Liver Disease

The female-to-male predominance of primary biliary cholangitis (PBC), formerly cirrhosis, is much lower than previously believed, according to data from Swedish national registers.

Looking at a number of diseases thought to have at least some basis in autoimmunity, researchers found that the relative risk of PBC for women, compared with men, was 4.1, suggesting that, although it remains a disease predominantly affecting women, its prevalence in men might actually be higher than previously thought.

Of the three other gastrointestinal conditions among the 32 autoimmune diseases examined, one showed a female predominance, one showed no difference, and one had a male predominance, reported Dr. Jianguang Ji and his associates at Lund (Sweden) University (J Autoimmune. 2016;69:102-6).

Celiac disease had a slight female predominance, with a relative risk for women of 1.8, compared with men. There was no difference for Crohn’s disease (RR, 1.1), and ulcerative colitis had a slight male predominance (RR, 0.9), the investigators reported.

The situation was similar for the larger group of conditions: Eighteen showed a female predominance, 7 had no difference, and 7 showed a male predominance, they noted.

“Most review papers claim that the vast majority of autoimmune diseases have a striking female predominance, and most of them cited that more than 80% of cases affected are women. In this population-based study of 32 specific autoimmune diseases with more than 20 years of follow-up, we found that the incidence in women was only 60% higher as compared to that in men,” Dr. Ji and his associates wrote.

The investigators searched the Swedish Hospital Discharge Register and the Swedish Outpatient Register and found data on 403,757 individuals who had been diagnosed with one or more of the 32 autoimmune diseases between 1987 and 2010. About 62% of the subjects were female.

Dr. Ji and his associates had no conflicts of interest to report. The study was supported by the Swedish Research Council and Region Skåne.

[email protected]

The female-to-male predominance of primary biliary cholangitis (PBC), formerly cirrhosis, is much lower than previously believed, according to data from Swedish national registers.

Looking at a number of diseases thought to have at least some basis in autoimmunity, researchers found that the relative risk of PBC for women, compared with men, was 4.1, suggesting that, although it remains a disease predominantly affecting women, its prevalence in men might actually be higher than previously thought.

Of the three other gastrointestinal conditions among the 32 autoimmune diseases examined, one showed a female predominance, one showed no difference, and one had a male predominance, reported Dr. Jianguang Ji and his associates at Lund (Sweden) University (J Autoimmune. 2016;69:102-6).

Celiac disease had a slight female predominance, with a relative risk for women of 1.8, compared with men. There was no difference for Crohn’s disease (RR, 1.1), and ulcerative colitis had a slight male predominance (RR, 0.9), the investigators reported.

The situation was similar for the larger group of conditions: Eighteen showed a female predominance, 7 had no difference, and 7 showed a male predominance, they noted.

“Most review papers claim that the vast majority of autoimmune diseases have a striking female predominance, and most of them cited that more than 80% of cases affected are women. In this population-based study of 32 specific autoimmune diseases with more than 20 years of follow-up, we found that the incidence in women was only 60% higher as compared to that in men,” Dr. Ji and his associates wrote.

The investigators searched the Swedish Hospital Discharge Register and the Swedish Outpatient Register and found data on 403,757 individuals who had been diagnosed with one or more of the 32 autoimmune diseases between 1987 and 2010. About 62% of the subjects were female.

Dr. Ji and his associates had no conflicts of interest to report. The study was supported by the Swedish Research Council and Region Skåne.

[email protected]

The female-to-male predominance of primary biliary cholangitis (PBC), formerly cirrhosis, is much lower than previously believed, according to data from Swedish national registers.

Looking at a number of diseases thought to have at least some basis in autoimmunity, researchers found that the relative risk of PBC for women, compared with men, was 4.1, suggesting that, although it remains a disease predominantly affecting women, its prevalence in men might actually be higher than previously thought.

Of the three other gastrointestinal conditions among the 32 autoimmune diseases examined, one showed a female predominance, one showed no difference, and one had a male predominance, reported Dr. Jianguang Ji and his associates at Lund (Sweden) University (J Autoimmune. 2016;69:102-6).

Celiac disease had a slight female predominance, with a relative risk for women of 1.8, compared with men. There was no difference for Crohn’s disease (RR, 1.1), and ulcerative colitis had a slight male predominance (RR, 0.9), the investigators reported.

The situation was similar for the larger group of conditions: Eighteen showed a female predominance, 7 had no difference, and 7 showed a male predominance, they noted.

“Most review papers claim that the vast majority of autoimmune diseases have a striking female predominance, and most of them cited that more than 80% of cases affected are women. In this population-based study of 32 specific autoimmune diseases with more than 20 years of follow-up, we found that the incidence in women was only 60% higher as compared to that in men,” Dr. Ji and his associates wrote.

The investigators searched the Swedish Hospital Discharge Register and the Swedish Outpatient Register and found data on 403,757 individuals who had been diagnosed with one or more of the 32 autoimmune diseases between 1987 and 2010. About 62% of the subjects were female.

Dr. Ji and his associates had no conflicts of interest to report. The study was supported by the Swedish Research Council and Region Skåne.

[email protected]

The United States can end hepatitis B and C transmission and prevent related morbidity and mortality given enough time, resources, and will to surmount a variety of barriers, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

A more feasible short-term goal is to control viral hepatitis by reducing the incidence and prevalence of hepatitis B (HBV) and C virus (HCV) infections, states the report, which is the first of a two-phase study. The second part, to be published in early 2017, will outline a strategy to achieve the goals.

