Liver Disease

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

[email protected]

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

[email protected]

LOS ANGELES – More than 20 years ago, Roy Taylor, MD, began working to further understand the pathogenesis of hepatic insulin resistance in people with type 2 diabetes. It became clear that the main determinant was the amount of fat in the liver.

Vidyard Video

“If you reduced the amount of fat, the resistance went down,” Dr. Taylor, professor of medicine and metabolism at Newcastle University (England), said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists. “We had a very clear picture of what might be controlling this awful matter of fasting glucose being too high.”

Then, Dr. Taylor read a study from Caterina Guidone, MD, and colleagues in Italy, which found that 1 week after patients with type 2 diabetes underwent gastric bypass surgery, their fasting plasma glucose levels became normal (Diabetes. 2006;55[7]:2025-31). “I was sitting at my desk and I thought, ‘This really changes type 2 diabetes,’ ” Dr. Taylor said. “It set in process a series of thoughts as to what was controlling what.”

This inspired ongoing work that Dr. Taylor termed the “twin-cycle hypothesis,” which postulates that chronic calorie excess leads to accumulation of liver fat, which spills over into the pancreas (Diabetologia. 2008;51[10]:1781-9).

“People with type 2 diabetes have been in positive calorie balance for a number of years,” he said. “That’s going to lead to an excess of fat in the body, and liver fat levels tend to rise with increasing body weight. If a person has normal insulin sensitivity in muscle tissue, then dealing with a meal is quite easy. Some 30 years ago, we showed using MR spectroscopy that you will have stored the carbohydrate from your breakfast in muscle, to the extent of about one-third of your breakfast, and the peak will be about 5 hours after breakfast. If you had your corn flakes at seven in the morning, by noon there will be peak in muscle, nicely stored away. However, if you happen to be insulin resistant in muscle, that doesn’t happen. There’s only one other pathway that the body can use, and that’s lipogenesis. The body can turn this very toxic substance [glucose] into safe storage [fat]. A lot of that happens in the liver. This means that people with insulin resistance tend to build up liver fat more rapidly than others.”

To test the twin-cycle hypothesis, Dr. Taylor and colleagues launched an 8-week study known as Counterpoint, which set out to induce negative calorie balance using a very low–calorie diet – about one-quarter of an average person’s daily food intake – in 11 people with diabetes (Diabetologia. 2011;54[10]:2506-14). The diet included consuming three packets of liquid formula food each day (46.4% carbohydrate, 32.5% protein, and 20.1% fat; plus vitamins, minerals, and trace elements), supplemented with portions of nonstarchy vegetables such that total energy intake was about 700 calories a day.

“On a liquid-formula diet, hunger is not a problem after the first 36 hours,” Dr. Taylor said. “This is one of the best-kept secrets of the obesity field. Our low-calorie diet was designed as something that people would be able to do in real life. We included nonstarchy vegetables to keep the bowels happy. That was important. It also fulfilled another point. People didn’t want just a liquid diet. They missed the sensation of chewing.”

The researchers also developed three-point Dixon MRI to measure pancreas and liver triacylglycerol content. “The pancreas was particularly challenging, and the full resources of the magnetic resonance physics team were needed to crack the technical problems,” he said.

After just 1 week of restricted energy intake, the fasting plasma glucose level normalized in the diabetic group, going from 9.2 to 5.9 mmol/L (P = .003), while insulin suppression of hepatic glucose output improved from 43% to 74 % (P = .003). By week 8, pancreatic triacylglycerol decreased from 8.0% to 1.1% (P = .03), and hepatic triacylglycerol content fell from 12.8% to 2.9% (P = .003).

“Within 7 days, there was a 30% drop in liver fat, and hepatic insulin resistance had disappeared,” Dr. Taylor said. “This is not a significant change – it’s a disappearance. For one individual, the amount of fat in the liver decreased from 36% to 2%. In fact, 2% [fat in the liver] was the average in the whole group. But what was simply amazing was the change in first-phase insulin response. It gradually increased throughout the 8 weeks of the study to become similar to the normal control group. We knew right away that a low-calorie diet would start correcting this central abnormality of type 2 diabetes.”

After the results from Counterpoint were published, Dr. Taylor received a “tsunami” of emails from researchers and from members of the public. “Some of the medical experts said it was a flash in the pan – interesting, but not relevant,” he said. “People with diabetes learned of it by the media, and it was talked about as a crash diet, which is unfortunate. First, it wasn’t a crash diet. This diet has to be very carefully planned, and people need to think about it in advance. They need to talk about it with their nearest and dearest, because it’s the spouse, the partner, the friends who will be supporting the individual through this journey. That’s critically important. People don’t eat as isolated individuals, they often eat as a family. We’re not talking about cure. We’re talking about reversal of the processes underpinning diabetes, with the aim of achieving remission.”

Dr. Taylor created a website devoted to providing information for clinicians and patients about the low-calorie diet and other tips on how to reverse type 2 diabetes. Soon afterward, he started to receive emails from people telling him about their experiences with the diet. “In the comfort of their own kitchens these people had lost the same amount of weight as in our trial subjects – about 33 pounds,” Dr. Taylor said. “Most of them had gotten rid of their type 2 diabetes. This was not something artificial as part of a research project. This was something that real people would do if the motivation was strong enough.”

To find out if the results from the Counterpoint study were sustainable, Dr. Taylor and his associates launched the Counterbalance study in 30 patients with type 2 diabetes who had a positive calorie imbalance and whom the researchers followed for 6 months. The 8-week diet consisted of consuming three packets of liquid formula a day comprising 43.0% carbohydrates, 34.0% protein, and 19.5% fat, as well as up to 240 g of nonstarchy vegetables (Diabetes Care. 2016;39[5]:808-15). “This was followed for a 6-month period of normal eating: Eating whatever foods they liked but in quantities to keep their weight steady,” Dr. Taylor explained. “These people gained no weight over the 6-month follow-up period. They achieved normalization of liver fat, and it remained normal.”

The patients’ hemoglobin A_1c levels fell from an average of 7.1% at baseline to less than 6.0%, and stayed at less than 6.0%. Patients who didn’t respond tended to have a longer duration of diabetes. Their beta cells had fallen to a level beyond that capable of recovery. “So the durability of the return to normal metabolic function was not in question, at least up to 6 months,” he said. “This study also gave us the opportunity to look at changes in pancreas fat. Was it likely that the liver fat was driving the pancreas fat? Yes.”

During the weight-loss period, the researchers found that there was the same degree of reduction of pancreas fat in the Counterbalance study as there’d been in the Counterpoint study. “Remarkably, it decreased slightly during the 6 months of follow-up,” Dr. Taylor said. “Those changes were significant. Type 2 diabetes seems to be caused by about a half a gram of fat within the cells of the pancreas.”

