Obeticholic acid reversed NASH liver fibrosis in phase 3 trial

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Daily treatment of patients with nonalcoholic steatohepatitis with obeticholic acid led to a near doubling of patients who had fibrosis regression in a phase 3 trial with 931 patients, making obeticholic acid the first agent proven to improve the course of this disease.

“There is no doubt that with these data we have changed the treatment” of nonalcoholic steatohepatitis (NASH), Zobair M. Younossi, MD, of Inova Fairfax Medical Campus in Falls Church, Va., said at the meeting sponsored by the European Association for the Study of the Liver. “We are at a watershed moment” in NASH treatment, Dr. Younossi added in a video interview.

Until now “we have had no effective treatments for NASH. This is the first success in a phase 3 trial; obeticholic acid looks very promising,” commented Philip N. Newsome, PhD, professor of experimental hepatology at the University of Birmingham (England).

Obeticholic acid (OCA), an agonist of the farnesoid X receptor, already has Food and Drug Administration marketing approval for the indication of primary biliary cholangitis, a much rarer disease than NASH.

Mitchel L. Zoler/MDedge News
Dr. Philip Newsome

The REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment) trial has so far enrolled 931 patients at about 350 sites in 20 countries, including the United States, and followed them during 18 months of treatment, the prespecified time for an interim analysis. The study enrolled adults with biopsy-proven NASH and generally focused on patients with either stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease activity score of at least 4. Enrolled patients averaged about 55 years old, slightly more than half the enrolled patients had type 2 diabetes, and more than half had stage 3 fibrosis.

 

 


The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.

For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.

The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.

Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.



Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.

REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.

Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.

REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.

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Daily treatment of patients with nonalcoholic steatohepatitis with obeticholic acid led to a near doubling of patients who had fibrosis regression in a phase 3 trial with 931 patients, making obeticholic acid the first agent proven to improve the course of this disease.

“There is no doubt that with these data we have changed the treatment” of nonalcoholic steatohepatitis (NASH), Zobair M. Younossi, MD, of Inova Fairfax Medical Campus in Falls Church, Va., said at the meeting sponsored by the European Association for the Study of the Liver. “We are at a watershed moment” in NASH treatment, Dr. Younossi added in a video interview.

Until now “we have had no effective treatments for NASH. This is the first success in a phase 3 trial; obeticholic acid looks very promising,” commented Philip N. Newsome, PhD, professor of experimental hepatology at the University of Birmingham (England).

Obeticholic acid (OCA), an agonist of the farnesoid X receptor, already has Food and Drug Administration marketing approval for the indication of primary biliary cholangitis, a much rarer disease than NASH.

Mitchel L. Zoler/MDedge News
Dr. Philip Newsome

The REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment) trial has so far enrolled 931 patients at about 350 sites in 20 countries, including the United States, and followed them during 18 months of treatment, the prespecified time for an interim analysis. The study enrolled adults with biopsy-proven NASH and generally focused on patients with either stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease activity score of at least 4. Enrolled patients averaged about 55 years old, slightly more than half the enrolled patients had type 2 diabetes, and more than half had stage 3 fibrosis.

 

 


The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.

For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.

The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.

Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.



Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.

REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.

Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.

REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.

Daily treatment of patients with nonalcoholic steatohepatitis with obeticholic acid led to a near doubling of patients who had fibrosis regression in a phase 3 trial with 931 patients, making obeticholic acid the first agent proven to improve the course of this disease.

“There is no doubt that with these data we have changed the treatment” of nonalcoholic steatohepatitis (NASH), Zobair M. Younossi, MD, of Inova Fairfax Medical Campus in Falls Church, Va., said at the meeting sponsored by the European Association for the Study of the Liver. “We are at a watershed moment” in NASH treatment, Dr. Younossi added in a video interview.

Until now “we have had no effective treatments for NASH. This is the first success in a phase 3 trial; obeticholic acid looks very promising,” commented Philip N. Newsome, PhD, professor of experimental hepatology at the University of Birmingham (England).

Obeticholic acid (OCA), an agonist of the farnesoid X receptor, already has Food and Drug Administration marketing approval for the indication of primary biliary cholangitis, a much rarer disease than NASH.

Mitchel L. Zoler/MDedge News
Dr. Philip Newsome

The REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment) trial has so far enrolled 931 patients at about 350 sites in 20 countries, including the United States, and followed them during 18 months of treatment, the prespecified time for an interim analysis. The study enrolled adults with biopsy-proven NASH and generally focused on patients with either stage 2 or 3 liver fibrosis and a nonalcoholic fatty liver disease activity score of at least 4. Enrolled patients averaged about 55 years old, slightly more than half the enrolled patients had type 2 diabetes, and more than half had stage 3 fibrosis.

 

 


The study design included two coprimary endpoints, and specified that a statistically significant finding for either outcome meant a positive trial result, but the design also prespecified that the benefit would need to meet a stringent definition of statistical significance, compared with placebo patients, with a P value of no more than .01. REGENERATE tested two different OCA dosages, 10 mg or 25 mg, once daily. The results showed a trend for benefit from the smaller dosage, but these effects did not achieve statistical significance.