“Disease elimination” once meant stopping all new infections in a population, but eliminating a public health problem “can be a less absolute goal,” Dr. Brian Strom, chancellor of Rutgers Biomedical and Health Sciences, wrote along with his associates. “The WHO has accepted a non-zero target in its work against viral hepatitis,” they added. “The organization’s provisional target is a 90% reduction in incidence, and a 65% reduction in mortality by 2030.”

Furthermore, those are global targets – countries should base their own strategies on their specific viral hepatitis disease burdens and epidemiologic features, Dr. Strom and his associates emphasized. For example, universal vaccination could eradicate HBV in the United States in two generations, but there is no cure for the 700,000-1.4 million Americans who are already infected. Mother-to-child HBV transmission is rare here, but better screening and surveillance could help prevent the 800-1,000 cases of vertical transmission that still occur annually.

More than a third of newborns in the United States do not receive the HBV vaccination on the day they are born, and 28% remain unvaccinated when they are 3 days old, “but childhood catch-up is possible,” the experts also wrote. Vaccinating adults is more complicated, but targeting high-risk groups such as prison inmates or patients at sexually transmitted disease clinics might work, they added. Vaccination is especially important, because chronically infected HBV patients need lifelong medical follow-up to prevent progression and death from cirrhosis and liver cancer, they emphasized.

The hepatitis C virus presents a different picture – there is no HCV vaccine, while the novel direct-acting antivirals can theoretically cure nearly all chronic infections. But in reality, high drug costs and the massive burden of undiagnosed HCV mean that only a small fraction of patients can be cured, the authors acknowledged. On an individual basis, the benefits of direct-acting antivirals outweigh the costs of treating genotype 1 HCV and associated morbidity, they add. But on a population level, “eliminating HCV infection would require near universal access to treatment, something that appears infeasible given the current pricing and policy environment.”

Several other barriers also impede progress against HBV and HCV. For example, only five states and two large cities receive enough funding for comprehensive viral hepatitis surveillance, Dr. Strom and his associates noted. If local and state public health departments cannot track infections, they cannot characterize their epidemics. In addition, viral hepatitis remains a source of stigma, adding to fear and avoidance of testing and undermining elimination efforts. Stigma, avoidance, and the fact that HBV and HCV are asymptomatic in the early stages all contribute to a large population of chronically infected patients who do not know their status.

Moreover, many state Medicaid programs will not cover foreigners until they have lived in the United States for 5 years, and the Affordable Care Act does not cover care for short-term residents and undocumented immigrants, the report stated. Newly infected HCV patients tend to have fewer resources, lower educational levels, and more often use injection drugs, making them harder to reach and screen through the health system. “Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high, and the staff time required to manage an inmate in treatment often far exceed the available resources,” the report stated.

The study was sponsored by the Centers for Disease Control and Prevention Office of Viral Hepatitis and the U.S. Department of Health and Human Services Office of Minority Health. The authors disclosed no conflicts of interest.

The United States can end hepatitis B and C transmission and prevent related morbidity and mortality given enough time, resources, and will to surmount a variety of barriers, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

A more feasible short-term goal is to control viral hepatitis by reducing the incidence and prevalence of hepatitis B (HBV) and C virus (HCV) infections, states the report, which is the first of a two-phase study. The second part, to be published in early 2017, will outline a strategy to achieve the goals.

“Disease elimination” once meant stopping all new infections in a population, but eliminating a public health problem “can be a less absolute goal,” Dr. Brian Strom, chancellor of Rutgers Biomedical and Health Sciences, wrote along with his associates. “The WHO has accepted a non-zero target in its work against viral hepatitis,” they added. “The organization’s provisional target is a 90% reduction in incidence, and a 65% reduction in mortality by 2030.”

Furthermore, those are global targets – countries should base their own strategies on their specific viral hepatitis disease burdens and epidemiologic features, Dr. Strom and his associates emphasized. For example, universal vaccination could eradicate HBV in the United States in two generations, but there is no cure for the 700,000-1.4 million Americans who are already infected. Mother-to-child HBV transmission is rare here, but better screening and surveillance could help prevent the 800-1,000 cases of vertical transmission that still occur annually.

More than a third of newborns in the United States do not receive the HBV vaccination on the day they are born, and 28% remain unvaccinated when they are 3 days old, “but childhood catch-up is possible,” the experts also wrote. Vaccinating adults is more complicated, but targeting high-risk groups such as prison inmates or patients at sexually transmitted disease clinics might work, they added. Vaccination is especially important, because chronically infected HBV patients need lifelong medical follow-up to prevent progression and death from cirrhosis and liver cancer, they emphasized.

The hepatitis C virus presents a different picture – there is no HCV vaccine, while the novel direct-acting antivirals can theoretically cure nearly all chronic infections. But in reality, high drug costs and the massive burden of undiagnosed HCV mean that only a small fraction of patients can be cured, the authors acknowledged. On an individual basis, the benefits of direct-acting antivirals outweigh the costs of treating genotype 1 HCV and associated morbidity, they add. But on a population level, “eliminating HCV infection would require near universal access to treatment, something that appears infeasible given the current pricing and policy environment.”