To investigate if a very low–calorie diet could be used as a routine treatment for type 2 diabetes, Dr. Taylor collaborated with his colleague, Mike Lean, MD, in launching the randomized controlled Diabetes Remission Clinical Trial (DiRECT) at 49 primary care practices in the United Kingdom (Diabetologia. 2018;61[3]:589-98). In all, 298 patients were randomized to either best-practice diabetes care alone (control arm) or with an additional evidence-based weight-management program (intervention arm). Remission was defined as having a hemoglobin A_1c level of less than 6.5% for at least 2 months without receiving glucose-lowering therapy.

At 1 year, 46% of patients in the intervention arm achieved remission, compared with 4% in the control arm (Lancet Diabetes Endocrinol. 2019;7[5]:344-55). At 2 years, 36% of patients in the intervention arm achieved remission, compared with 2% in the control arm. “The most common comment from study participants was, ‘I feel 10 years younger,’ ” Dr. Taylor said. “That’s important.”

The percentage of patients who achieved remission was 5% in those who lost less than 11 lb (5 kg), 29% in those who lost between 11 lb and 22 lb (5-10 kg), 60% in those who lost between 22 lb and 33 lb (10-15 kg), and 70% in those who lost 33 lb (15 kg) or more.

The researchers found that 62 patients achieved no remission at 12 or 24 months, 15 achieved remission at 12 but not at 24 months, and 48 achieved remission at 12 and 24 months. “We haven’t got this perfectly right yet,” Dr. Taylor said. “There is more work to do in understanding how to achieve prevention of weight gain, maybe with behavioral interventions and/or other agents such as [glucagonlike peptide–1] agonists. This is the start of a story, not the end of it.”

He and his associates also observed that delivery of fat from the liver to the rest of the body was increased in study participants who relapsed. “What effect did that have on the pancreas fat? The people who continued to be free of diabetes showed a slight fall in pancreatic fat between 5 and 24 months,” Dr. Taylor said. “In sharp contrast, the relapsers had a complete increase. Over the whole period of the study, the relapsers had not changed from baseline. It appears beyond reasonable doubt that excess pancreas fat seems to be driving the beta-cell problem underlying type 2 diabetes.”

Dr. Taylor reported that he has received lecture fees from Novartis, Lilly, and Janssen. He has also been an advisory board member for Wilmington Healthcare.

[email protected]

Hepatologists and gastroenterologists see multiple and substantial barriers to the use of palliative care in patients with end-stage liver disease, results of a recent survey show.

©Lighthaunter/Thinkstock

Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.

Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.

“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.

Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.

Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.

Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.

To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.

Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.

Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.

While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.

When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.

Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.

One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.

“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.

Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).

Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.

In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.

Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.

SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.

Hepatologists and gastroenterologists see multiple and substantial barriers to the use of palliative care in patients with end-stage liver disease, results of a recent survey show.

©Lighthaunter/Thinkstock

Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.

Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.

“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.

Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.

Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.

Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.

To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.

Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.

Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.

While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.

When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.

Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.

One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.

“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.

Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).

Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.

In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.

Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.

SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.

Hepatologists and gastroenterologists see multiple and substantial barriers to the use of palliative care in patients with end-stage liver disease, results of a recent survey show.

©Lighthaunter/Thinkstock

Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.

Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.

“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.

Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.

Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.

Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.

To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.

Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.

Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.

While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.

When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.

Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.

One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.

“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.

Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).

Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.

In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.

Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.

SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.

VIENNA – In patients with compensated cirrhosis infected with genotype 3 hepatitis C virus, adding ribavirin to a usual antiviral regimen of sofosbuvir and velpatasvir significantly boosted the rate of sustained virologic response in a review of more than 14,000 English residents entered in a national registry starting in 2017.

Mitchel L. Zoler/MDedge News

With ribavirin added to a sofosbuvir plus velpatasvir regimen for 12 weeks of treatment, the three-drug combination produced a 98% rate of sustained virologic response after 12 weeks (SVR12) in 196 treated patients, Kate Drysdale, MBBCh, said at the meeting sponsored by the European Association for the Study of the Liver. In contrast, 218 compensated cirrhosis patients who received a 12-week regimen of sofosbuvir plus velpatasvir (Epclusa) but without ribavirin had an SVR12 rate of just under 92%, a statistically significant difference, compared with the rate among patients who also received ribavirin, said Dr. Drysdale, a gastroenterologist at Bart’s Health and Queen Mary University of London. The SVR12 rate among 167 compensated cirrhotic patients treated for 12 weeks with the combination of glecaprevir plus pibrentasvir (Mavyret) was 96%, and not statistically different from the patients who received three drugs including ribavirin. The sofosbuvir, velpatasvir, ribavirin combination also outperformed the combination of sofosbuvir plus daclatasvir (Daklinza) and ribavirin, which produced an SVR12 of 92% in 868 patients. The SVR12 rate is the percentage of patients with undetectable hepatitis C virus (HCV) 12 or more weeks after the end of treatment.

Dr. Drysdale cautioned that the data have not yet been put through a multivariate analysis, but the results so far provide “a strong indication that ribavirin may not be as insignificant” as many have recently presumed. “Ribavirin has been set aside because it was thought not to add to the SVR12, but if patients get only one go at treatment, we must be sure their first treatment is the best one,” Dr. Drysdale said in an interview. If ribavirin can be shown to make a significant contribution to treatment efficacy “then we should think more widely about using it when patients tolerate it.”


The analysis included too few patients with either current decompensated cirrhosis or a history of decompensated cirrhosis to make any statistically meaningful comparisons of the treatment subgroups among these patients. And among patients with genotype 3 HCV infection and without cirrhosis, none of the treatments used in practice showed any statistically significant differences in the SVR12 rates they produced. Among patients without cirrhosis the most commonly used regimens by far were an 8-week course of glecaprevir plus pibrentasvir in 731 patients or a 12-week course of sofosbuvir plus velpatasvir in 1,184 patients. Both regimens had SVR12 rates in noncirrhotic patients of 97%, regardless of whether patients had no, mild, or moderate liver fibrosis.

The study used data collected in an English national registry of HCV-infected patients treated with direct-acting antiviral drugs starting in 2017. Dr. Drysdale and her associates narrowed down the total database of more than 37,000 English adults who received some HCV therapy during the period to 14,603 who received a complete, valid regimen and had follow-up SVR12 information available. The overall SVR12 rate among all these patients was 95.59%, and among the patients infected by genotype 3 virus the SVR12 rate was 95.03%. Dr. Drysdale’s analysis focused primarily on the roughly one-third of patients in the study group infected with genotype 3 HCV, the genotype that historically has presented unique treatment challenges (Drugs. 2017 Feb;77[2]:131-44).

