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Hot topics in 2017

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The 2017 Postgraduate Course started out with four hot topics that dominated the year – opioid dependence, a cure for hepatitis C, and understanding and then manipulating the microbiome. From David Dickerson, MD, we learned that abdominal pain is complex and with an evolving classification scheme. Ignoring the biopsychosocial aspects and origins of pain is a sure way to lead to addiction and “pain behavior.” He reviewed the opioid guidelines that involve a comprehensive approach to therapy – setting functional goals, assessing the risks and benefits, and using the lowest necessary doses of short-acting agents for a defined period of time and then reassessing. In patients with chronic pain and opioid dependence, the gastroenterologist should seek the help of a chronic pain specialist. We should also refer for nonpharmacologic therapy such as cognitive behavioral therapy and biofeedback.

Dr. Uma Mahadevan
From there, Octavia Pickett-Blakely MD, MHS, took us through the role of the microbiome in obesity (wouldn’t it be great to take probiotics or an annual fecal microbial transplant [FMT] to keep our weight under control?). She discussed the likely link between obesity and antibiotic use in early childhood and the different gut microbiota compositions in the obese and lean. Altered gut microbiota can affect energy homeostasis, which can then lead to obesity. She discussed the potential role of breastfeeding, low-fat, low-calorie, and high-fruit-vegetable-fiber diets on increasing microbial richness and reducing obesity. While diet and a sedentary lifestyle remain the primary drivers of obesity, host genetics, environment, and gut permeability all play a role.

Norah Terrault, MD, MPH, discussed management of chronic hepatitis C (HCV) after the cure, achievable in more than 95% of patients, which has resulted in a sharp decline in listings for liver transplant. A cure is defined as undetectable HCV RNA 12 weeks after completion of therapy. So what happens next? If the patient is at risk for reinfection, they should have HCV RNA testing annually or if their liver enzymes increase. Otherwise, if their pretreatment fibrosis is low stage, no further monitoring is needed and they can follow up with their primary care provider. Intermediate-stage fibrosis should be monitored for progression. Advanced-stage fibrosis needs long-term follow-up for hepatocellular carcinoma and variceal surveillance. Modifiable risk factors, i.e., metabolic fatty liver and alcohol abuse, should be identified with appropriate counseling provided.

We went back to the microbiome for our last talk: Larry Brandt, MD, AGAF, discussed FMT for Clostridium difficile infection (CDI). Patients should be considered for FMT if they have more than 3 recurrences of mild to moderate CDI and failure to respond to standard therapy; more than 2 episodes of CDI resulting in hospitalization and significant morbidity; moderate CDI with no response after 1 week of standard therapy; and severe CDI with no response to standard therapy within 48 hours. Serious adverse events associated with FMT include infections and perhaps new-onset immune-mediated disease such as Sjogren’s, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. It is hoped that the NIH-sponsored AGA national registry for FMT will help better define outcomes and adverse events over the next 10 years.
 

Dr. Mahadevan is professor of clinical medicine at UCSF Medical Center, San Francisco. This is a summary provided by the moderator of one of the AGA Postgraduate Courses held at DDW 2017.

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The 2017 Postgraduate Course started out with four hot topics that dominated the year – opioid dependence, a cure for hepatitis C, and understanding and then manipulating the microbiome. From David Dickerson, MD, we learned that abdominal pain is complex and with an evolving classification scheme. Ignoring the biopsychosocial aspects and origins of pain is a sure way to lead to addiction and “pain behavior.” He reviewed the opioid guidelines that involve a comprehensive approach to therapy – setting functional goals, assessing the risks and benefits, and using the lowest necessary doses of short-acting agents for a defined period of time and then reassessing. In patients with chronic pain and opioid dependence, the gastroenterologist should seek the help of a chronic pain specialist. We should also refer for nonpharmacologic therapy such as cognitive behavioral therapy and biofeedback.

Dr. Uma Mahadevan
From there, Octavia Pickett-Blakely MD, MHS, took us through the role of the microbiome in obesity (wouldn’t it be great to take probiotics or an annual fecal microbial transplant [FMT] to keep our weight under control?). She discussed the likely link between obesity and antibiotic use in early childhood and the different gut microbiota compositions in the obese and lean. Altered gut microbiota can affect energy homeostasis, which can then lead to obesity. She discussed the potential role of breastfeeding, low-fat, low-calorie, and high-fruit-vegetable-fiber diets on increasing microbial richness and reducing obesity. While diet and a sedentary lifestyle remain the primary drivers of obesity, host genetics, environment, and gut permeability all play a role.

Norah Terrault, MD, MPH, discussed management of chronic hepatitis C (HCV) after the cure, achievable in more than 95% of patients, which has resulted in a sharp decline in listings for liver transplant. A cure is defined as undetectable HCV RNA 12 weeks after completion of therapy. So what happens next? If the patient is at risk for reinfection, they should have HCV RNA testing annually or if their liver enzymes increase. Otherwise, if their pretreatment fibrosis is low stage, no further monitoring is needed and they can follow up with their primary care provider. Intermediate-stage fibrosis should be monitored for progression. Advanced-stage fibrosis needs long-term follow-up for hepatocellular carcinoma and variceal surveillance. Modifiable risk factors, i.e., metabolic fatty liver and alcohol abuse, should be identified with appropriate counseling provided.

We went back to the microbiome for our last talk: Larry Brandt, MD, AGAF, discussed FMT for Clostridium difficile infection (CDI). Patients should be considered for FMT if they have more than 3 recurrences of mild to moderate CDI and failure to respond to standard therapy; more than 2 episodes of CDI resulting in hospitalization and significant morbidity; moderate CDI with no response after 1 week of standard therapy; and severe CDI with no response to standard therapy within 48 hours. Serious adverse events associated with FMT include infections and perhaps new-onset immune-mediated disease such as Sjogren’s, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. It is hoped that the NIH-sponsored AGA national registry for FMT will help better define outcomes and adverse events over the next 10 years.
 

Dr. Mahadevan is professor of clinical medicine at UCSF Medical Center, San Francisco. This is a summary provided by the moderator of one of the AGA Postgraduate Courses held at DDW 2017.

 

The 2017 Postgraduate Course started out with four hot topics that dominated the year – opioid dependence, a cure for hepatitis C, and understanding and then manipulating the microbiome. From David Dickerson, MD, we learned that abdominal pain is complex and with an evolving classification scheme. Ignoring the biopsychosocial aspects and origins of pain is a sure way to lead to addiction and “pain behavior.” He reviewed the opioid guidelines that involve a comprehensive approach to therapy – setting functional goals, assessing the risks and benefits, and using the lowest necessary doses of short-acting agents for a defined period of time and then reassessing. In patients with chronic pain and opioid dependence, the gastroenterologist should seek the help of a chronic pain specialist. We should also refer for nonpharmacologic therapy such as cognitive behavioral therapy and biofeedback.

Dr. Uma Mahadevan
From there, Octavia Pickett-Blakely MD, MHS, took us through the role of the microbiome in obesity (wouldn’t it be great to take probiotics or an annual fecal microbial transplant [FMT] to keep our weight under control?). She discussed the likely link between obesity and antibiotic use in early childhood and the different gut microbiota compositions in the obese and lean. Altered gut microbiota can affect energy homeostasis, which can then lead to obesity. She discussed the potential role of breastfeeding, low-fat, low-calorie, and high-fruit-vegetable-fiber diets on increasing microbial richness and reducing obesity. While diet and a sedentary lifestyle remain the primary drivers of obesity, host genetics, environment, and gut permeability all play a role.