For the primary endpoint of regression of liver fibrosis by at least one stage with no worsening of NASH the intention-to-treat analysis showed after 18 months a 13% rate with placebo, a 21% rate with the 10-mg dosage, and a 23% rate with the 25-mg dosage, a statistically significant improvement over placebo for the higher dosage.

The second primary endpoint was resolution of NASH without worsening liver fibrosis, which occurred in 8% of placebo patients, 11% of patients on 10 mg OCA/day and 12% of those on 25 mg/day. The differences between each of the active groups and the controls were not statistically significant for this endpoint.

Among the 931 enrolled patients 668 (72%) actually received treatment fully consistent with the study protocol, and among these per-protocol patients the benefit from 25 mg/day OCA was even more striking: a 28% rate of fibrosis regression, compared with 13% in the control patients. Regression by at least two fibrotic stages occurred in 5% of placebo patients and 13% of those on 25 mg/day OCA. Many treated patients also showed normalizations of liver enzyme levels.



Adverse events on OCA were mostly mild or moderate, with similar rates of serious adverse events in the OCA groups and in control patients. The most common adverse effect on OCA treatment was pruritus, a previously described effect, reported by 51% of patients on the 25 mg/day dosage and by 19% of control patients.

REGENERATE will continue until a goal level of endpoint events occur, and may eventually enroll as many as 2,400 patients and extend for a few more years. By then, Dr. Younossi said, he hopes that an analysis will be possible of “harder” endpoints than fibrosis, such as development of cirrhosis. He noted, however, that the FDA has designated fibrosis regression as a valid surrogate endpoint for assessing treatment efficacy for NASH.

Already on the U.S. market, a single 10-mg OCA pill currently retails for almost $230; a 25-mg formulation is not currently marketed. Dr. Younossi said that subsequent studies will assess the cost-effectiveness of OCA treatment for NASH. He also hopes that further study of patient characteristics will identify which NASH patients are most likely to respond to OCA. Eventually, OCA may be part of a multidrug strategy for treating this disease, Dr. Younossi said.

REGENERATE was sponsored by Intercept, the company that markets obeticholic acid (Ocaliva). Dr. Younossi is a consultant to and has received research funding from Intercept. He has also been a consultant to Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Quest, Siemens, Terns Pharmaceutical, and Viking Therapeutics. Dr. Newsome has been a consultant or speaker for Intercept as well as Boehringer Ingelheim, Dignity Sciences, Johnson & Johnson, Novo Nordisk, and Shire, and he has received research funding from Pharmaxis and Boehringer Ingelheim.

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ACP launches program to better implement QI projects

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The American College of Physicians has launched a program – ACP Advance – to help organizations better implement quality improvement (QI) projects .

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The program includes 12 months of virtual coaching for a cost, and free online module training, according to Daisy Smith, MD, FACP, who spoke at a press conference at the annual meeting of the American College of Physicians.

Dr. Smith, the ACP’s vice president of clinical programs, discussed additional aspects of ACP Advance with Selam Wubu, director of the ACP’s Center for Quality, in a video interview.

“We launched ACP Advance to engage physicians and their teams [and] empower them to engage and implement quality improvement that results in meaningful improvement for them and their patients,” Ms. Wubu said.

Dr. Smith and Ms. Wubu have no relevant disclosures.

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The American College of Physicians has launched a program – ACP Advance – to help organizations better implement quality improvement (QI) projects .

Vidyard Video

The program includes 12 months of virtual coaching for a cost, and free online module training, according to Daisy Smith, MD, FACP, who spoke at a press conference at the annual meeting of the American College of Physicians.

Dr. Smith, the ACP’s vice president of clinical programs, discussed additional aspects of ACP Advance with Selam Wubu, director of the ACP’s Center for Quality, in a video interview.

“We launched ACP Advance to engage physicians and their teams [and] empower them to engage and implement quality improvement that results in meaningful improvement for them and their patients,” Ms. Wubu said.

Dr. Smith and Ms. Wubu have no relevant disclosures.

 

The American College of Physicians has launched a program – ACP Advance – to help organizations better implement quality improvement (QI) projects .

Vidyard Video

The program includes 12 months of virtual coaching for a cost, and free online module training, according to Daisy Smith, MD, FACP, who spoke at a press conference at the annual meeting of the American College of Physicians.

Dr. Smith, the ACP’s vice president of clinical programs, discussed additional aspects of ACP Advance with Selam Wubu, director of the ACP’s Center for Quality, in a video interview.

“We launched ACP Advance to engage physicians and their teams [and] empower them to engage and implement quality improvement that results in meaningful improvement for them and their patients,” Ms. Wubu said.

Dr. Smith and Ms. Wubu have no relevant disclosures.

