visceral adipose tissue showed a decrease in Lep and Fgf21 expression and resolution of adipocyte hypertrophy.

However, diet reversal did not reverse inflammatory changes in T-cell subsets. Administering anti-CD8a antibodies after diet reversal decreased Tc cells in all tissue types that were tested, signifying “a biochemical and histologic attenuation of the high-fat, high-fructose diet-induced NASH,” the investigators wrote. Treating the mice with antibodies targeting IL-17A did not attenuate NASH but did reduce hepatic inflammation.

The fact that “the most pronounced effect” on NASH resulted from correcting immune disruption in visceral adipose tissue underscored “the immense importance of adipose tissue inflammation in [NASH] pathogenesis,” the researchers wrote. The finding that diet reversal alone did not reverse inflammation in hepatic or visceral adipose tissue “challeng[es] our current understanding of the reversibility of NASH and other obesity-related conditions.” They called for studies of underlying mechanisms as part of “the search for a medical treatment for NASH.”

Funders included the University Research Fund, University of Antwerp, and Research Foundation Flanders. The researchers reported having no conflicts of interest except that one coinvestigator is the chief science officer at Biocellvia, which performed some histologic analyses.

SOURCE: Van Herck MA et al. Cell Molec Gastroenterol Hepatol. 2020 Apr 20. doi: 10.1016/j.jcmgh.2020.04.010.

Changes in a variety of T cells in the liver and visceral adipose tissue play a key role in the pathogenesis of nonalcoholic steatohepatitis, according to the results of a murine study.

Mikhaïl A. Van Herck, of the University of Antwerp (Belgium), and associates fed 8-week old mice a high-fat, high-fructose diet for 20 weeks, and then switched the mice to standard mouse chow for 12 weeks. The high-fat, high-fructose diet induced the metabolic syndrome and nonalcoholic steatohepatitis (NASH), accompanied by shifts in T cells. Interleukin-17–producing (Th17 cells increased in the liver, visceral adipose tissue, and blood, while regulatory T cells decreased in visceral adipose tissue, and cytotoxic T (Tc) cells rose in visceral adipose tissue while dropping in the blood and spleen.

These are “important immune disruptions,” the researchers wrote in Cellular and Molecular Gastroenterology and Hepatology. “In particular, visceral adipose tissue Tc cells are critically involved in NASH pathogenesis, linking adipose tissue inflammation to liver disease.”

After the mice were switched from the high-fat, high-fructose diet to standard mouse chow, their body weight, body fat, and plasma cholesterol significantly decreased and their glucose tolerance and insulin sensitivity improved to resemble the metrics of mice fed standard mouse chow throughout the study. Mice who underwent diet reversal also had significantly decreased liver weight and levels of plasma ALT, compared with mice that remained on the high-fat, high-fructose diet. Diet reversal also improved liver histology (nonalcoholic fatty liver disease activity scores), compared with the high-fat, high-fructose diet, the researchers wrote. “Importantly, the NASH was not significantly different between diet-reversal mice and mice fed the control diet for 32 weeks.”

Genetic tests supported these findings. On multiplex RNA analysis, hepatic expression of Acta2, Col1a1, and Col1a3 reverted to normal with diet reversal, indicating a normalization of hepatic collagen. Hepatic expression of the metabolic genes Ppara, Pparg, and Fgf21 also returned to normal, while visceral adipose tissue showed a decrease in Lep and Fgf21 expression and resolution of adipocyte hypertrophy.

However, diet reversal did not reverse inflammatory changes in T-cell subsets. Administering anti-CD8a antibodies after diet reversal decreased Tc cells in all tissue types that were tested, signifying “a biochemical and histologic attenuation of the high-fat, high-fructose diet-induced NASH,” the investigators wrote. Treating the mice with antibodies targeting IL-17A did not attenuate NASH but did reduce hepatic inflammation.

The fact that “the most pronounced effect” on NASH resulted from correcting immune disruption in visceral adipose tissue underscored “the immense importance of adipose tissue inflammation in [NASH] pathogenesis,” the researchers wrote. The finding that diet reversal alone did not reverse inflammation in hepatic or visceral adipose tissue “challeng[es] our current understanding of the reversibility of NASH and other obesity-related conditions.” They called for studies of underlying mechanisms as part of “the search for a medical treatment for NASH.”

Funders included the University Research Fund, University of Antwerp, and Research Foundation Flanders. The researchers reported having no conflicts of interest except that one coinvestigator is the chief science officer at Biocellvia, which performed some histologic analyses.

SOURCE: Van Herck MA et al. Cell Molec Gastroenterol Hepatol. 2020 Apr 20. doi: 10.1016/j.jcmgh.2020.04.010.

Changes in a variety of T cells in the liver and visceral adipose tissue play a key role in the pathogenesis of nonalcoholic steatohepatitis, according to the results of a murine study.

Mikhaïl A. Van Herck, of the University of Antwerp (Belgium), and associates fed 8-week old mice a high-fat, high-fructose diet for 20 weeks, and then switched the mice to standard mouse chow for 12 weeks. The high-fat, high-fructose diet induced the metabolic syndrome and nonalcoholic steatohepatitis (NASH), accompanied by shifts in T cells. Interleukin-17–producing (Th17 cells increased in the liver, visceral adipose tissue, and blood, while regulatory T cells decreased in visceral adipose tissue, and cytotoxic T (Tc) cells rose in visceral adipose tissue while dropping in the blood and spleen.

These are “important immune disruptions,” the researchers wrote in Cellular and Molecular Gastroenterology and Hepatology. “In particular, visceral adipose tissue Tc cells are critically involved in NASH pathogenesis, linking adipose tissue inflammation to liver disease.”

After the mice were switched from the high-fat, high-fructose diet to standard mouse chow, their body weight, body fat, and plasma cholesterol significantly decreased and their glucose tolerance and insulin sensitivity improved to resemble the metrics of mice fed standard mouse chow throughout the study. Mice who underwent diet reversal also had significantly decreased liver weight and levels of plasma ALT, compared with mice that remained on the high-fat, high-fructose diet. Diet reversal also improved liver histology (nonalcoholic fatty liver disease activity scores), compared with the high-fat, high-fructose diet, the researchers wrote. “Importantly, the NASH was not significantly different between diet-reversal mice and mice fed the control diet for 32 weeks.”

Genetic tests supported these findings. On multiplex RNA analysis, hepatic expression of Acta2, Col1a1, and Col1a3 reverted to normal with diet reversal, indicating a normalization of hepatic collagen. Hepatic expression of the metabolic genes Ppara, Pparg, and Fgf21 also returned to normal, while visceral adipose tissue showed a decrease in Lep and Fgf21 expression and resolution of adipocyte hypertrophy.

However, diet reversal did not reverse inflammatory changes in T-cell subsets. Administering anti-CD8a antibodies after diet reversal decreased Tc cells in all tissue types that were tested, signifying “a biochemical and histologic attenuation of the high-fat, high-fructose diet-induced NASH,” the investigators wrote. Treating the mice with antibodies targeting IL-17A did not attenuate NASH but did reduce hepatic inflammation.

The fact that “the most pronounced effect” on NASH resulted from correcting immune disruption in visceral adipose tissue underscored “the immense importance of adipose tissue inflammation in [NASH] pathogenesis,” the researchers wrote. The finding that diet reversal alone did not reverse inflammation in hepatic or visceral adipose tissue “challeng[es] our current understanding of the reversibility of NASH and other obesity-related conditions.” They called for studies of underlying mechanisms as part of “the search for a medical treatment for NASH.”

Funders included the University Research Fund, University of Antwerp, and Research Foundation Flanders. The researchers reported having no conflicts of interest except that one coinvestigator is the chief science officer at Biocellvia, which performed some histologic analyses.

SOURCE: Van Herck MA et al. Cell Molec Gastroenterol Hepatol. 2020 Apr 20. doi: 10.1016/j.jcmgh.2020.04.010.

In individuals with inflammatory bowel disease and primary sclerosing cholangitis, younger age at diagnosis, male sex, and Afro-Caribbean heritage were significant risk factors for liver transplantation and disease-related death, based on a 10-year prospective population-based study.

These factors should be incorporated into the design of clinical trials, models for predicting disease, and studies of prognostic biomarkers for primary sclerosing cholangitis, Palak T. Trivedi, MBBS, MRCP, of the Universty of Birmingham (England) wrote with his associates in Gastroenterology.

The researchers identified newly diagnosed cases from a national health care registry in England between 2006 and 2016 (data on outcomes were collected through mid-2019). In all, 284,560 individuals had a new diagnosis of inflammatory bowel disease, among whom 2,588 also had primary sclerosing cholangitis. The investigators tracked deaths, liver transplantation, colonic resection, cholecystectomy, and diagnoses of colorectal cancer, cholangiosarcoma, and cancers of the pancreas, gallbladder, and liver. They evaluated rates of these outcomes among individuals with both primary sclerosing cholangitis and inflammatory bowel disease (PSC-IBD) and those with IBD only.

After controlling for sex, race, socioeconomic level, comorbidities, and older age, the researchers found that both men and women with PSC-IBD had a significantly greater risk for all-cause mortality, compared with individuals with IBD alone (hazard ratio, 3.20; 95% confidence interval, 3.01-3.40; P less than .001). Strikingly, individuals who were diagnosed with PSC when they were younger than 40 years had a more than sevenfold higher rate of all-cause mortality, compared with individuals with IBD only. In contrast, the incidence rate ratio for individuals diagnosed with PSC when they were older than 60 years was less than 1.5, compared with IBD-only individuals.

Having PSC and ulcerative colitis, being younger when diagnosed with PSC, and being of Afro-Carribean heritage all correlated with higher incidence of liver transplantation or death related to PSC. Individuals with PSC-IBD who were of Afro-Caribbean heritage had an approximately twofold greater risk for liver transplantation or PSC-related death compared with Whites (adjusted HR, 2.05; 95% CI, 1.14-3.70; P = .016). In contrast, women with PSC-IBD were at significantly lower risk for liver transplantation or disease-related death than were men (adjusted HR, 0.74; 95% CI, 0.57-0.97; P = .026).

“The onset of PSC confers heightened risks of all hepatobiliary malignancies, although annual imaging surveillance may associate with a reduced risk of cancer-related death,” the investigators found. Among patients with hepatobiliary cancer, annual imaging was associated with a twofold decrease in risk for cancer-related death (HR, 0.43; 95% CI, 0.23-0.80; P = .037).

Colorectal cancer tended to occur at a younger age among individuals with PSC-IBD, compared with those with IBD alone (median ages at diagnosis, 59 vs. 69 years; P less than .001). Notably, individuals with PSC diagnosed under age 50 years had about a fivefold higher incidence of colorectal cancer than did those with IBD alone, while those diagnosed at older ages had only about a twofold increase. With regard to colectomy, men diagnosed with PSC at younger ages were at the greatest risk, compared with women or individuals diagnosed after age 50 years. Individuals with ulcerative colitis and PSC had a 40% greater risk for colectomy risk than did IBD-only individuals (time-dependent adjusted HR, 1.65; 95% CI, 1.45-1.85; P less than .001).

“Whilst all-cause mortality rates increase with age, younger patients [with PSC] show a disproportionately increased incidence of liver transplantation, PSC-related death, and colorectal cancer,” the researchers concluded. “Consideration of age at diagnosis should therefore be applied in the stratification of patients for future clinical trials, disease prediction models, and prognostic biomarker discovery.”

Dr. Trivedi disclosed support from the National Institute for Health Research Birmingham Biomedical Research Centre, at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. No other disclosures were reported.

SOURCE: Trivedi PJ et al. Gastroenterology. 2020 May 19. doi: 10.1053/j.gastro.2020.05.049.
 

In individuals with inflammatory bowel disease and primary sclerosing cholangitis, younger age at diagnosis, male sex, and Afro-Caribbean heritage were significant risk factors for liver transplantation and disease-related death, based on a 10-year prospective population-based study.

These factors should be incorporated into the design of clinical trials, models for predicting disease, and studies of prognostic biomarkers for primary sclerosing cholangitis, Palak T. Trivedi, MBBS, MRCP, of the Universty of Birmingham (England) wrote with his associates in Gastroenterology.