Norah Terrault, MD, MPH, discussed management of chronic hepatitis C (HCV) after the cure, achievable in more than 95% of patients, which has resulted in a sharp decline in listings for liver transplant. A cure is defined as undetectable HCV RNA 12 weeks after completion of therapy. So what happens next? If the patient is at risk for reinfection, they should have HCV RNA testing annually or if their liver enzymes increase. Otherwise, if their pretreatment fibrosis is low stage, no further monitoring is needed and they can follow up with their primary care provider. Intermediate-stage fibrosis should be monitored for progression. Advanced-stage fibrosis needs long-term follow-up for hepatocellular carcinoma and variceal surveillance. Modifiable risk factors, i.e., metabolic fatty liver and alcohol abuse, should be identified with appropriate counseling provided.

We went back to the microbiome for our last talk: Larry Brandt, MD, AGAF, discussed FMT for Clostridium difficile infection (CDI). Patients should be considered for FMT if they have more than 3 recurrences of mild to moderate CDI and failure to respond to standard therapy; more than 2 episodes of CDI resulting in hospitalization and significant morbidity; moderate CDI with no response after 1 week of standard therapy; and severe CDI with no response to standard therapy within 48 hours. Serious adverse events associated with FMT include infections and perhaps new-onset immune-mediated disease such as Sjogren’s, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. It is hoped that the NIH-sponsored AGA national registry for FMT will help better define outcomes and adverse events over the next 10 years.
 

Dr. Mahadevan is professor of clinical medicine at UCSF Medical Center, San Francisco. This is a summary provided by the moderator of one of the AGA Postgraduate Courses held at DDW 2017.

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NASH did not increase risk of poor liver transplantation outcomes

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Adults with nonalcoholic steatohepatitis (NASH) fared as well on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities, according to the results of a single-center retrospective cohort study.

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Adults with nonalcoholic steatohepatitis (NASH) fared as well on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities, according to the results of a single-center retrospective cohort study.

 

Adults with nonalcoholic steatohepatitis (NASH) fared as well on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities, according to the results of a single-center retrospective cohort study.

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FROM DIGESTIVE AND LIVER DISEASES

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Key clinical point: Adults with nonalcoholic steatohepatitis (NASH) fared as well as on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities.

Major finding: Patients with and without NASH had statistically similar rates of postoperative mortality (3% in both groups), 90-day graft survival (94% and 90%, respectively), and major postoperative complications.

Data source: A single-center retrospective cohort study of 169 adult liver transplant recipients, of whom 20% were transplanted for NASH cirrhosis.

Disclosures: The investigators received no funding for the study and reported having no conflicts of interest.

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FDA approves faster, pangenotypic cure for hep C virus

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The first pangenotypic treatment for the hepatitis C virus, which also shaves 4 weeks off current regimens, has just been approved by the Food and Drug Administration.

Manufactured by AbbVie, glecaprevir/pibrentasvir (Mavyret) combines a nonstructural protein 3/4A protease inhibitor with a next-generation NS5A protein inhibitor for a once-daily, ribavirin-free treatment for adults with any of the major genotypes of chronic hepatitis C virus (HCV) infection.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” Edward Cox, MD, director of the office of antimicrobial products in the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md., said in a statement.



The 8-week regimen is indicated in patients without cirrhosis or with compensated cirrhosis, who are new to treatment, and those with limited treatment options, such as patients with chronic kidney disease, including those on dialysis. The intervention also is indicated in adults with HCV genotype 1 who have been treated with either of the drugs in the combination, but not both. Glecaprevir/pibrentasvir is not recommended in patients with moderate cirrhosis and is contraindicated in patients with severe cirrhosis and in those taking the drugs atazanavir and rifampin.

The safety and efficacy of the treatment were evaluated in approximately 2,300 adults with genotype 1, 2, 3, 4, 5 or 6 HCV infection without cirrhosis or with mild cirrhosis. In the clinical trials, between 92% and 100% of patients treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks had no detectable serum levels of the virus 12 weeks after finishing treatment. The most commonly reported adverse reactions were headache, fatigue, and nausea.

The FDA directs health care professionals to test all patients for current or prior hepatitis B virus (HBV) infection prior to starting this direct-acting antiviral drug combination since HBV reactivation has been reported in adult patients coinfected with both viruses who were undergoing or had completed treatment with HCV direct-acting antivirals and who were not receiving HBV antiviral therapy.

The AGA HCV Clinical Service Line provides tools to help you become more efficient, understand quality standards and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/hepatitis-c

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The first pangenotypic treatment for the hepatitis C virus, which also shaves 4 weeks off current regimens, has just been approved by the Food and Drug Administration.

Manufactured by AbbVie, glecaprevir/pibrentasvir (Mavyret) combines a nonstructural protein 3/4A protease inhibitor with a next-generation NS5A protein inhibitor for a once-daily, ribavirin-free treatment for adults with any of the major genotypes of chronic hepatitis C virus (HCV) infection.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” Edward Cox, MD, director of the office of antimicrobial products in the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md., said in a statement.



The 8-week regimen is indicated in patients without cirrhosis or with compensated cirrhosis, who are new to treatment, and those with limited treatment options, such as patients with chronic kidney disease, including those on dialysis. The intervention also is indicated in adults with HCV genotype 1 who have been treated with either of the drugs in the combination, but not both. Glecaprevir/pibrentasvir is not recommended in patients with moderate cirrhosis and is contraindicated in patients with severe cirrhosis and in those taking the drugs atazanavir and rifampin.

The safety and efficacy of the treatment were evaluated in approximately 2,300 adults with genotype 1, 2, 3, 4, 5 or 6 HCV infection without cirrhosis or with mild cirrhosis. In the clinical trials, between 92% and 100% of patients treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks had no detectable serum levels of the virus 12 weeks after finishing treatment. The most commonly reported adverse reactions were headache, fatigue, and nausea.

The FDA directs health care professionals to test all patients for current or prior hepatitis B virus (HBV) infection prior to starting this direct-acting antiviral drug combination since HBV reactivation has been reported in adult patients coinfected with both viruses who were undergoing or had completed treatment with HCV direct-acting antivirals and who were not receiving HBV antiviral therapy.

The AGA HCV Clinical Service Line provides tools to help you become more efficient, understand quality standards and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/hepatitis-c

 



The first pangenotypic treatment for the hepatitis C virus, which also shaves 4 weeks off current regimens, has just been approved by the Food and Drug Administration.

Manufactured by AbbVie, glecaprevir/pibrentasvir (Mavyret) combines a nonstructural protein 3/4A protease inhibitor with a next-generation NS5A protein inhibitor for a once-daily, ribavirin-free treatment for adults with any of the major genotypes of chronic hepatitis C virus (HCV) infection.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” Edward Cox, MD, director of the office of antimicrobial products in the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md., said in a statement.



The 8-week regimen is indicated in patients without cirrhosis or with compensated cirrhosis, who are new to treatment, and those with limited treatment options, such as patients with chronic kidney disease, including those on dialysis. The intervention also is indicated in adults with HCV genotype 1 who have been treated with either of the drugs in the combination, but not both. Glecaprevir/pibrentasvir is not recommended in patients with moderate cirrhosis and is contraindicated in patients with severe cirrhosis and in those taking the drugs atazanavir and rifampin.