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Interventional endoscopic ultrasonography is hitting its stride

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SAN FRANCISCO – Interventional endoscopic ultrasonography (EUS) recently has brought transluminal stent placement to problems like walled off pancreatic necroses, Joo Ha Hwang, MD, PhD, professor of medicine at Stanford (Calif.) University, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. He sees EUS taking over surgical territory beyond the usual biopsies in the gastrointestinal and biliary tracts and soon moving into tumor treatment in these areas. The field is “rapidly expanding,” he said, and the value of these minimally invasive procedures means that the field will soon need to train more interventional endoscopists.

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SAN FRANCISCO – Interventional endoscopic ultrasonography (EUS) recently has brought transluminal stent placement to problems like walled off pancreatic necroses, Joo Ha Hwang, MD, PhD, professor of medicine at Stanford (Calif.) University, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. He sees EUS taking over surgical territory beyond the usual biopsies in the gastrointestinal and biliary tracts and soon moving into tumor treatment in these areas. The field is “rapidly expanding,” he said, and the value of these minimally invasive procedures means that the field will soon need to train more interventional endoscopists.

Vidyard Video

SAN FRANCISCO – Interventional endoscopic ultrasonography (EUS) recently has brought transluminal stent placement to problems like walled off pancreatic necroses, Joo Ha Hwang, MD, PhD, professor of medicine at Stanford (Calif.) University, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology. He sees EUS taking over surgical territory beyond the usual biopsies in the gastrointestinal and biliary tracts and soon moving into tumor treatment in these areas. The field is “rapidly expanding,” he said, and the value of these minimally invasive procedures means that the field will soon need to train more interventional endoscopists.

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Artificial intelligence and machine learning in gastroenterology

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SAN FRANCISCO – Artificial intelligence (AI) is using computer technology to solve particular kinds of medical problems, Sushovan Guha, MD, PhD, AGAF, chair, division of gastroenterology, University of Arizona, Phoenix, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology.

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Computers are good at doing many processes in a short period of time and executing repetitive tasks with no errors, whereas humans tend to introduce errors after many repetitions. Using algorithms by which physicians assess and diagnose colonic lesions, computer software can learn the criteria that diagnose adenomas and assist in the process of diagnosis, Dr. Guha said.

Computers are also ideal for managing and analyzing large amounts of data – this ability has so far been used to personalize cancer treatment – and is now being used to suggest the best treatment and predict remission in patients with inflammatory bowel disease. AI can use anatomical data combined with endoscopy to predict GI bleeding so that physicians can target therapy. Dr. Guha predicts that there will be an “explosion” of applications of AI in gastroenterology in the next 5-10 years.

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SAN FRANCISCO – Artificial intelligence (AI) is using computer technology to solve particular kinds of medical problems, Sushovan Guha, MD, PhD, AGAF, chair, division of gastroenterology, University of Arizona, Phoenix, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology.

Vidyard Video

Computers are good at doing many processes in a short period of time and executing repetitive tasks with no errors, whereas humans tend to introduce errors after many repetitions. Using algorithms by which physicians assess and diagnose colonic lesions, computer software can learn the criteria that diagnose adenomas and assist in the process of diagnosis, Dr. Guha said.

Computers are also ideal for managing and analyzing large amounts of data – this ability has so far been used to personalize cancer treatment – and is now being used to suggest the best treatment and predict remission in patients with inflammatory bowel disease. AI can use anatomical data combined with endoscopy to predict GI bleeding so that physicians can target therapy. Dr. Guha predicts that there will be an “explosion” of applications of AI in gastroenterology in the next 5-10 years.

SAN FRANCISCO – Artificial intelligence (AI) is using computer technology to solve particular kinds of medical problems, Sushovan Guha, MD, PhD, AGAF, chair, division of gastroenterology, University of Arizona, Phoenix, said in an interview at the AGA Tech Summit, sponsored by the AGA Center for GI Innovation and Technology.

Vidyard Video

Computers are good at doing many processes in a short period of time and executing repetitive tasks with no errors, whereas humans tend to introduce errors after many repetitions. Using algorithms by which physicians assess and diagnose colonic lesions, computer software can learn the criteria that diagnose adenomas and assist in the process of diagnosis, Dr. Guha said.

Computers are also ideal for managing and analyzing large amounts of data – this ability has so far been used to personalize cancer treatment – and is now being used to suggest the best treatment and predict remission in patients with inflammatory bowel disease. AI can use anatomical data combined with endoscopy to predict GI bleeding so that physicians can target therapy. Dr. Guha predicts that there will be an “explosion” of applications of AI in gastroenterology in the next 5-10 years.

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Research coalition issues plan for curing hepatitis B virus

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An international coalition of hepatitis B virus researchers, patients, and health organizations have released a comprehensive plan for developing a cure for this infection. They hope either to have a cure or to have made substantial progress toward this goal over the next 10 years.

Treatments already are on the market that effectively inhibit hepatitis B replication in infected patients (and an effective preventive vaccine also exists). Still, these treatments are not curative, and for the vast majority of patients treatment must continue indefinitely, while their risk for liver cancer and their virally induced immune system abnormalities remain, Peter A. Revill, PhD, said during a press briefing that introduced a strategy for hepatitis B virus (HBV) cure development from the International Coalition to Eliminate HBV. Concurrently with the briefing session, the strategy appeared in an article published online (Lancet Gastroenterol Hepatol. 2019 Apr 10. doi: 10.1016/s2468-1253(19)30119-0).