Several other barriers also impede progress against HBV and HCV. For example, only five states and two large cities receive enough funding for comprehensive viral hepatitis surveillance, Dr. Strom and his associates noted. If local and state public health departments cannot track infections, they cannot characterize their epidemics. In addition, viral hepatitis remains a source of stigma, adding to fear and avoidance of testing and undermining elimination efforts. Stigma, avoidance, and the fact that HBV and HCV are asymptomatic in the early stages all contribute to a large population of chronically infected patients who do not know their status.

Moreover, many state Medicaid programs will not cover foreigners until they have lived in the United States for 5 years, and the Affordable Care Act does not cover care for short-term residents and undocumented immigrants, the report stated. Newly infected HCV patients tend to have fewer resources, lower educational levels, and more often use injection drugs, making them harder to reach and screen through the health system. “Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high, and the staff time required to manage an inmate in treatment often far exceed the available resources,” the report stated.

The study was sponsored by the Centers for Disease Control and Prevention Office of Viral Hepatitis and the U.S. Department of Health and Human Services Office of Minority Health. The authors disclosed no conflicts of interest.

The United States can end hepatitis B and C transmission and prevent related morbidity and mortality given enough time, resources, and will to surmount a variety of barriers, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

A more feasible short-term goal is to control viral hepatitis by reducing the incidence and prevalence of hepatitis B (HBV) and C virus (HCV) infections, states the report, which is the first of a two-phase study. The second part, to be published in early 2017, will outline a strategy to achieve the goals.

“Disease elimination” once meant stopping all new infections in a population, but eliminating a public health problem “can be a less absolute goal,” Dr. Brian Strom, chancellor of Rutgers Biomedical and Health Sciences, wrote along with his associates. “The WHO has accepted a non-zero target in its work against viral hepatitis,” they added. “The organization’s provisional target is a 90% reduction in incidence, and a 65% reduction in mortality by 2030.”

Furthermore, those are global targets – countries should base their own strategies on their specific viral hepatitis disease burdens and epidemiologic features, Dr. Strom and his associates emphasized. For example, universal vaccination could eradicate HBV in the United States in two generations, but there is no cure for the 700,000-1.4 million Americans who are already infected. Mother-to-child HBV transmission is rare here, but better screening and surveillance could help prevent the 800-1,000 cases of vertical transmission that still occur annually.

More than a third of newborns in the United States do not receive the HBV vaccination on the day they are born, and 28% remain unvaccinated when they are 3 days old, “but childhood catch-up is possible,” the experts also wrote. Vaccinating adults is more complicated, but targeting high-risk groups such as prison inmates or patients at sexually transmitted disease clinics might work, they added. Vaccination is especially important, because chronically infected HBV patients need lifelong medical follow-up to prevent progression and death from cirrhosis and liver cancer, they emphasized.

The hepatitis C virus presents a different picture – there is no HCV vaccine, while the novel direct-acting antivirals can theoretically cure nearly all chronic infections. But in reality, high drug costs and the massive burden of undiagnosed HCV mean that only a small fraction of patients can be cured, the authors acknowledged. On an individual basis, the benefits of direct-acting antivirals outweigh the costs of treating genotype 1 HCV and associated morbidity, they add. But on a population level, “eliminating HCV infection would require near universal access to treatment, something that appears infeasible given the current pricing and policy environment.”

Several other barriers also impede progress against HBV and HCV. For example, only five states and two large cities receive enough funding for comprehensive viral hepatitis surveillance, Dr. Strom and his associates noted. If local and state public health departments cannot track infections, they cannot characterize their epidemics. In addition, viral hepatitis remains a source of stigma, adding to fear and avoidance of testing and undermining elimination efforts. Stigma, avoidance, and the fact that HBV and HCV are asymptomatic in the early stages all contribute to a large population of chronically infected patients who do not know their status.

Moreover, many state Medicaid programs will not cover foreigners until they have lived in the United States for 5 years, and the Affordable Care Act does not cover care for short-term residents and undocumented immigrants, the report stated. Newly infected HCV patients tend to have fewer resources, lower educational levels, and more often use injection drugs, making them harder to reach and screen through the health system. “Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high, and the staff time required to manage an inmate in treatment often far exceed the available resources,” the report stated.

The study was sponsored by the Centers for Disease Control and Prevention Office of Viral Hepatitis and the U.S. Department of Health and Human Services Office of Minority Health. The authors disclosed no conflicts of interest.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously voted in favor of accelerated approval for a novel drug to treat primary biliary cholangitis on April 7, 2016. The accelerated drug approval process allows for the use of alkaline phosphatase levels as a surrogate endpoint of efficacy.*

At the meeting of the FDA Gastrointestinal Drugs Advisory Committee, panelists wrestled with additional questions from the FDA regarding the use of obeticholic acid (OCA) for primary biliary cholangitis. Presented as discussion items, these included how to select appropriate populations for the novel drug, the proper dosing schema, and how to go forward in postmarketing confirmatory trials of OCA.

The exact indication for which the applicant, Intercept Pharmaceuticals, is seeking obeticholic acid approval is “treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.”

In discussion after the unanimous vote for accelerated approval, Dr. Maria Sjogren, a hepatologist at Walter Reed National Military Medical Center, Bethesda, Md. said, “I welcome this drug in the clinic. It will be a great addition for many patients.” Dr. Marina Silveira, of the division of gastroenterology at the Louis Stokes Cleveland VA Medical Center, agreed: “There is an unmet need, and there are no significant safety or tolerability concerns. But I do think there is more study that’s going to be needed.”