The safety and efficacy of the treatment were evaluated in approximately 2,300 adults with genotype 1, 2, 3, 4, 5 or 6 HCV infection without cirrhosis or with mild cirrhosis. In the clinical trials, between 92% and 100% of patients treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks had no detectable serum levels of the virus 12 weeks after finishing treatment. The most commonly reported adverse reactions were headache, fatigue, and nausea.

The FDA directs health care professionals to test all patients for current or prior hepatitis B virus (HBV) infection prior to starting this direct-acting antiviral drug combination since HBV reactivation has been reported in adult patients coinfected with both viruses who were undergoing or had completed treatment with HCV direct-acting antivirals and who were not receiving HBV antiviral therapy.

The AGA HCV Clinical Service Line provides tools to help you become more efficient, understand quality standards and improve the process of care for patients. Learn more at http://www.gastro.org/patient-care/conditions-diseases/hepatitis-c

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Flashback to 2014

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The development of therapies for chronic hepatitis C viral (HCV) infection has been a highlight of progress in hepatology and infectious disease over the last 25 years. From initial empiric approaches with interferon and ribavirin, to targeted and custom designed direct-acting antivirals (DAAs), there has been rapid improvement in efficacy and side effect profiles. Since we are dealing with a viral infection, loss of viremia after stopping therapy (sustained viral response, SVR) has been the marker of therapeutic success. SVR, however, is still a surrogate for clinical outcome and the analysis of 5-year follow-up in the December 2014 issue reported that in patients with SVR there was a reduction in risk of death, hepatocellular carcinoma, and liver transplantation.

Dec 2014 cover
Three years later, in the age of DAAs, can we say the same? The efficacy of DAAs is very clear with SVR in well over 90% of patients. The clinical trials in DAA’s, however, did not monitor mortality as an outcome because the natural history of liver disease from HCV is over many years. For these reasons, and because of the relatively short time that DAAs have been used, quality long-term data do not yet exist to conclusively answer if SVR as a result of DAAs reduces mortality, hepatocellular carcinoma, and liver transplantation.

Observational studies have the potential for significant biases as decisions to treat are frequently based on the likelihood of a successful outcome. A randomized clinical trial for DAAs compared to control would of course be unethical at this stage. The scale of use of DAAs should allow a clear answer to this question within the next 2 years.

Dr. Wajahat Mehal
Wahajat Mehal, MD, DPhil, is a hepatologist, an associate professor of medicine in the department of digestive diseases and hepatology, and the director of the Yale Weight Loss Program, Yale School of Medicine, New Haven, Conn. He is an Associate Editor for GI & Hepatology News.
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The development of therapies for chronic hepatitis C viral (HCV) infection has been a highlight of progress in hepatology and infectious disease over the last 25 years. From initial empiric approaches with interferon and ribavirin, to targeted and custom designed direct-acting antivirals (DAAs), there has been rapid improvement in efficacy and side effect profiles. Since we are dealing with a viral infection, loss of viremia after stopping therapy (sustained viral response, SVR) has been the marker of therapeutic success. SVR, however, is still a surrogate for clinical outcome and the analysis of 5-year follow-up in the December 2014 issue reported that in patients with SVR there was a reduction in risk of death, hepatocellular carcinoma, and liver transplantation.

Dec 2014 cover
Three years later, in the age of DAAs, can we say the same? The efficacy of DAAs is very clear with SVR in well over 90% of patients. The clinical trials in DAA’s, however, did not monitor mortality as an outcome because the natural history of liver disease from HCV is over many years. For these reasons, and because of the relatively short time that DAAs have been used, quality long-term data do not yet exist to conclusively answer if SVR as a result of DAAs reduces mortality, hepatocellular carcinoma, and liver transplantation.

Observational studies have the potential for significant biases as decisions to treat are frequently based on the likelihood of a successful outcome. A randomized clinical trial for DAAs compared to control would of course be unethical at this stage. The scale of use of DAAs should allow a clear answer to this question within the next 2 years.

Dr. Wajahat Mehal
Wahajat Mehal, MD, DPhil, is a hepatologist, an associate professor of medicine in the department of digestive diseases and hepatology, and the director of the Yale Weight Loss Program, Yale School of Medicine, New Haven, Conn. He is an Associate Editor for GI & Hepatology News.

 

The development of therapies for chronic hepatitis C viral (HCV) infection has been a highlight of progress in hepatology and infectious disease over the last 25 years. From initial empiric approaches with interferon and ribavirin, to targeted and custom designed direct-acting antivirals (DAAs), there has been rapid improvement in efficacy and side effect profiles. Since we are dealing with a viral infection, loss of viremia after stopping therapy (sustained viral response, SVR) has been the marker of therapeutic success. SVR, however, is still a surrogate for clinical outcome and the analysis of 5-year follow-up in the December 2014 issue reported that in patients with SVR there was a reduction in risk of death, hepatocellular carcinoma, and liver transplantation.

Dec 2014 cover
Three years later, in the age of DAAs, can we say the same? The efficacy of DAAs is very clear with SVR in well over 90% of patients. The clinical trials in DAA’s, however, did not monitor mortality as an outcome because the natural history of liver disease from HCV is over many years. For these reasons, and because of the relatively short time that DAAs have been used, quality long-term data do not yet exist to conclusively answer if SVR as a result of DAAs reduces mortality, hepatocellular carcinoma, and liver transplantation.

Observational studies have the potential for significant biases as decisions to treat are frequently based on the likelihood of a successful outcome. A randomized clinical trial for DAAs compared to control would of course be unethical at this stage. The scale of use of DAAs should allow a clear answer to this question within the next 2 years.

Dr. Wajahat Mehal
Wahajat Mehal, MD, DPhil, is a hepatologist, an associate professor of medicine in the department of digestive diseases and hepatology, and the director of the Yale Weight Loss Program, Yale School of Medicine, New Haven, Conn. He is an Associate Editor for GI & Hepatology News.
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FDA advisory panel backs safety of new hepatitis B vaccine for adults

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The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee approved licensure for Heplisav-B, a new two-dose recombinant hepatitis B vaccination, after voting that presented data proved the vaccine to be safe for adults 18 and over.

 

At an advisory meeting, after hearing testimony from government researchers and representatives of Dynavax Technologies Corporation, the manufacturer of Heplisav-B, 11 members voted to approve the drug, 1 member voted no, and 3 abstained.

There are more than 20,000 new infections each year, with a reported increase of 21% between 2014 and 2015, according to research presented by William Schaffner, MD, professor of preventative medicine and infectious diseases at Vanderbilt University, Nashville, Tenn.

There are two approved immunizations for hepatitis B: Engerix-B, manufactured by GlaxoSmithKline, and Recombivax HB, by Merck. Both are three-dose, recombinant vaccines produced from yeast cells.

Like the current vaccines, Heplisav-B is a recombinant hepatitis B surface antigen that is derived from yeast; however, this vaccine would be administered in two doses over 1 month, as opposed to three doses over 6 months as is the schedule for currently approved vaccines. Both manufacturing representatives and approving members of the committee stressed this as an important factor due to vaccination dropout rates.

“We have a problem with hepatitis B infections in this country as well as problems with the current vaccines,“ said John Ward, MD, director of the division of viral hepatitis at the Centers for Disease Control and Prevention, “and they happen in these populations where, in terms of data, both of those audiences have problems about going for the second and third dose.”