The way forward will likely be a “two-pronged approach or restoring immune responses and targeting the virus,” Dr. Revill, head of molecular virology at the Doherty Institute in Melbourne, said in a video interview.

Mitchel L. Zoler/MDedge News
Dr. Anna S. Lok

The new strategy recognizes the huge challenge of devising a treatment that produces a total cure that includes elimination of all traces of viral DNA from patients and for the immediate future focuses on the goal of functional cure. The term functional cure means a sustained period without detectable HBV surface antigen or HBV DNA in a patient’s serum, as well as suppressed virus release. Another feature of a functional cure would be a halt to progression of liver disease, replaced by liver regeneration, said Anna S. Lok, MD, professor of medicine and director of clinical hepatology at the University of Michigan, Ann Arbor, and a member of the strategy-writing group. She and her colleagues who wrote the strategy foresee the need for drug combinations with agents that can hit multiple viral targets as well as agents that restore normal immune function.

 

 



Mitchel L. Zoler/MDedge News
Dr. Fabien Zoulim

Several novel drug classes aimed at new viral targets, such as capsid inhibitors, are in various stages of clinical development, said Fabien Zoulim, MD, head of the gastroenterology and hepatology service at the Red Cross Hospital in Lyon, France, and another member of the writing panel. “We have many drug candidates” that use novel approaches to further restrict viral growth, roughly 50 agents in phase 1 and 2 studies, he said during the press briefing, held during the meeting sponsored by the European Association for the Study of the Liver. The other, immunologic aspect of the two-part cure strategy – restoring the “exhausted” HBV-specific T-cell population and stimulating production of neutralizing antibody to HBV – remains hypothetical right now, however. “It’s a concept that needs development,” Dr. Zoulim said.



A reason members of the coalition are optimistic about eventual prospects for a cure is that currently about 1% of patients on HBV antiviral treatments have a functional cure after relatively brief treatment, and the percentage of cured patients plateaus at about 10% among those who remain on current HBV antiviral drugs for several years. In addition, a substantial fraction of patients spontaneously resolve their HBV infection without any treatment. Experts estimate that more than 1 billion people worldwide have been infected by HBV and then later had their infection clear “naturally,” said Dr. Revill. But the mechanism by which this happens is currently a mystery. “We don’t know how or why” so many infected people are “cured” naturally, Dr. Revill admitted, but it gives him and his colleagues hope that the numbers can expand once more and better treatments for HBV infection are available.

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An international coalition of hepatitis B virus researchers, patients, and health organizations have released a comprehensive plan for developing a cure for this infection. They hope either to have a cure or to have made substantial progress toward this goal over the next 10 years.

Treatments already are on the market that effectively inhibit hepatitis B replication in infected patients (and an effective preventive vaccine also exists). Still, these treatments are not curative, and for the vast majority of patients treatment must continue indefinitely, while their risk for liver cancer and their virally induced immune system abnormalities remain, Peter A. Revill, PhD, said during a press briefing that introduced a strategy for hepatitis B virus (HBV) cure development from the International Coalition to Eliminate HBV. Concurrently with the briefing session, the strategy appeared in an article published online (Lancet Gastroenterol Hepatol. 2019 Apr 10. doi: 10.1016/s2468-1253(19)30119-0).

The way forward will likely be a “two-pronged approach or restoring immune responses and targeting the virus,” Dr. Revill, head of molecular virology at the Doherty Institute in Melbourne, said in a video interview.

Mitchel L. Zoler/MDedge News
Dr. Anna S. Lok

The new strategy recognizes the huge challenge of devising a treatment that produces a total cure that includes elimination of all traces of viral DNA from patients and for the immediate future focuses on the goal of functional cure. The term functional cure means a sustained period without detectable HBV surface antigen or HBV DNA in a patient’s serum, as well as suppressed virus release. Another feature of a functional cure would be a halt to progression of liver disease, replaced by liver regeneration, said Anna S. Lok, MD, professor of medicine and director of clinical hepatology at the University of Michigan, Ann Arbor, and a member of the strategy-writing group. She and her colleagues who wrote the strategy foresee the need for drug combinations with agents that can hit multiple viral targets as well as agents that restore normal immune function.

 

 



Mitchel L. Zoler/MDedge News
Dr. Fabien Zoulim

Several novel drug classes aimed at new viral targets, such as capsid inhibitors, are in various stages of clinical development, said Fabien Zoulim, MD, head of the gastroenterology and hepatology service at the Red Cross Hospital in Lyon, France, and another member of the writing panel. “We have many drug candidates” that use novel approaches to further restrict viral growth, roughly 50 agents in phase 1 and 2 studies, he said during the press briefing, held during the meeting sponsored by the European Association for the Study of the Liver. The other, immunologic aspect of the two-part cure strategy – restoring the “exhausted” HBV-specific T-cell population and stimulating production of neutralizing antibody to HBV – remains hypothetical right now, however. “It’s a concept that needs development,” Dr. Zoulim said.