The pivotal phase III clinical trial, POISE [PBC OCA International Study of Efficacy], showed that at the final 1-year assessment, 46% of patients treated with an initial 5 mg daily dose of OCA, and 47% of those treated with 10 mg daily, achieved the primary efficacy endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal, and/or had bilirubin levels less than the upper limit of normal and a 15% or greater reduction in ALP.

The drug was generally well tolerated at the doses used in the POISE trial. Pruritus was common but well-managed in both OCA treatment arms. No concerning hepatic safety signals were seen in the 5-mg titration arm or the 10-mg arm.

PBC (formerly known as primary biliary cirrhosis) is a progressive autoimmune disease of unknown etiology that causes cholestasis, resulting in destruction of the biliary system over time.

Currently, the only approved treatment for PBC is UDCA. Obeticholic acid (to be marketed as Ocaliva by Intercept Pharmaceuticals) is an agonist of the farnesoid X receptor (FXR), a nuclear receptor that controls bile acid homeostasis. The direct FXR agonist activity differs from the mechanism of action of UDCA, which has no nuclear receptor action. Dosing for OCA can thus be much lower, making it attractive for PBC patients who face a considerable pill burden with weight-based dosing of UDCA.

Though committee members acknowledged unmet needs for more and better therapies for PBC patients who don’t respond to or can’t tolerate UDCA, they repeatedly asked for high-quality longitudinal data collection and analysis. Clinical trial data show a signal for early low-density lipoprotein elevation with OCA, as well as long-term lowering of high-density lipoprotein levels.

Regarding the proposed dosing of OCA, FDA analysts agreed with the applicant that a starting dose of 5 mg daily is appropriate, since a dose-dependent increase in pruritus-related discontinuations was seen in phase III clinical trials. Also, a better tolerability profile is seen over time with a lower starting dose, with fewer discontinuations, fewer days of severe pruritus, and delayed time to the first episode of pruritus with the 5-mg starting dose.

Additionally, efficacy was preserved with dose titration, with similar efficacy seen at 1 year for the titration arm, compared with the 10-mg fixed-dose arm in the POISE trial that compared titration from 5 to 10 mg and fixed 10-mg dosing with placebo.

However, the FDA took issue with Intercept’s proposal not to adjust dosing in moderate or severe hepatic impairment, instead proposing a starting dose of 5 mg once weekly, and titrating up to 5 mg twice weekly and finally to a maximum of 10 mg twice weekly, depending on response and tolerability. The FDA’s rationale for this was the lack of clear benefit of high exposures to OCA in moderate or severe hepatic impairment. Another factor was the increased incidence of hepatic adverse events and the higher rate of discontinuation at higher exposures that were seen in earlier clinical trials that used higher doses of OCA.

Panelists, in their critique of the FDA’s proposed hepatic impairment dose adjustments, felt there was insufficient data to support this adjusted regimen and called for more study.

An especially thorny issue for panelists and the FDA was the design of the phase IV trial, which is a double-blind, placebo-controlled, multi-center international trial comparing OCA with placebo for PBC. This trial has already begun to enroll patients and will continue to recruit for a total of 2 years; follow-up will continue for 6 years with quarterly visits. Historical control data from a global PBC database are also available for analysis.

Panelist Dr. Timothy Lipman, emeritus chief of the GI-hepatology-nutrition center at the Department of Veterans Affairs Medical Center in Washington, said, “As a clinician who is very interested in clinical study methodology, I am concerned about possible bias. And the use of historical control data is a nonstarter,” since the study quality would suffer. “Changes in protocol as a study goes on are always problematic,” so the FDA’s request for feedback on how to tinker with study design was a concern.

But the biggest concern voiced by Dr. Lipman and others on the committee, including FDA representatives, was the huge barrier to enrollment that’s presented by a placebo-controlled study for a drug that has already been approved. “This is always a major issue for the FDA in approving drugs under accelerated approval,” acknowledged Dr. Amy Egan, deputy director of the FDA’s office of drug evaluation III, office of new drugs. The anticipation of difficulty in enrolling is one reason the historical control arm is held in reserve, she said. Intercept’s vice president for clinical development Dr. Leigh MacConell concurred, saying of the discussions with the FDA about study design, “It was a very difficult conversation, because we agree with your assessment regarding the feasibility” of the study.

The FDA noted remaining issues requiring ongoing study of OCA for PBC. Among these is the need to confirm the clinical benefit of OCA across the full spectrum of severity of PBC, from early stage to advanced disease. “FDA would also like to evaluate additional data on use of OCA as monotherapy,” said Dr. Lara Dimick-Santos, cross-discipline team leader at the FDA.

The course of PBC is variable; it affects women approximately 10 times more frequently than men. Occurring in approximately 1 in 1,000 women over the age of 40, its prevalence is thought to be increasing. PBC is usually asymptomatic for some time; when symptoms occur, fatigue and pruritis are the most common. Concomitant autoimmune diseases are common and an earlier age at diagnosis is often associated with a worse disease course. A significant number of those affected by PBC will progress to death or liver transplantation.

Intercept Pharmaceuticals is also studying OCA for use in other liver conditions, including nonalcoholic steatohepatitis (NASH).

