TBD Meeting (4952-21)

Patients with hepatocellular carcinoma (HCC) can be offered transarterial radioembolization (TARE) as a safe and effective first-line treatment or adjunct to other locoregional therapies, authors of a large multicenter study reported.

Among 422 patients with HCC treated with TARE in eight European countries, the median overall survival was 16.5 months, with fewer than 10% of patients experiencing grade 3 or greater adverse events, reported Frank Kolligs, MD, from Helios Hospital Berlin-Buch.

“This exploratory study evaluated factors that can influence the application and outcome of transarterial radioembolization in clinical practice. TARE is generally applied according to guideline recommendations, and randomized, controlled trials are needed to confirm the effect of personalized dosimetry on the effectiveness of TARE,” he said in an oral abstract presented at the meeting sponsored by the European Association for the Study of the Liver.

Intriguingly, the investigators found evidence suggesting that patients whose treatments were planned using a partition model had better survival outcomes than those patients who treatments were based on calculated body surface area or measured BSA (mBSA), but this finding will need to be explored in more detail, Dr. Kolligs said.

The partition model incorporates variables such as tumor volume and liver volume, shunt fractions, the ratio of radiation uptake between tumor and normal tissues, vascular anatomy and other factors to estimate the optimal dose.
 

Study design

Dr. Kolligs and colleagues looked at prospective data from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Registry for SIR-Spheres Therapy to evaluate the real-world clinical application of TARE with yttrium Y-90 resin microspheres in Europe, clinical outcomes, safety, and quality of life.

They selected data from centers with a minimum of 10 cases performed in the previous 12 months and at least 40 total cases overall.

The patients included adults 18 years and older scheduled for treatment with Y-90 resin microspheres for primary or metastatic liver tumors, with no specific exclusion criteria. The patients were followed for at least 24 months at recommended intervals of every 3 months. The first patient was enrolled in January 2015, and the last follow-up visit was in December 2019. A total of 422 registry patients had a diagnosis of HCC and were included in the study.

The median age was 68 years (range, 60-74), 80.8% were male, 70.9% had cirrhosis, 14.5% had ascites, and 8.5% had extrahepatic disease. About 32% of patients had one tumor nodule, 33% had two to five nodules, and the remainder had either more than five or an uncountable number.

In all, 14% of patients had Barcelona Clinic Liver Cancer stage A disease, 51.4% had stage B, 33.6% had stage C, and 0.9% stage D.

About one-third of patients had portal vein occlusion. Tumors were in both left and right lobes in 35.5%, the left lobe alone in 12.1%, and the right lobe alone in 52.4%.

Half of all patients (50.2%) received TARE as first-line therapy, 44.8% had it following surgery (17.1%), ablation (14.7%), and/or transarterial chemoembolization (; 23%). In addition, 9.7% of patients received systemic therapy prior to TARE, primarily with sorafenib (Nexavar).

Treatment intent was palliative for 57.3% of patients, and tumor downsizing/downstaging in 32.5% (remainder unspecified).
 

Survival and prognostic factors

As noted before, median overall survival was 16.5 months. Median progression-free survival was 6.1 months, and median hepatic PFS was 6.7 months.

Factors prognostic for better overall survival included hepatitis B or C virus as the cirrhosis cause versus alcohol (hazard ratio for death, 0.51 for each; P = .0060 for HBV and P = .0007 for HCV); unilobar versus bilobar tumors (HR, 0.67; P = .0422 for left-lobe; HR 0.55; P < .0001 for right); prior surgery (HR, 0.67; P = .0258); prior ablation (HR, 0.65; P = .0394); and curative versus palliative intent (HR, 0.53; P < .0001).

Factors associated with worse overall survival were presence of ascites (HR 1.75, P = .001); presence of extrahepatic disease before TARE (HR, 1.81, P = .0037); tumor burden greater than 5 nodules (HR, 1.67; P = .0073); main portal vein occlusion (HR, 2.14; P = .0064); lobar portal vein occlusion (HR, 1.77; P = .0083); total bilirubin greater than 1.5 mg/dL (HR, 1.69; P = .0094); albumin-bilirubin grade A2 (HR, 1.66; P = .0005); ALB1 grade A3 (HR, 3.92; P < .0001); and BSA/mBSA versus partition-model dosimetry (HR, 1.89; P < .0001).

The safety analysis showed that 36.7% of patients had at least one adverse event, but only 7.1% had at least one grade 3 or greater event.

Grade 3 or greater events were abdominal pain (nine patients), fatigue (six), nausea (three), radioembolization-induced liver disease (three), vomiting (two), and GI ulceration (one). Fifteen additional patients had other unspecified events.

The investigators acknowledged broad inclusion criteria, relatively high rates of loss to follow-up, and differences in national guidelines and local standards of practice as potential limitations to their findings.

In the question-and-answer following the presentation, session comoderator María Varela, MD, PhD, a pathologist in the liver unit at the Hospital Universitario Central de Asturia, Oviedo, Spain, questioned why about one-third of patients received TARE for downstaging, but only 13 underwent subsequent surgical resection.

“We don’t have a detailed analysis of this subgroup of patients who received curative intent as yet, ” Dr. Kolligs said.

Pierre Nahon, MD, from the University of Paris and Hôpital Jean Verdier in Bondy, France, commented that, among this heterogenous population, one of the best indications for TARE is probably localized HCC with adjacent portal vein thrombosis.

He asked whether the investigators had examined overall survival among patients with localized unilobar HCC with adjacent small portal vein thrombosis.

“We find that patients with portal vein occlusion have a worse prognosis in the total group,” Dr. Kolligs replied. “To look into the question whether partial thrombosis with a small tumor might benefit is an interesting question, and we should look into that, but I don’t have any data on that yet.”

Another audience member asked: “According to your data, which patients are the best candidates for radioembolization?”

“According to these data, the best candidates are of course patients with good liver function, ascites should ideally not be present, and what is probably is important is that we identify or include patients without extrahepatic disease,” he said.

The study was sponsored by CIRSE. Dr. Kolligs disclosed speaking activities and consulting for several companies. Dr. Varela disclosed speaking for several companies and advisory board activity for Bayer. Dr. Nahon disclosed honoraria and consulting fees from several companies.

Patients with hepatocellular carcinoma (HCC) can be offered transarterial radioembolization (TARE) as a safe and effective first-line treatment or adjunct to other locoregional therapies, authors of a large multicenter study reported.

Among 422 patients with HCC treated with TARE in eight European countries, the median overall survival was 16.5 months, with fewer than 10% of patients experiencing grade 3 or greater adverse events, reported Frank Kolligs, MD, from Helios Hospital Berlin-Buch.

“This exploratory study evaluated factors that can influence the application and outcome of transarterial radioembolization in clinical practice. TARE is generally applied according to guideline recommendations, and randomized, controlled trials are needed to confirm the effect of personalized dosimetry on the effectiveness of TARE,” he said in an oral abstract presented at the meeting sponsored by the European Association for the Study of the Liver.

Intriguingly, the investigators found evidence suggesting that patients whose treatments were planned using a partition model had better survival outcomes than those patients who treatments were based on calculated body surface area or measured BSA (mBSA), but this finding will need to be explored in more detail, Dr. Kolligs said.

The partition model incorporates variables such as tumor volume and liver volume, shunt fractions, the ratio of radiation uptake between tumor and normal tissues, vascular anatomy and other factors to estimate the optimal dose.
 

Study design

Dr. Kolligs and colleagues looked at prospective data from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Registry for SIR-Spheres Therapy to evaluate the real-world clinical application of TARE with yttrium Y-90 resin microspheres in Europe, clinical outcomes, safety, and quality of life.

They selected data from centers with a minimum of 10 cases performed in the previous 12 months and at least 40 total cases overall.

The patients included adults 18 years and older scheduled for treatment with Y-90 resin microspheres for primary or metastatic liver tumors, with no specific exclusion criteria. The patients were followed for at least 24 months at recommended intervals of every 3 months. The first patient was enrolled in January 2015, and the last follow-up visit was in December 2019. A total of 422 registry patients had a diagnosis of HCC and were included in the study.

The median age was 68 years (range, 60-74), 80.8% were male, 70.9% had cirrhosis, 14.5% had ascites, and 8.5% had extrahepatic disease. About 32% of patients had one tumor nodule, 33% had two to five nodules, and the remainder had either more than five or an uncountable number.

In all, 14% of patients had Barcelona Clinic Liver Cancer stage A disease, 51.4% had stage B, 33.6% had stage C, and 0.9% stage D.

About one-third of patients had portal vein occlusion. Tumors were in both left and right lobes in 35.5%, the left lobe alone in 12.1%, and the right lobe alone in 52.4%.

Half of all patients (50.2%) received TARE as first-line therapy, 44.8% had it following surgery (17.1%), ablation (14.7%), and/or transarterial chemoembolization (; 23%). In addition, 9.7% of patients received systemic therapy prior to TARE, primarily with sorafenib (Nexavar).

Treatment intent was palliative for 57.3% of patients, and tumor downsizing/downstaging in 32.5% (remainder unspecified).
 

Survival and prognostic factors

As noted before, median overall survival was 16.5 months. Median progression-free survival was 6.1 months, and median hepatic PFS was 6.7 months.

Factors prognostic for better overall survival included hepatitis B or C virus as the cirrhosis cause versus alcohol (hazard ratio for death, 0.51 for each; P = .0060 for HBV and P = .0007 for HCV); unilobar versus bilobar tumors (HR, 0.67; P = .0422 for left-lobe; HR 0.55; P < .0001 for right); prior surgery (HR, 0.67; P = .0258); prior ablation (HR, 0.65; P = .0394); and curative versus palliative intent (HR, 0.53; P < .0001).

Factors associated with worse overall survival were presence of ascites (HR 1.75, P = .001); presence of extrahepatic disease before TARE (HR, 1.81, P = .0037); tumor burden greater than 5 nodules (HR, 1.67; P = .0073); main portal vein occlusion (HR, 2.14; P = .0064); lobar portal vein occlusion (HR, 1.77; P = .0083); total bilirubin greater than 1.5 mg/dL (HR, 1.69; P = .0094); albumin-bilirubin grade A2 (HR, 1.66; P = .0005); ALB1 grade A3 (HR, 3.92; P < .0001); and BSA/mBSA versus partition-model dosimetry (HR, 1.89; P < .0001).

The safety analysis showed that 36.7% of patients had at least one adverse event, but only 7.1% had at least one grade 3 or greater event.

Grade 3 or greater events were abdominal pain (nine patients), fatigue (six), nausea (three), radioembolization-induced liver disease (three), vomiting (two), and GI ulceration (one). Fifteen additional patients had other unspecified events.

The investigators acknowledged broad inclusion criteria, relatively high rates of loss to follow-up, and differences in national guidelines and local standards of practice as potential limitations to their findings.

In the question-and-answer following the presentation, session comoderator María Varela, MD, PhD, a pathologist in the liver unit at the Hospital Universitario Central de Asturia, Oviedo, Spain, questioned why about one-third of patients received TARE for downstaging, but only 13 underwent subsequent surgical resection.