Another finding Dr. Drysdale reported was that as liver disease severity worsened from no fibrosis to mild or moderate fibrosis, and then to compensated cirrhosis or decompensation, the SVR12 rate steadily diminished. Among genotype 3 patients, the SVR12 rate fell from about 97% among patients without any fibrosis to about 87% among those with decompensated cirrhosis. Although this observation had been made before, this finding in such a large number of treated patients adds significant new evidence to support this pattern. It also adds further support to the idea of screening for HCV infection among higher-risk, asymptomatic people to optimize their prospects for virus eradication with treatment.

“If patients get much better treatment outcomes before they become cirrhotic then we should try to find these HCV-infected people before they develop symptoms,” Dr. Drysdale said.

Dr. Drysdale reported no disclosures.

[email protected]

SOURCE: Drysdale K et al. J Hepatol. 2019 April;70(1):e131.

VIENNA – In patients with compensated cirrhosis infected with genotype 3 hepatitis C virus, adding ribavirin to a usual antiviral regimen of sofosbuvir and velpatasvir significantly boosted the rate of sustained virologic response in a review of more than 14,000 English residents entered in a national registry starting in 2017.

Mitchel L. Zoler/MDedge News

With ribavirin added to a sofosbuvir plus velpatasvir regimen for 12 weeks of treatment, the three-drug combination produced a 98% rate of sustained virologic response after 12 weeks (SVR12) in 196 treated patients, Kate Drysdale, MBBCh, said at the meeting sponsored by the European Association for the Study of the Liver. In contrast, 218 compensated cirrhosis patients who received a 12-week regimen of sofosbuvir plus velpatasvir (Epclusa) but without ribavirin had an SVR12 rate of just under 92%, a statistically significant difference, compared with the rate among patients who also received ribavirin, said Dr. Drysdale, a gastroenterologist at Bart’s Health and Queen Mary University of London. The SVR12 rate among 167 compensated cirrhotic patients treated for 12 weeks with the combination of glecaprevir plus pibrentasvir (Mavyret) was 96%, and not statistically different from the patients who received three drugs including ribavirin. The sofosbuvir, velpatasvir, ribavirin combination also outperformed the combination of sofosbuvir plus daclatasvir (Daklinza) and ribavirin, which produced an SVR12 of 92% in 868 patients. The SVR12 rate is the percentage of patients with undetectable hepatitis C virus (HCV) 12 or more weeks after the end of treatment.

Dr. Drysdale cautioned that the data have not yet been put through a multivariate analysis, but the results so far provide “a strong indication that ribavirin may not be as insignificant” as many have recently presumed. “Ribavirin has been set aside because it was thought not to add to the SVR12, but if patients get only one go at treatment, we must be sure their first treatment is the best one,” Dr. Drysdale said in an interview. If ribavirin can be shown to make a significant contribution to treatment efficacy “then we should think more widely about using it when patients tolerate it.”


The analysis included too few patients with either current decompensated cirrhosis or a history of decompensated cirrhosis to make any statistically meaningful comparisons of the treatment subgroups among these patients. And among patients with genotype 3 HCV infection and without cirrhosis, none of the treatments used in practice showed any statistically significant differences in the SVR12 rates they produced. Among patients without cirrhosis the most commonly used regimens by far were an 8-week course of glecaprevir plus pibrentasvir in 731 patients or a 12-week course of sofosbuvir plus velpatasvir in 1,184 patients. Both regimens had SVR12 rates in noncirrhotic patients of 97%, regardless of whether patients had no, mild, or moderate liver fibrosis.

The study used data collected in an English national registry of HCV-infected patients treated with direct-acting antiviral drugs starting in 2017. Dr. Drysdale and her associates narrowed down the total database of more than 37,000 English adults who received some HCV therapy during the period to 14,603 who received a complete, valid regimen and had follow-up SVR12 information available. The overall SVR12 rate among all these patients was 95.59%, and among the patients infected by genotype 3 virus the SVR12 rate was 95.03%. Dr. Drysdale’s analysis focused primarily on the roughly one-third of patients in the study group infected with genotype 3 HCV, the genotype that historically has presented unique treatment challenges (Drugs. 2017 Feb;77[2]:131-44).

Another finding Dr. Drysdale reported was that as liver disease severity worsened from no fibrosis to mild or moderate fibrosis, and then to compensated cirrhosis or decompensation, the SVR12 rate steadily diminished. Among genotype 3 patients, the SVR12 rate fell from about 97% among patients without any fibrosis to about 87% among those with decompensated cirrhosis. Although this observation had been made before, this finding in such a large number of treated patients adds significant new evidence to support this pattern. It also adds further support to the idea of screening for HCV infection among higher-risk, asymptomatic people to optimize their prospects for virus eradication with treatment.

“If patients get much better treatment outcomes before they become cirrhotic then we should try to find these HCV-infected people before they develop symptoms,” Dr. Drysdale said.

Dr. Drysdale reported no disclosures.

[email protected]

SOURCE: Drysdale K et al. J Hepatol. 2019 April;70(1):e131.

VIENNA – In patients with compensated cirrhosis infected with genotype 3 hepatitis C virus, adding ribavirin to a usual antiviral regimen of sofosbuvir and velpatasvir significantly boosted the rate of sustained virologic response in a review of more than 14,000 English residents entered in a national registry starting in 2017.

Mitchel L. Zoler/MDedge News

With ribavirin added to a sofosbuvir plus velpatasvir regimen for 12 weeks of treatment, the three-drug combination produced a 98% rate of sustained virologic response after 12 weeks (SVR12) in 196 treated patients, Kate Drysdale, MBBCh, said at the meeting sponsored by the European Association for the Study of the Liver. In contrast, 218 compensated cirrhosis patients who received a 12-week regimen of sofosbuvir plus velpatasvir (Epclusa) but without ribavirin had an SVR12 rate of just under 92%, a statistically significant difference, compared with the rate among patients who also received ribavirin, said Dr. Drysdale, a gastroenterologist at Bart’s Health and Queen Mary University of London. The SVR12 rate among 167 compensated cirrhotic patients treated for 12 weeks with the combination of glecaprevir plus pibrentasvir (Mavyret) was 96%, and not statistically different from the patients who received three drugs including ribavirin. The sofosbuvir, velpatasvir, ribavirin combination also outperformed the combination of sofosbuvir plus daclatasvir (Daklinza) and ribavirin, which produced an SVR12 of 92% in 868 patients. The SVR12 rate is the percentage of patients with undetectable hepatitis C virus (HCV) 12 or more weeks after the end of treatment.

Dr. Drysdale cautioned that the data have not yet been put through a multivariate analysis, but the results so far provide “a strong indication that ribavirin may not be as insignificant” as many have recently presumed. “Ribavirin has been set aside because it was thought not to add to the SVR12, but if patients get only one go at treatment, we must be sure their first treatment is the best one,” Dr. Drysdale said in an interview. If ribavirin can be shown to make a significant contribution to treatment efficacy “then we should think more widely about using it when patients tolerate it.”