Patients that drop out before the third dose are at high risk of infection, as only 20%-50% of adults have the appropriate seroprotection after two doses. However, only 54% of patients in a vaccine safety Datalink study reported completing the vaccination series, with 81% reporting having received two doses, according to Dr. Schaffner.

While the committee did approve the safety research as sufficient to approve use of Heplisav-B in adults 18 years and older, members of the committee had an issue with the drug’s correlation with myocardial infarction.

In one of the studies presented, Heplisav-B’s acute myocardial infarction (AMI) events (14 patients) greatly outnumbered those of Engerix-B (1 patient), presenting an AMI relative risk of 6.97.

Dynavax representatives, in response to this concern, presented intention to conduct a postmarketing analysis of the risk of MI in patients who have been administered Heplisav-B, which committee members considered to be a crucial contingency for approval.

“I would like to say I am for the approval of this vaccine, I just think as a statistician that the safety was inconclusive,” said Mei-Ling Ting Lee, PhD, director of the Biostatistics and Risk Assessment Center at the University of Maryland. “But I think for the pharmacological vigilance plan, I think that it will be good to have specific analysis for the myocardial infarction and other risks.”

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License
With approval from the Vaccines and Related Biological Products Advisory Committee, Heplisav-B will be subject to review by the FDA, after which it will seek a recommendation from the CDC’s Advisory Committee on Immunization Practices during its October 2017 meeting.

Dynavax intends to introduce the vaccine commercially in the United States by the middle of 2018, according to a press release.

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The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee approved licensure for Heplisav-B, a new two-dose recombinant hepatitis B vaccination, after voting that presented data proved the vaccine to be safe for adults 18 and over.

 

At an advisory meeting, after hearing testimony from government researchers and representatives of Dynavax Technologies Corporation, the manufacturer of Heplisav-B, 11 members voted to approve the drug, 1 member voted no, and 3 abstained.

There are more than 20,000 new infections each year, with a reported increase of 21% between 2014 and 2015, according to research presented by William Schaffner, MD, professor of preventative medicine and infectious diseases at Vanderbilt University, Nashville, Tenn.

There are two approved immunizations for hepatitis B: Engerix-B, manufactured by GlaxoSmithKline, and Recombivax HB, by Merck. Both are three-dose, recombinant vaccines produced from yeast cells.

Like the current vaccines, Heplisav-B is a recombinant hepatitis B surface antigen that is derived from yeast; however, this vaccine would be administered in two doses over 1 month, as opposed to three doses over 6 months as is the schedule for currently approved vaccines. Both manufacturing representatives and approving members of the committee stressed this as an important factor due to vaccination dropout rates.

“We have a problem with hepatitis B infections in this country as well as problems with the current vaccines,“ said John Ward, MD, director of the division of viral hepatitis at the Centers for Disease Control and Prevention, “and they happen in these populations where, in terms of data, both of those audiences have problems about going for the second and third dose.”

Patients that drop out before the third dose are at high risk of infection, as only 20%-50% of adults have the appropriate seroprotection after two doses. However, only 54% of patients in a vaccine safety Datalink study reported completing the vaccination series, with 81% reporting having received two doses, according to Dr. Schaffner.

While the committee did approve the safety research as sufficient to approve use of Heplisav-B in adults 18 years and older, members of the committee had an issue with the drug’s correlation with myocardial infarction.

In one of the studies presented, Heplisav-B’s acute myocardial infarction (AMI) events (14 patients) greatly outnumbered those of Engerix-B (1 patient), presenting an AMI relative risk of 6.97.

Dynavax representatives, in response to this concern, presented intention to conduct a postmarketing analysis of the risk of MI in patients who have been administered Heplisav-B, which committee members considered to be a crucial contingency for approval.

“I would like to say I am for the approval of this vaccine, I just think as a statistician that the safety was inconclusive,” said Mei-Ling Ting Lee, PhD, director of the Biostatistics and Risk Assessment Center at the University of Maryland. “But I think for the pharmacological vigilance plan, I think that it will be good to have specific analysis for the myocardial infarction and other risks.”

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License
With approval from the Vaccines and Related Biological Products Advisory Committee, Heplisav-B will be subject to review by the FDA, after which it will seek a recommendation from the CDC’s Advisory Committee on Immunization Practices during its October 2017 meeting.

Dynavax intends to introduce the vaccine commercially in the United States by the middle of 2018, according to a press release.


The Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee approved licensure for Heplisav-B, a new two-dose recombinant hepatitis B vaccination, after voting that presented data proved the vaccine to be safe for adults 18 and over.

 

At an advisory meeting, after hearing testimony from government researchers and representatives of Dynavax Technologies Corporation, the manufacturer of Heplisav-B, 11 members voted to approve the drug, 1 member voted no, and 3 abstained.

There are more than 20,000 new infections each year, with a reported increase of 21% between 2014 and 2015, according to research presented by William Schaffner, MD, professor of preventative medicine and infectious diseases at Vanderbilt University, Nashville, Tenn.

There are two approved immunizations for hepatitis B: Engerix-B, manufactured by GlaxoSmithKline, and Recombivax HB, by Merck. Both are three-dose, recombinant vaccines produced from yeast cells.

Like the current vaccines, Heplisav-B is a recombinant hepatitis B surface antigen that is derived from yeast; however, this vaccine would be administered in two doses over 1 month, as opposed to three doses over 6 months as is the schedule for currently approved vaccines. Both manufacturing representatives and approving members of the committee stressed this as an important factor due to vaccination dropout rates.

“We have a problem with hepatitis B infections in this country as well as problems with the current vaccines,“ said John Ward, MD, director of the division of viral hepatitis at the Centers for Disease Control and Prevention, “and they happen in these populations where, in terms of data, both of those audiences have problems about going for the second and third dose.”

Patients that drop out before the third dose are at high risk of infection, as only 20%-50% of adults have the appropriate seroprotection after two doses. However, only 54% of patients in a vaccine safety Datalink study reported completing the vaccination series, with 81% reporting having received two doses, according to Dr. Schaffner.

While the committee did approve the safety research as sufficient to approve use of Heplisav-B in adults 18 years and older, members of the committee had an issue with the drug’s correlation with myocardial infarction.

In one of the studies presented, Heplisav-B’s acute myocardial infarction (AMI) events (14 patients) greatly outnumbered those of Engerix-B (1 patient), presenting an AMI relative risk of 6.97.

Dynavax representatives, in response to this concern, presented intention to conduct a postmarketing analysis of the risk of MI in patients who have been administered Heplisav-B, which committee members considered to be a crucial contingency for approval.

“I would like to say I am for the approval of this vaccine, I just think as a statistician that the safety was inconclusive,” said Mei-Ling Ting Lee, PhD, director of the Biostatistics and Risk Assessment Center at the University of Maryland. “But I think for the pharmacological vigilance plan, I think that it will be good to have specific analysis for the myocardial infarction and other risks.”

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License
With approval from the Vaccines and Related Biological Products Advisory Committee, Heplisav-B will be subject to review by the FDA, after which it will seek a recommendation from the CDC’s Advisory Committee on Immunization Practices during its October 2017 meeting.

Dynavax intends to introduce the vaccine commercially in the United States by the middle of 2018, according to a press release.