All committee members submitted information to the FDA regarding conflicts of interest. The FDA usually follows the recommendations of its advisory panels.

*Changes were made to this story on April 8, 2016.

[email protected]

On Twitter @karioakes

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously voted in favor of accelerated approval for a novel drug to treat primary biliary cholangitis on April 7, 2016. The accelerated drug approval process allows for the use of alkaline phosphatase levels as a surrogate endpoint of efficacy.*

At the meeting of the FDA Gastrointestinal Drugs Advisory Committee, panelists wrestled with additional questions from the FDA regarding the use of obeticholic acid (OCA) for primary biliary cholangitis. Presented as discussion items, these included how to select appropriate populations for the novel drug, the proper dosing schema, and how to go forward in postmarketing confirmatory trials of OCA.

The exact indication for which the applicant, Intercept Pharmaceuticals, is seeking obeticholic acid approval is “treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.”

In discussion after the unanimous vote for accelerated approval, Dr. Maria Sjogren, a hepatologist at Walter Reed National Military Medical Center, Bethesda, Md. said, “I welcome this drug in the clinic. It will be a great addition for many patients.” Dr. Marina Silveira, of the division of gastroenterology at the Louis Stokes Cleveland VA Medical Center, agreed: “There is an unmet need, and there are no significant safety or tolerability concerns. But I do think there is more study that’s going to be needed.”

The pivotal phase III clinical trial, POISE [PBC OCA International Study of Efficacy], showed that at the final 1-year assessment, 46% of patients treated with an initial 5 mg daily dose of OCA, and 47% of those treated with 10 mg daily, achieved the primary efficacy endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal, and/or had bilirubin levels less than the upper limit of normal and a 15% or greater reduction in ALP.

The drug was generally well tolerated at the doses used in the POISE trial. Pruritus was common but well-managed in both OCA treatment arms. No concerning hepatic safety signals were seen in the 5-mg titration arm or the 10-mg arm.

PBC (formerly known as primary biliary cirrhosis) is a progressive autoimmune disease of unknown etiology that causes cholestasis, resulting in destruction of the biliary system over time.

Currently, the only approved treatment for PBC is UDCA. Obeticholic acid (to be marketed as Ocaliva by Intercept Pharmaceuticals) is an agonist of the farnesoid X receptor (FXR), a nuclear receptor that controls bile acid homeostasis. The direct FXR agonist activity differs from the mechanism of action of UDCA, which has no nuclear receptor action. Dosing for OCA can thus be much lower, making it attractive for PBC patients who face a considerable pill burden with weight-based dosing of UDCA.

Though committee members acknowledged unmet needs for more and better therapies for PBC patients who don’t respond to or can’t tolerate UDCA, they repeatedly asked for high-quality longitudinal data collection and analysis. Clinical trial data show a signal for early low-density lipoprotein elevation with OCA, as well as long-term lowering of high-density lipoprotein levels.

Regarding the proposed dosing of OCA, FDA analysts agreed with the applicant that a starting dose of 5 mg daily is appropriate, since a dose-dependent increase in pruritus-related discontinuations was seen in phase III clinical trials. Also, a better tolerability profile is seen over time with a lower starting dose, with fewer discontinuations, fewer days of severe pruritus, and delayed time to the first episode of pruritus with the 5-mg starting dose.

Additionally, efficacy was preserved with dose titration, with similar efficacy seen at 1 year for the titration arm, compared with the 10-mg fixed-dose arm in the POISE trial that compared titration from 5 to 10 mg and fixed 10-mg dosing with placebo.

However, the FDA took issue with Intercept’s proposal not to adjust dosing in moderate or severe hepatic impairment, instead proposing a starting dose of 5 mg once weekly, and titrating up to 5 mg twice weekly and finally to a maximum of 10 mg twice weekly, depending on response and tolerability. The FDA’s rationale for this was the lack of clear benefit of high exposures to OCA in moderate or severe hepatic impairment. Another factor was the increased incidence of hepatic adverse events and the higher rate of discontinuation at higher exposures that were seen in earlier clinical trials that used higher doses of OCA.

Panelists, in their critique of the FDA’s proposed hepatic impairment dose adjustments, felt there was insufficient data to support this adjusted regimen and called for more study.

An especially thorny issue for panelists and the FDA was the design of the phase IV trial, which is a double-blind, placebo-controlled, multi-center international trial comparing OCA with placebo for PBC. This trial has already begun to enroll patients and will continue to recruit for a total of 2 years; follow-up will continue for 6 years with quarterly visits. Historical control data from a global PBC database are also available for analysis.

Panelist Dr. Timothy Lipman, emeritus chief of the GI-hepatology-nutrition center at the Department of Veterans Affairs Medical Center in Washington, said, “As a clinician who is very interested in clinical study methodology, I am concerned about possible bias. And the use of historical control data is a nonstarter,” since the study quality would suffer. “Changes in protocol as a study goes on are always problematic,” so the FDA’s request for feedback on how to tinker with study design was a concern.

But the biggest concern voiced by Dr. Lipman and others on the committee, including FDA representatives, was the huge barrier to enrollment that’s presented by a placebo-controlled study for a drug that has already been approved. “This is always a major issue for the FDA in approving drugs under accelerated approval,” acknowledged Dr. Amy Egan, deputy director of the FDA’s office of drug evaluation III, office of new drugs. The anticipation of difficulty in enrolling is one reason the historical control arm is held in reserve, she said. Intercept’s vice president for clinical development Dr. Leigh MacConell concurred, saying of the discussions with the FDA about study design, “It was a very difficult conversation, because we agree with your assessment regarding the feasibility” of the study.