A reason members of the coalition are optimistic about eventual prospects for a cure is that currently about 1% of patients on HBV antiviral treatments have a functional cure after relatively brief treatment, and the percentage of cured patients plateaus at about 10% among those who remain on current HBV antiviral drugs for several years. In addition, a substantial fraction of patients spontaneously resolve their HBV infection without any treatment. Experts estimate that more than 1 billion people worldwide have been infected by HBV and then later had their infection clear “naturally,” said Dr. Revill. But the mechanism by which this happens is currently a mystery. “We don’t know how or why” so many infected people are “cured” naturally, Dr. Revill admitted, but it gives him and his colleagues hope that the numbers can expand once more and better treatments for HBV infection are available.

An international coalition of hepatitis B virus researchers, patients, and health organizations have released a comprehensive plan for developing a cure for this infection. They hope either to have a cure or to have made substantial progress toward this goal over the next 10 years.

Treatments already are on the market that effectively inhibit hepatitis B replication in infected patients (and an effective preventive vaccine also exists). Still, these treatments are not curative, and for the vast majority of patients treatment must continue indefinitely, while their risk for liver cancer and their virally induced immune system abnormalities remain, Peter A. Revill, PhD, said during a press briefing that introduced a strategy for hepatitis B virus (HBV) cure development from the International Coalition to Eliminate HBV. Concurrently with the briefing session, the strategy appeared in an article published online (Lancet Gastroenterol Hepatol. 2019 Apr 10. doi: 10.1016/s2468-1253(19)30119-0).

The way forward will likely be a “two-pronged approach or restoring immune responses and targeting the virus,” Dr. Revill, head of molecular virology at the Doherty Institute in Melbourne, said in a video interview.

Mitchel L. Zoler/MDedge News
Dr. Anna S. Lok

The new strategy recognizes the huge challenge of devising a treatment that produces a total cure that includes elimination of all traces of viral DNA from patients and for the immediate future focuses on the goal of functional cure. The term functional cure means a sustained period without detectable HBV surface antigen or HBV DNA in a patient’s serum, as well as suppressed virus release. Another feature of a functional cure would be a halt to progression of liver disease, replaced by liver regeneration, said Anna S. Lok, MD, professor of medicine and director of clinical hepatology at the University of Michigan, Ann Arbor, and a member of the strategy-writing group. She and her colleagues who wrote the strategy foresee the need for drug combinations with agents that can hit multiple viral targets as well as agents that restore normal immune function.

 

 



Mitchel L. Zoler/MDedge News
Dr. Fabien Zoulim

Several novel drug classes aimed at new viral targets, such as capsid inhibitors, are in various stages of clinical development, said Fabien Zoulim, MD, head of the gastroenterology and hepatology service at the Red Cross Hospital in Lyon, France, and another member of the writing panel. “We have many drug candidates” that use novel approaches to further restrict viral growth, roughly 50 agents in phase 1 and 2 studies, he said during the press briefing, held during the meeting sponsored by the European Association for the Study of the Liver. The other, immunologic aspect of the two-part cure strategy – restoring the “exhausted” HBV-specific T-cell population and stimulating production of neutralizing antibody to HBV – remains hypothetical right now, however. “It’s a concept that needs development,” Dr. Zoulim said.



A reason members of the coalition are optimistic about eventual prospects for a cure is that currently about 1% of patients on HBV antiviral treatments have a functional cure after relatively brief treatment, and the percentage of cured patients plateaus at about 10% among those who remain on current HBV antiviral drugs for several years. In addition, a substantial fraction of patients spontaneously resolve their HBV infection without any treatment. Experts estimate that more than 1 billion people worldwide have been infected by HBV and then later had their infection clear “naturally,” said Dr. Revill. But the mechanism by which this happens is currently a mystery. “We don’t know how or why” so many infected people are “cured” naturally, Dr. Revill admitted, but it gives him and his colleagues hope that the numbers can expand once more and better treatments for HBV infection are available.

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Geroscience brings bench science to the real-world problems of aging

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Fri, 08/06/2021 - 13:51

– Patients ask their doctors whether dietary manipulation can extend lifespan and promote healthy aging. Right now, basic scientists and clinicians from many disciplines are teaming up under the broad umbrella of the field of geroscience to try to answer these and other concerns relevant to an aging population.

“The idea here is that, instead of going after each disease one at a time, as we do ... [we] instead go after disease vulnerability – and this is something that is shared, as a function of age,” Rozalyn Anderson, PhD, said of this new discipline. The work touches on disparate diseases such as cancer, dementia, and diabetes, she pointed out during a video interview at the annual meeting of the Endocrine Society.

“I separate these things out into ‘front-end’ and ‘back-end,’ work,” said Dr. Anderson of the University of Wisconsin-Madison’s aging and caloric restriction program. She explained that the caloric restriction she researches is back-end work to support the rapidly evolving field of nutritional modulation of aging.