The analysis included too few patients with either current decompensated cirrhosis or a history of decompensated cirrhosis to make any statistically meaningful comparisons of the treatment subgroups among these patients. And among patients with genotype 3 HCV infection and without cirrhosis, none of the treatments used in practice showed any statistically significant differences in the SVR12 rates they produced. Among patients without cirrhosis the most commonly used regimens by far were an 8-week course of glecaprevir plus pibrentasvir in 731 patients or a 12-week course of sofosbuvir plus velpatasvir in 1,184 patients. Both regimens had SVR12 rates in noncirrhotic patients of 97%, regardless of whether patients had no, mild, or moderate liver fibrosis.

The study used data collected in an English national registry of HCV-infected patients treated with direct-acting antiviral drugs starting in 2017. Dr. Drysdale and her associates narrowed down the total database of more than 37,000 English adults who received some HCV therapy during the period to 14,603 who received a complete, valid regimen and had follow-up SVR12 information available. The overall SVR12 rate among all these patients was 95.59%, and among the patients infected by genotype 3 virus the SVR12 rate was 95.03%. Dr. Drysdale’s analysis focused primarily on the roughly one-third of patients in the study group infected with genotype 3 HCV, the genotype that historically has presented unique treatment challenges (Drugs. 2017 Feb;77[2]:131-44).

Another finding Dr. Drysdale reported was that as liver disease severity worsened from no fibrosis to mild or moderate fibrosis, and then to compensated cirrhosis or decompensation, the SVR12 rate steadily diminished. Among genotype 3 patients, the SVR12 rate fell from about 97% among patients without any fibrosis to about 87% among those with decompensated cirrhosis. Although this observation had been made before, this finding in such a large number of treated patients adds significant new evidence to support this pattern. It also adds further support to the idea of screening for HCV infection among higher-risk, asymptomatic people to optimize their prospects for virus eradication with treatment.

“If patients get much better treatment outcomes before they become cirrhotic then we should try to find these HCV-infected people before they develop symptoms,” Dr. Drysdale said.

Dr. Drysdale reported no disclosures.

[email protected]

SOURCE: Drysdale K et al. J Hepatol. 2019 April;70(1):e131.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.

snyferok/ThinkStock

Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.

The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.

Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.

By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.

Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.

Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.

SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.

VIENNA – A single, oral treatment with fecal microbiota transplant was safe and well tolerated, and showed suggestive evidence of clinical improvement in patients with cirrhosis and recurrent hepatic encephalopathy in a phase 1 randomized study with 20 patients.

Mitchel L. Zoler/MDedge News

The oral fecal microbiota transplant (FMT), modeled on guideline-directed treatment for Clostridium difficile (Clin Infect Dis. 2018 April 1;66[7]:e1-48), was linked with a cut in hospitalizations and serious adverse events, as well as a clinically meaningful improvement in a cognitive measure specific for hepatic encephalopathy, Jasmohan S. Bajaj, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Given the preliminary scope of the study, the next step is to assess the treatment in more patients and to evaluate delivery of the FMT specifically to the upper or lower gastrointestinal tract, said Dr. Bajaj, a hepatologist at Virginia Commonwealth University and McGuire VA Medical Center, both in Richmond.

The study included 20 patients with recurrent hepatic encephalopathy (RHE) and a history of at least two encephalopathy episodes despite treatment with lactulose and rifaximin (Xifaxan). After a baseline assessment, 10 patients received a single, oral dose of FMT contained in 15 capsules and composed of fecal material from the OpenBiome collection, and 10 patients received placebo capsules. All of the FMT material came from a single donor and contained a high level of beneficial microbial types, specifically Lachnospiraceae and Ruminococcaceae species. Patients averaged 64 years of age.


During 5 months of follow-up, 6 of the 10 placebo patients had a serious adverse event versus 1 of the 10 patients treated with an active FMT; altogether, there were 11 serious adverse events among the placebo patients versus only 1 event among the FMT patients, Dr. Bajaj reported. Three patients in the control arm had a total of seven hepatic encephalopathy events, compared with a single patient with one event in the intervention arm.

Enrolled patients also underwent two cognitive tests at baseline and during follow-up. Using a Stroop smartphone app (EncephalApp) designed to assess patients with RHE (Hepatology. 2013 Sept;58[3]:1122-32), the researchers found an average 51-second improvement in OffTime+OnTime, a statistically significant and clinically meaningful improvement in the patients treated with FMT, whereas the control patients showed no statistically significant change in this parameter. The second cognitive measure was the average performance by patients using the Psychometric Hepatic Encephalopathy Score (Curr Gastroenterol Rep. 2014 Jan;16[1]:362), which showed no significant change after treatment in either study arm. The actively treated patients also showed favorable changes in the microbial composition of their stool and mucosa, as well as an enhanced small intestinal barrier, following treatment, Dr. Bajaj said.

[email protected]

SOURCE: Bajaj JS et al. J Hepatol. 2019 April;70[1]:e55.

VIENNA – A single, oral treatment with fecal microbiota transplant was safe and well tolerated, and showed suggestive evidence of clinical improvement in patients with cirrhosis and recurrent hepatic encephalopathy in a phase 1 randomized study with 20 patients.

Mitchel L. Zoler/MDedge News

The oral fecal microbiota transplant (FMT), modeled on guideline-directed treatment for Clostridium difficile (Clin Infect Dis. 2018 April 1;66[7]:e1-48), was linked with a cut in hospitalizations and serious adverse events, as well as a clinically meaningful improvement in a cognitive measure specific for hepatic encephalopathy, Jasmohan S. Bajaj, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Given the preliminary scope of the study, the next step is to assess the treatment in more patients and to evaluate delivery of the FMT specifically to the upper or lower gastrointestinal tract, said Dr. Bajaj, a hepatologist at Virginia Commonwealth University and McGuire VA Medical Center, both in Richmond.

The study included 20 patients with recurrent hepatic encephalopathy (RHE) and a history of at least two encephalopathy episodes despite treatment with lactulose and rifaximin (Xifaxan). After a baseline assessment, 10 patients received a single, oral dose of FMT contained in 15 capsules and composed of fecal material from the OpenBiome collection, and 10 patients received placebo capsules. All of the FMT material came from a single donor and contained a high level of beneficial microbial types, specifically Lachnospiraceae and Ruminococcaceae species. Patients averaged 64 years of age.


During 5 months of follow-up, 6 of the 10 placebo patients had a serious adverse event versus 1 of the 10 patients treated with an active FMT; altogether, there were 11 serious adverse events among the placebo patients versus only 1 event among the FMT patients, Dr. Bajaj reported. Three patients in the control arm had a total of seven hepatic encephalopathy events, compared with a single patient with one event in the intervention arm.