The FDA noted remaining issues requiring ongoing study of OCA for PBC. Among these is the need to confirm the clinical benefit of OCA across the full spectrum of severity of PBC, from early stage to advanced disease. “FDA would also like to evaluate additional data on use of OCA as monotherapy,” said Dr. Lara Dimick-Santos, cross-discipline team leader at the FDA.

The course of PBC is variable; it affects women approximately 10 times more frequently than men. Occurring in approximately 1 in 1,000 women over the age of 40, its prevalence is thought to be increasing. PBC is usually asymptomatic for some time; when symptoms occur, fatigue and pruritis are the most common. Concomitant autoimmune diseases are common and an earlier age at diagnosis is often associated with a worse disease course. A significant number of those affected by PBC will progress to death or liver transplantation.

Intercept Pharmaceuticals is also studying OCA for use in other liver conditions, including nonalcoholic steatohepatitis (NASH).

All committee members submitted information to the FDA regarding conflicts of interest. The FDA usually follows the recommendations of its advisory panels.

*Changes were made to this story on April 8, 2016.

[email protected]

On Twitter @karioakes

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously voted in favor of accelerated approval for a novel drug to treat primary biliary cholangitis on April 7, 2016. The accelerated drug approval process allows for the use of alkaline phosphatase levels as a surrogate endpoint of efficacy.*

At the meeting of the FDA Gastrointestinal Drugs Advisory Committee, panelists wrestled with additional questions from the FDA regarding the use of obeticholic acid (OCA) for primary biliary cholangitis. Presented as discussion items, these included how to select appropriate populations for the novel drug, the proper dosing schema, and how to go forward in postmarketing confirmatory trials of OCA.

The exact indication for which the applicant, Intercept Pharmaceuticals, is seeking obeticholic acid approval is “treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.”

In discussion after the unanimous vote for accelerated approval, Dr. Maria Sjogren, a hepatologist at Walter Reed National Military Medical Center, Bethesda, Md. said, “I welcome this drug in the clinic. It will be a great addition for many patients.” Dr. Marina Silveira, of the division of gastroenterology at the Louis Stokes Cleveland VA Medical Center, agreed: “There is an unmet need, and there are no significant safety or tolerability concerns. But I do think there is more study that’s going to be needed.”

The pivotal phase III clinical trial, POISE [PBC OCA International Study of Efficacy], showed that at the final 1-year assessment, 46% of patients treated with an initial 5 mg daily dose of OCA, and 47% of those treated with 10 mg daily, achieved the primary efficacy endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal, and/or had bilirubin levels less than the upper limit of normal and a 15% or greater reduction in ALP.

The drug was generally well tolerated at the doses used in the POISE trial. Pruritus was common but well-managed in both OCA treatment arms. No concerning hepatic safety signals were seen in the 5-mg titration arm or the 10-mg arm.

PBC (formerly known as primary biliary cirrhosis) is a progressive autoimmune disease of unknown etiology that causes cholestasis, resulting in destruction of the biliary system over time.

Currently, the only approved treatment for PBC is UDCA. Obeticholic acid (to be marketed as Ocaliva by Intercept Pharmaceuticals) is an agonist of the farnesoid X receptor (FXR), a nuclear receptor that controls bile acid homeostasis. The direct FXR agonist activity differs from the mechanism of action of UDCA, which has no nuclear receptor action. Dosing for OCA can thus be much lower, making it attractive for PBC patients who face a considerable pill burden with weight-based dosing of UDCA.

Though committee members acknowledged unmet needs for more and better therapies for PBC patients who don’t respond to or can’t tolerate UDCA, they repeatedly asked for high-quality longitudinal data collection and analysis. Clinical trial data show a signal for early low-density lipoprotein elevation with OCA, as well as long-term lowering of high-density lipoprotein levels.

Regarding the proposed dosing of OCA, FDA analysts agreed with the applicant that a starting dose of 5 mg daily is appropriate, since a dose-dependent increase in pruritus-related discontinuations was seen in phase III clinical trials. Also, a better tolerability profile is seen over time with a lower starting dose, with fewer discontinuations, fewer days of severe pruritus, and delayed time to the first episode of pruritus with the 5-mg starting dose.

Additionally, efficacy was preserved with dose titration, with similar efficacy seen at 1 year for the titration arm, compared with the 10-mg fixed-dose arm in the POISE trial that compared titration from 5 to 10 mg and fixed 10-mg dosing with placebo.

However, the FDA took issue with Intercept’s proposal not to adjust dosing in moderate or severe hepatic impairment, instead proposing a starting dose of 5 mg once weekly, and titrating up to 5 mg twice weekly and finally to a maximum of 10 mg twice weekly, depending on response and tolerability. The FDA’s rationale for this was the lack of clear benefit of high exposures to OCA in moderate or severe hepatic impairment. Another factor was the increased incidence of hepatic adverse events and the higher rate of discontinuation at higher exposures that were seen in earlier clinical trials that used higher doses of OCA.

Panelists, in their critique of the FDA’s proposed hepatic impairment dose adjustments, felt there was insufficient data to support this adjusted regimen and called for more study.