“We don’t have a detailed analysis of this subgroup of patients who received curative intent as yet, ” Dr. Kolligs said.

Pierre Nahon, MD, from the University of Paris and Hôpital Jean Verdier in Bondy, France, commented that, among this heterogenous population, one of the best indications for TARE is probably localized HCC with adjacent portal vein thrombosis.

He asked whether the investigators had examined overall survival among patients with localized unilobar HCC with adjacent small portal vein thrombosis.

“We find that patients with portal vein occlusion have a worse prognosis in the total group,” Dr. Kolligs replied. “To look into the question whether partial thrombosis with a small tumor might benefit is an interesting question, and we should look into that, but I don’t have any data on that yet.”

Another audience member asked: “According to your data, which patients are the best candidates for radioembolization?”

“According to these data, the best candidates are of course patients with good liver function, ascites should ideally not be present, and what is probably is important is that we identify or include patients without extrahepatic disease,” he said.

The study was sponsored by CIRSE. Dr. Kolligs disclosed speaking activities and consulting for several companies. Dr. Varela disclosed speaking for several companies and advisory board activity for Bayer. Dr. Nahon disclosed honoraria and consulting fees from several companies.

Patients with hepatocellular carcinoma (HCC) can be offered transarterial radioembolization (TARE) as a safe and effective first-line treatment or adjunct to other locoregional therapies, authors of a large multicenter study reported.

Among 422 patients with HCC treated with TARE in eight European countries, the median overall survival was 16.5 months, with fewer than 10% of patients experiencing grade 3 or greater adverse events, reported Frank Kolligs, MD, from Helios Hospital Berlin-Buch.

“This exploratory study evaluated factors that can influence the application and outcome of transarterial radioembolization in clinical practice. TARE is generally applied according to guideline recommendations, and randomized, controlled trials are needed to confirm the effect of personalized dosimetry on the effectiveness of TARE,” he said in an oral abstract presented at the meeting sponsored by the European Association for the Study of the Liver.

Intriguingly, the investigators found evidence suggesting that patients whose treatments were planned using a partition model had better survival outcomes than those patients who treatments were based on calculated body surface area or measured BSA (mBSA), but this finding will need to be explored in more detail, Dr. Kolligs said.

The partition model incorporates variables such as tumor volume and liver volume, shunt fractions, the ratio of radiation uptake between tumor and normal tissues, vascular anatomy and other factors to estimate the optimal dose.
 

Study design

Dr. Kolligs and colleagues looked at prospective data from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Registry for SIR-Spheres Therapy to evaluate the real-world clinical application of TARE with yttrium Y-90 resin microspheres in Europe, clinical outcomes, safety, and quality of life.

They selected data from centers with a minimum of 10 cases performed in the previous 12 months and at least 40 total cases overall.

The patients included adults 18 years and older scheduled for treatment with Y-90 resin microspheres for primary or metastatic liver tumors, with no specific exclusion criteria. The patients were followed for at least 24 months at recommended intervals of every 3 months. The first patient was enrolled in January 2015, and the last follow-up visit was in December 2019. A total of 422 registry patients had a diagnosis of HCC and were included in the study.

The median age was 68 years (range, 60-74), 80.8% were male, 70.9% had cirrhosis, 14.5% had ascites, and 8.5% had extrahepatic disease. About 32% of patients had one tumor nodule, 33% had two to five nodules, and the remainder had either more than five or an uncountable number.

In all, 14% of patients had Barcelona Clinic Liver Cancer stage A disease, 51.4% had stage B, 33.6% had stage C, and 0.9% stage D.

About one-third of patients had portal vein occlusion. Tumors were in both left and right lobes in 35.5%, the left lobe alone in 12.1%, and the right lobe alone in 52.4%.

Half of all patients (50.2%) received TARE as first-line therapy, 44.8% had it following surgery (17.1%), ablation (14.7%), and/or transarterial chemoembolization (; 23%). In addition, 9.7% of patients received systemic therapy prior to TARE, primarily with sorafenib (Nexavar).

Treatment intent was palliative for 57.3% of patients, and tumor downsizing/downstaging in 32.5% (remainder unspecified).
 

Survival and prognostic factors

As noted before, median overall survival was 16.5 months. Median progression-free survival was 6.1 months, and median hepatic PFS was 6.7 months.

Factors prognostic for better overall survival included hepatitis B or C virus as the cirrhosis cause versus alcohol (hazard ratio for death, 0.51 for each; P = .0060 for HBV and P = .0007 for HCV); unilobar versus bilobar tumors (HR, 0.67; P = .0422 for left-lobe; HR 0.55; P < .0001 for right); prior surgery (HR, 0.67; P = .0258); prior ablation (HR, 0.65; P = .0394); and curative versus palliative intent (HR, 0.53; P < .0001).

Factors associated with worse overall survival were presence of ascites (HR 1.75, P = .001); presence of extrahepatic disease before TARE (HR, 1.81, P = .0037); tumor burden greater than 5 nodules (HR, 1.67; P = .0073); main portal vein occlusion (HR, 2.14; P = .0064); lobar portal vein occlusion (HR, 1.77; P = .0083); total bilirubin greater than 1.5 mg/dL (HR, 1.69; P = .0094); albumin-bilirubin grade A2 (HR, 1.66; P = .0005); ALB1 grade A3 (HR, 3.92; P < .0001); and BSA/mBSA versus partition-model dosimetry (HR, 1.89; P < .0001).

The safety analysis showed that 36.7% of patients had at least one adverse event, but only 7.1% had at least one grade 3 or greater event.

Grade 3 or greater events were abdominal pain (nine patients), fatigue (six), nausea (three), radioembolization-induced liver disease (three), vomiting (two), and GI ulceration (one). Fifteen additional patients had other unspecified events.

The investigators acknowledged broad inclusion criteria, relatively high rates of loss to follow-up, and differences in national guidelines and local standards of practice as potential limitations to their findings.

In the question-and-answer following the presentation, session comoderator María Varela, MD, PhD, a pathologist in the liver unit at the Hospital Universitario Central de Asturia, Oviedo, Spain, questioned why about one-third of patients received TARE for downstaging, but only 13 underwent subsequent surgical resection.

“We don’t have a detailed analysis of this subgroup of patients who received curative intent as yet, ” Dr. Kolligs said.

Pierre Nahon, MD, from the University of Paris and Hôpital Jean Verdier in Bondy, France, commented that, among this heterogenous population, one of the best indications for TARE is probably localized HCC with adjacent portal vein thrombosis.

He asked whether the investigators had examined overall survival among patients with localized unilobar HCC with adjacent small portal vein thrombosis.

“We find that patients with portal vein occlusion have a worse prognosis in the total group,” Dr. Kolligs replied. “To look into the question whether partial thrombosis with a small tumor might benefit is an interesting question, and we should look into that, but I don’t have any data on that yet.”

Another audience member asked: “According to your data, which patients are the best candidates for radioembolization?”

“According to these data, the best candidates are of course patients with good liver function, ascites should ideally not be present, and what is probably is important is that we identify or include patients without extrahepatic disease,” he said.

The study was sponsored by CIRSE. Dr. Kolligs disclosed speaking activities and consulting for several companies. Dr. Varela disclosed speaking for several companies and advisory board activity for Bayer. Dr. Nahon disclosed honoraria and consulting fees from several companies.

Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.

In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.

“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.

The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.

A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.

“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.

“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.

Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
 

Managing asymptomatic patients

Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.

This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.

They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.

The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).

The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
 

Findings and outcomes

During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.

There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.

Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.

Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.

The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.

Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.

Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”

Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.

The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.

Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.

In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.

“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.

The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.

A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.

“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.

“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.

Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
 

Managing asymptomatic patients

Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.

This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.

They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.

The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).

The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
 

Findings and outcomes

During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.

There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.

Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.

Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.

The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.

Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.

Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”

Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.

The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.

Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.

In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.

“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.

The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.

A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.

“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.

“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.

Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
 

Managing asymptomatic patients

Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.

This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.

They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.

The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).

The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
 

Findings and outcomes

During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.

There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.

Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.

Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.

The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.

Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.

Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”

Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.

The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.

Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.

In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.

“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.

The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
 

Is it safe?

Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.

Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.

The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).

They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.

The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.

The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
 

Immune-related proteins

The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.

A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.

The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.

The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.

Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.

Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.

“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
 

Timing of expression patterns

During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”

“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”

Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.

The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.

Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.

In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.

“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.

The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
 

Is it safe?

Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.

Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.

The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).

They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.

The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.

The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
 

Immune-related proteins

The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.

A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.

The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.

The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.

Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.

Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.

“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
 

Timing of expression patterns

During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”

“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”

Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.

The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.

Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.

In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.

“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.

The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
 

Is it safe?

Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.

Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.

The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).

They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.

The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.

The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
 

Immune-related proteins

The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.

A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.

The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.

The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.

Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.

Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.

“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
 

Timing of expression patterns

During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”

“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”

Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.

The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.

A proposed rapid diagnostic test for hepatitis C viral infections that combines an inexpensive but lower-sensitivity core-antigen test with lab RNA confirmation of negative tests could expand testing and same-day initiation of antiviral therapy in places where resources are limited, investigators said.

Applying the proposed method to the Republic of Georgia, with a hepatitis C virus (HCV) prevalence of 5.4% as reported by the World Health Organization, would result in a 95.4% diagnosis rate, compared with 78.8% for lab-based RNA testing, which is the standard of care. Applied to Malaysia, the proposed method would boost diagnosis rates from 57.0% to 91.2%, reported Madeline Adee, MPH, from Massachusetts General Hospital’s Institute for Technology Assessment in Boston and colleagues.

“We found that a novel core antigen rapid diagnostic test for HCV could improve the diagnosis rate and result in cost savings. Although not yet developed, such a test could be a game changer and have a substantial impact on the feasibility and cost of HCV elimination, especially in low and middle-income countries,” they wrote in a poster presented at the meeting sponsored by the European Association for the Study of the Liver.

Although rapid diagnostic tests for HCV can improve diagnosis and treatment rates, currently available molecular tests are expensive and require a solid clinical laboratory infrastructure, which can put such tests out of the reach for clinicians in low- or middle-income countries. Rapid immunoassays based on HCV core antigens are comparative bargains, but their sensitivity ranges from 70% to 90%; in contrast, the third-generation HCV enzyme immunoassay has about a 98% sensitivity.
 

Could it work?

The proposed testing method would be likely to improve diagnosis, but whether that would translate into increased treatment is uncertain, commented Lesley Miller, MD, who specializes in HCV screening and treatment in underserved populations at Emory University, Atlanta.

“When we’re talking about hepatitis C, it’s all about the care cascade, the drop-off at each step from those who have the disease and aren’t diagnosed, to those who are tested and only partially diagnosed because they don’t have a confirmed infection, to those that get into care, get treated, and get cured,” she said in an interview.

“It’s all about closing the gaps in the care cascade in order to achieve elimination of the virus, which is what we’re all trying to do,” she added.

She pointed that there are certain at-risk populations in the United States, such as injectable-drug users, who might be able to benefit from such a system.