The researchers identified newly diagnosed cases from a national health care registry in England between 2006 and 2016 (data on outcomes were collected through mid-2019). In all, 284,560 individuals had a new diagnosis of inflammatory bowel disease, among whom 2,588 also had primary sclerosing cholangitis. The investigators tracked deaths, liver transplantation, colonic resection, cholecystectomy, and diagnoses of colorectal cancer, cholangiosarcoma, and cancers of the pancreas, gallbladder, and liver. They evaluated rates of these outcomes among individuals with both primary sclerosing cholangitis and inflammatory bowel disease (PSC-IBD) and those with IBD only.

After controlling for sex, race, socioeconomic level, comorbidities, and older age, the researchers found that both men and women with PSC-IBD had a significantly greater risk for all-cause mortality, compared with individuals with IBD alone (hazard ratio, 3.20; 95% confidence interval, 3.01-3.40; P less than .001). Strikingly, individuals who were diagnosed with PSC when they were younger than 40 years had a more than sevenfold higher rate of all-cause mortality, compared with individuals with IBD only. In contrast, the incidence rate ratio for individuals diagnosed with PSC when they were older than 60 years was less than 1.5, compared with IBD-only individuals.

Having PSC and ulcerative colitis, being younger when diagnosed with PSC, and being of Afro-Carribean heritage all correlated with higher incidence of liver transplantation or death related to PSC. Individuals with PSC-IBD who were of Afro-Caribbean heritage had an approximately twofold greater risk for liver transplantation or PSC-related death compared with Whites (adjusted HR, 2.05; 95% CI, 1.14-3.70; P = .016). In contrast, women with PSC-IBD were at significantly lower risk for liver transplantation or disease-related death than were men (adjusted HR, 0.74; 95% CI, 0.57-0.97; P = .026).

“The onset of PSC confers heightened risks of all hepatobiliary malignancies, although annual imaging surveillance may associate with a reduced risk of cancer-related death,” the investigators found. Among patients with hepatobiliary cancer, annual imaging was associated with a twofold decrease in risk for cancer-related death (HR, 0.43; 95% CI, 0.23-0.80; P = .037).

Colorectal cancer tended to occur at a younger age among individuals with PSC-IBD, compared with those with IBD alone (median ages at diagnosis, 59 vs. 69 years; P less than .001). Notably, individuals with PSC diagnosed under age 50 years had about a fivefold higher incidence of colorectal cancer than did those with IBD alone, while those diagnosed at older ages had only about a twofold increase. With regard to colectomy, men diagnosed with PSC at younger ages were at the greatest risk, compared with women or individuals diagnosed after age 50 years. Individuals with ulcerative colitis and PSC had a 40% greater risk for colectomy risk than did IBD-only individuals (time-dependent adjusted HR, 1.65; 95% CI, 1.45-1.85; P less than .001).

“Whilst all-cause mortality rates increase with age, younger patients [with PSC] show a disproportionately increased incidence of liver transplantation, PSC-related death, and colorectal cancer,” the researchers concluded. “Consideration of age at diagnosis should therefore be applied in the stratification of patients for future clinical trials, disease prediction models, and prognostic biomarker discovery.”

Dr. Trivedi disclosed support from the National Institute for Health Research Birmingham Biomedical Research Centre, at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. No other disclosures were reported.

SOURCE: Trivedi PJ et al. Gastroenterology. 2020 May 19. doi: 10.1053/j.gastro.2020.05.049.
 

In individuals with inflammatory bowel disease and primary sclerosing cholangitis, younger age at diagnosis, male sex, and Afro-Caribbean heritage were significant risk factors for liver transplantation and disease-related death, based on a 10-year prospective population-based study.

These factors should be incorporated into the design of clinical trials, models for predicting disease, and studies of prognostic biomarkers for primary sclerosing cholangitis, Palak T. Trivedi, MBBS, MRCP, of the Universty of Birmingham (England) wrote with his associates in Gastroenterology.

The researchers identified newly diagnosed cases from a national health care registry in England between 2006 and 2016 (data on outcomes were collected through mid-2019). In all, 284,560 individuals had a new diagnosis of inflammatory bowel disease, among whom 2,588 also had primary sclerosing cholangitis. The investigators tracked deaths, liver transplantation, colonic resection, cholecystectomy, and diagnoses of colorectal cancer, cholangiosarcoma, and cancers of the pancreas, gallbladder, and liver. They evaluated rates of these outcomes among individuals with both primary sclerosing cholangitis and inflammatory bowel disease (PSC-IBD) and those with IBD only.

After controlling for sex, race, socioeconomic level, comorbidities, and older age, the researchers found that both men and women with PSC-IBD had a significantly greater risk for all-cause mortality, compared with individuals with IBD alone (hazard ratio, 3.20; 95% confidence interval, 3.01-3.40; P less than .001). Strikingly, individuals who were diagnosed with PSC when they were younger than 40 years had a more than sevenfold higher rate of all-cause mortality, compared with individuals with IBD only. In contrast, the incidence rate ratio for individuals diagnosed with PSC when they were older than 60 years was less than 1.5, compared with IBD-only individuals.

Having PSC and ulcerative colitis, being younger when diagnosed with PSC, and being of Afro-Carribean heritage all correlated with higher incidence of liver transplantation or death related to PSC. Individuals with PSC-IBD who were of Afro-Caribbean heritage had an approximately twofold greater risk for liver transplantation or PSC-related death compared with Whites (adjusted HR, 2.05; 95% CI, 1.14-3.70; P = .016). In contrast, women with PSC-IBD were at significantly lower risk for liver transplantation or disease-related death than were men (adjusted HR, 0.74; 95% CI, 0.57-0.97; P = .026).

“The onset of PSC confers heightened risks of all hepatobiliary malignancies, although annual imaging surveillance may associate with a reduced risk of cancer-related death,” the investigators found. Among patients with hepatobiliary cancer, annual imaging was associated with a twofold decrease in risk for cancer-related death (HR, 0.43; 95% CI, 0.23-0.80; P = .037).

Colorectal cancer tended to occur at a younger age among individuals with PSC-IBD, compared with those with IBD alone (median ages at diagnosis, 59 vs. 69 years; P less than .001). Notably, individuals with PSC diagnosed under age 50 years had about a fivefold higher incidence of colorectal cancer than did those with IBD alone, while those diagnosed at older ages had only about a twofold increase. With regard to colectomy, men diagnosed with PSC at younger ages were at the greatest risk, compared with women or individuals diagnosed after age 50 years. Individuals with ulcerative colitis and PSC had a 40% greater risk for colectomy risk than did IBD-only individuals (time-dependent adjusted HR, 1.65; 95% CI, 1.45-1.85; P less than .001).

“Whilst all-cause mortality rates increase with age, younger patients [with PSC] show a disproportionately increased incidence of liver transplantation, PSC-related death, and colorectal cancer,” the researchers concluded. “Consideration of age at diagnosis should therefore be applied in the stratification of patients for future clinical trials, disease prediction models, and prognostic biomarker discovery.”

Dr. Trivedi disclosed support from the National Institute for Health Research Birmingham Biomedical Research Centre, at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. No other disclosures were reported.

SOURCE: Trivedi PJ et al. Gastroenterology. 2020 May 19. doi: 10.1053/j.gastro.2020.05.049.
 

In heavy drinkers with alcohol-related liver disease, a Markov model based on age, sex, body mass index, and duration and extent of alcohol use predicted risk for disease progression, researchers reported in Clinical Gastroenterology and Hepatology.

The study included 2,334 hospitalized adults with consistently abnormal liver test results who had consumed at least 50 grams of alcohol (about 3.5-4 drinks) per day for the previous 5 years. The model was developed using data from 1,599 individuals with baseline liver biopsies and validated in 735 individuals with no baseline liver biopsies but available data on the presence or absence of hepatic decompensation.

For a 40-year-old man with F0-F2 fibrosis who had been drinking alcohol for 15 years, who drank 150 grams of alcohol daily, and who had a body mass index (BMI) of 22 kg/m², the model predicted a 31.8% likelihood of having a normal liver at baseline, a 61.5% probability of baseline steatosis, and a 6.7% probability of baseline steatohepatitis. In women with the same baseline variables, respective probabilities were 25.1%, 66.5%, and 8.4%. Based on these findings, the 5-year weighted risk for liver complications ranged from 0.2% for men with normal initial liver findings to 10.3% for men with baseline steatohepatitis. Among women, the corresponding risk estimates ranged from 0.5% to 14.7%, wrote PhD student Claire Delacôte of Centre Hospitalier Universitaire de Lille (France), and associates.

“This tool might be used by general practitioners or hepatologists to identify heavy drinkers at high risk for alcohol-related liver disease progression,” the investigators added. “This model might be used to adapt patient care pathways.”

The patients in this study were admitted to the hepatogastroenterology unit of a French hospital between 1982 and 1997. The Markov model incorporated seven stages of alcohol-related liver disease: normal liver (no fibrosis or steatosis), steatosis and F0-F2 fibrosis, alcohol-induced steatohepatitis and F0-F2 fibrosis, steatosis and F3-F4 fibrosis, alcohol-induced steatohepatitis and F3-F4 fibrosis, liver complications without steatohepatitis, and liver complications with alcohol-induced steatohepatitis. Liver complications were defined as hepatocellular carcinoma or liver decompensation (bilirubin >50 mmol/L, gastrointestinal hemorrhage, or ascites). Risk for progressing to liver complications was based on METAVIR score and onset of alcohol-induced steatohepatitis.

The researchers also looked specifically at F3-F4 (severe) fibrosis because of its clinical significance and common use as a study endpoint. Among 40-year-olds with a 15-year history of heavy drinking, the estimated prevalence of alcohol-induced steatohepatitis was 30.0% for men and 33.3% for women. The 5-year risk for liver complications was higher in women (30.1%) than men (24.5%) and was highest among women with baseline alcohol-induced steatohepatitis (41.0%). Overall, women had a 24.8% greater risk for disease progression than men (hazard ratio, 1.248).

Risk for liver complications also increased with age, and each 1-year increase in age at the beginning of heavy drinking heightened the risk for disease progression by 3.8%, regardless of stage of liver disease. “Based on these predictions, 50-year-old women are a high-risk subgroup of [alcohol-related liver] disease progression and should receive close follow-up,” the researchers wrote.

In addition, obese individuals (BMI, 30) had an 11.8% greater risk for progression of alcohol-related liver disease, compared with those with a BMI of 22. Consuming an additional 10 grams of alcohol per day had less impact on risk, the researchers noted.

“If patients are identified as being heavy drinkers by the general practitioner with no evaluation of fibrosis, these patients should be referred to a hepatologist. Nevertheless, we think that the threshold defining the high-risk population, which has been arbitrarily fixed at 5%, should be discussed by experts because it affects the patient’s care pathway. An online application is being developed to help clinicians and general practitioners in their daily practice,” they wrote.

No funding sources were reported. Ms. Delacôte reported having no conflicts of interest. Three coinvestigators disclosed ties to AbbVie, Bayer Healthcare, Eisai, Gilead, MSD, Novartis, Sanofi, and Servier. The others reported having no conflicts.
 

SOURCE: Delacôte C et al. Clin Gastroenterol Hepatol. 2020 Jan 11. doi: 10.1016/j.cgh.2019.12.041.
 

In heavy drinkers with alcohol-related liver disease, a Markov model based on age, sex, body mass index, and duration and extent of alcohol use predicted risk for disease progression, researchers reported in Clinical Gastroenterology and Hepatology.

The study included 2,334 hospitalized adults with consistently abnormal liver test results who had consumed at least 50 grams of alcohol (about 3.5-4 drinks) per day for the previous 5 years. The model was developed using data from 1,599 individuals with baseline liver biopsies and validated in 735 individuals with no baseline liver biopsies but available data on the presence or absence of hepatic decompensation.

For a 40-year-old man with F0-F2 fibrosis who had been drinking alcohol for 15 years, who drank 150 grams of alcohol daily, and who had a body mass index (BMI) of 22 kg/m², the model predicted a 31.8% likelihood of having a normal liver at baseline, a 61.5% probability of baseline steatosis, and a 6.7% probability of baseline steatohepatitis. In women with the same baseline variables, respective probabilities were 25.1%, 66.5%, and 8.4%. Based on these findings, the 5-year weighted risk for liver complications ranged from 0.2% for men with normal initial liver findings to 10.3% for men with baseline steatohepatitis. Among women, the corresponding risk estimates ranged from 0.5% to 14.7%, wrote PhD student Claire Delacôte of Centre Hospitalier Universitaire de Lille (France), and associates.