An especially thorny issue for panelists and the FDA was the design of the phase IV trial, which is a double-blind, placebo-controlled, multi-center international trial comparing OCA with placebo for PBC. This trial has already begun to enroll patients and will continue to recruit for a total of 2 years; follow-up will continue for 6 years with quarterly visits. Historical control data from a global PBC database are also available for analysis.

Panelist Dr. Timothy Lipman, emeritus chief of the GI-hepatology-nutrition center at the Department of Veterans Affairs Medical Center in Washington, said, “As a clinician who is very interested in clinical study methodology, I am concerned about possible bias. And the use of historical control data is a nonstarter,” since the study quality would suffer. “Changes in protocol as a study goes on are always problematic,” so the FDA’s request for feedback on how to tinker with study design was a concern.

But the biggest concern voiced by Dr. Lipman and others on the committee, including FDA representatives, was the huge barrier to enrollment that’s presented by a placebo-controlled study for a drug that has already been approved. “This is always a major issue for the FDA in approving drugs under accelerated approval,” acknowledged Dr. Amy Egan, deputy director of the FDA’s office of drug evaluation III, office of new drugs. The anticipation of difficulty in enrolling is one reason the historical control arm is held in reserve, she said. Intercept’s vice president for clinical development Dr. Leigh MacConell concurred, saying of the discussions with the FDA about study design, “It was a very difficult conversation, because we agree with your assessment regarding the feasibility” of the study.

The FDA noted remaining issues requiring ongoing study of OCA for PBC. Among these is the need to confirm the clinical benefit of OCA across the full spectrum of severity of PBC, from early stage to advanced disease. “FDA would also like to evaluate additional data on use of OCA as monotherapy,” said Dr. Lara Dimick-Santos, cross-discipline team leader at the FDA.

The course of PBC is variable; it affects women approximately 10 times more frequently than men. Occurring in approximately 1 in 1,000 women over the age of 40, its prevalence is thought to be increasing. PBC is usually asymptomatic for some time; when symptoms occur, fatigue and pruritis are the most common. Concomitant autoimmune diseases are common and an earlier age at diagnosis is often associated with a worse disease course. A significant number of those affected by PBC will progress to death or liver transplantation.

Intercept Pharmaceuticals is also studying OCA for use in other liver conditions, including nonalcoholic steatohepatitis (NASH).

All committee members submitted information to the FDA regarding conflicts of interest. The FDA usually follows the recommendations of its advisory panels.

*Changes were made to this story on April 8, 2016.

[email protected]

On Twitter @karioakes

If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.

In the United States, hepatitis C virus (HCV)-associated mortality is increasing. From 2003-2013, the number of deaths associated with HCV has now surpassed 60 other nationally notifiable infectious conditions combined.

Courtesy NIH

Chronic hepatitis B infection increased mortality and complexity among a cohort of HIV-coinfected patients in South Africa, according to a study in HIV Medicine. Researchers found that mortality was increased for chronic hepatitis B patients with hepatitis B virus DNA levels greater than 10,000 copies/mL, compared with non-coinfected patients.

A study in the Journal of Infectious Diseases found that Interferon Lambda (IFNL) genotypes were individually linked to higher rates of fibrosis in HIV–hepatitis C co-infection. Investigators said IFNL genotypes may be useful to target hepatitis C virus treatments to those who are at higher risk of liver disease.

A phase I study of a new NS3/4A protease inhibitor for treatment of chronic hepatitis C virus genotype 1-4 infection yielded positive tolerability, efficacy, and pharmacokinetic results, indicating further evaluation is warranted. The drug, GS-9857, produced by Gilead Sciences, achieved mean and median maximum reductions in HCV RNA of greater than or equal to 3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3, or 4 infection.

High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in hepatitis C-infected patients treated with sofosbuvir-containing regimens, according to a study in the Journal of Viral Hepatitis. Among 499 previously stable patients in the cohort, the incidence of decompensation/events was 4.5%, and the mortality rate was 0.6%.

A meta-analysis of national-level hepatitis C virus prevalence in the Arabian Gulf region found that it is comparable to global levels, although higher HCV prevalence is found in specific expatriate populations reflecting the prevalence in their countries of origin.

A resistance analysis of the drug GS-9190, a NS5B non-nucleoside analogue for the treatment of hepatitis C virus infection, found that the Y448H mutation was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Researchers concluded that Y448H confers reduced susceptibility to GS-9190 and other non-nucleoside inhibitors and persisted in most patients for months post-treatment.

A study published in the International Journal of Infectious Diseases found that hepatitis delta virus (HDV) patients in the Amazon region can be treated with a combination of Pegylated Interferon Alpha and Entecavir for 48 weeks, with good chances of negative HDV RNA at week 24. The results suggest that HDV-3 in the native population may be an “easy to treat” variant compared to HDV-1.

Development of acute hepatitis B virus disease in successfully vaccinated individuals is a rare event, affirmed a study of the Italian Surveillance System for Acute Viral Hepatitis (SEIEVA) from 1993 to 2014. Only 3.2% of acute hepatitis B cases had been vaccinated. Investigators said further efforts are needed to enhance the vaccine coverage rate in people at increased risk of infection, as hepatitis B is a vaccine-preventable disease.