“These folks often have less access to traditional care, so bringing rapid testing and care to where those folks are is really important, so if we can deploy mobile units to areas where there is high prevalence and do it at the point of care, it simplifies the entire process,” she said.

Thomas J. Hoerger, PhD, a senior fellow in health economics and financing at the nonprofit research group RTI International in Research Triangle Park, N.C., said in an interview that the proposed model could eliminate the step in testing in which patients are required to return for confirmation.

“People don’t always come back for further testing, so if you can do it immediately and have the results of a screening test, you might be able to get people to come back more quickly. You still have the problem of the high cost of treatment, but this would at least make it a little more convenient,” he said.

He noted that the success of the strategy would be dependent on the sensitivity of the rapid core antigen test, it’s cost relative to HCV RNA testing, and whether the availability of the rapid test would translate into an improvement in follow-up.

Neither Dr. Miller nor Dr. Hoerger were involved in the study.
 

Evaluating the approach

To determine whether a lower-cost rapid test could be cost effective, the researchers created a microsimulation model of the natural history of HCV to compare potential outcomes from either core antigen rapid diagnostic testing with a base case sensitivity for HCV viremia of 80% with lab-based RNA confirmation for negative results or the current standard of care with lab-based RNA confirmation only.

The model incorporated METAVIR stage F0-F4, decompensated cirrhosis, hepatocellular carcinoma, and liver-related death. The investigators determined the baseline characteristics of HCV patients in each country based on different distributions of sex, HCV genotype, and METAVIR fibrosis stage.

They simulated outcomes for 10,000 adults in the Republic of Georgia, with an HCV prevalence of 5.4%, and Malaysia, with an HCV prevalence of 1.5%.

The model considers costs from a health care payer’s perspective, and the investigations performed deterministic and probabilistic sensitivity analyses to evaluate how the cost-effectiveness of testing pathways might change when various factors were plugged into the model.

As noted before, the investigators determined that the core antigen rapid test algorithm would improve diagnosis rates in Georgia from 78.8% to 95.4% and in Malaysia from 57.9% to 91.2%.

The use of the rapid test would also increase quality-adjusted life-years in Georgia by 207 per 10,000 and in Malaysia by 146 per 10,000.

Cost savings, primarily from averting the costs of care for patients with HCV, begin within the first year of the model. Over 50 years, the lifetime horizon cost savings in Georgia would be $232,000 per 10,000 people, and the corresponding savings in Malaysia would be $504,000 per 10,000 people.

Even when allowing for variations in parameters, the core antigen rapid diagnostic test approach remained the preferred model, the investigators reported.

The study was supported by the global health agency Unitaid. The researchers, Dr. Miller, and Dr. Hoerger reported no conflicts of interest relevant to the study.

A proposed rapid diagnostic test for hepatitis C viral infections that combines an inexpensive but lower-sensitivity core-antigen test with lab RNA confirmation of negative tests could expand testing and same-day initiation of antiviral therapy in places where resources are limited, investigators said.

Applying the proposed method to the Republic of Georgia, with a hepatitis C virus (HCV) prevalence of 5.4% as reported by the World Health Organization, would result in a 95.4% diagnosis rate, compared with 78.8% for lab-based RNA testing, which is the standard of care. Applied to Malaysia, the proposed method would boost diagnosis rates from 57.0% to 91.2%, reported Madeline Adee, MPH, from Massachusetts General Hospital’s Institute for Technology Assessment in Boston and colleagues.

“We found that a novel core antigen rapid diagnostic test for HCV could improve the diagnosis rate and result in cost savings. Although not yet developed, such a test could be a game changer and have a substantial impact on the feasibility and cost of HCV elimination, especially in low and middle-income countries,” they wrote in a poster presented at the meeting sponsored by the European Association for the Study of the Liver.

Although rapid diagnostic tests for HCV can improve diagnosis and treatment rates, currently available molecular tests are expensive and require a solid clinical laboratory infrastructure, which can put such tests out of the reach for clinicians in low- or middle-income countries. Rapid immunoassays based on HCV core antigens are comparative bargains, but their sensitivity ranges from 70% to 90%; in contrast, the third-generation HCV enzyme immunoassay has about a 98% sensitivity.
 

Could it work?

The proposed testing method would be likely to improve diagnosis, but whether that would translate into increased treatment is uncertain, commented Lesley Miller, MD, who specializes in HCV screening and treatment in underserved populations at Emory University, Atlanta.

“When we’re talking about hepatitis C, it’s all about the care cascade, the drop-off at each step from those who have the disease and aren’t diagnosed, to those who are tested and only partially diagnosed because they don’t have a confirmed infection, to those that get into care, get treated, and get cured,” she said in an interview.

“It’s all about closing the gaps in the care cascade in order to achieve elimination of the virus, which is what we’re all trying to do,” she added.

She pointed that there are certain at-risk populations in the United States, such as injectable-drug users, who might be able to benefit from such a system.

“These folks often have less access to traditional care, so bringing rapid testing and care to where those folks are is really important, so if we can deploy mobile units to areas where there is high prevalence and do it at the point of care, it simplifies the entire process,” she said.

Thomas J. Hoerger, PhD, a senior fellow in health economics and financing at the nonprofit research group RTI International in Research Triangle Park, N.C., said in an interview that the proposed model could eliminate the step in testing in which patients are required to return for confirmation.

“People don’t always come back for further testing, so if you can do it immediately and have the results of a screening test, you might be able to get people to come back more quickly. You still have the problem of the high cost of treatment, but this would at least make it a little more convenient,” he said.

He noted that the success of the strategy would be dependent on the sensitivity of the rapid core antigen test, it’s cost relative to HCV RNA testing, and whether the availability of the rapid test would translate into an improvement in follow-up.

Neither Dr. Miller nor Dr. Hoerger were involved in the study.
 

Evaluating the approach

To determine whether a lower-cost rapid test could be cost effective, the researchers created a microsimulation model of the natural history of HCV to compare potential outcomes from either core antigen rapid diagnostic testing with a base case sensitivity for HCV viremia of 80% with lab-based RNA confirmation for negative results or the current standard of care with lab-based RNA confirmation only.

The model incorporated METAVIR stage F0-F4, decompensated cirrhosis, hepatocellular carcinoma, and liver-related death. The investigators determined the baseline characteristics of HCV patients in each country based on different distributions of sex, HCV genotype, and METAVIR fibrosis stage.

They simulated outcomes for 10,000 adults in the Republic of Georgia, with an HCV prevalence of 5.4%, and Malaysia, with an HCV prevalence of 1.5%.

The model considers costs from a health care payer’s perspective, and the investigations performed deterministic and probabilistic sensitivity analyses to evaluate how the cost-effectiveness of testing pathways might change when various factors were plugged into the model.

As noted before, the investigators determined that the core antigen rapid test algorithm would improve diagnosis rates in Georgia from 78.8% to 95.4% and in Malaysia from 57.9% to 91.2%.

The use of the rapid test would also increase quality-adjusted life-years in Georgia by 207 per 10,000 and in Malaysia by 146 per 10,000.

Cost savings, primarily from averting the costs of care for patients with HCV, begin within the first year of the model. Over 50 years, the lifetime horizon cost savings in Georgia would be $232,000 per 10,000 people, and the corresponding savings in Malaysia would be $504,000 per 10,000 people.

Even when allowing for variations in parameters, the core antigen rapid diagnostic test approach remained the preferred model, the investigators reported.

The study was supported by the global health agency Unitaid. The researchers, Dr. Miller, and Dr. Hoerger reported no conflicts of interest relevant to the study.

A proposed rapid diagnostic test for hepatitis C viral infections that combines an inexpensive but lower-sensitivity core-antigen test with lab RNA confirmation of negative tests could expand testing and same-day initiation of antiviral therapy in places where resources are limited, investigators said.

Applying the proposed method to the Republic of Georgia, with a hepatitis C virus (HCV) prevalence of 5.4% as reported by the World Health Organization, would result in a 95.4% diagnosis rate, compared with 78.8% for lab-based RNA testing, which is the standard of care. Applied to Malaysia, the proposed method would boost diagnosis rates from 57.0% to 91.2%, reported Madeline Adee, MPH, from Massachusetts General Hospital’s Institute for Technology Assessment in Boston and colleagues.

“We found that a novel core antigen rapid diagnostic test for HCV could improve the diagnosis rate and result in cost savings. Although not yet developed, such a test could be a game changer and have a substantial impact on the feasibility and cost of HCV elimination, especially in low and middle-income countries,” they wrote in a poster presented at the meeting sponsored by the European Association for the Study of the Liver.

Although rapid diagnostic tests for HCV can improve diagnosis and treatment rates, currently available molecular tests are expensive and require a solid clinical laboratory infrastructure, which can put such tests out of the reach for clinicians in low- or middle-income countries. Rapid immunoassays based on HCV core antigens are comparative bargains, but their sensitivity ranges from 70% to 90%; in contrast, the third-generation HCV enzyme immunoassay has about a 98% sensitivity.
 

Could it work?

The proposed testing method would be likely to improve diagnosis, but whether that would translate into increased treatment is uncertain, commented Lesley Miller, MD, who specializes in HCV screening and treatment in underserved populations at Emory University, Atlanta.

“When we’re talking about hepatitis C, it’s all about the care cascade, the drop-off at each step from those who have the disease and aren’t diagnosed, to those who are tested and only partially diagnosed because they don’t have a confirmed infection, to those that get into care, get treated, and get cured,” she said in an interview.

“It’s all about closing the gaps in the care cascade in order to achieve elimination of the virus, which is what we’re all trying to do,” she added.

She pointed that there are certain at-risk populations in the United States, such as injectable-drug users, who might be able to benefit from such a system.

“These folks often have less access to traditional care, so bringing rapid testing and care to where those folks are is really important, so if we can deploy mobile units to areas where there is high prevalence and do it at the point of care, it simplifies the entire process,” she said.

Thomas J. Hoerger, PhD, a senior fellow in health economics and financing at the nonprofit research group RTI International in Research Triangle Park, N.C., said in an interview that the proposed model could eliminate the step in testing in which patients are required to return for confirmation.

“People don’t always come back for further testing, so if you can do it immediately and have the results of a screening test, you might be able to get people to come back more quickly. You still have the problem of the high cost of treatment, but this would at least make it a little more convenient,” he said.

He noted that the success of the strategy would be dependent on the sensitivity of the rapid core antigen test, it’s cost relative to HCV RNA testing, and whether the availability of the rapid test would translate into an improvement in follow-up.

Neither Dr. Miller nor Dr. Hoerger were involved in the study.
 

Evaluating the approach

To determine whether a lower-cost rapid test could be cost effective, the researchers created a microsimulation model of the natural history of HCV to compare potential outcomes from either core antigen rapid diagnostic testing with a base case sensitivity for HCV viremia of 80% with lab-based RNA confirmation for negative results or the current standard of care with lab-based RNA confirmation only.

The model incorporated METAVIR stage F0-F4, decompensated cirrhosis, hepatocellular carcinoma, and liver-related death. The investigators determined the baseline characteristics of HCV patients in each country based on different distributions of sex, HCV genotype, and METAVIR fibrosis stage.