Enrolled patients also underwent two cognitive tests at baseline and during follow-up. Using a Stroop smartphone app (EncephalApp) designed to assess patients with RHE (Hepatology. 2013 Sept;58[3]:1122-32), the researchers found an average 51-second improvement in OffTime+OnTime, a statistically significant and clinically meaningful improvement in the patients treated with FMT, whereas the control patients showed no statistically significant change in this parameter. The second cognitive measure was the average performance by patients using the Psychometric Hepatic Encephalopathy Score (Curr Gastroenterol Rep. 2014 Jan;16[1]:362), which showed no significant change after treatment in either study arm. The actively treated patients also showed favorable changes in the microbial composition of their stool and mucosa, as well as an enhanced small intestinal barrier, following treatment, Dr. Bajaj said.

[email protected]

SOURCE: Bajaj JS et al. J Hepatol. 2019 April;70[1]:e55.

VIENNA – A single, oral treatment with fecal microbiota transplant was safe and well tolerated, and showed suggestive evidence of clinical improvement in patients with cirrhosis and recurrent hepatic encephalopathy in a phase 1 randomized study with 20 patients.

Mitchel L. Zoler/MDedge News

The oral fecal microbiota transplant (FMT), modeled on guideline-directed treatment for Clostridium difficile (Clin Infect Dis. 2018 April 1;66[7]:e1-48), was linked with a cut in hospitalizations and serious adverse events, as well as a clinically meaningful improvement in a cognitive measure specific for hepatic encephalopathy, Jasmohan S. Bajaj, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Given the preliminary scope of the study, the next step is to assess the treatment in more patients and to evaluate delivery of the FMT specifically to the upper or lower gastrointestinal tract, said Dr. Bajaj, a hepatologist at Virginia Commonwealth University and McGuire VA Medical Center, both in Richmond.

The study included 20 patients with recurrent hepatic encephalopathy (RHE) and a history of at least two encephalopathy episodes despite treatment with lactulose and rifaximin (Xifaxan). After a baseline assessment, 10 patients received a single, oral dose of FMT contained in 15 capsules and composed of fecal material from the OpenBiome collection, and 10 patients received placebo capsules. All of the FMT material came from a single donor and contained a high level of beneficial microbial types, specifically Lachnospiraceae and Ruminococcaceae species. Patients averaged 64 years of age.


During 5 months of follow-up, 6 of the 10 placebo patients had a serious adverse event versus 1 of the 10 patients treated with an active FMT; altogether, there were 11 serious adverse events among the placebo patients versus only 1 event among the FMT patients, Dr. Bajaj reported. Three patients in the control arm had a total of seven hepatic encephalopathy events, compared with a single patient with one event in the intervention arm.

Enrolled patients also underwent two cognitive tests at baseline and during follow-up. Using a Stroop smartphone app (EncephalApp) designed to assess patients with RHE (Hepatology. 2013 Sept;58[3]:1122-32), the researchers found an average 51-second improvement in OffTime+OnTime, a statistically significant and clinically meaningful improvement in the patients treated with FMT, whereas the control patients showed no statistically significant change in this parameter. The second cognitive measure was the average performance by patients using the Psychometric Hepatic Encephalopathy Score (Curr Gastroenterol Rep. 2014 Jan;16[1]:362), which showed no significant change after treatment in either study arm. The actively treated patients also showed favorable changes in the microbial composition of their stool and mucosa, as well as an enhanced small intestinal barrier, following treatment, Dr. Bajaj said.

[email protected]

SOURCE: Bajaj JS et al. J Hepatol. 2019 April;70[1]:e55.

VIENNA – A novel RNA-inhibitor drug, givosiran, produced a large cut in acute porphyria attacks in a pivotal trial with 94 patients with acute hepatic porphyria.

Vidyard Video

Although the study also identified some safety issues with givosiran, an RNA-inhibitor molecule delivered by subcutaneous injection once a month, the increases in liver enzyme levels it produced in some patients as well as decreased renal function did not seem severe or frequent enough to counterbalance the benefits to treated patients, who often have significant comorbidities and adverse effects because of their disease, Manisha Balwani, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Among the 48 patients assigned to the givosiran group, one patient dropped out because of an adverse effect of treatment.

The results put givosiran on track to become the first Food and Drug Administration–approved treatment for acute hepatic porphyria, a set of similar, rare genetic diseases that produce symptoms in about 1 in every 10,000 people, although asymptomatic disease is likely more common (Hepatol Commun. 2019 Feb;3[2]:193-206). The trial outcomes were also notable for the dramatic improvements in life-disrupting symptoms like pain, nausea, and fatigue that many treated patients experienced.

Patients’ lives were “completely transformed” by givosiran treatment, Dr. Balwani said in a video interview. Patients also had a reduced need for analgesics, including opioids, said Dr. Balwani, a medical geneticist at the Icahn School of Medicine at Mount Sinai in New York.

The ENVISION (A Study to Evaluate the Efficacy and Safety of Givosiran [ALN-AS1] in Patients With Acute Hepatic Porphyrias) study randomized 94 patients who were at least 12 years old and diagnosed with an acute hepatic porphyria, and had experienced at least two porphyria attacks during the prior 6 months. The study ran at 36 sites in 18 countries. Enrolled patients averaged about 39 years old, and had been diagnosed with a hepatic porphyria for an average of about 6 years. During the study, patients did not receive hemin (Panhematin) prophylaxis.

 

 

The study’s primary endpoint was the average annualized rate of porphyria attacks during 6 months of treatment, which was 3.2 attacks in 46 patients evaluable for efficacy on givosiran treatment and 12.5 attacks in 43 patients evaluable for efficacy in the control group, a 74% reduction in attacks with givosiran that was statistically significant, Dr. Balwani reported. The percentage of patients with no attacks during the study was 16% among control patients and 50% among those on givosiran. Future analysis of the study data will attempt to identify the patients with the best responses to givosiran.

Among the full cohort of 94 patients enrolled in the study, 21% of the givosiran-treated patients had a adverse reaction, and 17% had a severe adverse reaction, compared with rates of 9% and 11%, respectively, among controls. Three of the serious adverse reactions were judged related to givosiran treatment: one patient with pyrexia, one with abnormal liver function test results, and one patient who developed chronic kidney disease. A total of two patients in the givosiran group developed chronic kidney disease that warranted elective hospitalization for diagnostic evaluation, and an additional three patients on the drug developed chronic kidney disease that did not require hospitalization. Nausea affected 27% of patients on givosiran and 11% of the control patients. Injection-site reactions occurred in 17% of those on givosiran and in none of the placebo patients. An elevation in the serum level of alanine aminotransferase to more than three times the upper limit of normal of baseline occurred in 15% of the givosiran-treated patients and in 2% of the placebo patients.