“This tool might be used by general practitioners or hepatologists to identify heavy drinkers at high risk for alcohol-related liver disease progression,” the investigators added. “This model might be used to adapt patient care pathways.”

The patients in this study were admitted to the hepatogastroenterology unit of a French hospital between 1982 and 1997. The Markov model incorporated seven stages of alcohol-related liver disease: normal liver (no fibrosis or steatosis), steatosis and F0-F2 fibrosis, alcohol-induced steatohepatitis and F0-F2 fibrosis, steatosis and F3-F4 fibrosis, alcohol-induced steatohepatitis and F3-F4 fibrosis, liver complications without steatohepatitis, and liver complications with alcohol-induced steatohepatitis. Liver complications were defined as hepatocellular carcinoma or liver decompensation (bilirubin >50 mmol/L, gastrointestinal hemorrhage, or ascites). Risk for progressing to liver complications was based on METAVIR score and onset of alcohol-induced steatohepatitis.

The researchers also looked specifically at F3-F4 (severe) fibrosis because of its clinical significance and common use as a study endpoint. Among 40-year-olds with a 15-year history of heavy drinking, the estimated prevalence of alcohol-induced steatohepatitis was 30.0% for men and 33.3% for women. The 5-year risk for liver complications was higher in women (30.1%) than men (24.5%) and was highest among women with baseline alcohol-induced steatohepatitis (41.0%). Overall, women had a 24.8% greater risk for disease progression than men (hazard ratio, 1.248).

Risk for liver complications also increased with age, and each 1-year increase in age at the beginning of heavy drinking heightened the risk for disease progression by 3.8%, regardless of stage of liver disease. “Based on these predictions, 50-year-old women are a high-risk subgroup of [alcohol-related liver] disease progression and should receive close follow-up,” the researchers wrote.

In addition, obese individuals (BMI, 30) had an 11.8% greater risk for progression of alcohol-related liver disease, compared with those with a BMI of 22. Consuming an additional 10 grams of alcohol per day had less impact on risk, the researchers noted.

“If patients are identified as being heavy drinkers by the general practitioner with no evaluation of fibrosis, these patients should be referred to a hepatologist. Nevertheless, we think that the threshold defining the high-risk population, which has been arbitrarily fixed at 5%, should be discussed by experts because it affects the patient’s care pathway. An online application is being developed to help clinicians and general practitioners in their daily practice,” they wrote.

No funding sources were reported. Ms. Delacôte reported having no conflicts of interest. Three coinvestigators disclosed ties to AbbVie, Bayer Healthcare, Eisai, Gilead, MSD, Novartis, Sanofi, and Servier. The others reported having no conflicts.
 

SOURCE: Delacôte C et al. Clin Gastroenterol Hepatol. 2020 Jan 11. doi: 10.1016/j.cgh.2019.12.041.
 

In heavy drinkers with alcohol-related liver disease, a Markov model based on age, sex, body mass index, and duration and extent of alcohol use predicted risk for disease progression, researchers reported in Clinical Gastroenterology and Hepatology.

The study included 2,334 hospitalized adults with consistently abnormal liver test results who had consumed at least 50 grams of alcohol (about 3.5-4 drinks) per day for the previous 5 years. The model was developed using data from 1,599 individuals with baseline liver biopsies and validated in 735 individuals with no baseline liver biopsies but available data on the presence or absence of hepatic decompensation.

For a 40-year-old man with F0-F2 fibrosis who had been drinking alcohol for 15 years, who drank 150 grams of alcohol daily, and who had a body mass index (BMI) of 22 kg/m², the model predicted a 31.8% likelihood of having a normal liver at baseline, a 61.5% probability of baseline steatosis, and a 6.7% probability of baseline steatohepatitis. In women with the same baseline variables, respective probabilities were 25.1%, 66.5%, and 8.4%. Based on these findings, the 5-year weighted risk for liver complications ranged from 0.2% for men with normal initial liver findings to 10.3% for men with baseline steatohepatitis. Among women, the corresponding risk estimates ranged from 0.5% to 14.7%, wrote PhD student Claire Delacôte of Centre Hospitalier Universitaire de Lille (France), and associates.

“This tool might be used by general practitioners or hepatologists to identify heavy drinkers at high risk for alcohol-related liver disease progression,” the investigators added. “This model might be used to adapt patient care pathways.”

The patients in this study were admitted to the hepatogastroenterology unit of a French hospital between 1982 and 1997. The Markov model incorporated seven stages of alcohol-related liver disease: normal liver (no fibrosis or steatosis), steatosis and F0-F2 fibrosis, alcohol-induced steatohepatitis and F0-F2 fibrosis, steatosis and F3-F4 fibrosis, alcohol-induced steatohepatitis and F3-F4 fibrosis, liver complications without steatohepatitis, and liver complications with alcohol-induced steatohepatitis. Liver complications were defined as hepatocellular carcinoma or liver decompensation (bilirubin >50 mmol/L, gastrointestinal hemorrhage, or ascites). Risk for progressing to liver complications was based on METAVIR score and onset of alcohol-induced steatohepatitis.

The researchers also looked specifically at F3-F4 (severe) fibrosis because of its clinical significance and common use as a study endpoint. Among 40-year-olds with a 15-year history of heavy drinking, the estimated prevalence of alcohol-induced steatohepatitis was 30.0% for men and 33.3% for women. The 5-year risk for liver complications was higher in women (30.1%) than men (24.5%) and was highest among women with baseline alcohol-induced steatohepatitis (41.0%). Overall, women had a 24.8% greater risk for disease progression than men (hazard ratio, 1.248).

Risk for liver complications also increased with age, and each 1-year increase in age at the beginning of heavy drinking heightened the risk for disease progression by 3.8%, regardless of stage of liver disease. “Based on these predictions, 50-year-old women are a high-risk subgroup of [alcohol-related liver] disease progression and should receive close follow-up,” the researchers wrote.

In addition, obese individuals (BMI, 30) had an 11.8% greater risk for progression of alcohol-related liver disease, compared with those with a BMI of 22. Consuming an additional 10 grams of alcohol per day had less impact on risk, the researchers noted.

“If patients are identified as being heavy drinkers by the general practitioner with no evaluation of fibrosis, these patients should be referred to a hepatologist. Nevertheless, we think that the threshold defining the high-risk population, which has been arbitrarily fixed at 5%, should be discussed by experts because it affects the patient’s care pathway. An online application is being developed to help clinicians and general practitioners in their daily practice,” they wrote.

No funding sources were reported. Ms. Delacôte reported having no conflicts of interest. Three coinvestigators disclosed ties to AbbVie, Bayer Healthcare, Eisai, Gilead, MSD, Novartis, Sanofi, and Servier. The others reported having no conflicts.
 

SOURCE: Delacôte C et al. Clin Gastroenterol Hepatol. 2020 Jan 11. doi: 10.1016/j.cgh.2019.12.041.
 

New guidelines from the Centers for Disease Control and Prevention outline a “test and treat” strategy for health care personnel (HCP) with potential occupational exposure to hepatitis C virus (HCV).

The new guidance was developed in part as a result of an increase in the incidence of acute HCV infection in the United States, which increases the risk for occupational exposure among HCP. “[I]n certain health care settings, HCP might be exposed to source patients with early HCV infection before those patients develop serologic evidence of infection or symptoms indicative of viral hepatitis,” wrote the authors of the report, published online July 24 in the CDC’s Morbidity and Mortality Weekly Report.

The guidelines, which no longer recommend waiting for spontaneous resolution upon initial diagnosis, include recommendations and algorithms for baseline and follow-up testing, appropriate test type, and recommendations for clinical management. The recommendations were developed on the basis of a current literature review, expert opinion from subject matter experts, and recent guidance from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
 

Baseline testing ASAP

Baseline testing of the source patient and the HCP should be performed as soon as possible, preferably within 48 hours of exposure. The source patient should be tested for HCV RNA using a nucleic acid test. Alternatively, screening anti-HCV serology can be performed in patients at low risk for HCV and a nucleic acid test performed if serology is positive.

Baseline testing for the HCP should include anti-HCV testing and, if positive, HCV RNA testing is recommended. HCPs who test positive for HCV RNA at baseline are considered to have a preexisting HCV infection and should be referred for treatment.
 

Follow-up testing

For HCPs with exposure to blood or body fluids from a patient who is anti-HCV positive but HCV RNA negative, follow-up testing is not required.

If the source patient is HCV RNA positive, or if status of the source patient is unknown, the authors recommend that exposed HCPs have HCV RNA follow-up testing at 3-6 weeks post exposure, in addition to baseline testing. A final anti-HCV test is recommended at 4-6 months post exposure as there can be potential periods of aviremia during acute HCV infection.

Exposed HCPs who develop signs of illness indicative of HCV infection at any time should be tested for HCV RNA.

HCPs with positive HCV RNA test results should be referred for care and curative antiviral therapy.
 

Postexposure prophylaxis is not recommended

Recent data have shown that the risk for HCV infection from percutaneous exposure is 0.2% and from mucocutaneous exposure is 0%. On the basis of this information, the CDC guidelines no longer recommend routine postexposure prophylaxis for HCPs with occupational exposure to HCV. Rather, curative antiviral regimens should be reserved for instances of documented HCV transmission.

The authors disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

New guidelines from the Centers for Disease Control and Prevention outline a “test and treat” strategy for health care personnel (HCP) with potential occupational exposure to hepatitis C virus (HCV).

The new guidance was developed in part as a result of an increase in the incidence of acute HCV infection in the United States, which increases the risk for occupational exposure among HCP. “[I]n certain health care settings, HCP might be exposed to source patients with early HCV infection before those patients develop serologic evidence of infection or symptoms indicative of viral hepatitis,” wrote the authors of the report, published online July 24 in the CDC’s Morbidity and Mortality Weekly Report.

The guidelines, which no longer recommend waiting for spontaneous resolution upon initial diagnosis, include recommendations and algorithms for baseline and follow-up testing, appropriate test type, and recommendations for clinical management. The recommendations were developed on the basis of a current literature review, expert opinion from subject matter experts, and recent guidance from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
 

Baseline testing ASAP

Baseline testing of the source patient and the HCP should be performed as soon as possible, preferably within 48 hours of exposure. The source patient should be tested for HCV RNA using a nucleic acid test. Alternatively, screening anti-HCV serology can be performed in patients at low risk for HCV and a nucleic acid test performed if serology is positive.

Baseline testing for the HCP should include anti-HCV testing and, if positive, HCV RNA testing is recommended. HCPs who test positive for HCV RNA at baseline are considered to have a preexisting HCV infection and should be referred for treatment.
 

Follow-up testing

For HCPs with exposure to blood or body fluids from a patient who is anti-HCV positive but HCV RNA negative, follow-up testing is not required.

If the source patient is HCV RNA positive, or if status of the source patient is unknown, the authors recommend that exposed HCPs have HCV RNA follow-up testing at 3-6 weeks post exposure, in addition to baseline testing. A final anti-HCV test is recommended at 4-6 months post exposure as there can be potential periods of aviremia during acute HCV infection.

Exposed HCPs who develop signs of illness indicative of HCV infection at any time should be tested for HCV RNA.

HCPs with positive HCV RNA test results should be referred for care and curative antiviral therapy.
 

Postexposure prophylaxis is not recommended

Recent data have shown that the risk for HCV infection from percutaneous exposure is 0.2% and from mucocutaneous exposure is 0%. On the basis of this information, the CDC guidelines no longer recommend routine postexposure prophylaxis for HCPs with occupational exposure to HCV. Rather, curative antiviral regimens should be reserved for instances of documented HCV transmission.

The authors disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

New guidelines from the Centers for Disease Control and Prevention outline a “test and treat” strategy for health care personnel (HCP) with potential occupational exposure to hepatitis C virus (HCV).