They simulated outcomes for 10,000 adults in the Republic of Georgia, with an HCV prevalence of 5.4%, and Malaysia, with an HCV prevalence of 1.5%.

The model considers costs from a health care payer’s perspective, and the investigations performed deterministic and probabilistic sensitivity analyses to evaluate how the cost-effectiveness of testing pathways might change when various factors were plugged into the model.

As noted before, the investigators determined that the core antigen rapid test algorithm would improve diagnosis rates in Georgia from 78.8% to 95.4% and in Malaysia from 57.9% to 91.2%.

The use of the rapid test would also increase quality-adjusted life-years in Georgia by 207 per 10,000 and in Malaysia by 146 per 10,000.

Cost savings, primarily from averting the costs of care for patients with HCV, begin within the first year of the model. Over 50 years, the lifetime horizon cost savings in Georgia would be $232,000 per 10,000 people, and the corresponding savings in Malaysia would be $504,000 per 10,000 people.

Even when allowing for variations in parameters, the core antigen rapid diagnostic test approach remained the preferred model, the investigators reported.

The study was supported by the global health agency Unitaid. The researchers, Dr. Miller, and Dr. Hoerger reported no conflicts of interest relevant to the study.

An investigational liver dialysis device (DIALIVE) was associated with significantly greater survival of patients with acute-on-chronic liver failure (ACLF), compared with the standard of care in a multicenter randomized study.

Among 30 evaluable patients with ACLF from alcoholic cirrhosis randomized to treatment with the DIALIVE system or standard of care, two-thirds of patients assigned to DIALIVE had both survived and experienced resolution of ACLF by 28 days, compared with one-third of patients assigned to standard of care, reported Banwari Agarwal, MBBS, MD from the Royal Free Hospital in London at the meeting sponsored by the European Association for the Study of the Liver.
 

Different from MARS

The DIALIVE system differs from the Molecular Adsorbent Recirculating System (MARS) liver dialysis system in that DIALIVE removes and replaces albumin, including proinflammatory albumin, rather than filtering and recirculating it, he explained.

“It addresses systemic inflammation, which wasn’t quite the case with MARS,” he said in the question-and-answer portion of his presentation in a general session.

In patients with ACLF, the risk of 28-day mortality increases substantially as the grade of ACLF increases.

“ACLF, however, is potentially reversible, and the initial grade at presentation undergoes changes over time during the natural course of the illness, with some patients deteriorating, some improving, and some even achieving complete ACLF resolution. The final grade is reached by days 3-7, and it is this final grade which determines their future outcome trajectory. I therefore propose that ACLF resolution in itself is an important therapeutic target,” he said.
 

Study details

Dr. Agarwal and coinvestigators from eight centers in six European countries enrolled patients with a history indicative of alcohol-related cirrhosis, at least one acute decompensation event, and progression to ACLF grades 1, 2, or 3a.

Patients with an international normalized ratio above 3 were excluded, as were those with more than three organ failures, uncontrolled infections, patients with primary respiratory organ failure, and those with hemodynamic instability refractory to volume resuscitation and low-dose vasopressors.

A total of 32 patients, of whom 30 were evaluable, were randomized to receive liver dialysis in three to five DIALIVE sessions lasting 8-12 hours each (15 evaluable patients) or to standard of care at participating institutions (15 patients).

The investigators looked at safety of the device (the primary endpoint) in all patients who received at least one DIALIVE treatment (safety population), and a modified safety population of patients who received at least three DIALIVE treatments.

The median patient age in each arm was 49 years, and all patients had alcoholic cirrhosis, with alcoholic hepatitis accounting for at least one decompensation event. In addition, about 25% of patients in each arm had decompensation with infections and/or sepsis as precipitating factors.
 

Safety

Serious adverse events on days 1-10 occurred in 11 of 17 patients in the DIALIVE arm, and in 8 in the standard-of-care arm. In the DIALIVE arm, there were seven treatment-related serious device events, three unexpected serious device events (anemia, septic shock, and hypotension), and one patient discontinued dialysis after having unsafe levels of thrombocytopenia.

Four patients in the DIALIVE arm died on study. The first two died on day 1 one from hypotension, coagulopathy, and multiorgan failure, and this prompted a change in the protocol mandating that DIALIVE be conducted only in an ICU setting with more invasive monitoring and more frequent lab analysis of clotting and other biochemical parameters. Of the two other patients in the DIALIVE arm who on died on study, one died from non-MI cardiac arrest on day 8, and one patient with ACLF grade 3 and a European Foundation for the study of chronic liver failure (CLIF)–ACLF score of 68 died from multiorgan failure.

“I must emphasize that even this very sick patient tolerated the device very, very well,” Dr. Agarwal said.

In the standard-of-care arm, two patients died from progressive liver failure on days 17 and 27, respectively, and one died on day 17 from bacterial infections, bleeding, and progressive liver failure.

There were eight instances of filters clotting out of 64 filters used in total, and four episodes of device deficiency, including two instances where tubing could not be disconnected from an Oxiris filter during setup of the DIALIVE circuit, requiring use of new DIALIVE kits; one use of an incorrect dialysis fluid; and one incorrect setup of the DIALIVE circuit.
 

Significant improvements in many scores

In the DIALIVE group, there were significant improvements over baseline at day 10 in both liver scores (P < .05) and brain scores (P < .001). In contrast, in the standard-of-care group there were no improvements in individual organ scores, and respiration scores were significantly worse (P < .01).

DIALIVE was also associated with significant improvements in CLIF-C organ failure scores, compared with standard of care at day 5 and day 10 (P = .021 and .001, respectively); CLIF-C–ACLF scores at days 5 and 10 (P = .045 and .023); and Model for End-Stage Liver Disease scores at day 5 (P = .028).

In the DIALIVE group, ­40% of patients had ACLF resolution by day 5, and 66.7% had resolution by day 10. In the standard-of-care arm, 15% had resolution on day 5, and 33.3% had resolution on day 10. DIALIVE was also associated with a significantly faster median time to resolution, compared with standard of care (10 days vs. not reached; P = .0307). At 28 days, 10 of 15 evaluable patients were alive and had resolution of ACLF with DIALIVE versus 5 of 15 with standard of care (P = .0281).

Dr. Agarwal said that the data justify the implementation of late-phase clinical trials of the liver dialysis device.
 

‘Hopeful’ findings

“It’s very early, but we’re really desperate in finding something to bridge to transplantation,” commented Tobias Boettler, MD, from the University of Freiburg (Germany), who was not involved in the study.

“I think this is very hopeful,” said Dr. Boettler, who moderated the briefing where Dr. Agarwal summarized the study findings.

In the question and answer following the talk in a general session, moderator Philip N. Newsome, MD, from University Hospitals Birmingham (England) asked whether patients who were not treated should have been included in the analysis.

Dr. Agarwal replied that “the whole idea behind this study was to understand what this device does to these patients, and how these patients react to this device, so really not looking at the efficacy.”

The study was supported by the European Union’s Horizon 2020 initiative. Dr. Agarwal received a study grant from the initiative, but had no other relevant disclosures. Dr. Boettler and Dr. Newsome had no disclosures relevant to the study.

An investigational liver dialysis device (DIALIVE) was associated with significantly greater survival of patients with acute-on-chronic liver failure (ACLF), compared with the standard of care in a multicenter randomized study.

Among 30 evaluable patients with ACLF from alcoholic cirrhosis randomized to treatment with the DIALIVE system or standard of care, two-thirds of patients assigned to DIALIVE had both survived and experienced resolution of ACLF by 28 days, compared with one-third of patients assigned to standard of care, reported Banwari Agarwal, MBBS, MD from the Royal Free Hospital in London at the meeting sponsored by the European Association for the Study of the Liver.
 

Different from MARS

The DIALIVE system differs from the Molecular Adsorbent Recirculating System (MARS) liver dialysis system in that DIALIVE removes and replaces albumin, including proinflammatory albumin, rather than filtering and recirculating it, he explained.

“It addresses systemic inflammation, which wasn’t quite the case with MARS,” he said in the question-and-answer portion of his presentation in a general session.

In patients with ACLF, the risk of 28-day mortality increases substantially as the grade of ACLF increases.

“ACLF, however, is potentially reversible, and the initial grade at presentation undergoes changes over time during the natural course of the illness, with some patients deteriorating, some improving, and some even achieving complete ACLF resolution. The final grade is reached by days 3-7, and it is this final grade which determines their future outcome trajectory. I therefore propose that ACLF resolution in itself is an important therapeutic target,” he said.
 

Study details

Dr. Agarwal and coinvestigators from eight centers in six European countries enrolled patients with a history indicative of alcohol-related cirrhosis, at least one acute decompensation event, and progression to ACLF grades 1, 2, or 3a.

Patients with an international normalized ratio above 3 were excluded, as were those with more than three organ failures, uncontrolled infections, patients with primary respiratory organ failure, and those with hemodynamic instability refractory to volume resuscitation and low-dose vasopressors.

A total of 32 patients, of whom 30 were evaluable, were randomized to receive liver dialysis in three to five DIALIVE sessions lasting 8-12 hours each (15 evaluable patients) or to standard of care at participating institutions (15 patients).

The investigators looked at safety of the device (the primary endpoint) in all patients who received at least one DIALIVE treatment (safety population), and a modified safety population of patients who received at least three DIALIVE treatments.

The median patient age in each arm was 49 years, and all patients had alcoholic cirrhosis, with alcoholic hepatitis accounting for at least one decompensation event. In addition, about 25% of patients in each arm had decompensation with infections and/or sepsis as precipitating factors.
 

Safety

Serious adverse events on days 1-10 occurred in 11 of 17 patients in the DIALIVE arm, and in 8 in the standard-of-care arm. In the DIALIVE arm, there were seven treatment-related serious device events, three unexpected serious device events (anemia, septic shock, and hypotension), and one patient discontinued dialysis after having unsafe levels of thrombocytopenia.

Four patients in the DIALIVE arm died on study. The first two died on day 1 one from hypotension, coagulopathy, and multiorgan failure, and this prompted a change in the protocol mandating that DIALIVE be conducted only in an ICU setting with more invasive monitoring and more frequent lab analysis of clotting and other biochemical parameters. Of the two other patients in the DIALIVE arm who on died on study, one died from non-MI cardiac arrest on day 8, and one patient with ACLF grade 3 and a European Foundation for the study of chronic liver failure (CLIF)–ACLF score of 68 died from multiorgan failure.

“I must emphasize that even this very sick patient tolerated the device very, very well,” Dr. Agarwal said.

In the standard-of-care arm, two patients died from progressive liver failure on days 17 and 27, respectively, and one died on day 17 from bacterial infections, bleeding, and progressive liver failure.

There were eight instances of filters clotting out of 64 filters used in total, and four episodes of device deficiency, including two instances where tubing could not be disconnected from an Oxiris filter during setup of the DIALIVE circuit, requiring use of new DIALIVE kits; one use of an incorrect dialysis fluid; and one incorrect setup of the DIALIVE circuit.
 