Givosiran’s small RNA molecule inhibits production of 5‐aminolevulinic acid synthase 1 (ALAS‐1), the rate-limiting enzyme that drives production of the heme precursor molecules that are pathophysiologic in patients with acute hepatic porphyria.

[email protected]

SOURCE: Balwani M et al. J Hepatol. 2019 April 70(1):e81-2.

VIENNA – A novel RNA-inhibitor drug, givosiran, produced a large cut in acute porphyria attacks in a pivotal trial with 94 patients with acute hepatic porphyria.

Vidyard Video

Although the study also identified some safety issues with givosiran, an RNA-inhibitor molecule delivered by subcutaneous injection once a month, the increases in liver enzyme levels it produced in some patients as well as decreased renal function did not seem severe or frequent enough to counterbalance the benefits to treated patients, who often have significant comorbidities and adverse effects because of their disease, Manisha Balwani, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Among the 48 patients assigned to the givosiran group, one patient dropped out because of an adverse effect of treatment.

The results put givosiran on track to become the first Food and Drug Administration–approved treatment for acute hepatic porphyria, a set of similar, rare genetic diseases that produce symptoms in about 1 in every 10,000 people, although asymptomatic disease is likely more common (Hepatol Commun. 2019 Feb;3[2]:193-206). The trial outcomes were also notable for the dramatic improvements in life-disrupting symptoms like pain, nausea, and fatigue that many treated patients experienced.

Patients’ lives were “completely transformed” by givosiran treatment, Dr. Balwani said in a video interview. Patients also had a reduced need for analgesics, including opioids, said Dr. Balwani, a medical geneticist at the Icahn School of Medicine at Mount Sinai in New York.

The ENVISION (A Study to Evaluate the Efficacy and Safety of Givosiran [ALN-AS1] in Patients With Acute Hepatic Porphyrias) study randomized 94 patients who were at least 12 years old and diagnosed with an acute hepatic porphyria, and had experienced at least two porphyria attacks during the prior 6 months. The study ran at 36 sites in 18 countries. Enrolled patients averaged about 39 years old, and had been diagnosed with a hepatic porphyria for an average of about 6 years. During the study, patients did not receive hemin (Panhematin) prophylaxis.

 

 

The study’s primary endpoint was the average annualized rate of porphyria attacks during 6 months of treatment, which was 3.2 attacks in 46 patients evaluable for efficacy on givosiran treatment and 12.5 attacks in 43 patients evaluable for efficacy in the control group, a 74% reduction in attacks with givosiran that was statistically significant, Dr. Balwani reported. The percentage of patients with no attacks during the study was 16% among control patients and 50% among those on givosiran. Future analysis of the study data will attempt to identify the patients with the best responses to givosiran.

Among the full cohort of 94 patients enrolled in the study, 21% of the givosiran-treated patients had a adverse reaction, and 17% had a severe adverse reaction, compared with rates of 9% and 11%, respectively, among controls. Three of the serious adverse reactions were judged related to givosiran treatment: one patient with pyrexia, one with abnormal liver function test results, and one patient who developed chronic kidney disease. A total of two patients in the givosiran group developed chronic kidney disease that warranted elective hospitalization for diagnostic evaluation, and an additional three patients on the drug developed chronic kidney disease that did not require hospitalization. Nausea affected 27% of patients on givosiran and 11% of the control patients. Injection-site reactions occurred in 17% of those on givosiran and in none of the placebo patients. An elevation in the serum level of alanine aminotransferase to more than three times the upper limit of normal of baseline occurred in 15% of the givosiran-treated patients and in 2% of the placebo patients.

Givosiran’s small RNA molecule inhibits production of 5‐aminolevulinic acid synthase 1 (ALAS‐1), the rate-limiting enzyme that drives production of the heme precursor molecules that are pathophysiologic in patients with acute hepatic porphyria.

[email protected]

SOURCE: Balwani M et al. J Hepatol. 2019 April 70(1):e81-2.

VIENNA – A novel RNA-inhibitor drug, givosiran, produced a large cut in acute porphyria attacks in a pivotal trial with 94 patients with acute hepatic porphyria.

Vidyard Video

Although the study also identified some safety issues with givosiran, an RNA-inhibitor molecule delivered by subcutaneous injection once a month, the increases in liver enzyme levels it produced in some patients as well as decreased renal function did not seem severe or frequent enough to counterbalance the benefits to treated patients, who often have significant comorbidities and adverse effects because of their disease, Manisha Balwani, MD, said at the meeting sponsored by the European Association for the Study of the Liver. Among the 48 patients assigned to the givosiran group, one patient dropped out because of an adverse effect of treatment.

The results put givosiran on track to become the first Food and Drug Administration–approved treatment for acute hepatic porphyria, a set of similar, rare genetic diseases that produce symptoms in about 1 in every 10,000 people, although asymptomatic disease is likely more common (Hepatol Commun. 2019 Feb;3[2]:193-206). The trial outcomes were also notable for the dramatic improvements in life-disrupting symptoms like pain, nausea, and fatigue that many treated patients experienced.

Patients’ lives were “completely transformed” by givosiran treatment, Dr. Balwani said in a video interview. Patients also had a reduced need for analgesics, including opioids, said Dr. Balwani, a medical geneticist at the Icahn School of Medicine at Mount Sinai in New York.

The ENVISION (A Study to Evaluate the Efficacy and Safety of Givosiran [ALN-AS1] in Patients With Acute Hepatic Porphyrias) study randomized 94 patients who were at least 12 years old and diagnosed with an acute hepatic porphyria, and had experienced at least two porphyria attacks during the prior 6 months. The study ran at 36 sites in 18 countries. Enrolled patients averaged about 39 years old, and had been diagnosed with a hepatic porphyria for an average of about 6 years. During the study, patients did not receive hemin (Panhematin) prophylaxis.

 

 

The study’s primary endpoint was the average annualized rate of porphyria attacks during 6 months of treatment, which was 3.2 attacks in 46 patients evaluable for efficacy on givosiran treatment and 12.5 attacks in 43 patients evaluable for efficacy in the control group, a 74% reduction in attacks with givosiran that was statistically significant, Dr. Balwani reported. The percentage of patients with no attacks during the study was 16% among control patients and 50% among those on givosiran. Future analysis of the study data will attempt to identify the patients with the best responses to givosiran.