When the basic science builds the framework, physicians and scientists can turn to front-end research, looking at humans to see which dietary manipulations are effective – and which are achievable.

“Take a paradigm that works, and then try to understand how it works,” said Dr. Anderson. “So [for example], we have this paradigm, and it’s tremendously effective in rodents. It’s effective in flies, in worms, in yeast, in spiders, in dogs – and in nonhuman primates.” Then, she and her team try to pull out clues “about the biology of aging itself, and what creates disease vulnerability as a function of age,” she said.

“The most important thing of all is that we can modify aging. This is not a foregone conclusion – no one would have believed it. But even in a primate species, we can change how they age. And the way in which we change is through nutrition.”

Dr Anderson added that “the paradigm of caloric restriction is tremendously effective, but [in reality], people are not going to do it.” It’s simply not practical to ask individuals to restrict calories by 30% or more over a lifespan, so “things such as intermittent fasting and time-restricted feeding come [into play] because they are achievable paradigms in normal human subjects.”

Dr. Anderson reported no relevant conflicts of interest or disclosures.

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– Patients ask their doctors whether dietary manipulation can extend lifespan and promote healthy aging. Right now, basic scientists and clinicians from many disciplines are teaming up under the broad umbrella of the field of geroscience to try to answer these and other concerns relevant to an aging population.

“The idea here is that, instead of going after each disease one at a time, as we do ... [we] instead go after disease vulnerability – and this is something that is shared, as a function of age,” Rozalyn Anderson, PhD, said of this new discipline. The work touches on disparate diseases such as cancer, dementia, and diabetes, she pointed out during a video interview at the annual meeting of the Endocrine Society.

“I separate these things out into ‘front-end’ and ‘back-end,’ work,” said Dr. Anderson of the University of Wisconsin-Madison’s aging and caloric restriction program. She explained that the caloric restriction she researches is back-end work to support the rapidly evolving field of nutritional modulation of aging.

When the basic science builds the framework, physicians and scientists can turn to front-end research, looking at humans to see which dietary manipulations are effective – and which are achievable.

“Take a paradigm that works, and then try to understand how it works,” said Dr. Anderson. “So [for example], we have this paradigm, and it’s tremendously effective in rodents. It’s effective in flies, in worms, in yeast, in spiders, in dogs – and in nonhuman primates.” Then, she and her team try to pull out clues “about the biology of aging itself, and what creates disease vulnerability as a function of age,” she said.

“The most important thing of all is that we can modify aging. This is not a foregone conclusion – no one would have believed it. But even in a primate species, we can change how they age. And the way in which we change is through nutrition.”

Dr Anderson added that “the paradigm of caloric restriction is tremendously effective, but [in reality], people are not going to do it.” It’s simply not practical to ask individuals to restrict calories by 30% or more over a lifespan, so “things such as intermittent fasting and time-restricted feeding come [into play] because they are achievable paradigms in normal human subjects.”

Dr. Anderson reported no relevant conflicts of interest or disclosures.

– Patients ask their doctors whether dietary manipulation can extend lifespan and promote healthy aging. Right now, basic scientists and clinicians from many disciplines are teaming up under the broad umbrella of the field of geroscience to try to answer these and other concerns relevant to an aging population.

“The idea here is that, instead of going after each disease one at a time, as we do ... [we] instead go after disease vulnerability – and this is something that is shared, as a function of age,” Rozalyn Anderson, PhD, said of this new discipline. The work touches on disparate diseases such as cancer, dementia, and diabetes, she pointed out during a video interview at the annual meeting of the Endocrine Society.

“I separate these things out into ‘front-end’ and ‘back-end,’ work,” said Dr. Anderson of the University of Wisconsin-Madison’s aging and caloric restriction program. She explained that the caloric restriction she researches is back-end work to support the rapidly evolving field of nutritional modulation of aging.

When the basic science builds the framework, physicians and scientists can turn to front-end research, looking at humans to see which dietary manipulations are effective – and which are achievable.

“Take a paradigm that works, and then try to understand how it works,” said Dr. Anderson. “So [for example], we have this paradigm, and it’s tremendously effective in rodents. It’s effective in flies, in worms, in yeast, in spiders, in dogs – and in nonhuman primates.” Then, she and her team try to pull out clues “about the biology of aging itself, and what creates disease vulnerability as a function of age,” she said.

“The most important thing of all is that we can modify aging. This is not a foregone conclusion – no one would have believed it. But even in a primate species, we can change how they age. And the way in which we change is through nutrition.”

Dr Anderson added that “the paradigm of caloric restriction is tremendously effective, but [in reality], people are not going to do it.” It’s simply not practical to ask individuals to restrict calories by 30% or more over a lifespan, so “things such as intermittent fasting and time-restricted feeding come [into play] because they are achievable paradigms in normal human subjects.”

Dr. Anderson reported no relevant conflicts of interest or disclosures.

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Intermittent, but prolonged, calorie restriction may improve metabolic markers

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Thu, 06/29/2023 - 16:01

– Can a physician-supervised, intermittent fasting strategy improve metabolic risk? Yes, according to Valter Longo, PhD.