Significant improvements in many scores

In the DIALIVE group, there were significant improvements over baseline at day 10 in both liver scores (P < .05) and brain scores (P < .001). In contrast, in the standard-of-care group there were no improvements in individual organ scores, and respiration scores were significantly worse (P < .01).

DIALIVE was also associated with significant improvements in CLIF-C organ failure scores, compared with standard of care at day 5 and day 10 (P = .021 and .001, respectively); CLIF-C–ACLF scores at days 5 and 10 (P = .045 and .023); and Model for End-Stage Liver Disease scores at day 5 (P = .028).

In the DIALIVE group, ­40% of patients had ACLF resolution by day 5, and 66.7% had resolution by day 10. In the standard-of-care arm, 15% had resolution on day 5, and 33.3% had resolution on day 10. DIALIVE was also associated with a significantly faster median time to resolution, compared with standard of care (10 days vs. not reached; P = .0307). At 28 days, 10 of 15 evaluable patients were alive and had resolution of ACLF with DIALIVE versus 5 of 15 with standard of care (P = .0281).

Dr. Agarwal said that the data justify the implementation of late-phase clinical trials of the liver dialysis device.
 

‘Hopeful’ findings

“It’s very early, but we’re really desperate in finding something to bridge to transplantation,” commented Tobias Boettler, MD, from the University of Freiburg (Germany), who was not involved in the study.

“I think this is very hopeful,” said Dr. Boettler, who moderated the briefing where Dr. Agarwal summarized the study findings.

In the question and answer following the talk in a general session, moderator Philip N. Newsome, MD, from University Hospitals Birmingham (England) asked whether patients who were not treated should have been included in the analysis.

Dr. Agarwal replied that “the whole idea behind this study was to understand what this device does to these patients, and how these patients react to this device, so really not looking at the efficacy.”

The study was supported by the European Union’s Horizon 2020 initiative. Dr. Agarwal received a study grant from the initiative, but had no other relevant disclosures. Dr. Boettler and Dr. Newsome had no disclosures relevant to the study.

An investigational liver dialysis device (DIALIVE) was associated with significantly greater survival of patients with acute-on-chronic liver failure (ACLF), compared with the standard of care in a multicenter randomized study.

Among 30 evaluable patients with ACLF from alcoholic cirrhosis randomized to treatment with the DIALIVE system or standard of care, two-thirds of patients assigned to DIALIVE had both survived and experienced resolution of ACLF by 28 days, compared with one-third of patients assigned to standard of care, reported Banwari Agarwal, MBBS, MD from the Royal Free Hospital in London at the meeting sponsored by the European Association for the Study of the Liver.
 

Different from MARS

The DIALIVE system differs from the Molecular Adsorbent Recirculating System (MARS) liver dialysis system in that DIALIVE removes and replaces albumin, including proinflammatory albumin, rather than filtering and recirculating it, he explained.

“It addresses systemic inflammation, which wasn’t quite the case with MARS,” he said in the question-and-answer portion of his presentation in a general session.

In patients with ACLF, the risk of 28-day mortality increases substantially as the grade of ACLF increases.

“ACLF, however, is potentially reversible, and the initial grade at presentation undergoes changes over time during the natural course of the illness, with some patients deteriorating, some improving, and some even achieving complete ACLF resolution. The final grade is reached by days 3-7, and it is this final grade which determines their future outcome trajectory. I therefore propose that ACLF resolution in itself is an important therapeutic target,” he said.
 

Study details

Dr. Agarwal and coinvestigators from eight centers in six European countries enrolled patients with a history indicative of alcohol-related cirrhosis, at least one acute decompensation event, and progression to ACLF grades 1, 2, or 3a.

Patients with an international normalized ratio above 3 were excluded, as were those with more than three organ failures, uncontrolled infections, patients with primary respiratory organ failure, and those with hemodynamic instability refractory to volume resuscitation and low-dose vasopressors.

A total of 32 patients, of whom 30 were evaluable, were randomized to receive liver dialysis in three to five DIALIVE sessions lasting 8-12 hours each (15 evaluable patients) or to standard of care at participating institutions (15 patients).

The investigators looked at safety of the device (the primary endpoint) in all patients who received at least one DIALIVE treatment (safety population), and a modified safety population of patients who received at least three DIALIVE treatments.

The median patient age in each arm was 49 years, and all patients had alcoholic cirrhosis, with alcoholic hepatitis accounting for at least one decompensation event. In addition, about 25% of patients in each arm had decompensation with infections and/or sepsis as precipitating factors.
 

Safety

Serious adverse events on days 1-10 occurred in 11 of 17 patients in the DIALIVE arm, and in 8 in the standard-of-care arm. In the DIALIVE arm, there were seven treatment-related serious device events, three unexpected serious device events (anemia, septic shock, and hypotension), and one patient discontinued dialysis after having unsafe levels of thrombocytopenia.

Four patients in the DIALIVE arm died on study. The first two died on day 1 one from hypotension, coagulopathy, and multiorgan failure, and this prompted a change in the protocol mandating that DIALIVE be conducted only in an ICU setting with more invasive monitoring and more frequent lab analysis of clotting and other biochemical parameters. Of the two other patients in the DIALIVE arm who on died on study, one died from non-MI cardiac arrest on day 8, and one patient with ACLF grade 3 and a European Foundation for the study of chronic liver failure (CLIF)–ACLF score of 68 died from multiorgan failure.

“I must emphasize that even this very sick patient tolerated the device very, very well,” Dr. Agarwal said.

In the standard-of-care arm, two patients died from progressive liver failure on days 17 and 27, respectively, and one died on day 17 from bacterial infections, bleeding, and progressive liver failure.

There were eight instances of filters clotting out of 64 filters used in total, and four episodes of device deficiency, including two instances where tubing could not be disconnected from an Oxiris filter during setup of the DIALIVE circuit, requiring use of new DIALIVE kits; one use of an incorrect dialysis fluid; and one incorrect setup of the DIALIVE circuit.
 

Significant improvements in many scores

In the DIALIVE group, there were significant improvements over baseline at day 10 in both liver scores (P < .05) and brain scores (P < .001). In contrast, in the standard-of-care group there were no improvements in individual organ scores, and respiration scores were significantly worse (P < .01).

DIALIVE was also associated with significant improvements in CLIF-C organ failure scores, compared with standard of care at day 5 and day 10 (P = .021 and .001, respectively); CLIF-C–ACLF scores at days 5 and 10 (P = .045 and .023); and Model for End-Stage Liver Disease scores at day 5 (P = .028).

In the DIALIVE group, ­40% of patients had ACLF resolution by day 5, and 66.7% had resolution by day 10. In the standard-of-care arm, 15% had resolution on day 5, and 33.3% had resolution on day 10. DIALIVE was also associated with a significantly faster median time to resolution, compared with standard of care (10 days vs. not reached; P = .0307). At 28 days, 10 of 15 evaluable patients were alive and had resolution of ACLF with DIALIVE versus 5 of 15 with standard of care (P = .0281).

Dr. Agarwal said that the data justify the implementation of late-phase clinical trials of the liver dialysis device.
 

‘Hopeful’ findings

“It’s very early, but we’re really desperate in finding something to bridge to transplantation,” commented Tobias Boettler, MD, from the University of Freiburg (Germany), who was not involved in the study.

“I think this is very hopeful,” said Dr. Boettler, who moderated the briefing where Dr. Agarwal summarized the study findings.

In the question and answer following the talk in a general session, moderator Philip N. Newsome, MD, from University Hospitals Birmingham (England) asked whether patients who were not treated should have been included in the analysis.

Dr. Agarwal replied that “the whole idea behind this study was to understand what this device does to these patients, and how these patients react to this device, so really not looking at the efficacy.”

The study was supported by the European Union’s Horizon 2020 initiative. Dr. Agarwal received a study grant from the initiative, but had no other relevant disclosures. Dr. Boettler and Dr. Newsome had no disclosures relevant to the study.

Autoimmune hepatitis that recurs following a liver transplant can impair both graft survival and overall survival, results of a large international study showed.

Among 736 patients with autoimmune hepatitis who underwent liver transplant and were followed for up to 20 years, those who had recurrent AIH had a more than 10-fold higher risk for graft failure and a more than twofold higher risk of death, compared with patients who did not have recurrences, reported Aldo J. Montano-Loza, MD, MSc, PhD, from the University of Alberta, Edmonton.

“Recurrent disease impacts graft and overall survival, highlighting the need for improved management strategies,” he said in an oral abstract presentation during the International Liver Congress sponsored by the European Association for the Study of the Liver.

AIH is characterized by the presence of high IgG levels, autoantibodies, and histologic evidence of interface hepatitis. Most patients with AIH respond to immunosuppressive therapy, but some have progression to end-stage liver disease; for these patients, a liver transplant can be lifesaving, with 1-year survival of approximately 90%, and 5-year survival of about 70%, he said.

AIH frequently recurs after transplant, and although previous studies have suggested that recurrent disease does not adversely affect either graft survival or long-term survival, those studies had limited patient numbers and inadequate follow-up, Dr. Montano-Loza said.

He cited two recent studies, one from UNOS, the United Network for Organ Sharing, and the other from ELTR, the European Liver Transplant Registry, that showed that overall survival after liver transplant was worse for patients with AIH, compared with those who underwent transplant for other autoimmune liver diseases.
 

Multicenter retrospective study

To get a better picture of long-term posttransplant outcomes in patients with AIH, investigators in 33 centers in North and South America, Europe, and Asia conducted a retrospective cohort study. Their goal was to establish the frequency of recurrent AIH, identify clinical factors and biomarkers for higher risk of recurrence, and evaluate the association between recurrent AIH and both patient and graft survival.

They accomplished this by performing chart reviews, including data on demographics, IgG levels before transplant, and Model for End-Stage Liver Disease scores.

They also collected data on serum liver function tests within the first year after transplant, posttransplant infections, rejection episodes, and immunosuppressive regimens, as well as variables such as donor age and sex, sex mismatch between donor and recipients, calendar year of transplant, and transplant volume for AIH at each center.

Of the 736 patients, 563 (76%) were female. The mean age at AIH diagnosis was 34 years, and the mean age at transplant was 42 years. About one-fifth of patients (21%) had concomitant autoimmune diseases.

Posttransplant immunosuppression regimens included the usual suspects: tacrolimus in 78% of patients, cyclosporine in 11%, prednisone in 76%, mycophenolate mofetil in 55%, and azathioprine in 10%.

In all, 147 of the 736 patients had a diagnosis of recurrent AIH. The investigators found that the cumulative probability of recurrent AIH was 49% after 20 years of follow-up.
 

Risk factors identified

In multivariate analysis controlling for age, concomitant disease, immunosuppressive regimens, organ-sex mismatch, acute rejection, liver function tests, bilirubin, and IgG, factors significantly associated with AIH recurrence included age 42 or younger at the time of transplant (hazard ratio, 3.15; P = .02), use of mycophenolate mofetil after transplant (HR, 3.06; P = .005), donor/recipient sex mismatch (HR, 2.57; P = .003), and high IgG levels pretransplant (HR, 1.04; P = .004).