Among the full cohort of 94 patients enrolled in the study, 21% of the givosiran-treated patients had a adverse reaction, and 17% had a severe adverse reaction, compared with rates of 9% and 11%, respectively, among controls. Three of the serious adverse reactions were judged related to givosiran treatment: one patient with pyrexia, one with abnormal liver function test results, and one patient who developed chronic kidney disease. A total of two patients in the givosiran group developed chronic kidney disease that warranted elective hospitalization for diagnostic evaluation, and an additional three patients on the drug developed chronic kidney disease that did not require hospitalization. Nausea affected 27% of patients on givosiran and 11% of the control patients. Injection-site reactions occurred in 17% of those on givosiran and in none of the placebo patients. An elevation in the serum level of alanine aminotransferase to more than three times the upper limit of normal of baseline occurred in 15% of the givosiran-treated patients and in 2% of the placebo patients.

Givosiran’s small RNA molecule inhibits production of 5‐aminolevulinic acid synthase 1 (ALAS‐1), the rate-limiting enzyme that drives production of the heme precursor molecules that are pathophysiologic in patients with acute hepatic porphyria.

[email protected]

SOURCE: Balwani M et al. J Hepatol. 2019 April 70(1):e81-2.

VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.

Mitchel L. Zoler/MDedge News

This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).

However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).

Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.

At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).

The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.

During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.

In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.

As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.

Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb. 

[email protected]

SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.

VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.

Mitchel L. Zoler/MDedge News

This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).

However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).

Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.

At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).

The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.

During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.

In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.

As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.

Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb. 

[email protected]

SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.

VIENNA – Treatment of individuals chronically infected with hepatitis B virus (HBV) with the nucleotide analog tenofovir disoproxil fumarate significantly linked with a substantial cut in the incidence of hepatocellular carcinoma (HCC) compared with those who received the nucleoside analog entecavir, according to a review of more than 29,000 Hong Kong patients.

Mitchel L. Zoler/MDedge News

This is the second reported study to find that association. In January 2019, a study of more than 24,000 Korean residents chronically infected with HBV showed a similar, statistically significant link between treatment with tenofovir disoproxil fumarate (Viread) and a lower incidence of HCC compared with patients treated with entecavir (Baraclude) (JAMA Oncol. 2019 Jan;5[1]:30-6), Grace L.H. Wong, MD, said at the meeting, sponsored by the European Association for the Study of the Liver (EASL).

However, another report published just a few days before Dr. Wong spoke failed to find an association between tenofovir disoproxil treatment of HBV and the subsequent rate of HCC compared with patients treated with entecavir. That study comprised nearly 2,900 HBV patients treated at any of four Korean medical centers (J Hepatol. 2019 Apr. doi: 10.1016/j.jhep.2019.03.028).

Dr. Wong noted that although current guidelines from EASL cite both tenofovir disoproxil and entecavir (as well as tenofovir alafenamide [Vemlidy]) as first-line treatments for chronic HBV infection (J Hepatol. 2017 Aug;67[2]:370-98), some evidence suggests that tenofovir disoproxil might produce effects subtly different from those of entecavir.

At the meeting in Vienna, for example, a report on 176 Japanese patients with chronic HBV showed that those who were treated with a nucleotide analog such as tenofovir disoproxil produced higher serum levels of interferon-lamda3 compared with patients treated with entecavir, and increased levels of this interferon could improve clearance of HBV surface antigen (J Hepatol. 2019 April;70[1]:e477). The most recent EASL guidelines for treatment of chronic hepatitis B infection also list tenofovir disoproxil, entecavir, and tenofovir alafenamide as preferred agents (Hepatology. 2018 April;67[4]:1560-99).

The data Dr. Wong and her associates analyzed came from health records kept for about 80% of Hong Kong’s population in the Clinical Data Analysis and Recording System of the Hospital Authority of Hong Kong. From January 2010 to June 2018, this database included 28,041 consecutive patients chronically infected with HBV and treated with entecavir, and 1,309 consecutive patients treated with tenofovir disoproxil. These numbers excluded patients treated for less than 6 months, patients coinfected with hepatitis C or D virus, patients with cancer diagnosed or a liver transplanted before or during their first 6 months on treatment, and patients previously treated with an interferon or nucleos(t)ide.

During an average follow-up of 2.8 years of tenofovir disoproxil treatment, 8 patients developed HCC, and during an average follow-up of 3.7 years of entecavir treatment, 1,386 patients developed HCC, reported Dr. Wong, a hepatologist and professor of medicine at the Chinese University of Hong Kong.

In a multivariate analysis that adjusted for demographic and clinical differences, treatment with tenofovir disoproxil linked with a statistically significant 68% reduced rate of HCC development compared with the entecavir-treated patients, she said. In a propensity score–weighted analysis, tenofovir disoproxil linked with a statistically significant 64% reduced rate of incident HCC, and in a propensity score–matched analysis tenofovir disoproxil linked with a 58% reduced rate of HCC, although in this analysis, which excluded many of the entecavir-treated patients and hence had less statistical power, the difference just missed statistical significance.

As an additional step to try to rule out the possible effect of unadjusted confounders, Dr. Wong and associates analyzed the links between tenofovir disoproxil and entecavir treatment and two negative-control outcomes, the incidence of lung cancer and the incidence of acute myocardial infarction. Neither of these outcomes showed a statistically significant link with one of the HBV treatments, suggesting that the link between treatment and HCC incidence did not appear because of an unadjusted confounding bias, Dr. Wong said. The Hong Kong database did not include enough patients treated with tenofovir alafenamide to allow assessment of this drug, she added.

Dr. Wong has been an adviser to Gilead and a speaker for Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Roche. Tenofovir disoproxil fumarate is marketed by Gilead, and entecavir is marketed by Bristol-Myers Squibb. 

[email protected]

SOURCE: Wong GL et al. J Hepatol. 2019 April;70[1]:e128.

VIENNA – Patients with persistent liver abnormalities from primary biliary cholangitis despite combined treatment with ursodeoxycholic acid and obeticholic acid often responded to additional treatment with bezafibrate in a single-center study of 10 patients treated for 6 months.

Mitchel L. Zoler/MDedge News

In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.

Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.

Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).

The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.

The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).

Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.

Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).

[email protected]

SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.

VIENNA – Patients with persistent liver abnormalities from primary biliary cholangitis despite combined treatment with ursodeoxycholic acid and obeticholic acid often responded to additional treatment with bezafibrate in a single-center study of 10 patients treated for 6 months.

Mitchel L. Zoler/MDedge News

In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.

Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.

Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).

The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.

The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).

Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.

Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).

[email protected]

SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.

VIENNA – Patients with persistent liver abnormalities from primary biliary cholangitis despite combined treatment with ursodeoxycholic acid and obeticholic acid often responded to additional treatment with bezafibrate in a single-center study of 10 patients treated for 6 months.

Mitchel L. Zoler/MDedge News

In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.

Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.

Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).

The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.

The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).

Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.

Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).

[email protected]

SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.

Mitochondrial damage and iron accumulation from hepatitis C virus are linked to the development of hepatocellular carcinoma (HCC), according to an extensive literature review.