The new guidance was developed in part as a result of an increase in the incidence of acute HCV infection in the United States, which increases the risk for occupational exposure among HCP. “[I]n certain health care settings, HCP might be exposed to source patients with early HCV infection before those patients develop serologic evidence of infection or symptoms indicative of viral hepatitis,” wrote the authors of the report, published online July 24 in the CDC’s Morbidity and Mortality Weekly Report.

The guidelines, which no longer recommend waiting for spontaneous resolution upon initial diagnosis, include recommendations and algorithms for baseline and follow-up testing, appropriate test type, and recommendations for clinical management. The recommendations were developed on the basis of a current literature review, expert opinion from subject matter experts, and recent guidance from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.
 

Baseline testing ASAP

Baseline testing of the source patient and the HCP should be performed as soon as possible, preferably within 48 hours of exposure. The source patient should be tested for HCV RNA using a nucleic acid test. Alternatively, screening anti-HCV serology can be performed in patients at low risk for HCV and a nucleic acid test performed if serology is positive.

Baseline testing for the HCP should include anti-HCV testing and, if positive, HCV RNA testing is recommended. HCPs who test positive for HCV RNA at baseline are considered to have a preexisting HCV infection and should be referred for treatment.
 

Follow-up testing

For HCPs with exposure to blood or body fluids from a patient who is anti-HCV positive but HCV RNA negative, follow-up testing is not required.

If the source patient is HCV RNA positive, or if status of the source patient is unknown, the authors recommend that exposed HCPs have HCV RNA follow-up testing at 3-6 weeks post exposure, in addition to baseline testing. A final anti-HCV test is recommended at 4-6 months post exposure as there can be potential periods of aviremia during acute HCV infection.

Exposed HCPs who develop signs of illness indicative of HCV infection at any time should be tested for HCV RNA.

HCPs with positive HCV RNA test results should be referred for care and curative antiviral therapy.
 

Postexposure prophylaxis is not recommended

Recent data have shown that the risk for HCV infection from percutaneous exposure is 0.2% and from mucocutaneous exposure is 0%. On the basis of this information, the CDC guidelines no longer recommend routine postexposure prophylaxis for HCPs with occupational exposure to HCV. Rather, curative antiviral regimens should be reserved for instances of documented HCV transmission.

The authors disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee narrowly recommended, by an 8-7 vote, that the agency grant marketing approval to terlipressin for the treatment of hepatorenal syndrome type 1, a severe, rare, and often rapidly lethal disease. No drugs are currently licensed in the United States for this indication.

The advisory committee’s discussion and vote on July 15 showcased the struggle the 15 members faced parsing data that hinted at efficacy but also featured clear flaws and limitations, with meager evidence showing clinically meaningful patient improvements.

Several advisory committee members voiced their dilemma balancing the desperation of patients and clinicians to have an effective agent to treat a frequently fatal condition against spotty evidence of efficacy.

Their uncertainty over benefit was exacerbated by the substantial rate of serious adverse events, compared with placebo. These events included respiratory failure, which occurred an absolute 9% more often among patients treated with terlipressin than among those who received placebo in the drug’s recent pivotal trial, and sepsis and septic shock, with an absolute 7% excess rate with terlipressin in comparison with placebo.

“This is an important, unmet need, and I want this drug, but the data are not clear that the benefits outweigh the risks,” commented Steven F. Solga, MD, a transplant hepatologist at the University of Pennsylvania, Philadelphia, who is a committee member.

“When you have sick patients with few treatment options, you grope for something to use, but I worry that this won’t help patients,” he said when explaining his vote against approval.

“I look forward to using this medication if I could figure out which patients could benefit from it,” he said.
 

‘Allow patients to decide if they want this treatment’

Experts estimate that the annual incidence of hepatorenal syndrome type 1 in the United States is about 35,000 patients.

“I would have liked to vote yes, because terlipressin was associated with a short-term increase in renal function, but there was also clear evidence for the risk of sepsis and respiratory failure, and no evidence that it improved survival,” said panel member Patrick H. Nachman, MD.

Dr. Nachman, professor of medicine and director of the division of nephrology and hypertension at the University of Minnesota, Minneapolis, voted against approval.

Several who voted in favor of terlipressin also shared these misgivings.

“The trend for benefit was quite small, I’m very worried about respiratory failure, and I’m uncomfortable with the postrandomization analyses” used by the developer of terlipressin (Mallinckrodt) to buttress the efficacy claims, explained panel member Paul M. Ridker, MD.

“So why did I vote yes? The problem is the enormous unmet need. Patients are in desperate shape, and the standard treatments are used off label, with no data. Here, we have data, and the primary endpoint was met,” said Dr. Ridker, who is professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.

The effects of terlipressin appear to give clinicians a way to “stabilize renal function and buy time,” making it more feasible to try to rush the patient to liver transplantation or at least to “stop their downward spiral» as patients with decompensated liver failure develop inadequate renal blood flow that produces an acute fall in kidney function,” explained David N. Assis, MD, a hepatologist at Yale University, New Haven, Conn.

“The reality is, nothing else is available, aside from renal replacement therapy and pressors. There is a need for a treatment that buys time,” he said. He voted to recommend approval.

That sentiment was notably echoed in comments from the two nonclinical members of the advisory committee.

“This treatment addresses a major gap in care,” said Jacqueline D. Alikhaani, the panel’s consumer representative. “Allow patients to decide if they want this treatment,” said Daniel Bonner, the committee’s patient representative. Both voted in favor of FDA approval.

Terlipressin has been a long-standing linchpin for treating hepatorenal syndrome type 1 in Europe and other places outside the United States and Canada.

The most recent guidelines for managing patients with decompensated cirrhosis from the European Association for the Study of the Liver say that “[t]erlipressin plus albumin should be considered as the first-line therapeutic option for the treatment of hepatorenal syndrome and acute kidney injury” (J Hepatol. 2018 Aug 1;69).

According to company representatives who presented the case for terlipressin during the meeting, bringing the drug onto the U.S. market has been a 17-year journey, featuring three sequential trials.

• A 112-patient  that the FDA accepted as the first of the two supportive trials needed for approval.
• A with 196 patients that tested terlipressin plus albumin against placebo plus albumin and showed a nominal benefit from terlipressin that failed to achieve statistical significance.
• The most recent trial, , which directly led to the advisory committee session. That trial enrolled 300 patients and met its primary endpoint. Data have not yet been published but have been at meetings.

One of the sources of controversy over the benefit from terlipressin centered on the primary endpoint used in CONFIRM, which required that the patient have two consecutive, low readings for serum creatinine, with levels no greater than 1.5 mg/dL while on treatment, and remain alive and free from need for renal replacement therapy for at least 10 days beyond this.

The FDA agreed to accept this as a primary endpoint but nonetheless considered it a surrogate.

According to FDA staffers who presented their take on the application, the agency accepted this primary endpoint “with the understanding that favorable trends in clinical outcomes, thought to be predicted by successful treatment of hepatic renal syndrome type 1, would be expected.”

The lack of many favorable trends in clinical outcomes helped foster the advisory committee’s divided response. The FDA’s staff uses its discretion when considering an advisory committee’s recommendations and making a final determination.

None of the advisory committee members disclosed any relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee narrowly recommended, by an 8-7 vote, that the agency grant marketing approval to terlipressin for the treatment of hepatorenal syndrome type 1, a severe, rare, and often rapidly lethal disease. No drugs are currently licensed in the United States for this indication.

The advisory committee’s discussion and vote on July 15 showcased the struggle the 15 members faced parsing data that hinted at efficacy but also featured clear flaws and limitations, with meager evidence showing clinically meaningful patient improvements.

Several advisory committee members voiced their dilemma balancing the desperation of patients and clinicians to have an effective agent to treat a frequently fatal condition against spotty evidence of efficacy.

Their uncertainty over benefit was exacerbated by the substantial rate of serious adverse events, compared with placebo. These events included respiratory failure, which occurred an absolute 9% more often among patients treated with terlipressin than among those who received placebo in the drug’s recent pivotal trial, and sepsis and septic shock, with an absolute 7% excess rate with terlipressin in comparison with placebo.

“This is an important, unmet need, and I want this drug, but the data are not clear that the benefits outweigh the risks,” commented Steven F. Solga, MD, a transplant hepatologist at the University of Pennsylvania, Philadelphia, who is a committee member.

“When you have sick patients with few treatment options, you grope for something to use, but I worry that this won’t help patients,” he said when explaining his vote against approval.

“I look forward to using this medication if I could figure out which patients could benefit from it,” he said.
 

‘Allow patients to decide if they want this treatment’

Experts estimate that the annual incidence of hepatorenal syndrome type 1 in the United States is about 35,000 patients.

“I would have liked to vote yes, because terlipressin was associated with a short-term increase in renal function, but there was also clear evidence for the risk of sepsis and respiratory failure, and no evidence that it improved survival,” said panel member Patrick H. Nachman, MD.

Dr. Nachman, professor of medicine and director of the division of nephrology and hypertension at the University of Minnesota, Minneapolis, voted against approval.

Several who voted in favor of terlipressin also shared these misgivings.

“The trend for benefit was quite small, I’m very worried about respiratory failure, and I’m uncomfortable with the postrandomization analyses” used by the developer of terlipressin (Mallinckrodt) to buttress the efficacy claims, explained panel member Paul M. Ridker, MD.

“So why did I vote yes? The problem is the enormous unmet need. Patients are in desperate shape, and the standard treatments are used off label, with no data. Here, we have data, and the primary endpoint was met,” said Dr. Ridker, who is professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.

The effects of terlipressin appear to give clinicians a way to “stabilize renal function and buy time,” making it more feasible to try to rush the patient to liver transplantation or at least to “stop their downward spiral» as patients with decompensated liver failure develop inadequate renal blood flow that produces an acute fall in kidney function,” explained David N. Assis, MD, a hepatologist at Yale University, New Haven, Conn.

“The reality is, nothing else is available, aside from renal replacement therapy and pressors. There is a need for a treatment that buys time,” he said. He voted to recommend approval.

That sentiment was notably echoed in comments from the two nonclinical members of the advisory committee.

“This treatment addresses a major gap in care,” said Jacqueline D. Alikhaani, the panel’s consumer representative. “Allow patients to decide if they want this treatment,” said Daniel Bonner, the committee’s patient representative. Both voted in favor of FDA approval.

Terlipressin has been a long-standing linchpin for treating hepatorenal syndrome type 1 in Europe and other places outside the United States and Canada.

The most recent guidelines for managing patients with decompensated cirrhosis from the European Association for the Study of the Liver say that “[t]erlipressin plus albumin should be considered as the first-line therapeutic option for the treatment of hepatorenal syndrome and acute kidney injury” (J Hepatol. 2018 Aug 1;69).

According to company representatives who presented the case for terlipressin during the meeting, bringing the drug onto the U.S. market has been a 17-year journey, featuring three sequential trials.

• A 112-patient  that the FDA accepted as the first of the two supportive trials needed for approval.
• A with 196 patients that tested terlipressin plus albumin against placebo plus albumin and showed a nominal benefit from terlipressin that failed to achieve statistical significance.
• The most recent trial, , which directly led to the advisory committee session. That trial enrolled 300 patients and met its primary endpoint. Data have not yet been published but have been at meetings.

One of the sources of controversy over the benefit from terlipressin centered on the primary endpoint used in CONFIRM, which required that the patient have two consecutive, low readings for serum creatinine, with levels no greater than 1.5 mg/dL while on treatment, and remain alive and free from need for renal replacement therapy for at least 10 days beyond this.

The FDA agreed to accept this as a primary endpoint but nonetheless considered it a surrogate.

According to FDA staffers who presented their take on the application, the agency accepted this primary endpoint “with the understanding that favorable trends in clinical outcomes, thought to be predicted by successful treatment of hepatic renal syndrome type 1, would be expected.”

The lack of many favorable trends in clinical outcomes helped foster the advisory committee’s divided response. The FDA’s staff uses its discretion when considering an advisory committee’s recommendations and making a final determination.

None of the advisory committee members disclosed any relevant financial relationships.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee narrowly recommended, by an 8-7 vote, that the agency grant marketing approval to terlipressin for the treatment of hepatorenal syndrome type 1, a severe, rare, and often rapidly lethal disease. No drugs are currently licensed in the United States for this indication.

The advisory committee’s discussion and vote on July 15 showcased the struggle the 15 members faced parsing data that hinted at efficacy but also featured clear flaws and limitations, with meager evidence showing clinically meaningful patient improvements.