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NLR useful for predicting 1-year mortality in PBC patients

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An elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a poor 1-year mortality rate in hospitalized primary biliary cholangitis (PBC) patients, according to Lin Lin, MD, of Tianjin (China) Medical University General Hospital and the Tianjin Institute of Digestive Diseases and associates.

A retrospective analysis of 88 PBC patients hospitalized between June 2009 and January 2014 was performed for the study. NLR was a significant predictor of survival, with an odds ratio of 1.5, a sensitivity of 100%, and a specificity of 67.1%. A baseline NLR value of 2.18 was selected as the cutoff for 1-year mortality. Of the 33 patients above this value at initial hospitalization, 6 died, whereas none of the 55 patients below this value died.

The results of the retrospective study were confirmed in a prospective 1-year cohort that included 63 people with PBC. The patients with a baseline NLR of less than 2.18 had significantly longer survival times than those who had a baseline NLR of 2.18 or higher.

“NLR – an affordable, widely available and reproducible index – is closely related to short-term mortality in patients with PBC. Further studies are warranted to externally cross-validate our findings in other populations,” the investigators concluded.

Find the full study in BMJ Open (2017. doi: 10.1136/bmjopen-2016-015304).
 

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An elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a poor 1-year mortality rate in hospitalized primary biliary cholangitis (PBC) patients, according to Lin Lin, MD, of Tianjin (China) Medical University General Hospital and the Tianjin Institute of Digestive Diseases and associates.

A retrospective analysis of 88 PBC patients hospitalized between June 2009 and January 2014 was performed for the study. NLR was a significant predictor of survival, with an odds ratio of 1.5, a sensitivity of 100%, and a specificity of 67.1%. A baseline NLR value of 2.18 was selected as the cutoff for 1-year mortality. Of the 33 patients above this value at initial hospitalization, 6 died, whereas none of the 55 patients below this value died.

The results of the retrospective study were confirmed in a prospective 1-year cohort that included 63 people with PBC. The patients with a baseline NLR of less than 2.18 had significantly longer survival times than those who had a baseline NLR of 2.18 or higher.

“NLR – an affordable, widely available and reproducible index – is closely related to short-term mortality in patients with PBC. Further studies are warranted to externally cross-validate our findings in other populations,” the investigators concluded.

Find the full study in BMJ Open (2017. doi: 10.1136/bmjopen-2016-015304).
 

 

An elevated baseline neutrophil-to-lymphocyte ratio (NLR) was associated with a poor 1-year mortality rate in hospitalized primary biliary cholangitis (PBC) patients, according to Lin Lin, MD, of Tianjin (China) Medical University General Hospital and the Tianjin Institute of Digestive Diseases and associates.

A retrospective analysis of 88 PBC patients hospitalized between June 2009 and January 2014 was performed for the study. NLR was a significant predictor of survival, with an odds ratio of 1.5, a sensitivity of 100%, and a specificity of 67.1%. A baseline NLR value of 2.18 was selected as the cutoff for 1-year mortality. Of the 33 patients above this value at initial hospitalization, 6 died, whereas none of the 55 patients below this value died.

The results of the retrospective study were confirmed in a prospective 1-year cohort that included 63 people with PBC. The patients with a baseline NLR of less than 2.18 had significantly longer survival times than those who had a baseline NLR of 2.18 or higher.

“NLR – an affordable, widely available and reproducible index – is closely related to short-term mortality in patients with PBC. Further studies are warranted to externally cross-validate our findings in other populations,” the investigators concluded.

Find the full study in BMJ Open (2017. doi: 10.1136/bmjopen-2016-015304).
 

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Hepatitis B elimination: Is it possible?

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Despite the availability of safe and effective vaccines for more than three decades, the 2017 World Health Organization (WHO) Global Hepatitis Report estimated that worldwide more than 250 million persons are chronically infected with hepatitis B virus (www.who.int/hepatitis/publications/global-hepatitis-report2017/). In the United States, as many as 2.2 million persons may be chronically infected but only one-third are aware of their infection. In 2015, the WHO declared that hepatitis B and C should be eliminated as public health problems by the year 2030. In March 2017, the National Academies of Science, Engineering and Medicine (NASEM) set targets for HBV elimination in the United States by 2030 as follows: 50% reduction in deaths, 45% reduction in cirrhosis, and 33% reduction in hepatocellular carcinoma (HCC) compared to 2015. For these targets, 90% of persons chronically infected need to be diagnosed, 90% of those diagnosed linked to care, and treatment initiated in 80% of those with treatment indications. In addition, new infections among children should be eliminated through complete prevention of mother-to-child transmission.

Dr. Anna Lok
HBV vaccination, particularly when initiated in newborns, is the most effective method of preventing HBV infection and its sequelae because the risk of chronicity is around 90% when infection occurs in newborns. Countries in which universal vaccination of newborns was initiated in the 1980s have witnessed a marked decline in HBV infection as well as HBV-related HCC in children and young adults. However, while 96% of countries worldwide have initiated nationwide HBV vaccine programs for infants, global birth dose coverage is only 39%, leaving many infants susceptible to infection during the first few months of life. Recent studies showed that administration of hepatitis B immunoglobulin and HBV vaccine within 24 hours of birth is inadequate in preventing infection of infants born to carrier mothers with high viremia. Antiviral medicine administered to highly viremic mothers during the third trimester of pregnancy is necessary to completely prevent the risk of mother-to-child transmission (Hepatology. 2016;63:261-83).

For persons who are chronically infected, antiviral therapy can suppress HBV replication, reduce hepatic inflammation, reverse hepatic fibrosis, and prevent progression to cirrhosis, hepatic decompensation, and HCC. However, currently approved treatments are associated with low rates of hepatitis B surface antigen (HBsAg) clearance and decreased but continued risk of HCC. New treatments aimed at cure are desired but complete cure of HBV may not be feasible as HBV persists in the liver even in patients with serologic recovery after transient acute HBV infection.

Functional cure aimed at restoring chronic hepatitis B patients to a state akin to those with spontaneous HBsAg clearance might be a more realistic goal. With improved understanding of the biology of HBV, including recent identification of its entry receptor, better in vitro and animal models, and revival of interest in hepatitis B research, it is conceivable that combinations of antiviral targeting different steps in HBV life cyle and immunomodulatory therapies aimed to boost T-cell response to HBV and/or remove inhibitory signals can result in functional cure (HBsAg clearance) in a high percentage of patients after a finite course of treatment (Hepatology 2017; in press).

The HBV elimination goals set by WHO and NASEM are lofty, but as both organizations stated, these goals are feasible if all stakeholders make elimination of HBV a priority and allocate resources to make it happen.
 

Dr. Lok is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine, University of Michigan Health System in Ann Arbor. Her comments were made during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

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Despite the availability of safe and effective vaccines for more than three decades, the 2017 World Health Organization (WHO) Global Hepatitis Report estimated that worldwide more than 250 million persons are chronically infected with hepatitis B virus (www.who.int/hepatitis/publications/global-hepatitis-report2017/). In the United States, as many as 2.2 million persons may be chronically infected but only one-third are aware of their infection. In 2015, the WHO declared that hepatitis B and C should be eliminated as public health problems by the year 2030. In March 2017, the National Academies of Science, Engineering and Medicine (NASEM) set targets for HBV elimination in the United States by 2030 as follows: 50% reduction in deaths, 45% reduction in cirrhosis, and 33% reduction in hepatocellular carcinoma (HCC) compared to 2015. For these targets, 90% of persons chronically infected need to be diagnosed, 90% of those diagnosed linked to care, and treatment initiated in 80% of those with treatment indications. In addition, new infections among children should be eliminated through complete prevention of mother-to-child transmission.