E.H. Cook, Jr./CDC

Although the mechanisms underlying the hepatocellular carcinoma development are not fully understood, it is known that oxidative stress exists to a greater degree in hepatitis C virus (HCV) infection, compared with other inflammatory liver diseases. Such stress has been proposed as a major mechanism of liver injury in patients with chronic HCV, the authors reported in Free Radical Biology and Medicine.

Patients with HCV have significant hepatocellular mitochondrial alterations, and iron accumulation is also a well-known characteristic in patients with chronic HCV. Such alterations in mitochondria and iron accumulation are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction, according to the review.

“The greatest concern is whether mitochondrial damage and iron metabolic dysregulation persist even after HCV eradication and to what extent such pathological conditions affect the development of HCC. Determining the molecular signaling that underlies the mitophagy induced by iron depletion is another topic of interest and is expected to lead to potential therapeutic approaches for multiple diseases,” the researchers concluded.

Support was from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development. The authors reported no disclosures.

[email protected]

SOURCE: Keisuke H et al. Free Radic Biol Med. 2019;133:193-9.

Mitochondrial damage and iron accumulation from hepatitis C virus are linked to the development of hepatocellular carcinoma (HCC), according to an extensive literature review.

E.H. Cook, Jr./CDC

Although the mechanisms underlying the hepatocellular carcinoma development are not fully understood, it is known that oxidative stress exists to a greater degree in hepatitis C virus (HCV) infection, compared with other inflammatory liver diseases. Such stress has been proposed as a major mechanism of liver injury in patients with chronic HCV, the authors reported in Free Radical Biology and Medicine.

Patients with HCV have significant hepatocellular mitochondrial alterations, and iron accumulation is also a well-known characteristic in patients with chronic HCV. Such alterations in mitochondria and iron accumulation are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction, according to the review.

“The greatest concern is whether mitochondrial damage and iron metabolic dysregulation persist even after HCV eradication and to what extent such pathological conditions affect the development of HCC. Determining the molecular signaling that underlies the mitophagy induced by iron depletion is another topic of interest and is expected to lead to potential therapeutic approaches for multiple diseases,” the researchers concluded.

Support was from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development. The authors reported no disclosures.

[email protected]

SOURCE: Keisuke H et al. Free Radic Biol Med. 2019;133:193-9.

Mitochondrial damage and iron accumulation from hepatitis C virus are linked to the development of hepatocellular carcinoma (HCC), according to an extensive literature review.

E.H. Cook, Jr./CDC

Although the mechanisms underlying the hepatocellular carcinoma development are not fully understood, it is known that oxidative stress exists to a greater degree in hepatitis C virus (HCV) infection, compared with other inflammatory liver diseases. Such stress has been proposed as a major mechanism of liver injury in patients with chronic HCV, the authors reported in Free Radical Biology and Medicine.

Patients with HCV have significant hepatocellular mitochondrial alterations, and iron accumulation is also a well-known characteristic in patients with chronic HCV. Such alterations in mitochondria and iron accumulation are closely related to oxidative stress, since the mitochondria are the main site of reactive oxygen species generation, and iron produces hydroxy radicals via the Fenton reaction, according to the review.

“The greatest concern is whether mitochondrial damage and iron metabolic dysregulation persist even after HCV eradication and to what extent such pathological conditions affect the development of HCC. Determining the molecular signaling that underlies the mitophagy induced by iron depletion is another topic of interest and is expected to lead to potential therapeutic approaches for multiple diseases,” the researchers concluded.

Support was from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development. The authors reported no disclosures.

[email protected]

SOURCE: Keisuke H et al. Free Radic Biol Med. 2019;133:193-9.

VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.

Mitchel L. Zoler/MDedge News

The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.

“Low cardiac reserve may improve clinical risk prediction algorithms for hepatorenal syndrome, and identify patients who may benefit from intensified surveillance and treatment,” said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.

The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.

The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.

Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.

Dr. Koshy had no disclosures.

[email protected]

SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.

VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.

Mitchel L. Zoler/MDedge News

The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.

“Low cardiac reserve may improve clinical risk prediction algorithms for hepatorenal syndrome, and identify patients who may benefit from intensified surveillance and treatment,” said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.

The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.

The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.

Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.

Dr. Koshy had no disclosures.

[email protected]

SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.

VIENNA – Patients with cirrhosis and undergoing work-up for a possible liver transplant who had low cardiac reserve had a nearly fourfold increased rate of developing hepatorenal syndrome (HRS) during an average 17 months of follow-up, compared with patients with normal cardiac reserve, in a review of 560 Australian patients assessed for a possible liver transplant.

Mitchel L. Zoler/MDedge News

The findings suggest that patients with advanced liver disease should routinely undergo assessment for low cardiac reserve, Anoop N. Koshy, MBBS, said at the meeting sponsored by the European Association for the Study of the Liver.

“Low cardiac reserve may improve clinical risk prediction algorithms for hepatorenal syndrome, and identify patients who may benefit from intensified surveillance and treatment,” said Dr. Koshy, a cardiologist with Austin Health in Melbourne. “We propose that it’s not low cardiac output that leads to HRS, but an inability of patients to increase their cardiac output” in response to usual stimuli.

The findings also add to the concerns about using nonselective beta-blocker drugs in patients with cirrhosis because of the potential of these drugs to further blunt increases in cardiac output; they also suggest that noninvasive measurement of cardiac reserve could identify patients with low cardiac reserve who could benefit from closer monitoring and new approaches to treatment, he suggested. About 10%-30% of patients with cirrhosis develop HRS, and the new finding suggests a noninvasive way to identify patients with the highest risk for this complication.

The study included 560 consecutive patients with cirrhosis and end-stage liver disease who were awaiting a liver transplant at the Victoria Liver Transplant Unit in Melbourne and underwent assessment by stress echocardiography using low-dose dobutamine (10 mcg/kg per min) during 2010-2017 as part of their standard pretransplant work-up. Exclusion of patients with known cardiac disease prior to their stress echo examination or incomplete measurement left 488 patients, of whom 424 were free from HRS at baseline. Patients with HRS at the time of their stress echo assessment had on average a cardiac output that was about 25% higher than patients without HRS, a statistically significant difference driven by both a significantly increased heart rate and stroke volume.

Among the 424 patients free from HRS at baseline, 85 developed HRS during an average 17-month follow-up. Patients with low cardiac reserve after dobutamine challenge, defined as an increase in cardiac output of less than 25%, had a 3.9-fold increased rate of incident HRS during follow-up, compared with patients who had a larger rise in their cardiac output after adjustment for several clinical and echocardiographic baseline variables, Dr. Koshy reported. In this analysis low cardiac reserve was the strongest predictor of subsequent HRS, he said.

Dr. Koshy had no disclosures.

[email protected]

SOURCE: Koshy AN et al. J Hepatol. 2019 April;70(1):e56.