Among 529 patients who had a liver biopsy after transplant, factors that remained as significant predictors of AIH recurrence were posttransplant mycophenolate mofetil (HR, 2.75; P = .003), donor/recipient sex mismatch (HR, 2.03; P = .02), and pretransplant IgG levels (HR, 1.04 per each g/L; P = .001).

An analysis of features associated with graft survival showed that recurrent AIH was associated with significantly increased risk for graft failure (HR, 10.79; P < .001). Patients with high bilirubin levels 1 year after transplantation were also at higher risk for failure (HR, 1.004 per micromol/L; P < .001).

Factors significantly associated with survival were recurrence of AIH (HR for death, 2.53; P = .001), elevated ALT at 12 months after transplant (HR, 1.002; P = .004), and elevated bilirubin at 12 months (HR, 1.003 per micromol/L; P < .001).

The investigators acknowledged that the study was limited by the retrospective design and by the fact that the diagnosis of recurrent AIH may have differed between centers that performed liver biopsy according to protocol and those that performed them only when clinically indicated, which may have resulted in differences in time to diagnosis.
 

Possible explanations for risk factors

In the question-and-answer session following his presentation, comoderator moderator Philip N. Newsome, PhD, from University Hospitals Birmingham (England), asked: “In terms of age, is that a reflection of worse disease, or is it adherence, or is it a combination, and should we be managing those patients more aggressively with immunosuppression?”

“We consider age is more a reflection of an aggressive disease,” Dr. Montano-Loza said. “Basically, in the univariate analysis we found that patients with a diagnosis at a younger age and even a transplant at a younger age were definitely associated with a higher risk of recurrence, so we think this is more related to an aggressive [disease] behavior in younger patient that translates into worse clinical outcomes.”

He added that patients younger than 40 who require transplants should be closely monitored for recurrence.

“Actually, we could make the argument that maybe these patients will benefit from protocol biopsies,” he said.

He noted that 15% of patients had significant fibrosis at the time of recurrent AIH diagnosis, and that the recurrences were not detected by laboratory monitoring alone.

Asked by an audience member why mycophenolate mofetil was associated with increased risk for recurrence, Dr. Montano-Loza replied that the retrospective nature of the data precludes the possibility of a definitive answer, but he noted that, for patients with other autoimmune liver diseases, the type of immunosuppression used has an impact on recurrence rates.

“For example, cyclosporine has a protective effect for patients transplanted for primary biliary cholangitis,” he said.

He said it may also be possible that there is a rebound effect leading to recurrence when patients are taken off mycophenolate or switched to another agent.

The study was supported by grants to individual researchers. Dr. Montano-Loza and Dr. Newsome reported having no relevant conflicts of interest.

Autoimmune hepatitis that recurs following a liver transplant can impair both graft survival and overall survival, results of a large international study showed.

Among 736 patients with autoimmune hepatitis who underwent liver transplant and were followed for up to 20 years, those who had recurrent AIH had a more than 10-fold higher risk for graft failure and a more than twofold higher risk of death, compared with patients who did not have recurrences, reported Aldo J. Montano-Loza, MD, MSc, PhD, from the University of Alberta, Edmonton.

“Recurrent disease impacts graft and overall survival, highlighting the need for improved management strategies,” he said in an oral abstract presentation during the International Liver Congress sponsored by the European Association for the Study of the Liver.

AIH is characterized by the presence of high IgG levels, autoantibodies, and histologic evidence of interface hepatitis. Most patients with AIH respond to immunosuppressive therapy, but some have progression to end-stage liver disease; for these patients, a liver transplant can be lifesaving, with 1-year survival of approximately 90%, and 5-year survival of about 70%, he said.

AIH frequently recurs after transplant, and although previous studies have suggested that recurrent disease does not adversely affect either graft survival or long-term survival, those studies had limited patient numbers and inadequate follow-up, Dr. Montano-Loza said.

He cited two recent studies, one from UNOS, the United Network for Organ Sharing, and the other from ELTR, the European Liver Transplant Registry, that showed that overall survival after liver transplant was worse for patients with AIH, compared with those who underwent transplant for other autoimmune liver diseases.
 

Multicenter retrospective study

To get a better picture of long-term posttransplant outcomes in patients with AIH, investigators in 33 centers in North and South America, Europe, and Asia conducted a retrospective cohort study. Their goal was to establish the frequency of recurrent AIH, identify clinical factors and biomarkers for higher risk of recurrence, and evaluate the association between recurrent AIH and both patient and graft survival.

They accomplished this by performing chart reviews, including data on demographics, IgG levels before transplant, and Model for End-Stage Liver Disease scores.

They also collected data on serum liver function tests within the first year after transplant, posttransplant infections, rejection episodes, and immunosuppressive regimens, as well as variables such as donor age and sex, sex mismatch between donor and recipients, calendar year of transplant, and transplant volume for AIH at each center.

Of the 736 patients, 563 (76%) were female. The mean age at AIH diagnosis was 34 years, and the mean age at transplant was 42 years. About one-fifth of patients (21%) had concomitant autoimmune diseases.

Posttransplant immunosuppression regimens included the usual suspects: tacrolimus in 78% of patients, cyclosporine in 11%, prednisone in 76%, mycophenolate mofetil in 55%, and azathioprine in 10%.

In all, 147 of the 736 patients had a diagnosis of recurrent AIH. The investigators found that the cumulative probability of recurrent AIH was 49% after 20 years of follow-up.
 

Risk factors identified

In multivariate analysis controlling for age, concomitant disease, immunosuppressive regimens, organ-sex mismatch, acute rejection, liver function tests, bilirubin, and IgG, factors significantly associated with AIH recurrence included age 42 or younger at the time of transplant (hazard ratio, 3.15; P = .02), use of mycophenolate mofetil after transplant (HR, 3.06; P = .005), donor/recipient sex mismatch (HR, 2.57; P = .003), and high IgG levels pretransplant (HR, 1.04; P = .004).

Among 529 patients who had a liver biopsy after transplant, factors that remained as significant predictors of AIH recurrence were posttransplant mycophenolate mofetil (HR, 2.75; P = .003), donor/recipient sex mismatch (HR, 2.03; P = .02), and pretransplant IgG levels (HR, 1.04 per each g/L; P = .001).

An analysis of features associated with graft survival showed that recurrent AIH was associated with significantly increased risk for graft failure (HR, 10.79; P < .001). Patients with high bilirubin levels 1 year after transplantation were also at higher risk for failure (HR, 1.004 per micromol/L; P < .001).

Factors significantly associated with survival were recurrence of AIH (HR for death, 2.53; P = .001), elevated ALT at 12 months after transplant (HR, 1.002; P = .004), and elevated bilirubin at 12 months (HR, 1.003 per micromol/L; P < .001).

The investigators acknowledged that the study was limited by the retrospective design and by the fact that the diagnosis of recurrent AIH may have differed between centers that performed liver biopsy according to protocol and those that performed them only when clinically indicated, which may have resulted in differences in time to diagnosis.
 

Possible explanations for risk factors

In the question-and-answer session following his presentation, comoderator moderator Philip N. Newsome, PhD, from University Hospitals Birmingham (England), asked: “In terms of age, is that a reflection of worse disease, or is it adherence, or is it a combination, and should we be managing those patients more aggressively with immunosuppression?”

“We consider age is more a reflection of an aggressive disease,” Dr. Montano-Loza said. “Basically, in the univariate analysis we found that patients with a diagnosis at a younger age and even a transplant at a younger age were definitely associated with a higher risk of recurrence, so we think this is more related to an aggressive [disease] behavior in younger patient that translates into worse clinical outcomes.”

He added that patients younger than 40 who require transplants should be closely monitored for recurrence.

“Actually, we could make the argument that maybe these patients will benefit from protocol biopsies,” he said.

He noted that 15% of patients had significant fibrosis at the time of recurrent AIH diagnosis, and that the recurrences were not detected by laboratory monitoring alone.

Asked by an audience member why mycophenolate mofetil was associated with increased risk for recurrence, Dr. Montano-Loza replied that the retrospective nature of the data precludes the possibility of a definitive answer, but he noted that, for patients with other autoimmune liver diseases, the type of immunosuppression used has an impact on recurrence rates.

“For example, cyclosporine has a protective effect for patients transplanted for primary biliary cholangitis,” he said.

He said it may also be possible that there is a rebound effect leading to recurrence when patients are taken off mycophenolate or switched to another agent.

The study was supported by grants to individual researchers. Dr. Montano-Loza and Dr. Newsome reported having no relevant conflicts of interest.

Autoimmune hepatitis that recurs following a liver transplant can impair both graft survival and overall survival, results of a large international study showed.

Among 736 patients with autoimmune hepatitis who underwent liver transplant and were followed for up to 20 years, those who had recurrent AIH had a more than 10-fold higher risk for graft failure and a more than twofold higher risk of death, compared with patients who did not have recurrences, reported Aldo J. Montano-Loza, MD, MSc, PhD, from the University of Alberta, Edmonton.

“Recurrent disease impacts graft and overall survival, highlighting the need for improved management strategies,” he said in an oral abstract presentation during the International Liver Congress sponsored by the European Association for the Study of the Liver.

AIH is characterized by the presence of high IgG levels, autoantibodies, and histologic evidence of interface hepatitis. Most patients with AIH respond to immunosuppressive therapy, but some have progression to end-stage liver disease; for these patients, a liver transplant can be lifesaving, with 1-year survival of approximately 90%, and 5-year survival of about 70%, he said.

AIH frequently recurs after transplant, and although previous studies have suggested that recurrent disease does not adversely affect either graft survival or long-term survival, those studies had limited patient numbers and inadequate follow-up, Dr. Montano-Loza said.

He cited two recent studies, one from UNOS, the United Network for Organ Sharing, and the other from ELTR, the European Liver Transplant Registry, that showed that overall survival after liver transplant was worse for patients with AIH, compared with those who underwent transplant for other autoimmune liver diseases.
 

Multicenter retrospective study

To get a better picture of long-term posttransplant outcomes in patients with AIH, investigators in 33 centers in North and South America, Europe, and Asia conducted a retrospective cohort study. Their goal was to establish the frequency of recurrent AIH, identify clinical factors and biomarkers for higher risk of recurrence, and evaluate the association between recurrent AIH and both patient and graft survival.

They accomplished this by performing chart reviews, including data on demographics, IgG levels before transplant, and Model for End-Stage Liver Disease scores.

They also collected data on serum liver function tests within the first year after transplant, posttransplant infections, rejection episodes, and immunosuppressive regimens, as well as variables such as donor age and sex, sex mismatch between donor and recipients, calendar year of transplant, and transplant volume for AIH at each center.

Of the 736 patients, 563 (76%) were female. The mean age at AIH diagnosis was 34 years, and the mean age at transplant was 42 years. About one-fifth of patients (21%) had concomitant autoimmune diseases.

Posttransplant immunosuppression regimens included the usual suspects: tacrolimus in 78% of patients, cyclosporine in 11%, prednisone in 76%, mycophenolate mofetil in 55%, and azathioprine in 10%.