Several advisory committee members voiced their dilemma balancing the desperation of patients and clinicians to have an effective agent to treat a frequently fatal condition against spotty evidence of efficacy.

Their uncertainty over benefit was exacerbated by the substantial rate of serious adverse events, compared with placebo. These events included respiratory failure, which occurred an absolute 9% more often among patients treated with terlipressin than among those who received placebo in the drug’s recent pivotal trial, and sepsis and septic shock, with an absolute 7% excess rate with terlipressin in comparison with placebo.

“This is an important, unmet need, and I want this drug, but the data are not clear that the benefits outweigh the risks,” commented Steven F. Solga, MD, a transplant hepatologist at the University of Pennsylvania, Philadelphia, who is a committee member.

“When you have sick patients with few treatment options, you grope for something to use, but I worry that this won’t help patients,” he said when explaining his vote against approval.

“I look forward to using this medication if I could figure out which patients could benefit from it,” he said.
 

‘Allow patients to decide if they want this treatment’

Experts estimate that the annual incidence of hepatorenal syndrome type 1 in the United States is about 35,000 patients.

“I would have liked to vote yes, because terlipressin was associated with a short-term increase in renal function, but there was also clear evidence for the risk of sepsis and respiratory failure, and no evidence that it improved survival,” said panel member Patrick H. Nachman, MD.

Dr. Nachman, professor of medicine and director of the division of nephrology and hypertension at the University of Minnesota, Minneapolis, voted against approval.

Several who voted in favor of terlipressin also shared these misgivings.

“The trend for benefit was quite small, I’m very worried about respiratory failure, and I’m uncomfortable with the postrandomization analyses” used by the developer of terlipressin (Mallinckrodt) to buttress the efficacy claims, explained panel member Paul M. Ridker, MD.

“So why did I vote yes? The problem is the enormous unmet need. Patients are in desperate shape, and the standard treatments are used off label, with no data. Here, we have data, and the primary endpoint was met,” said Dr. Ridker, who is professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, both in Boston.

The effects of terlipressin appear to give clinicians a way to “stabilize renal function and buy time,” making it more feasible to try to rush the patient to liver transplantation or at least to “stop their downward spiral» as patients with decompensated liver failure develop inadequate renal blood flow that produces an acute fall in kidney function,” explained David N. Assis, MD, a hepatologist at Yale University, New Haven, Conn.

“The reality is, nothing else is available, aside from renal replacement therapy and pressors. There is a need for a treatment that buys time,” he said. He voted to recommend approval.

That sentiment was notably echoed in comments from the two nonclinical members of the advisory committee.

“This treatment addresses a major gap in care,” said Jacqueline D. Alikhaani, the panel’s consumer representative. “Allow patients to decide if they want this treatment,” said Daniel Bonner, the committee’s patient representative. Both voted in favor of FDA approval.

Terlipressin has been a long-standing linchpin for treating hepatorenal syndrome type 1 in Europe and other places outside the United States and Canada.

The most recent guidelines for managing patients with decompensated cirrhosis from the European Association for the Study of the Liver say that “[t]erlipressin plus albumin should be considered as the first-line therapeutic option for the treatment of hepatorenal syndrome and acute kidney injury” (J Hepatol. 2018 Aug 1;69).

According to company representatives who presented the case for terlipressin during the meeting, bringing the drug onto the U.S. market has been a 17-year journey, featuring three sequential trials.

• A 112-patient  that the FDA accepted as the first of the two supportive trials needed for approval.
• A with 196 patients that tested terlipressin plus albumin against placebo plus albumin and showed a nominal benefit from terlipressin that failed to achieve statistical significance.
• The most recent trial, , which directly led to the advisory committee session. That trial enrolled 300 patients and met its primary endpoint. Data have not yet been published but have been at meetings.

One of the sources of controversy over the benefit from terlipressin centered on the primary endpoint used in CONFIRM, which required that the patient have two consecutive, low readings for serum creatinine, with levels no greater than 1.5 mg/dL while on treatment, and remain alive and free from need for renal replacement therapy for at least 10 days beyond this.

The FDA agreed to accept this as a primary endpoint but nonetheless considered it a surrogate.

According to FDA staffers who presented their take on the application, the agency accepted this primary endpoint “with the understanding that favorable trends in clinical outcomes, thought to be predicted by successful treatment of hepatic renal syndrome type 1, would be expected.”

The lack of many favorable trends in clinical outcomes helped foster the advisory committee’s divided response. The FDA’s staff uses its discretion when considering an advisory committee’s recommendations and making a final determination.

None of the advisory committee members disclosed any relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Women have a lower risk of nonalcoholic fatty liver disease compared with men, but those who do develop the disease are significantly more likely than are men to develop advanced fibrosis, according to data from a meta-analysis of more than 62,000 individuals.

Sex disparity persists in most chronic liver diseases, with more cases and risk of progression reported in men, but the effect of sex on nonalcoholic fatty liver disease (NAFLD) remains unclear, wrote Maya Balakrishnan, MD, of Baylor College of Medicine, Houston, and colleagues. “Knowing whether and how [sex] influences the risk and severity of NAFLD is important for risk stratification, risk modification as well as prognostication,” they said.

In a study published in Clinical Gastroenterology and Hepatology, the researchers conducted a review and meta-analysis of 54 studies, including data from 62,239 patients with NAFLD, 5,428 with nonalcoholic steatohepatitis (NASH), and 6,444 with advanced NAFLD fibrosis.

Overall, women had a 19% lower risk of developing NAFLD compared with men (pooled risk ratio 0.81), a similar risk to men of developing NASH (RR, 1.00), and a 37% increased risk of advanced fibrosis (RR, 1.37) compared with men.

The risk of more severe disease in women increased with age. Among women aged 50 years and older, the risks of NASH and advanced fibrosis were significantly higher, at 17% and 56%, respectively (RR, 1.17 and RR, 1.56). The sex-specific prevalence of advanced fibrosis was not significantly different in patients younger than 50 years.

“Our findings of an increased prevalence of severe phenotypes of NAFLD – NASH and advanced fibrosis – among older women fits well into the current understanding of disease pathogenesis,” the researchers noted.

The findings were limited by several factors, including the cross-sectional nature and heterogeneity of the included studies and lack of data on possible contributions to NASH and NAFLD such as polycystic ovarian syndrome, cumulative use of hormone therapy, and pregnancy, the researchers noted.

However, the results were strengthened by the large patient population. “Given the higher risk of advanced fibrosis observed among women compared to men with NAFLD in our meta-analysis, it is plausible that cirrhosis and its complications may occur with greater frequency among women than in men,” the researchers said. Consequently, women older than 50 years with NAFLD should be evaluated frequently for advanced disease, they noted. In addition, “more focused and intensified efforts may be warranted to target lifestyle modifications and weight loss among young women with NAFLD, particularly in the presence of NASH and/or advanced fibrosis,” the researchers concluded.

Conducting the study at this time was important because of conjectures of sex-based differences in NAFLD prevalence and NAFLD progression, Dr. Balakrishnan said in an interview. “However, the findings from studies conducted across different study populations have been disparate. Therefore, it was important to perform a systematic review and meta-analysis to determine whether there are differences in NAFLD and NAFLD severity risk between the [sexes],” she said.

Dr. Balakrishnan said she was surprised by the higher risk of severe NASH fibrosis in women compared with men once NAFLD is established. “This was surprising and sets NAFLD apart from other highly prevalent chronic liver disease etiologies,” she said. “Other common liver diseases, for example hepatitis B and hepatitis C, tend to be more common among men and tend to progress more rapidly, and tend to be more severe among men compared to women,” she noted.

The take-home message for clinicians is that NAFLD is at least equally, if not more, aggressive in women compared with men, and should be evaluated with equal aggressiveness, Dr. Balakrishnan emphasized. “Moreover, in the future we may expect to see the burden of cirrhosis distributed more equally among women and men than we have to date. This has implications for liver disease screening and women’s health,” she said. The next steps for research are to determine the specific reasons for the higher risk of NAFLD fibrosis in women compared with men, she added.

The study was supported in part by the National Institutes of Health. The researchers had no financial conflicts to disclose.

SOURCE: Balakrishnan M et al. Clin Gastroenterol Hepatol. 2020 Apr 30. doi: 10.1016/j.cgh.2020.04.067.

AGA offers education on the latest challenges, trends and solutions for diagnosing and managing nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) at http://ow.ly/Bz1Q30qYMw0. Help your patients better understand their risk of NASH and NAFLD by sharing AGA patient education at http://ow.ly/GoY630qYOmY.

Women have a lower risk of nonalcoholic fatty liver disease compared with men, but those who do develop the disease are significantly more likely than are men to develop advanced fibrosis, according to data from a meta-analysis of more than 62,000 individuals.

Sex disparity persists in most chronic liver diseases, with more cases and risk of progression reported in men, but the effect of sex on nonalcoholic fatty liver disease (NAFLD) remains unclear, wrote Maya Balakrishnan, MD, of Baylor College of Medicine, Houston, and colleagues. “Knowing whether and how [sex] influences the risk and severity of NAFLD is important for risk stratification, risk modification as well as prognostication,” they said.

In a study published in Clinical Gastroenterology and Hepatology, the researchers conducted a review and meta-analysis of 54 studies, including data from 62,239 patients with NAFLD, 5,428 with nonalcoholic steatohepatitis (NASH), and 6,444 with advanced NAFLD fibrosis.

Overall, women had a 19% lower risk of developing NAFLD compared with men (pooled risk ratio 0.81), a similar risk to men of developing NASH (RR, 1.00), and a 37% increased risk of advanced fibrosis (RR, 1.37) compared with men.

The risk of more severe disease in women increased with age. Among women aged 50 years and older, the risks of NASH and advanced fibrosis were significantly higher, at 17% and 56%, respectively (RR, 1.17 and RR, 1.56). The sex-specific prevalence of advanced fibrosis was not significantly different in patients younger than 50 years.

“Our findings of an increased prevalence of severe phenotypes of NAFLD – NASH and advanced fibrosis – among older women fits well into the current understanding of disease pathogenesis,” the researchers noted.

The findings were limited by several factors, including the cross-sectional nature and heterogeneity of the included studies and lack of data on possible contributions to NASH and NAFLD such as polycystic ovarian syndrome, cumulative use of hormone therapy, and pregnancy, the researchers noted.

However, the results were strengthened by the large patient population. “Given the higher risk of advanced fibrosis observed among women compared to men with NAFLD in our meta-analysis, it is plausible that cirrhosis and its complications may occur with greater frequency among women than in men,” the researchers said. Consequently, women older than 50 years with NAFLD should be evaluated frequently for advanced disease, they noted. In addition, “more focused and intensified efforts may be warranted to target lifestyle modifications and weight loss among young women with NAFLD, particularly in the presence of NASH and/or advanced fibrosis,” the researchers concluded.

Conducting the study at this time was important because of conjectures of sex-based differences in NAFLD prevalence and NAFLD progression, Dr. Balakrishnan said in an interview. “However, the findings from studies conducted across different study populations have been disparate. Therefore, it was important to perform a systematic review and meta-analysis to determine whether there are differences in NAFLD and NAFLD severity risk between the [sexes],” she said.

Dr. Balakrishnan said she was surprised by the higher risk of severe NASH fibrosis in women compared with men once NAFLD is established. “This was surprising and sets NAFLD apart from other highly prevalent chronic liver disease etiologies,” she said. “Other common liver diseases, for example hepatitis B and hepatitis C, tend to be more common among men and tend to progress more rapidly, and tend to be more severe among men compared to women,” she noted.

The take-home message for clinicians is that NAFLD is at least equally, if not more, aggressive in women compared with men, and should be evaluated with equal aggressiveness, Dr. Balakrishnan emphasized. “Moreover, in the future we may expect to see the burden of cirrhosis distributed more equally among women and men than we have to date. This has implications for liver disease screening and women’s health,” she said. The next steps for research are to determine the specific reasons for the higher risk of NAFLD fibrosis in women compared with men, she added.

The study was supported in part by the National Institutes of Health. The researchers had no financial conflicts to disclose.