Dr. Longo is a proponent of 5 days of reduced calories, performed once monthly or even less frequently for at-risk individuals. He calls this the “fasting-mimicking diet.”

“If somebody is obese or overweight, and has high cholesterol, high fasting glucose, and is perhaps prediabetic, then a doctor may decide to do the diet once a month for 5 days, and for the rest of the month, the person can go back to whatever it is that they do,” he said in a video interview at the annual meeting of the Endocrine Society.

“We think we are going to see more and more of this approach in the future,” said Dr. Longo, the Edna M. Jones Professor of Gerontology at the University of Southern California, Los Angeles.

Dr. Longo sees two chief practical benefits from the diet. First, patients “don’t feel they are being pushed to revolutionize their lives” because they aren’t asked to make radical lifestyle changes that have to be adhered to on a daily basis, and second, “we are starting to see that the patient slowly moves in the direction of a better diet without being asked to do it.”

A clinical trial with about 100 patients showed improvements in many metabolic markers after 3 months of a once-monthly, 5-day cycle of the low-calorie diet, which includes some healthy fats from olive oil and nuts. Fasting blood glucose, blood pressure, and insulinlike growth factor 1 levels and other metabolic markers were all reduced in the randomized crossover trial after 3 months of the diet plan.

Dr. Longo noted that in the clinical trial, effects were more pronounced for individuals with a higher risk for disease.

Dr. Longo has a majority stake in L-Nutra, which markets a commercially available fasting-mimicking diet package. He donates his proceeds to a nonprofit corporation he founded.

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– Can a physician-supervised, intermittent fasting strategy improve metabolic risk? Yes, according to Valter Longo, PhD.

Dr. Longo is a proponent of 5 days of reduced calories, performed once monthly or even less frequently for at-risk individuals. He calls this the “fasting-mimicking diet.”

“If somebody is obese or overweight, and has high cholesterol, high fasting glucose, and is perhaps prediabetic, then a doctor may decide to do the diet once a month for 5 days, and for the rest of the month, the person can go back to whatever it is that they do,” he said in a video interview at the annual meeting of the Endocrine Society.

“We think we are going to see more and more of this approach in the future,” said Dr. Longo, the Edna M. Jones Professor of Gerontology at the University of Southern California, Los Angeles.

Dr. Longo sees two chief practical benefits from the diet. First, patients “don’t feel they are being pushed to revolutionize their lives” because they aren’t asked to make radical lifestyle changes that have to be adhered to on a daily basis, and second, “we are starting to see that the patient slowly moves in the direction of a better diet without being asked to do it.”

A clinical trial with about 100 patients showed improvements in many metabolic markers after 3 months of a once-monthly, 5-day cycle of the low-calorie diet, which includes some healthy fats from olive oil and nuts. Fasting blood glucose, blood pressure, and insulinlike growth factor 1 levels and other metabolic markers were all reduced in the randomized crossover trial after 3 months of the diet plan.

Dr. Longo noted that in the clinical trial, effects were more pronounced for individuals with a higher risk for disease.

Dr. Longo has a majority stake in L-Nutra, which markets a commercially available fasting-mimicking diet package. He donates his proceeds to a nonprofit corporation he founded.

– Can a physician-supervised, intermittent fasting strategy improve metabolic risk? Yes, according to Valter Longo, PhD.

Dr. Longo is a proponent of 5 days of reduced calories, performed once monthly or even less frequently for at-risk individuals. He calls this the “fasting-mimicking diet.”

“If somebody is obese or overweight, and has high cholesterol, high fasting glucose, and is perhaps prediabetic, then a doctor may decide to do the diet once a month for 5 days, and for the rest of the month, the person can go back to whatever it is that they do,” he said in a video interview at the annual meeting of the Endocrine Society.

“We think we are going to see more and more of this approach in the future,” said Dr. Longo, the Edna M. Jones Professor of Gerontology at the University of Southern California, Los Angeles.

Dr. Longo sees two chief practical benefits from the diet. First, patients “don’t feel they are being pushed to revolutionize their lives” because they aren’t asked to make radical lifestyle changes that have to be adhered to on a daily basis, and second, “we are starting to see that the patient slowly moves in the direction of a better diet without being asked to do it.”

A clinical trial with about 100 patients showed improvements in many metabolic markers after 3 months of a once-monthly, 5-day cycle of the low-calorie diet, which includes some healthy fats from olive oil and nuts. Fasting blood glucose, blood pressure, and insulinlike growth factor 1 levels and other metabolic markers were all reduced in the randomized crossover trial after 3 months of the diet plan.

Dr. Longo noted that in the clinical trial, effects were more pronounced for individuals with a higher risk for disease.

Dr. Longo has a majority stake in L-Nutra, which markets a commercially available fasting-mimicking diet package. He donates his proceeds to a nonprofit corporation he founded.

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Expert gives tips on timing, managing lupus pregnancies

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Fri, 06/04/2021 - 17:01

– Not that many years ago, women with systemic lupus erythematosus were told not to get pregnant. It was just one more lupus heartbreak.