In all, 147 of the 736 patients had a diagnosis of recurrent AIH. The investigators found that the cumulative probability of recurrent AIH was 49% after 20 years of follow-up.
 

Risk factors identified

In multivariate analysis controlling for age, concomitant disease, immunosuppressive regimens, organ-sex mismatch, acute rejection, liver function tests, bilirubin, and IgG, factors significantly associated with AIH recurrence included age 42 or younger at the time of transplant (hazard ratio, 3.15; P = .02), use of mycophenolate mofetil after transplant (HR, 3.06; P = .005), donor/recipient sex mismatch (HR, 2.57; P = .003), and high IgG levels pretransplant (HR, 1.04; P = .004).

Among 529 patients who had a liver biopsy after transplant, factors that remained as significant predictors of AIH recurrence were posttransplant mycophenolate mofetil (HR, 2.75; P = .003), donor/recipient sex mismatch (HR, 2.03; P = .02), and pretransplant IgG levels (HR, 1.04 per each g/L; P = .001).

An analysis of features associated with graft survival showed that recurrent AIH was associated with significantly increased risk for graft failure (HR, 10.79; P < .001). Patients with high bilirubin levels 1 year after transplantation were also at higher risk for failure (HR, 1.004 per micromol/L; P < .001).

Factors significantly associated with survival were recurrence of AIH (HR for death, 2.53; P = .001), elevated ALT at 12 months after transplant (HR, 1.002; P = .004), and elevated bilirubin at 12 months (HR, 1.003 per micromol/L; P < .001).

The investigators acknowledged that the study was limited by the retrospective design and by the fact that the diagnosis of recurrent AIH may have differed between centers that performed liver biopsy according to protocol and those that performed them only when clinically indicated, which may have resulted in differences in time to diagnosis.
 

Possible explanations for risk factors

In the question-and-answer session following his presentation, comoderator moderator Philip N. Newsome, PhD, from University Hospitals Birmingham (England), asked: “In terms of age, is that a reflection of worse disease, or is it adherence, or is it a combination, and should we be managing those patients more aggressively with immunosuppression?”

“We consider age is more a reflection of an aggressive disease,” Dr. Montano-Loza said. “Basically, in the univariate analysis we found that patients with a diagnosis at a younger age and even a transplant at a younger age were definitely associated with a higher risk of recurrence, so we think this is more related to an aggressive [disease] behavior in younger patient that translates into worse clinical outcomes.”

He added that patients younger than 40 who require transplants should be closely monitored for recurrence.

“Actually, we could make the argument that maybe these patients will benefit from protocol biopsies,” he said.

He noted that 15% of patients had significant fibrosis at the time of recurrent AIH diagnosis, and that the recurrences were not detected by laboratory monitoring alone.

Asked by an audience member why mycophenolate mofetil was associated with increased risk for recurrence, Dr. Montano-Loza replied that the retrospective nature of the data precludes the possibility of a definitive answer, but he noted that, for patients with other autoimmune liver diseases, the type of immunosuppression used has an impact on recurrence rates.

“For example, cyclosporine has a protective effect for patients transplanted for primary biliary cholangitis,” he said.

He said it may also be possible that there is a rebound effect leading to recurrence when patients are taken off mycophenolate or switched to another agent.

The study was supported by grants to individual researchers. Dr. Montano-Loza and Dr. Newsome reported having no relevant conflicts of interest.

Intermittent calorie restriction offers only modest advantages over a low-carbohydrate, high-fat (LCHF) diet for treating nonalcoholic fatty liver disease (NAFLD), researchers say.

The intermittent diet offers more benefit for liver stiffness and LDL cholesterol, and might be easier to maintain, said Magnus Holmer, MD, head of the hepatology unit at the Karolinska Institute in Stockholm.

But the intermittent diet also has drawbacks and the differences between the two were slight, he said in an interview.

“They were more or less identically effective in reducing liver steatosis in NAFLD and also reducing body weight,” he said. “And from this, we can say that the composition of macronutrients such as fat or sugar seems to be less important than how many calories you eat.”

Dr. Holmer and colleagues presented their findings at the meeting sponsored by the European Association for the Study of the Liver and published them in JHEP Reports

While previous studies have shown that dieting can effectively treat NAFLD, researchers have debated whether popular LCHF diets might cause more harm than good.

At the same time, intermittent-calorie restriction diets have also been gaining in popularity, particularly the 5:2 diet in which participants eat normally for 5 days a week and restrict their calories the other 2 days.
 

How do the two diets compare?

To see if one was more effective than the other, the researchers recruited 74 people with NAFLD. They diagnosed the patients either by radiologic assessment or a combination of controlled attenuation parameter (CAP) greater than 280 dB/m and obesity, or a CAP greater than 280 dB/m, elevated ALT, and overweight. Sixteen of the patients were being treated with statins.

The researchers randomly assigned 25 people to an LCHF diet, 25 to a 5:2 diet, and 24 to standard care. The groups were similar in diet, age, body mass index, liver stiffness, and most other criteria at baseline, although there were more women in the standard-care group.

At the start of the study, the participants in the standard-care group consulted with a hepatologist who advised them to avoid sweets and saturated fats, eat three meals a day, and avoid large portions.

The researchers asked women in the 5:2 diet to eat up to 500 kcal/day each of 2 days per week and up to 2,000 kcal/day each of the other 5 days. They asked men in the group to eat up to 600 kcal/day each of 2 days per week and up to 2,400 kcal/day the other 5 days.

They provided all the 5:2 participants with recipes that followed the Nordic Nutrition Recommendations, an adaptation of the Mediterranean diet that emphasizes foods traditional in Nordic countries, particularly grains such as whole-grain rye, oats, and barley; fruits such as apples, pears, berries, and plums; root vegetables, cabbages, onions, peas, beans, fish, boiled potatoes, and dairy products; and the use of rapeseed (canola) oil. The calories provided in the recipes were composed of 45%-60% carbohydrates, 25% fat, and 10%-20% protein.

The researchers asked women in the LCHF diet to eat an average of 1,600 kcal/day and men to eat an average of 1,900 kcal/day. All the participants used recipes based on meat, fish, eggs, low-carbohydrate vegetables, and dairy fat. Participants avoided sugar, bread, pasta, rice, pies, potatoes, and fruit. The calories in the recipes were composed of 5%-10% carbohydrates, 50%-80% fat, and 15%-40% protein.

All the participants reported what they ate over the previous 3 days, both at the start of the study and after 12 weeks. Participants in the 5:2 and LCHF groups also received follow-up calls to report their past 24 hours of eating at 2, 4, 8, and 12 weeks, and also at week 6, when they visited a dietitian.

In addition, the researchers measured the participants’ linoleic acid and alpha-linolenic acid intake to verify that the participants’ diets were different among the groups.

After 12 weeks, all three groups lost a significant amount of liver fat, but the LCHF and 5:2 groups lost more than the standard care group. Liver stiffness decreased significantly in the 5:2 and standard care groups, but not in the LCHF group.

The differences in steatosis change between the standard care and LCHF groups was statistically significant (P = .001), as it was between the standard care and 5:2 groups (P = .029). The differences between the LCHF and 5:2 groups were not statistically significant for weight or steatosis, but they were statistically significant for liver stiffness.

In addition, the 5:2 group significantly reduced total and LDL cholesterol, while the standard care group did not. In the LCHF group, levels of LDL cholesterol, HDL cholesterol, and total cholesterol all increased.

The long-term implications of the cholesterol findings are unclear, Dr. Holmer said. He hopes to follow up on these patients after 18-24 months. But the initial cholesterol findings are perhaps enough to constitute a red flag for anyone with a history of cardiovascular disease.
 

Diet adherence

Only one person dropped out of the 5:2 group, compared with five in the LCHF group and four in the standard-care group. More people in the LCHF group reported adverse events, such as gastrointestinal upset.

“With LCHF, it’s a drastic change for most people,” Dr. Holmer said. “Many patients are a bit shocked when they realize how much fat they are supposed to eat for breakfast, for lunch, and for dinner. They might eat bacon and eggs for breakfast every day.” The diet could be challenging for people who want to reduce their consumption of meat for environmental reasons.

The 5:2 group offers the advantage that people can choose what they want to eat as long as they adhere to the calorie restrictions, he pointed out. Still, he cautioned that the diet would not work well for people with insulin-dependent diabetes because of the difficulty of adjusting insulin levels on fasting days. He also recommended against this diet for people with cirrhosis because they need to eat frequent meals.
 

LCHF and 5:2 diets can work

But for most people the good news is that a variety of diets will work to treat NAFLD, Dr. Holmer said.

“I begin with saying to my patients that this can be completely cured, as long as you’re able to lose weight,” he said. “Then the next question is, how are they going to go ahead with that task? And if they’re already interested in some sort of specific diet, then I can, based on these findings, encourage that.”

Stephen Harrison, MD, a visiting professor of hepatology at Radcliffe Department of Medicine, University of Oxford, England, said that longer-term results will be important. For example, it will be interesting to see if the diets had effects on ballooning or inflammation.

Another limitation of the study is that it is relatively small in size, he said. He pointed out that people with NAFLD should increase their physical activity as well as eating less.

Still, Dr. Harrison greeted the findings enthusiastically, saying: “This is an important study.”

It’s useful to compare two popular diets head to head, and it’s also encouraging to get confirmation that either one can work, he added.

The study was supported by grants from the Stockholm County Council, the Dietary Science Foundation (Kostfonden), the Skandia Research Foundation, and the Åke Wiberg Foundation. Dr. Holmer has disclosed no relevant financial relationships. Harrison is a consultant to Madrigal Pharmaceuticals.

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

Intermittent calorie restriction offers only modest advantages over a low-carbohydrate, high-fat (LCHF) diet for treating nonalcoholic fatty liver disease (NAFLD), researchers say.

The intermittent diet offers more benefit for liver stiffness and LDL cholesterol, and might be easier to maintain, said Magnus Holmer, MD, head of the hepatology unit at the Karolinska Institute in Stockholm.

But the intermittent diet also has drawbacks and the differences between the two were slight, he said in an interview.

“They were more or less identically effective in reducing liver steatosis in NAFLD and also reducing body weight,” he said. “And from this, we can say that the composition of macronutrients such as fat or sugar seems to be less important than how many calories you eat.”

Dr. Holmer and colleagues presented their findings at the meeting sponsored by the European Association for the Study of the Liver and published them in JHEP Reports

While previous studies have shown that dieting can effectively treat NAFLD, researchers have debated whether popular LCHF diets might cause more harm than good.

At the same time, intermittent-calorie restriction diets have also been gaining in popularity, particularly the 5:2 diet in which participants eat normally for 5 days a week and restrict their calories the other 2 days.
 

How do the two diets compare?

To see if one was more effective than the other, the researchers recruited 74 people with NAFLD. They diagnosed the patients either by radiologic assessment or a combination of controlled attenuation parameter (CAP) greater than 280 dB/m and obesity, or a CAP greater than 280 dB/m, elevated ALT, and overweight. Sixteen of the patients were being treated with statins.