SOURCE: Balakrishnan M et al. Clin Gastroenterol Hepatol. 2020 Apr 30. doi: 10.1016/j.cgh.2020.04.067.

AGA offers education on the latest challenges, trends and solutions for diagnosing and managing nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) at http://ow.ly/Bz1Q30qYMw0. Help your patients better understand their risk of NASH and NAFLD by sharing AGA patient education at http://ow.ly/GoY630qYOmY.

Women have a lower risk of nonalcoholic fatty liver disease compared with men, but those who do develop the disease are significantly more likely than are men to develop advanced fibrosis, according to data from a meta-analysis of more than 62,000 individuals.

Sex disparity persists in most chronic liver diseases, with more cases and risk of progression reported in men, but the effect of sex on nonalcoholic fatty liver disease (NAFLD) remains unclear, wrote Maya Balakrishnan, MD, of Baylor College of Medicine, Houston, and colleagues. “Knowing whether and how [sex] influences the risk and severity of NAFLD is important for risk stratification, risk modification as well as prognostication,” they said.

In a study published in Clinical Gastroenterology and Hepatology, the researchers conducted a review and meta-analysis of 54 studies, including data from 62,239 patients with NAFLD, 5,428 with nonalcoholic steatohepatitis (NASH), and 6,444 with advanced NAFLD fibrosis.

Overall, women had a 19% lower risk of developing NAFLD compared with men (pooled risk ratio 0.81), a similar risk to men of developing NASH (RR, 1.00), and a 37% increased risk of advanced fibrosis (RR, 1.37) compared with men.

The risk of more severe disease in women increased with age. Among women aged 50 years and older, the risks of NASH and advanced fibrosis were significantly higher, at 17% and 56%, respectively (RR, 1.17 and RR, 1.56). The sex-specific prevalence of advanced fibrosis was not significantly different in patients younger than 50 years.

“Our findings of an increased prevalence of severe phenotypes of NAFLD – NASH and advanced fibrosis – among older women fits well into the current understanding of disease pathogenesis,” the researchers noted.

The findings were limited by several factors, including the cross-sectional nature and heterogeneity of the included studies and lack of data on possible contributions to NASH and NAFLD such as polycystic ovarian syndrome, cumulative use of hormone therapy, and pregnancy, the researchers noted.

However, the results were strengthened by the large patient population. “Given the higher risk of advanced fibrosis observed among women compared to men with NAFLD in our meta-analysis, it is plausible that cirrhosis and its complications may occur with greater frequency among women than in men,” the researchers said. Consequently, women older than 50 years with NAFLD should be evaluated frequently for advanced disease, they noted. In addition, “more focused and intensified efforts may be warranted to target lifestyle modifications and weight loss among young women with NAFLD, particularly in the presence of NASH and/or advanced fibrosis,” the researchers concluded.

Conducting the study at this time was important because of conjectures of sex-based differences in NAFLD prevalence and NAFLD progression, Dr. Balakrishnan said in an interview. “However, the findings from studies conducted across different study populations have been disparate. Therefore, it was important to perform a systematic review and meta-analysis to determine whether there are differences in NAFLD and NAFLD severity risk between the [sexes],” she said.

Dr. Balakrishnan said she was surprised by the higher risk of severe NASH fibrosis in women compared with men once NAFLD is established. “This was surprising and sets NAFLD apart from other highly prevalent chronic liver disease etiologies,” she said. “Other common liver diseases, for example hepatitis B and hepatitis C, tend to be more common among men and tend to progress more rapidly, and tend to be more severe among men compared to women,” she noted.

The take-home message for clinicians is that NAFLD is at least equally, if not more, aggressive in women compared with men, and should be evaluated with equal aggressiveness, Dr. Balakrishnan emphasized. “Moreover, in the future we may expect to see the burden of cirrhosis distributed more equally among women and men than we have to date. This has implications for liver disease screening and women’s health,” she said. The next steps for research are to determine the specific reasons for the higher risk of NAFLD fibrosis in women compared with men, she added.

The study was supported in part by the National Institutes of Health. The researchers had no financial conflicts to disclose.

SOURCE: Balakrishnan M et al. Clin Gastroenterol Hepatol. 2020 Apr 30. doi: 10.1016/j.cgh.2020.04.067.

AGA offers education on the latest challenges, trends and solutions for diagnosing and managing nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) at http://ow.ly/Bz1Q30qYMw0. Help your patients better understand their risk of NASH and NAFLD by sharing AGA patient education at http://ow.ly/GoY630qYOmY.

An inexpensive two-drug regimen of sofosbuvir (Sovaldi, Gilead Sciences) plus daclatasvir (Daklinza, Bristol-Myers Squibb) taken for 14 days significantly reduced time to recovery from COVID-19 and improved survival in people hospitalized with severe disease, research from an open-label Iranian study shows.

And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.

But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.

“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.

Three Trials, 176 Patients

Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.

All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.

The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.

All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.

More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.

However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).

The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.

A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.

The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.

However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.

Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.

These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”

But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.

Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.

“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.

“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
 

This article first appeared on Medscape.com.

An inexpensive two-drug regimen of sofosbuvir (Sovaldi, Gilead Sciences) plus daclatasvir (Daklinza, Bristol-Myers Squibb) taken for 14 days significantly reduced time to recovery from COVID-19 and improved survival in people hospitalized with severe disease, research from an open-label Iranian study shows.

And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.

But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.

“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.

Three Trials, 176 Patients

Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.

All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.

The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.

All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.

More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.

However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).

The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.

A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.

The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.

However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.

Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.

These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”

But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.

Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.

“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.

“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
 

This article first appeared on Medscape.com.

An inexpensive two-drug regimen of sofosbuvir (Sovaldi, Gilead Sciences) plus daclatasvir (Daklinza, Bristol-Myers Squibb) taken for 14 days significantly reduced time to recovery from COVID-19 and improved survival in people hospitalized with severe disease, research from an open-label Iranian study shows.

And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.

But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.

“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.

Three Trials, 176 Patients

Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.

All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.

The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.

All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.

More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.

However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).

The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.

A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.

The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.

However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.

Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.

These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”

But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.

Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.

“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.

“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
 

This article first appeared on Medscape.com.

The American Gastroenterological Association has released a new guideline for consultative management of patients with COVID-19.

The recommendations, which were written by Shahnaz Sultan, MD, AGAF, chair of the AGA Clinical Guidelines Committee, of the University of Minnesota, Minneapolis, and colleagues, were based on a meta-analysis of data from 47 studies involving 10,890 unique patients.

“We seek to summarize international data on the GI and liver manifestations of COVID-19 infection and treatment,” the panelists wrote in Gastroenterology. “Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.”

The guideline includes seven best practice statements.

The first three statements relate to COVID-19–related GI symptoms, which are estimated to occur in less than 10% of patients, and rarely in the absence of other COVID-19–related symptoms, according to Dr. Sultan and her copanelists.

“The overall prevalence of GI symptoms in the context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously,” the panelists wrote, referencing a previous meta-analysis by Ka Shing Cheung, MBBS, and colleagues that showed a prevalence of 17.6%.

“It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known.”

Since GI issues may precede other symptoms of COVID-19, the guideline recommends questioning outpatients with new-onset GI symptoms about other symptoms of COVID-19, with viral testing recommended in areas of high prevalence. Conversely, the panelists recommended that patients with suspected or known COVID-19 should undergo thorough history taking for GI symptoms, “including onset, characteristics, duration, and severity.”

The fourth practice statement advises against COVID-19 stool testing in routine clinical practice, either for diagnostic or monitoring purposes.

Although Dr. Cheung and colleagues reported that 48.1% of fecal specimens from patients with COVID-19 contained viral RNA, the panelists concluded that the practical relevance of this finding remains unknown.

“Stool infectivity and transmission have not been confirmed,” the panelists wrote, citing a lack of evidence and conflicting findings.

The final three practice statements address liver concerns.

First, any patient with suspected or confirmed COVID-19 who has elevated liver function tests should be evaluated for alternative etiologies. Second, hospitalized patients with suspected or confirmed COVID-19 should undergo baseline liver function testing, followed by liver monitoring throughout their stay, “particularly in the context of drug treatment for COVID-19.” And third, any patient receiving drugs to treat COVID-19 should be monitored for treatment-related hepatic and GI adverse effects.

Dr. Sultan and colleagues found that approximately 15% of patients with COVID-19 included in their meta-analysis had abnormal liver function tests, more often because of secondary effects rather than virally induced liver injury.

Although liver function test abnormalities were inconsistently reported across studies, and when available, often lacked relevant contextual data, such as information about underlying liver disease, published data suggest that abnormal liver values could predict more severe COVID-19, supporting baseline and serial liver testing, the panelists wrote.

Following these recommendations, the guideline includes a discussion of GI and hepatic adverse effects related to specific COVID-19 treatments.

According to the panelists, chloroquine and hydroxychloroquine may infrequently lead to GI disturbances, and rarely, liver injury, with the latter thought to be a sequela of a hypersensitivity reaction; among antiviral medications, lopinavir/ritonavir and favipiravir may cause GI adverse effects in approximately 5%-15% of patients, with potentially higher rates in children and those receiving higher doses.

“In particular, GI adverse events are poorly understood for both favipiravir and remdesivir,” the panelists wrote.

Hepatic adverse effects, ranging from mild elevations in aminotransferases to acute liver failure, have been documented, albeit rarely, among patients receiving lopinavir/ritonavir, according to the panelists. For remdesivir, liver injury has also been reported, although frequency is unknown, and for favipiravir, hepatic adverse events may be seen in 3% of patients, although, again, the panelists noted a scarcity of relevant findings.

In their concluding remarks, Dr. Sultan and colleagues called for more high-quality data, and encouraged clinicians to contribute to international registries, as these could help guide COVID-19 recommendations for patient subgroups.

The article was funded by the American Gastroenterological Association Institute.

SOURCE: Sultan S et al. Gastroenterology. 2020 May 11. doi: 10.1053/j.gastro.2020.05.001.

The American Gastroenterological Association has released a new guideline for consultative management of patients with COVID-19.

The recommendations, which were written by Shahnaz Sultan, MD, AGAF, chair of the AGA Clinical Guidelines Committee, of the University of Minnesota, Minneapolis, and colleagues, were based on a meta-analysis of data from 47 studies involving 10,890 unique patients.

“We seek to summarize international data on the GI and liver manifestations of COVID-19 infection and treatment,” the panelists wrote in Gastroenterology. “Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.”

The guideline includes seven best practice statements.

The first three statements relate to COVID-19–related GI symptoms, which are estimated to occur in less than 10% of patients, and rarely in the absence of other COVID-19–related symptoms, according to Dr. Sultan and her copanelists.

“The overall prevalence of GI symptoms in the context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously,” the panelists wrote, referencing a previous meta-analysis by Ka Shing Cheung, MBBS, and colleagues that showed a prevalence of 17.6%.

“It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known.”

Since GI issues may precede other symptoms of COVID-19, the guideline recommends questioning outpatients with new-onset GI symptoms about other symptoms of COVID-19, with viral testing recommended in areas of high prevalence. Conversely, the panelists recommended that patients with suspected or known COVID-19 should undergo thorough history taking for GI symptoms, “including onset, characteristics, duration, and severity.”

The fourth practice statement advises against COVID-19 stool testing in routine clinical practice, either for diagnostic or monitoring purposes.

Although Dr. Cheung and colleagues reported that 48.1% of fecal specimens from patients with COVID-19 contained viral RNA, the panelists concluded that the practical relevance of this finding remains unknown.

“Stool infectivity and transmission have not been confirmed,” the panelists wrote, citing a lack of evidence and conflicting findings.

The final three practice statements address liver concerns.

First, any patient with suspected or confirmed COVID-19 who has elevated liver function tests should be evaluated for alternative etiologies. Second, hospitalized patients with suspected or confirmed COVID-19 should undergo baseline liver function testing, followed by liver monitoring throughout their stay, “particularly in the context of drug treatment for COVID-19.” And third, any patient receiving drugs to treat COVID-19 should be monitored for treatment-related hepatic and GI adverse effects.

Dr. Sultan and colleagues found that approximately 15% of patients with COVID-19 included in their meta-analysis had abnormal liver function tests, more often because of secondary effects rather than virally induced liver injury.