Times have changed, according to Lisa Sammaritano, MD, a lupus specialist and associate professor of clinical medicine at Weill Cornell Medical College, New York.

While lupus certainly complicates pregnancy, it by no means rules it out these days. With careful management, the dream of motherhood can become a reality for many women. Dr. Sammaritano shared her insights about timing and treatment at an international congress on systemic lupus erythematosus.

It’s important that the disease is under control as much as possible; that means that timing – and contraception – are key. Antiphospholipid antibodies, common in lupus, complicate matters, but there are workarounds, she said.

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– Not that many years ago, women with systemic lupus erythematosus were told not to get pregnant. It was just one more lupus heartbreak.

Times have changed, according to Lisa Sammaritano, MD, a lupus specialist and associate professor of clinical medicine at Weill Cornell Medical College, New York.

While lupus certainly complicates pregnancy, it by no means rules it out these days. With careful management, the dream of motherhood can become a reality for many women. Dr. Sammaritano shared her insights about timing and treatment at an international congress on systemic lupus erythematosus.

It’s important that the disease is under control as much as possible; that means that timing – and contraception – are key. Antiphospholipid antibodies, common in lupus, complicate matters, but there are workarounds, she said.

– Not that many years ago, women with systemic lupus erythematosus were told not to get pregnant. It was just one more lupus heartbreak.

Times have changed, according to Lisa Sammaritano, MD, a lupus specialist and associate professor of clinical medicine at Weill Cornell Medical College, New York.

While lupus certainly complicates pregnancy, it by no means rules it out these days. With careful management, the dream of motherhood can become a reality for many women. Dr. Sammaritano shared her insights about timing and treatment at an international congress on systemic lupus erythematosus.

It’s important that the disease is under control as much as possible; that means that timing – and contraception – are key. Antiphospholipid antibodies, common in lupus, complicate matters, but there are workarounds, she said.

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AT LUPUS 2019

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HM19: Lessons from the Update in Hospital Medicine session

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Fri, 04/05/2019 - 17:52
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In the second of two episodes, Amith Skandhan, MD, FHM, of Southeast Alabama Medical Center, Dothan, Ala., and Raman Palabindala, MD, SFHM, of the University of Mississippi Medical Center, Jackson, Miss., discuss more of their favorite lessons from the annual meeting of the Society of Hospital Medicine. Dr. Skandhan and Dr. Palabindala share practice-changing takeaways from the Update in Hospital Medicine session.

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Vidyard Video

In the second of two episodes, Amith Skandhan, MD, FHM, of Southeast Alabama Medical Center, Dothan, Ala., and Raman Palabindala, MD, SFHM, of the University of Mississippi Medical Center, Jackson, Miss., discuss more of their favorite lessons from the annual meeting of the Society of Hospital Medicine. Dr. Skandhan and Dr. Palabindala share practice-changing takeaways from the Update in Hospital Medicine session.

Vidyard Video

In the second of two episodes, Amith Skandhan, MD, FHM, of Southeast Alabama Medical Center, Dothan, Ala., and Raman Palabindala, MD, SFHM, of the University of Mississippi Medical Center, Jackson, Miss., discuss more of their favorite lessons from the annual meeting of the Society of Hospital Medicine. Dr. Skandhan and Dr. Palabindala share practice-changing takeaways from the Update in Hospital Medicine session.

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HM19: Key takeaways on quality and innovation

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Fri, 04/05/2019 - 17:39
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In the first of two episodes, Amith Skandhan, MD, FHM, of Southeast Alabama Medical Center, Dothan, Ala., and Raman Palabindala, MD, SFHM, of the University of Mississippi Medical Center, Jackson, Miss., discuss their favorite lessons from the annual meeting of the Society of Hospital Medicine. Dr. Skandhan and Dr. Palabindala review key points from sessions on quality and patient safety, caring for the complex medically ill, using data analytics to drive clinical change, and the best studies from the Research and Innovation poster competition.

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Vidyard Video

In the first of two episodes, Amith Skandhan, MD, FHM, of Southeast Alabama Medical Center, Dothan, Ala., and Raman Palabindala, MD, SFHM, of the University of Mississippi Medical Center, Jackson, Miss., discuss their favorite lessons from the annual meeting of the Society of Hospital Medicine. Dr. Skandhan and Dr. Palabindala review key points from sessions on quality and patient safety, caring for the complex medically ill, using data analytics to drive clinical change, and the best studies from the Research and Innovation poster competition.

Vidyard Video

In the first of two episodes, Amith Skandhan, MD, FHM, of Southeast Alabama Medical Center, Dothan, Ala., and Raman Palabindala, MD, SFHM, of the University of Mississippi Medical Center, Jackson, Miss., discuss their favorite lessons from the annual meeting of the Society of Hospital Medicine. Dr. Skandhan and Dr. Palabindala review key points from sessions on quality and patient safety, caring for the complex medically ill, using data analytics to drive clinical change, and the best studies from the Research and Innovation poster competition.

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