Dr. Anna Lok
HBV vaccination, particularly when initiated in newborns, is the most effective method of preventing HBV infection and its sequelae because the risk of chronicity is around 90% when infection occurs in newborns. Countries in which universal vaccination of newborns was initiated in the 1980s have witnessed a marked decline in HBV infection as well as HBV-related HCC in children and young adults. However, while 96% of countries worldwide have initiated nationwide HBV vaccine programs for infants, global birth dose coverage is only 39%, leaving many infants susceptible to infection during the first few months of life. Recent studies showed that administration of hepatitis B immunoglobulin and HBV vaccine within 24 hours of birth is inadequate in preventing infection of infants born to carrier mothers with high viremia. Antiviral medicine administered to highly viremic mothers during the third trimester of pregnancy is necessary to completely prevent the risk of mother-to-child transmission (Hepatology. 2016;63:261-83).

For persons who are chronically infected, antiviral therapy can suppress HBV replication, reduce hepatic inflammation, reverse hepatic fibrosis, and prevent progression to cirrhosis, hepatic decompensation, and HCC. However, currently approved treatments are associated with low rates of hepatitis B surface antigen (HBsAg) clearance and decreased but continued risk of HCC. New treatments aimed at cure are desired but complete cure of HBV may not be feasible as HBV persists in the liver even in patients with serologic recovery after transient acute HBV infection.

Functional cure aimed at restoring chronic hepatitis B patients to a state akin to those with spontaneous HBsAg clearance might be a more realistic goal. With improved understanding of the biology of HBV, including recent identification of its entry receptor, better in vitro and animal models, and revival of interest in hepatitis B research, it is conceivable that combinations of antiviral targeting different steps in HBV life cyle and immunomodulatory therapies aimed to boost T-cell response to HBV and/or remove inhibitory signals can result in functional cure (HBsAg clearance) in a high percentage of patients after a finite course of treatment (Hepatology 2017; in press).

The HBV elimination goals set by WHO and NASEM are lofty, but as both organizations stated, these goals are feasible if all stakeholders make elimination of HBV a priority and allocate resources to make it happen.
 

Dr. Lok is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine, University of Michigan Health System in Ann Arbor. Her comments were made during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

 

Despite the availability of safe and effective vaccines for more than three decades, the 2017 World Health Organization (WHO) Global Hepatitis Report estimated that worldwide more than 250 million persons are chronically infected with hepatitis B virus (www.who.int/hepatitis/publications/global-hepatitis-report2017/). In the United States, as many as 2.2 million persons may be chronically infected but only one-third are aware of their infection. In 2015, the WHO declared that hepatitis B and C should be eliminated as public health problems by the year 2030. In March 2017, the National Academies of Science, Engineering and Medicine (NASEM) set targets for HBV elimination in the United States by 2030 as follows: 50% reduction in deaths, 45% reduction in cirrhosis, and 33% reduction in hepatocellular carcinoma (HCC) compared to 2015. For these targets, 90% of persons chronically infected need to be diagnosed, 90% of those diagnosed linked to care, and treatment initiated in 80% of those with treatment indications. In addition, new infections among children should be eliminated through complete prevention of mother-to-child transmission.

Dr. Anna Lok
HBV vaccination, particularly when initiated in newborns, is the most effective method of preventing HBV infection and its sequelae because the risk of chronicity is around 90% when infection occurs in newborns. Countries in which universal vaccination of newborns was initiated in the 1980s have witnessed a marked decline in HBV infection as well as HBV-related HCC in children and young adults. However, while 96% of countries worldwide have initiated nationwide HBV vaccine programs for infants, global birth dose coverage is only 39%, leaving many infants susceptible to infection during the first few months of life. Recent studies showed that administration of hepatitis B immunoglobulin and HBV vaccine within 24 hours of birth is inadequate in preventing infection of infants born to carrier mothers with high viremia. Antiviral medicine administered to highly viremic mothers during the third trimester of pregnancy is necessary to completely prevent the risk of mother-to-child transmission (Hepatology. 2016;63:261-83).

For persons who are chronically infected, antiviral therapy can suppress HBV replication, reduce hepatic inflammation, reverse hepatic fibrosis, and prevent progression to cirrhosis, hepatic decompensation, and HCC. However, currently approved treatments are associated with low rates of hepatitis B surface antigen (HBsAg) clearance and decreased but continued risk of HCC. New treatments aimed at cure are desired but complete cure of HBV may not be feasible as HBV persists in the liver even in patients with serologic recovery after transient acute HBV infection.

Functional cure aimed at restoring chronic hepatitis B patients to a state akin to those with spontaneous HBsAg clearance might be a more realistic goal. With improved understanding of the biology of HBV, including recent identification of its entry receptor, better in vitro and animal models, and revival of interest in hepatitis B research, it is conceivable that combinations of antiviral targeting different steps in HBV life cyle and immunomodulatory therapies aimed to boost T-cell response to HBV and/or remove inhibitory signals can result in functional cure (HBsAg clearance) in a high percentage of patients after a finite course of treatment (Hepatology 2017; in press).

The HBV elimination goals set by WHO and NASEM are lofty, but as both organizations stated, these goals are feasible if all stakeholders make elimination of HBV a priority and allocate resources to make it happen.
 

Dr. Lok is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine, University of Michigan Health System in Ann Arbor. Her comments were made during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.

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Acute liver failure in the ED

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Acute liver failure (ALF), is a life-threatening deterioration of liver function in people without preexisting cirrhosis. It can be caused by acetaminophen toxicity, pregnancy, ischemia, hepatitis A infection, and Wilson disease, among other things.

In emergency medicine, ALF can pose serious dilemmas. While transplantation has drastically improved survival rates in recent decades, it is not always required, and no firm criteria for transplantation exist.

But delays in the decision to go ahead with a liver transplant can lead to death.

A new literature review aims to distill the decision-making process for emergency medicine practitioners. Knowing which candidates will benefit and when to perform transplantation “is crucial in improving the likelihood of survival,” its authors say, because of the many factors involved.

In a paper published online in May in The American Journal of Emergency Medicine (2017 May. doi. 10.1016/j.ajem.2017.05.028), Hamid Shokoohi, MD, and his colleagues at George Washington University Medical Center in Washington say that establishing the cause of acute liver failure is essential to making treatment decisions, as some causes are associated with poorer prognosis without transplantation.

“We wanted to improve awareness among emergency medicine physicians, who are the first in the chain of command for transferring patients to a transplant site,” said Ali Pourmand, MD, of George Washington University, Washington, and the corresponding author of the study. “The high risk of early death among these cases makes it necessary for emergency physicians to consider coexisting etiology, be aware of indications and criteria available to determine the need for emergent transplantation, and be able to expedite patient transfer to a transplant center, when indicated.”

As patients presenting with ALF are likely too impaired be able to provide a history, and physical exam findings may be nonspecific, laboratory findings are key in establishing both severity and likely cause. ALF patients in general will have a prolonged prothrombin time, markedly elevated aminotransferase levels, elevated bilirubin, and low platelet count.