Although liver function test abnormalities were inconsistently reported across studies, and when available, often lacked relevant contextual data, such as information about underlying liver disease, published data suggest that abnormal liver values could predict more severe COVID-19, supporting baseline and serial liver testing, the panelists wrote.

Following these recommendations, the guideline includes a discussion of GI and hepatic adverse effects related to specific COVID-19 treatments.

According to the panelists, chloroquine and hydroxychloroquine may infrequently lead to GI disturbances, and rarely, liver injury, with the latter thought to be a sequela of a hypersensitivity reaction; among antiviral medications, lopinavir/ritonavir and favipiravir may cause GI adverse effects in approximately 5%-15% of patients, with potentially higher rates in children and those receiving higher doses.

“In particular, GI adverse events are poorly understood for both favipiravir and remdesivir,” the panelists wrote.

Hepatic adverse effects, ranging from mild elevations in aminotransferases to acute liver failure, have been documented, albeit rarely, among patients receiving lopinavir/ritonavir, according to the panelists. For remdesivir, liver injury has also been reported, although frequency is unknown, and for favipiravir, hepatic adverse events may be seen in 3% of patients, although, again, the panelists noted a scarcity of relevant findings.

In their concluding remarks, Dr. Sultan and colleagues called for more high-quality data, and encouraged clinicians to contribute to international registries, as these could help guide COVID-19 recommendations for patient subgroups.

The article was funded by the American Gastroenterological Association Institute.

SOURCE: Sultan S et al. Gastroenterology. 2020 May 11. doi: 10.1053/j.gastro.2020.05.001.

The American Gastroenterological Association has released a new guideline for consultative management of patients with COVID-19.

The recommendations, which were written by Shahnaz Sultan, MD, AGAF, chair of the AGA Clinical Guidelines Committee, of the University of Minnesota, Minneapolis, and colleagues, were based on a meta-analysis of data from 47 studies involving 10,890 unique patients.

“We seek to summarize international data on the GI and liver manifestations of COVID-19 infection and treatment,” the panelists wrote in Gastroenterology. “Additionally, this document provides evidence-based clinical guidance on clinical questions that gastroenterologists may be consulted for.”

The guideline includes seven best practice statements.

The first three statements relate to COVID-19–related GI symptoms, which are estimated to occur in less than 10% of patients, and rarely in the absence of other COVID-19–related symptoms, according to Dr. Sultan and her copanelists.

“The overall prevalence of GI symptoms in the context of COVID-19, including nausea, vomiting, abdominal pain, and diarrhea, is lower than estimated previously,” the panelists wrote, referencing a previous meta-analysis by Ka Shing Cheung, MBBS, and colleagues that showed a prevalence of 17.6%.

“It is important to note that the majority of studies were focused on hospitalized patients with COVID-19, and the prevalence of diarrhea in patients with mild symptoms who were not hospitalized is not known.”

Since GI issues may precede other symptoms of COVID-19, the guideline recommends questioning outpatients with new-onset GI symptoms about other symptoms of COVID-19, with viral testing recommended in areas of high prevalence. Conversely, the panelists recommended that patients with suspected or known COVID-19 should undergo thorough history taking for GI symptoms, “including onset, characteristics, duration, and severity.”

The fourth practice statement advises against COVID-19 stool testing in routine clinical practice, either for diagnostic or monitoring purposes.

Although Dr. Cheung and colleagues reported that 48.1% of fecal specimens from patients with COVID-19 contained viral RNA, the panelists concluded that the practical relevance of this finding remains unknown.

“Stool infectivity and transmission have not been confirmed,” the panelists wrote, citing a lack of evidence and conflicting findings.

The final three practice statements address liver concerns.

First, any patient with suspected or confirmed COVID-19 who has elevated liver function tests should be evaluated for alternative etiologies. Second, hospitalized patients with suspected or confirmed COVID-19 should undergo baseline liver function testing, followed by liver monitoring throughout their stay, “particularly in the context of drug treatment for COVID-19.” And third, any patient receiving drugs to treat COVID-19 should be monitored for treatment-related hepatic and GI adverse effects.

Dr. Sultan and colleagues found that approximately 15% of patients with COVID-19 included in their meta-analysis had abnormal liver function tests, more often because of secondary effects rather than virally induced liver injury.

Although liver function test abnormalities were inconsistently reported across studies, and when available, often lacked relevant contextual data, such as information about underlying liver disease, published data suggest that abnormal liver values could predict more severe COVID-19, supporting baseline and serial liver testing, the panelists wrote.

Following these recommendations, the guideline includes a discussion of GI and hepatic adverse effects related to specific COVID-19 treatments.

According to the panelists, chloroquine and hydroxychloroquine may infrequently lead to GI disturbances, and rarely, liver injury, with the latter thought to be a sequela of a hypersensitivity reaction; among antiviral medications, lopinavir/ritonavir and favipiravir may cause GI adverse effects in approximately 5%-15% of patients, with potentially higher rates in children and those receiving higher doses.

“In particular, GI adverse events are poorly understood for both favipiravir and remdesivir,” the panelists wrote.

Hepatic adverse effects, ranging from mild elevations in aminotransferases to acute liver failure, have been documented, albeit rarely, among patients receiving lopinavir/ritonavir, according to the panelists. For remdesivir, liver injury has also been reported, although frequency is unknown, and for favipiravir, hepatic adverse events may be seen in 3% of patients, although, again, the panelists noted a scarcity of relevant findings.

In their concluding remarks, Dr. Sultan and colleagues called for more high-quality data, and encouraged clinicians to contribute to international registries, as these could help guide COVID-19 recommendations for patient subgroups.

The article was funded by the American Gastroenterological Association Institute.

SOURCE: Sultan S et al. Gastroenterology. 2020 May 11. doi: 10.1053/j.gastro.2020.05.001.

Overall survival after liver cancer surgery was similar regardless of whether patients were treated at minority-serving hospitals or at hospitals with proportionally fewer African American or Hispanic patients, investigators have found.

“[T]reatment of racial minorities is largely restricted to a subset of hospitals, often referred to as minority-serving hospitals. We sought to examine whether racial and ethnic minorities with hepatocellular carcinoma receive their surgical care at minority-serving hospitals, and whether treatment at minority-serving hospitals is associated with differences in overall survival,” explained Winta T. Mehtsun, MD, MPH, of Dana-Farber Cancer Institute in Boston and associates in an abstract released as part of the annual Digestive Disease Week.^®

Hepatocellular carcinoma continues to have a low 5-year survival rate and exhibits marked racial and ethnic disparities in diagnosis, treatment, and outcomes. In a recent study of Surveillance Epidemiology and End Results (SEER) data, African American patients with hepatocellular carcinoma were significantly younger at diagnosis, were more likely to have metastatic disease, and were less likely to receive surgical treatment compared with whites (Am J Prevent Med 2018;55:S40-48). Among patients with early-stage liver cancer, Hispanic and African American patients are less likely to receive curative therapy and die sooner, on average, than do other patients (Clin Gastroenterol Hepatol. 2019;17:551-9).

Minority-serving hospitals also have improved significantly less over time on measures of critical care, length of stay, and mortality, but whether these issues extend to hepatocellular carcinoma remains unclear. Therefore, Dr. Mehtsun and her associates studied all 2,609 patients in the National Cancer Database who received surgical resection (not transplantation or local therapy) for nonmetastatic hepatocellular carcinoma between 2004 and 2014. They compared survival at minority-serving hospitals – those in the top 10% based on the proportion of patients who were African American or Hispanic – with survival at other hospitals.

“There was no association between minority-serving hospital and overall survival,” the researchers reported (multivariable hazard ratio for death, 0.89; 95% confidence interval, 0.72-1.11). In contrast, survival was significantly shorter among patients with more advanced disease (HR, 2.5; 95% CI, 2.1-2.8), patients who were treated at a community cancer program (HR, 1.7; 95% CI, 1.3-2.4), and patients whose Charlson Comorbidity Index was greater than 2 (HR, 1.2; 95% CI, 1.1-1.4).

Stage at diagnosis, comorbidities, and sex were not significantly related to hospital type, the investigators noted. A total of 298 patients (11%) were treated at minority-serving hospitals. Patients treated at minority-serving hospitals were significantly more likely to be uninsured (11% vs. 4% at other hospitals) and significantly less likely to be treated at an academic center (55% vs. 69%; both P less than .001).

Dr. Mehtsun reported having no relevant conflicts of interest.

SOURCE: Mehtsun WT et al. DDW 2020, Abstract Tu2043.

Overall survival after liver cancer surgery was similar regardless of whether patients were treated at minority-serving hospitals or at hospitals with proportionally fewer African American or Hispanic patients, investigators have found.

“[T]reatment of racial minorities is largely restricted to a subset of hospitals, often referred to as minority-serving hospitals. We sought to examine whether racial and ethnic minorities with hepatocellular carcinoma receive their surgical care at minority-serving hospitals, and whether treatment at minority-serving hospitals is associated with differences in overall survival,” explained Winta T. Mehtsun, MD, MPH, of Dana-Farber Cancer Institute in Boston and associates in an abstract released as part of the annual Digestive Disease Week.^®

Hepatocellular carcinoma continues to have a low 5-year survival rate and exhibits marked racial and ethnic disparities in diagnosis, treatment, and outcomes. In a recent study of Surveillance Epidemiology and End Results (SEER) data, African American patients with hepatocellular carcinoma were significantly younger at diagnosis, were more likely to have metastatic disease, and were less likely to receive surgical treatment compared with whites (Am J Prevent Med 2018;55:S40-48). Among patients with early-stage liver cancer, Hispanic and African American patients are less likely to receive curative therapy and die sooner, on average, than do other patients (Clin Gastroenterol Hepatol. 2019;17:551-9).

Minority-serving hospitals also have improved significantly less over time on measures of critical care, length of stay, and mortality, but whether these issues extend to hepatocellular carcinoma remains unclear. Therefore, Dr. Mehtsun and her associates studied all 2,609 patients in the National Cancer Database who received surgical resection (not transplantation or local therapy) for nonmetastatic hepatocellular carcinoma between 2004 and 2014. They compared survival at minority-serving hospitals – those in the top 10% based on the proportion of patients who were African American or Hispanic – with survival at other hospitals.

“There was no association between minority-serving hospital and overall survival,” the researchers reported (multivariable hazard ratio for death, 0.89; 95% confidence interval, 0.72-1.11). In contrast, survival was significantly shorter among patients with more advanced disease (HR, 2.5; 95% CI, 2.1-2.8), patients who were treated at a community cancer program (HR, 1.7; 95% CI, 1.3-2.4), and patients whose Charlson Comorbidity Index was greater than 2 (HR, 1.2; 95% CI, 1.1-1.4).

Stage at diagnosis, comorbidities, and sex were not significantly related to hospital type, the investigators noted. A total of 298 patients (11%) were treated at minority-serving hospitals. Patients treated at minority-serving hospitals were significantly more likely to be uninsured (11% vs. 4% at other hospitals) and significantly less likely to be treated at an academic center (55% vs. 69%; both P less than .001).

Dr. Mehtsun reported having no relevant conflicts of interest.

SOURCE: Mehtsun WT et al. DDW 2020, Abstract Tu2043.

Overall survival after liver cancer surgery was similar regardless of whether patients were treated at minority-serving hospitals or at hospitals with proportionally fewer African American or Hispanic patients, investigators have found.

“[T]reatment of racial minorities is largely restricted to a subset of hospitals, often referred to as minority-serving hospitals. We sought to examine whether racial and ethnic minorities with hepatocellular carcinoma receive their surgical care at minority-serving hospitals, and whether treatment at minority-serving hospitals is associated with differences in overall survival,” explained Winta T. Mehtsun, MD, MPH, of Dana-Farber Cancer Institute in Boston and associates in an abstract released as part of the annual Digestive Disease Week.^®

Hepatocellular carcinoma continues to have a low 5-year survival rate and exhibits marked racial and ethnic disparities in diagnosis, treatment, and outcomes. In a recent study of Surveillance Epidemiology and End Results (SEER) data, African American patients with hepatocellular carcinoma were significantly younger at diagnosis, were more likely to have metastatic disease, and were less likely to receive surgical treatment compared with whites (Am J Prevent Med 2018;55:S40-48). Among patients with early-stage liver cancer, Hispanic and African American patients are less likely to receive curative therapy and die sooner, on average, than do other patients (Clin Gastroenterol Hepatol. 2019;17:551-9).