The researchers randomly assigned 25 people to an LCHF diet, 25 to a 5:2 diet, and 24 to standard care. The groups were similar in diet, age, body mass index, liver stiffness, and most other criteria at baseline, although there were more women in the standard-care group.

At the start of the study, the participants in the standard-care group consulted with a hepatologist who advised them to avoid sweets and saturated fats, eat three meals a day, and avoid large portions.

The researchers asked women in the 5:2 diet to eat up to 500 kcal/day each of 2 days per week and up to 2,000 kcal/day each of the other 5 days. They asked men in the group to eat up to 600 kcal/day each of 2 days per week and up to 2,400 kcal/day the other 5 days.

They provided all the 5:2 participants with recipes that followed the Nordic Nutrition Recommendations, an adaptation of the Mediterranean diet that emphasizes foods traditional in Nordic countries, particularly grains such as whole-grain rye, oats, and barley; fruits such as apples, pears, berries, and plums; root vegetables, cabbages, onions, peas, beans, fish, boiled potatoes, and dairy products; and the use of rapeseed (canola) oil. The calories provided in the recipes were composed of 45%-60% carbohydrates, 25% fat, and 10%-20% protein.

The researchers asked women in the LCHF diet to eat an average of 1,600 kcal/day and men to eat an average of 1,900 kcal/day. All the participants used recipes based on meat, fish, eggs, low-carbohydrate vegetables, and dairy fat. Participants avoided sugar, bread, pasta, rice, pies, potatoes, and fruit. The calories in the recipes were composed of 5%-10% carbohydrates, 50%-80% fat, and 15%-40% protein.

All the participants reported what they ate over the previous 3 days, both at the start of the study and after 12 weeks. Participants in the 5:2 and LCHF groups also received follow-up calls to report their past 24 hours of eating at 2, 4, 8, and 12 weeks, and also at week 6, when they visited a dietitian.

In addition, the researchers measured the participants’ linoleic acid and alpha-linolenic acid intake to verify that the participants’ diets were different among the groups.

After 12 weeks, all three groups lost a significant amount of liver fat, but the LCHF and 5:2 groups lost more than the standard care group. Liver stiffness decreased significantly in the 5:2 and standard care groups, but not in the LCHF group.

The differences in steatosis change between the standard care and LCHF groups was statistically significant (P = .001), as it was between the standard care and 5:2 groups (P = .029). The differences between the LCHF and 5:2 groups were not statistically significant for weight or steatosis, but they were statistically significant for liver stiffness.

In addition, the 5:2 group significantly reduced total and LDL cholesterol, while the standard care group did not. In the LCHF group, levels of LDL cholesterol, HDL cholesterol, and total cholesterol all increased.

The long-term implications of the cholesterol findings are unclear, Dr. Holmer said. He hopes to follow up on these patients after 18-24 months. But the initial cholesterol findings are perhaps enough to constitute a red flag for anyone with a history of cardiovascular disease.
 

Diet adherence

Only one person dropped out of the 5:2 group, compared with five in the LCHF group and four in the standard-care group. More people in the LCHF group reported adverse events, such as gastrointestinal upset.

“With LCHF, it’s a drastic change for most people,” Dr. Holmer said. “Many patients are a bit shocked when they realize how much fat they are supposed to eat for breakfast, for lunch, and for dinner. They might eat bacon and eggs for breakfast every day.” The diet could be challenging for people who want to reduce their consumption of meat for environmental reasons.

The 5:2 group offers the advantage that people can choose what they want to eat as long as they adhere to the calorie restrictions, he pointed out. Still, he cautioned that the diet would not work well for people with insulin-dependent diabetes because of the difficulty of adjusting insulin levels on fasting days. He also recommended against this diet for people with cirrhosis because they need to eat frequent meals.
 

LCHF and 5:2 diets can work

But for most people the good news is that a variety of diets will work to treat NAFLD, Dr. Holmer said.

“I begin with saying to my patients that this can be completely cured, as long as you’re able to lose weight,” he said. “Then the next question is, how are they going to go ahead with that task? And if they’re already interested in some sort of specific diet, then I can, based on these findings, encourage that.”

Stephen Harrison, MD, a visiting professor of hepatology at Radcliffe Department of Medicine, University of Oxford, England, said that longer-term results will be important. For example, it will be interesting to see if the diets had effects on ballooning or inflammation.

Another limitation of the study is that it is relatively small in size, he said. He pointed out that people with NAFLD should increase their physical activity as well as eating less.

Still, Dr. Harrison greeted the findings enthusiastically, saying: “This is an important study.”

It’s useful to compare two popular diets head to head, and it’s also encouraging to get confirmation that either one can work, he added.

The study was supported by grants from the Stockholm County Council, the Dietary Science Foundation (Kostfonden), the Skandia Research Foundation, and the Åke Wiberg Foundation. Dr. Holmer has disclosed no relevant financial relationships. Harrison is a consultant to Madrigal Pharmaceuticals.

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

Intermittent calorie restriction offers only modest advantages over a low-carbohydrate, high-fat (LCHF) diet for treating nonalcoholic fatty liver disease (NAFLD), researchers say.

The intermittent diet offers more benefit for liver stiffness and LDL cholesterol, and might be easier to maintain, said Magnus Holmer, MD, head of the hepatology unit at the Karolinska Institute in Stockholm.

But the intermittent diet also has drawbacks and the differences between the two were slight, he said in an interview.

“They were more or less identically effective in reducing liver steatosis in NAFLD and also reducing body weight,” he said. “And from this, we can say that the composition of macronutrients such as fat or sugar seems to be less important than how many calories you eat.”

Dr. Holmer and colleagues presented their findings at the meeting sponsored by the European Association for the Study of the Liver and published them in JHEP Reports

While previous studies have shown that dieting can effectively treat NAFLD, researchers have debated whether popular LCHF diets might cause more harm than good.

At the same time, intermittent-calorie restriction diets have also been gaining in popularity, particularly the 5:2 diet in which participants eat normally for 5 days a week and restrict their calories the other 2 days.
 

How do the two diets compare?

To see if one was more effective than the other, the researchers recruited 74 people with NAFLD. They diagnosed the patients either by radiologic assessment or a combination of controlled attenuation parameter (CAP) greater than 280 dB/m and obesity, or a CAP greater than 280 dB/m, elevated ALT, and overweight. Sixteen of the patients were being treated with statins.

The researchers randomly assigned 25 people to an LCHF diet, 25 to a 5:2 diet, and 24 to standard care. The groups were similar in diet, age, body mass index, liver stiffness, and most other criteria at baseline, although there were more women in the standard-care group.

At the start of the study, the participants in the standard-care group consulted with a hepatologist who advised them to avoid sweets and saturated fats, eat three meals a day, and avoid large portions.

The researchers asked women in the 5:2 diet to eat up to 500 kcal/day each of 2 days per week and up to 2,000 kcal/day each of the other 5 days. They asked men in the group to eat up to 600 kcal/day each of 2 days per week and up to 2,400 kcal/day the other 5 days.

They provided all the 5:2 participants with recipes that followed the Nordic Nutrition Recommendations, an adaptation of the Mediterranean diet that emphasizes foods traditional in Nordic countries, particularly grains such as whole-grain rye, oats, and barley; fruits such as apples, pears, berries, and plums; root vegetables, cabbages, onions, peas, beans, fish, boiled potatoes, and dairy products; and the use of rapeseed (canola) oil. The calories provided in the recipes were composed of 45%-60% carbohydrates, 25% fat, and 10%-20% protein.

The researchers asked women in the LCHF diet to eat an average of 1,600 kcal/day and men to eat an average of 1,900 kcal/day. All the participants used recipes based on meat, fish, eggs, low-carbohydrate vegetables, and dairy fat. Participants avoided sugar, bread, pasta, rice, pies, potatoes, and fruit. The calories in the recipes were composed of 5%-10% carbohydrates, 50%-80% fat, and 15%-40% protein.

All the participants reported what they ate over the previous 3 days, both at the start of the study and after 12 weeks. Participants in the 5:2 and LCHF groups also received follow-up calls to report their past 24 hours of eating at 2, 4, 8, and 12 weeks, and also at week 6, when they visited a dietitian.

In addition, the researchers measured the participants’ linoleic acid and alpha-linolenic acid intake to verify that the participants’ diets were different among the groups.

After 12 weeks, all three groups lost a significant amount of liver fat, but the LCHF and 5:2 groups lost more than the standard care group. Liver stiffness decreased significantly in the 5:2 and standard care groups, but not in the LCHF group.

The differences in steatosis change between the standard care and LCHF groups was statistically significant (P = .001), as it was between the standard care and 5:2 groups (P = .029). The differences between the LCHF and 5:2 groups were not statistically significant for weight or steatosis, but they were statistically significant for liver stiffness.

In addition, the 5:2 group significantly reduced total and LDL cholesterol, while the standard care group did not. In the LCHF group, levels of LDL cholesterol, HDL cholesterol, and total cholesterol all increased.

The long-term implications of the cholesterol findings are unclear, Dr. Holmer said. He hopes to follow up on these patients after 18-24 months. But the initial cholesterol findings are perhaps enough to constitute a red flag for anyone with a history of cardiovascular disease.
 

Diet adherence

Only one person dropped out of the 5:2 group, compared with five in the LCHF group and four in the standard-care group. More people in the LCHF group reported adverse events, such as gastrointestinal upset.

“With LCHF, it’s a drastic change for most people,” Dr. Holmer said. “Many patients are a bit shocked when they realize how much fat they are supposed to eat for breakfast, for lunch, and for dinner. They might eat bacon and eggs for breakfast every day.” The diet could be challenging for people who want to reduce their consumption of meat for environmental reasons.

The 5:2 group offers the advantage that people can choose what they want to eat as long as they adhere to the calorie restrictions, he pointed out. Still, he cautioned that the diet would not work well for people with insulin-dependent diabetes because of the difficulty of adjusting insulin levels on fasting days. He also recommended against this diet for people with cirrhosis because they need to eat frequent meals.
 

LCHF and 5:2 diets can work

But for most people the good news is that a variety of diets will work to treat NAFLD, Dr. Holmer said.

“I begin with saying to my patients that this can be completely cured, as long as you’re able to lose weight,” he said. “Then the next question is, how are they going to go ahead with that task? And if they’re already interested in some sort of specific diet, then I can, based on these findings, encourage that.”

Stephen Harrison, MD, a visiting professor of hepatology at Radcliffe Department of Medicine, University of Oxford, England, said that longer-term results will be important. For example, it will be interesting to see if the diets had effects on ballooning or inflammation.

Another limitation of the study is that it is relatively small in size, he said. He pointed out that people with NAFLD should increase their physical activity as well as eating less.

Still, Dr. Harrison greeted the findings enthusiastically, saying: “This is an important study.”

It’s useful to compare two popular diets head to head, and it’s also encouraging to get confirmation that either one can work, he added.

The study was supported by grants from the Stockholm County Council, the Dietary Science Foundation (Kostfonden), the Skandia Research Foundation, and the Åke Wiberg Foundation. Dr. Holmer has disclosed no relevant financial relationships. Harrison is a consultant to Madrigal Pharmaceuticals.

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