Patients with ALF caused by acetaminophen toxicity (the most common cause of ALF in the United States) are likely to present with very high aminotransferase levels, low bilirubin, and high international normalized ratio (INR). Those with viral causes of ALF, meanwhile, tend to have aminotransferase levels of 1,000-2,000 IU/L, and alanine transaminase higher than aspartate transaminase.

Prognosis without transplantation is considerably poorer in patients with severe ALF caused by Wilson disease, Budd-Chiari syndrome, or idiosyncratic drug reactions, compared with those who experience viral hepatitis or acetaminophen toxicity.

Dr. Shokoohi and his colleagues noted that two validated scoring systems can be used to assess prognosis for severe ALF. The King’s College Criteria can be used to establish prognosis for ALF caused by acetaminophen, and ALF from other causes, while the MELD score, recommended by the American Association for the Study of Liver Diseases, incorporates bilirubin, INR, sodium, and creatinine levels to predict prognosis. Both of these scoring systems can be used to inform decisions about transplantation. 

Finally, the authors advised that patients with alcoholic liver disease be considered under the same criteria for transplantation as those with other causes of ALF. “Recent research has shown that only a minority of patients ... will have poor follow-up and noncompliance to therapy and/or will revert to heavy alcohol use or abuse after transplant,” they wrote in their analysis. The researchers disclosed no outside funding of conflicts of interest related to their article.

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Acute liver failure (ALF), is a life-threatening deterioration of liver function in people without preexisting cirrhosis. It can be caused by acetaminophen toxicity, pregnancy, ischemia, hepatitis A infection, and Wilson disease, among other things.

In emergency medicine, ALF can pose serious dilemmas. While transplantation has drastically improved survival rates in recent decades, it is not always required, and no firm criteria for transplantation exist.

But delays in the decision to go ahead with a liver transplant can lead to death.

A new literature review aims to distill the decision-making process for emergency medicine practitioners. Knowing which candidates will benefit and when to perform transplantation “is crucial in improving the likelihood of survival,” its authors say, because of the many factors involved.

In a paper published online in May in The American Journal of Emergency Medicine (2017 May. doi. 10.1016/j.ajem.2017.05.028), Hamid Shokoohi, MD, and his colleagues at George Washington University Medical Center in Washington say that establishing the cause of acute liver failure is essential to making treatment decisions, as some causes are associated with poorer prognosis without transplantation.

“We wanted to improve awareness among emergency medicine physicians, who are the first in the chain of command for transferring patients to a transplant site,” said Ali Pourmand, MD, of George Washington University, Washington, and the corresponding author of the study. “The high risk of early death among these cases makes it necessary for emergency physicians to consider coexisting etiology, be aware of indications and criteria available to determine the need for emergent transplantation, and be able to expedite patient transfer to a transplant center, when indicated.”

As patients presenting with ALF are likely too impaired be able to provide a history, and physical exam findings may be nonspecific, laboratory findings are key in establishing both severity and likely cause. ALF patients in general will have a prolonged prothrombin time, markedly elevated aminotransferase levels, elevated bilirubin, and low platelet count.

Patients with ALF caused by acetaminophen toxicity (the most common cause of ALF in the United States) are likely to present with very high aminotransferase levels, low bilirubin, and high international normalized ratio (INR). Those with viral causes of ALF, meanwhile, tend to have aminotransferase levels of 1,000-2,000 IU/L, and alanine transaminase higher than aspartate transaminase.

Prognosis without transplantation is considerably poorer in patients with severe ALF caused by Wilson disease, Budd-Chiari syndrome, or idiosyncratic drug reactions, compared with those who experience viral hepatitis or acetaminophen toxicity.

Dr. Shokoohi and his colleagues noted that two validated scoring systems can be used to assess prognosis for severe ALF. The King’s College Criteria can be used to establish prognosis for ALF caused by acetaminophen, and ALF from other causes, while the MELD score, recommended by the American Association for the Study of Liver Diseases, incorporates bilirubin, INR, sodium, and creatinine levels to predict prognosis. Both of these scoring systems can be used to inform decisions about transplantation. 

Finally, the authors advised that patients with alcoholic liver disease be considered under the same criteria for transplantation as those with other causes of ALF. “Recent research has shown that only a minority of patients ... will have poor follow-up and noncompliance to therapy and/or will revert to heavy alcohol use or abuse after transplant,” they wrote in their analysis. The researchers disclosed no outside funding of conflicts of interest related to their article.

 

Acute liver failure (ALF), is a life-threatening deterioration of liver function in people without preexisting cirrhosis. It can be caused by acetaminophen toxicity, pregnancy, ischemia, hepatitis A infection, and Wilson disease, among other things.

In emergency medicine, ALF can pose serious dilemmas. While transplantation has drastically improved survival rates in recent decades, it is not always required, and no firm criteria for transplantation exist.

But delays in the decision to go ahead with a liver transplant can lead to death.

A new literature review aims to distill the decision-making process for emergency medicine practitioners. Knowing which candidates will benefit and when to perform transplantation “is crucial in improving the likelihood of survival,” its authors say, because of the many factors involved.

In a paper published online in May in The American Journal of Emergency Medicine (2017 May. doi. 10.1016/j.ajem.2017.05.028), Hamid Shokoohi, MD, and his colleagues at George Washington University Medical Center in Washington say that establishing the cause of acute liver failure is essential to making treatment decisions, as some causes are associated with poorer prognosis without transplantation.

“We wanted to improve awareness among emergency medicine physicians, who are the first in the chain of command for transferring patients to a transplant site,” said Ali Pourmand, MD, of George Washington University, Washington, and the corresponding author of the study. “The high risk of early death among these cases makes it necessary for emergency physicians to consider coexisting etiology, be aware of indications and criteria available to determine the need for emergent transplantation, and be able to expedite patient transfer to a transplant center, when indicated.”

As patients presenting with ALF are likely too impaired be able to provide a history, and physical exam findings may be nonspecific, laboratory findings are key in establishing both severity and likely cause. ALF patients in general will have a prolonged prothrombin time, markedly elevated aminotransferase levels, elevated bilirubin, and low platelet count.

Patients with ALF caused by acetaminophen toxicity (the most common cause of ALF in the United States) are likely to present with very high aminotransferase levels, low bilirubin, and high international normalized ratio (INR). Those with viral causes of ALF, meanwhile, tend to have aminotransferase levels of 1,000-2,000 IU/L, and alanine transaminase higher than aspartate transaminase.

Prognosis without transplantation is considerably poorer in patients with severe ALF caused by Wilson disease, Budd-Chiari syndrome, or idiosyncratic drug reactions, compared with those who experience viral hepatitis or acetaminophen toxicity.

Dr. Shokoohi and his colleagues noted that two validated scoring systems can be used to assess prognosis for severe ALF. The King’s College Criteria can be used to establish prognosis for ALF caused by acetaminophen, and ALF from other causes, while the MELD score, recommended by the American Association for the Study of Liver Diseases, incorporates bilirubin, INR, sodium, and creatinine levels to predict prognosis. Both of these scoring systems can be used to inform decisions about transplantation. 

Finally, the authors advised that patients with alcoholic liver disease be considered under the same criteria for transplantation as those with other causes of ALF. “Recent research has shown that only a minority of patients ... will have poor follow-up and noncompliance to therapy and/or will revert to heavy alcohol use or abuse after transplant,” they wrote in their analysis. The researchers disclosed no outside funding of conflicts of interest related to their article.