Minority-serving hospitals also have improved significantly less over time on measures of critical care, length of stay, and mortality, but whether these issues extend to hepatocellular carcinoma remains unclear. Therefore, Dr. Mehtsun and her associates studied all 2,609 patients in the National Cancer Database who received surgical resection (not transplantation or local therapy) for nonmetastatic hepatocellular carcinoma between 2004 and 2014. They compared survival at minority-serving hospitals – those in the top 10% based on the proportion of patients who were African American or Hispanic – with survival at other hospitals.

“There was no association between minority-serving hospital and overall survival,” the researchers reported (multivariable hazard ratio for death, 0.89; 95% confidence interval, 0.72-1.11). In contrast, survival was significantly shorter among patients with more advanced disease (HR, 2.5; 95% CI, 2.1-2.8), patients who were treated at a community cancer program (HR, 1.7; 95% CI, 1.3-2.4), and patients whose Charlson Comorbidity Index was greater than 2 (HR, 1.2; 95% CI, 1.1-1.4).

Stage at diagnosis, comorbidities, and sex were not significantly related to hospital type, the investigators noted. A total of 298 patients (11%) were treated at minority-serving hospitals. Patients treated at minority-serving hospitals were significantly more likely to be uninsured (11% vs. 4% at other hospitals) and significantly less likely to be treated at an academic center (55% vs. 69%; both P less than .001).

Dr. Mehtsun reported having no relevant conflicts of interest.

SOURCE: Mehtsun WT et al. DDW 2020, Abstract Tu2043.

When performing transient elastography (FibroScan) to evaluate patients for hepatic steatosis, using an M probe instead of an XL probe may significantly underestimate hepatic fat content, according to investigators.

The findings, which were independent of body weight, suggest that probe-specific controlled attenuation parameter (CAP) thresholds are needed to accurately interpret FibroScan results, reported lead author Cyrielle Caussy, MD, PhD, of the University of California, San Diego, and colleagues.

“We have previously determined the optimal threshold of CAP using either [an] M or XL probe for the detection of ... nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, head-to-head comparison of consecutive measurements of CAP with both the M and XL probes versus MRI-PDFF [proton density fat fraction] ... has not been reported yet.”

Dr. Caussy and colleagues set out to do just that. They enrolled 105 individuals with and without NAFLD who had a mean body mass index (BMI) of 30.6 kg/m², as this represented a typical population screened for NAFLD. After evaluation for other causes of hepatic steatosis and liver disease, participants underwent MRI-PDFF, which served as a gold standard, followed by FibroScan using both M and XL probes on the same day.

The primary outcome was hepatic steatosis (MRI-PDFF of at least 5%), while the secondary outcome was MRI-PDFF–detected hepatic fat content of at least 10%, the latter of which has been “used in several therapeutic trials as inclusion criteria,” the investigators noted.

A total of 100 participants were included in the final analysis, of whom two-thirds (66%) underwent MRI and FibroScan on the same day, with a mean interval between test types of 11 days. Most participants (68%) had an MRI-PDFF of at least 5%, while almost half (48%) exceeded an MRI-PDFF of 10%.

The mean CAP measurement with the M probe was 310 dB/m, which was significantly lower than the mean value detected by the XL probe, which was 317 dB/m (P = .007). In participants with hepatic steatosis, when the M probe was used for those with a BMI of less than 30, and the XL probe was used for those with a BMI of 30 or more, the M probe still provided a significantly lower measure of hepatic fat content (312 vs. 345 dB/m; P = .0035).

“[T]hese results have direct application in routine clinical practice,” the investigators wrote, “as [they] will help clinicians interpreting CAP measurements depending on the type of probe used.”

Dr. Caussy and colleagues went on to offer a diagnostic algorithm involving optimal probe-specific thresholds for CAP based on hepatic fat content. Individuals screened with an M probe who have a CAP of 294 dB/m or more should be considered positive for NAFLD, while patients screened with an XL probe need to have a CAP of at least 307 dB/m to be NAFLD positive.

For the XL probe, but not the M probe, diagnostic accuracy depended upon an interquartile range of less than 30 dB/m. The investigators noted that this finding should alter the interpretation of a 2019 study by Eddowes and colleagues, which concluded that interquartile range was unrelated to diagnostic accuracy.

“As Eddowes et al. did not perform head-to-head comparison of CAP measurement with both the M and XL probes, this important difference could not have been observed,” the investigators wrote, noting that “an interquartile range of CAP below 30 dB/m should be considered as a quality indicator that significantly improves the diagnostic performance of CAP using the XL probe for the detection of hepatic steatosis in NAFLD.”

The investigators concluded by suggesting that their findings will drive research forward.

“The use of these new thresholds will help to further assess the clinical utility of CAP for the detection of hepatic steatosis and its cost-effectiveness, compared with other modalities, to develop optimal strategies for the screening of NAFLD,” they wrote.

The study was funded by Atlantic Philanthropies, the John A. Hartford Foundation, the American Gastroenterological Association, and others. The investigators disclosed no conflicts of interest.

SOURCE: Caussy C et al. Clin Gastro Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.060.

When performing transient elastography (FibroScan) to evaluate patients for hepatic steatosis, using an M probe instead of an XL probe may significantly underestimate hepatic fat content, according to investigators.

The findings, which were independent of body weight, suggest that probe-specific controlled attenuation parameter (CAP) thresholds are needed to accurately interpret FibroScan results, reported lead author Cyrielle Caussy, MD, PhD, of the University of California, San Diego, and colleagues.

“We have previously determined the optimal threshold of CAP using either [an] M or XL probe for the detection of ... nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, head-to-head comparison of consecutive measurements of CAP with both the M and XL probes versus MRI-PDFF [proton density fat fraction] ... has not been reported yet.”

Dr. Caussy and colleagues set out to do just that. They enrolled 105 individuals with and without NAFLD who had a mean body mass index (BMI) of 30.6 kg/m², as this represented a typical population screened for NAFLD. After evaluation for other causes of hepatic steatosis and liver disease, participants underwent MRI-PDFF, which served as a gold standard, followed by FibroScan using both M and XL probes on the same day.

The primary outcome was hepatic steatosis (MRI-PDFF of at least 5%), while the secondary outcome was MRI-PDFF–detected hepatic fat content of at least 10%, the latter of which has been “used in several therapeutic trials as inclusion criteria,” the investigators noted.

A total of 100 participants were included in the final analysis, of whom two-thirds (66%) underwent MRI and FibroScan on the same day, with a mean interval between test types of 11 days. Most participants (68%) had an MRI-PDFF of at least 5%, while almost half (48%) exceeded an MRI-PDFF of 10%.

The mean CAP measurement with the M probe was 310 dB/m, which was significantly lower than the mean value detected by the XL probe, which was 317 dB/m (P = .007). In participants with hepatic steatosis, when the M probe was used for those with a BMI of less than 30, and the XL probe was used for those with a BMI of 30 or more, the M probe still provided a significantly lower measure of hepatic fat content (312 vs. 345 dB/m; P = .0035).

“[T]hese results have direct application in routine clinical practice,” the investigators wrote, “as [they] will help clinicians interpreting CAP measurements depending on the type of probe used.”

Dr. Caussy and colleagues went on to offer a diagnostic algorithm involving optimal probe-specific thresholds for CAP based on hepatic fat content. Individuals screened with an M probe who have a CAP of 294 dB/m or more should be considered positive for NAFLD, while patients screened with an XL probe need to have a CAP of at least 307 dB/m to be NAFLD positive.

For the XL probe, but not the M probe, diagnostic accuracy depended upon an interquartile range of less than 30 dB/m. The investigators noted that this finding should alter the interpretation of a 2019 study by Eddowes and colleagues, which concluded that interquartile range was unrelated to diagnostic accuracy.

“As Eddowes et al. did not perform head-to-head comparison of CAP measurement with both the M and XL probes, this important difference could not have been observed,” the investigators wrote, noting that “an interquartile range of CAP below 30 dB/m should be considered as a quality indicator that significantly improves the diagnostic performance of CAP using the XL probe for the detection of hepatic steatosis in NAFLD.”

The investigators concluded by suggesting that their findings will drive research forward.

“The use of these new thresholds will help to further assess the clinical utility of CAP for the detection of hepatic steatosis and its cost-effectiveness, compared with other modalities, to develop optimal strategies for the screening of NAFLD,” they wrote.

The study was funded by Atlantic Philanthropies, the John A. Hartford Foundation, the American Gastroenterological Association, and others. The investigators disclosed no conflicts of interest.

SOURCE: Caussy C et al. Clin Gastro Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.060.

When performing transient elastography (FibroScan) to evaluate patients for hepatic steatosis, using an M probe instead of an XL probe may significantly underestimate hepatic fat content, according to investigators.

The findings, which were independent of body weight, suggest that probe-specific controlled attenuation parameter (CAP) thresholds are needed to accurately interpret FibroScan results, reported lead author Cyrielle Caussy, MD, PhD, of the University of California, San Diego, and colleagues.

“We have previously determined the optimal threshold of CAP using either [an] M or XL probe for the detection of ... nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, head-to-head comparison of consecutive measurements of CAP with both the M and XL probes versus MRI-PDFF [proton density fat fraction] ... has not been reported yet.”

Dr. Caussy and colleagues set out to do just that. They enrolled 105 individuals with and without NAFLD who had a mean body mass index (BMI) of 30.6 kg/m², as this represented a typical population screened for NAFLD. After evaluation for other causes of hepatic steatosis and liver disease, participants underwent MRI-PDFF, which served as a gold standard, followed by FibroScan using both M and XL probes on the same day.

The primary outcome was hepatic steatosis (MRI-PDFF of at least 5%), while the secondary outcome was MRI-PDFF–detected hepatic fat content of at least 10%, the latter of which has been “used in several therapeutic trials as inclusion criteria,” the investigators noted.

A total of 100 participants were included in the final analysis, of whom two-thirds (66%) underwent MRI and FibroScan on the same day, with a mean interval between test types of 11 days. Most participants (68%) had an MRI-PDFF of at least 5%, while almost half (48%) exceeded an MRI-PDFF of 10%.

The mean CAP measurement with the M probe was 310 dB/m, which was significantly lower than the mean value detected by the XL probe, which was 317 dB/m (P = .007). In participants with hepatic steatosis, when the M probe was used for those with a BMI of less than 30, and the XL probe was used for those with a BMI of 30 or more, the M probe still provided a significantly lower measure of hepatic fat content (312 vs. 345 dB/m; P = .0035).

“[T]hese results have direct application in routine clinical practice,” the investigators wrote, “as [they] will help clinicians interpreting CAP measurements depending on the type of probe used.”

Dr. Caussy and colleagues went on to offer a diagnostic algorithm involving optimal probe-specific thresholds for CAP based on hepatic fat content. Individuals screened with an M probe who have a CAP of 294 dB/m or more should be considered positive for NAFLD, while patients screened with an XL probe need to have a CAP of at least 307 dB/m to be NAFLD positive.

For the XL probe, but not the M probe, diagnostic accuracy depended upon an interquartile range of less than 30 dB/m. The investigators noted that this finding should alter the interpretation of a 2019 study by Eddowes and colleagues, which concluded that interquartile range was unrelated to diagnostic accuracy.

“As Eddowes et al. did not perform head-to-head comparison of CAP measurement with both the M and XL probes, this important difference could not have been observed,” the investigators wrote, noting that “an interquartile range of CAP below 30 dB/m should be considered as a quality indicator that significantly improves the diagnostic performance of CAP using the XL probe for the detection of hepatic steatosis in NAFLD.”

The investigators concluded by suggesting that their findings will drive research forward.

“The use of these new thresholds will help to further assess the clinical utility of CAP for the detection of hepatic steatosis and its cost-effectiveness, compared with other modalities, to develop optimal strategies for the screening of NAFLD,” they wrote.

The study was funded by Atlantic Philanthropies, the John A. Hartford Foundation, the American Gastroenterological Association, and others. The investigators disclosed no conflicts of interest.

SOURCE: Caussy C et al. Clin Gastro Hepatol. 2019 Dec 13. doi: 10.1016/j.cgh.2019.11.060.