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FDA approves new treatment for adults with HCV

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The Food and Drug Administration announced on July 18 the approval of Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with mild cirrhosis.

Vosevi is now the first treatment for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A. The new drug is a fixed-dose, combination tablet containing sofosbuvir and velpatasvir (both approved before) and a new drug – voxilaprevir.

In two phase 3 clinical trials, 750 adults without cirrhosis or with mild cirrhosis were enrolled. The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug; those with genotypes 2-6 received Vosevi. The second trial compared 12 weeks of Vosevi with sofosbuvir and velpatasvir in adults with genotypes 1, 2, or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug. Results of both trials showed that 96%-97% of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, indicating that patients’ infection had been cured.

It is noted that treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history. Vosevi is contraindicated in patients taking the drug rifampin.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.

Read the full press release on the FDA’s website.

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The Food and Drug Administration announced on July 18 the approval of Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with mild cirrhosis.

Vosevi is now the first treatment for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A. The new drug is a fixed-dose, combination tablet containing sofosbuvir and velpatasvir (both approved before) and a new drug – voxilaprevir.

In two phase 3 clinical trials, 750 adults without cirrhosis or with mild cirrhosis were enrolled. The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug; those with genotypes 2-6 received Vosevi. The second trial compared 12 weeks of Vosevi with sofosbuvir and velpatasvir in adults with genotypes 1, 2, or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug. Results of both trials showed that 96%-97% of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, indicating that patients’ infection had been cured.

It is noted that treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history. Vosevi is contraindicated in patients taking the drug rifampin.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.

Read the full press release on the FDA’s website.

 

The Food and Drug Administration announced on July 18 the approval of Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis or with mild cirrhosis.

Vosevi is now the first treatment for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A. The new drug is a fixed-dose, combination tablet containing sofosbuvir and velpatasvir (both approved before) and a new drug – voxilaprevir.

In two phase 3 clinical trials, 750 adults without cirrhosis or with mild cirrhosis were enrolled. The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug; those with genotypes 2-6 received Vosevi. The second trial compared 12 weeks of Vosevi with sofosbuvir and velpatasvir in adults with genotypes 1, 2, or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug. Results of both trials showed that 96%-97% of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, indicating that patients’ infection had been cured.

It is noted that treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history. Vosevi is contraindicated in patients taking the drug rifampin.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press release.

Read the full press release on the FDA’s website.

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Liver cancer risk lower after sustained response to DAAs

Do direct-acting antivirals benefit or harm patients with hepatitis C?
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Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.

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The study showed the incidence of HCC among patients with SVR was 0.90/100 person-years, compared with 3.45/100 person-years in those without (Gastroenterology. 2017 Jun 19. doi: 10.1053/j.gastro.2017.06.012).

“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”

The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.

“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.

Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).

While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.

Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.

“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.

Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).

Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.

“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”

The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.

Body

The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.

 

Dr. Anna S. Lok
DAAs have only been available for a few years, yet increasingly, data show that SVR achieved with DAAs has beneficial effects similar to those seen with interferon-based therapies. The most dramatic benefit is observed in patients with decompensated cirrhosis, in whom improvement in liver function and reversal of cirrhosis complications can occur within a few months of treatment, allowing some of these patients to be taken off the transplant waiting list.3 A potential concern for harm was raised by several studies suggesting DAAs may increase the risk of HCC, but these studies involved small numbers of patients. The recent study by Kanwal et al. with 22,500 patients treated with DAAs showed the incidence of HCC in patients who achieved SVR after DAA therapy was 72% lower than those who did not achieve SVR.4 They also found that patients treated in the DAA era were older and more likely to have cirrhosis and comorbidities that increase the risk of HCC, compared with those treated in the interferon era, highlighting the pitfalls of comparison with historical data. This large study did not find any evidence of harm but rather benefits of DAAs and support for early, rather than late, initiation of treatment.

 

Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.

References

1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.

Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.

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The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.

 

Dr. Anna S. Lok
DAAs have only been available for a few years, yet increasingly, data show that SVR achieved with DAAs has beneficial effects similar to those seen with interferon-based therapies. The most dramatic benefit is observed in patients with decompensated cirrhosis, in whom improvement in liver function and reversal of cirrhosis complications can occur within a few months of treatment, allowing some of these patients to be taken off the transplant waiting list.3 A potential concern for harm was raised by several studies suggesting DAAs may increase the risk of HCC, but these studies involved small numbers of patients. The recent study by Kanwal et al. with 22,500 patients treated with DAAs showed the incidence of HCC in patients who achieved SVR after DAA therapy was 72% lower than those who did not achieve SVR.4 They also found that patients treated in the DAA era were older and more likely to have cirrhosis and comorbidities that increase the risk of HCC, compared with those treated in the interferon era, highlighting the pitfalls of comparison with historical data. This large study did not find any evidence of harm but rather benefits of DAAs and support for early, rather than late, initiation of treatment.

 

Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.

References

1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.

Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.

Body

The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.

 

Dr. Anna S. Lok
DAAs have only been available for a few years, yet increasingly, data show that SVR achieved with DAAs has beneficial effects similar to those seen with interferon-based therapies. The most dramatic benefit is observed in patients with decompensated cirrhosis, in whom improvement in liver function and reversal of cirrhosis complications can occur within a few months of treatment, allowing some of these patients to be taken off the transplant waiting list.3 A potential concern for harm was raised by several studies suggesting DAAs may increase the risk of HCC, but these studies involved small numbers of patients. The recent study by Kanwal et al. with 22,500 patients treated with DAAs showed the incidence of HCC in patients who achieved SVR after DAA therapy was 72% lower than those who did not achieve SVR.4 They also found that patients treated in the DAA era were older and more likely to have cirrhosis and comorbidities that increase the risk of HCC, compared with those treated in the interferon era, highlighting the pitfalls of comparison with historical data. This large study did not find any evidence of harm but rather benefits of DAAs and support for early, rather than late, initiation of treatment.

 

Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.

References

1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.

Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.

Title
Do direct-acting antivirals benefit or harm patients with hepatitis C?
Do direct-acting antivirals benefit or harm patients with hepatitis C?

 

Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.

s-c-s/Thinkstock
The study showed the incidence of HCC among patients with SVR was 0.90/100 person-years, compared with 3.45/100 person-years in those without (Gastroenterology. 2017 Jun 19. doi: 10.1053/j.gastro.2017.06.012).

“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”

The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.

“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.

Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).

While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.

Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.

“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.

Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).

Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.

“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”

The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.

 

Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.

s-c-s/Thinkstock
The study showed the incidence of HCC among patients with SVR was 0.90/100 person-years, compared with 3.45/100 person-years in those without (Gastroenterology. 2017 Jun 19. doi: 10.1053/j.gastro.2017.06.012).

“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”

The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.

“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.

Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).

While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.

Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.

“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.

Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).

Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.

“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”

The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.

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Key clinical point: A sustained virologic response to direct-acting antivirals for hepatitis C infection was associated with a significantly lower risk of hepatocellular carcinoma.

Major finding: Individuals who achieved an SVR to antiviral treatment for hepatitis C infection had a 72% lower risk of hepatocellular carcinoma than those who do not show a sustained response.

Data source: Retrospective cohort study in 22,500 U.S. veterans with hepatitis C.

Disclosures: The study was partly supported by the Department of Veterans Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.

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