Lab-made hepatocyte transplantation has therapeutic potential as a bridge or even alternative to whole organ liver transplantation, but researchers say deficiencies and uncertainties must be addressed in future studies aimed at developing liver cell therapies with such hepatocytes.

A major concern in potential liver transplant candidates is of unintended harm by achieving sustained viral response rates to direct-acting antiviral treatment, but without improvement in hepatic function to an extent where the patients might function well. A review essay in the Journal of Viral Hepatitis says there is a growing sentiment in some transplant quarters that those with decompensated liver disease awaiting liver transplant be treated for HCV after liver transplant instead of pre-transplant. The authors say it is essential that to develop robust predictors of improvement in liver function so patients can be carefully selected for therapy in the context of liver transplantation.

Treating mild-stage hepatitis C infection in people who inject drugs had virtually no impact on HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC) within 15 years, a recent study found, but the long timescale of liver disease means relatively few people who inject drugs reach cirrhosis before cessation of injecting. Investigators said strategies focusing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

AGA Resource

AGA offers a Hepatitis C Clinical Service Line to provide gastroenterologists with tools to support high-quality patient care.

[email protected]

On Twitter @richpizzi

If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.

In the United States, hepatitis C virus (HCV)-associated mortality is increasing. From 2003-2013, the number of deaths associated with HCV has now surpassed 60 other nationally notifiable infectious conditions combined.

Courtesy NIH

Chronic hepatitis B infection increased mortality and complexity among a cohort of HIV-coinfected patients in South Africa, according to a study in HIV Medicine. Researchers found that mortality was increased for chronic hepatitis B patients with hepatitis B virus DNA levels greater than 10,000 copies/mL, compared with non-coinfected patients.

A study in the Journal of Infectious Diseases found that Interferon Lambda (IFNL) genotypes were individually linked to higher rates of fibrosis in HIV–hepatitis C co-infection. Investigators said IFNL genotypes may be useful to target hepatitis C virus treatments to those who are at higher risk of liver disease.

A phase I study of a new NS3/4A protease inhibitor for treatment of chronic hepatitis C virus genotype 1-4 infection yielded positive tolerability, efficacy, and pharmacokinetic results, indicating further evaluation is warranted. The drug, GS-9857, produced by Gilead Sciences, achieved mean and median maximum reductions in HCV RNA of greater than or equal to 3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3, or 4 infection.

High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in hepatitis C-infected patients treated with sofosbuvir-containing regimens, according to a study in the Journal of Viral Hepatitis. Among 499 previously stable patients in the cohort, the incidence of decompensation/events was 4.5%, and the mortality rate was 0.6%.

A meta-analysis of national-level hepatitis C virus prevalence in the Arabian Gulf region found that it is comparable to global levels, although higher HCV prevalence is found in specific expatriate populations reflecting the prevalence in their countries of origin.

A resistance analysis of the drug GS-9190, a NS5B non-nucleoside analogue for the treatment of hepatitis C virus infection, found that the Y448H mutation was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Researchers concluded that Y448H confers reduced susceptibility to GS-9190 and other non-nucleoside inhibitors and persisted in most patients for months post-treatment.

A study published in the International Journal of Infectious Diseases found that hepatitis delta virus (HDV) patients in the Amazon region can be treated with a combination of Pegylated Interferon Alpha and Entecavir for 48 weeks, with good chances of negative HDV RNA at week 24. The results suggest that HDV-3 in the native population may be an “easy to treat” variant compared to HDV-1.

Development of acute hepatitis B virus disease in successfully vaccinated individuals is a rare event, affirmed a study of the Italian Surveillance System for Acute Viral Hepatitis (SEIEVA) from 1993 to 2014. Only 3.2% of acute hepatitis B cases had been vaccinated. Investigators said further efforts are needed to enhance the vaccine coverage rate in people at increased risk of infection, as hepatitis B is a vaccine-preventable disease.

Lab-made hepatocyte transplantation has therapeutic potential as a bridge or even alternative to whole organ liver transplantation, but researchers say deficiencies and uncertainties must be addressed in future studies aimed at developing liver cell therapies with such hepatocytes.

A major concern in potential liver transplant candidates is of unintended harm by achieving sustained viral response rates to direct-acting antiviral treatment, but without improvement in hepatic function to an extent where the patients might function well. A review essay in the Journal of Viral Hepatitis says there is a growing sentiment in some transplant quarters that those with decompensated liver disease awaiting liver transplant be treated for HCV after liver transplant instead of pre-transplant. The authors say it is essential that to develop robust predictors of improvement in liver function so patients can be carefully selected for therapy in the context of liver transplantation.

Treating mild-stage hepatitis C infection in people who inject drugs had virtually no impact on HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC) within 15 years, a recent study found, but the long timescale of liver disease means relatively few people who inject drugs reach cirrhosis before cessation of injecting. Investigators said strategies focusing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

AGA Resource

AGA offers a Hepatitis C Clinical Service Line to provide gastroenterologists with tools to support high-quality patient care.

[email protected]

On Twitter @richpizzi

If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.

In the United States, hepatitis C virus (HCV)-associated mortality is increasing. From 2003-2013, the number of deaths associated with HCV has now surpassed 60 other nationally notifiable infectious conditions combined.

Courtesy NIH

Chronic hepatitis B infection increased mortality and complexity among a cohort of HIV-coinfected patients in South Africa, according to a study in HIV Medicine. Researchers found that mortality was increased for chronic hepatitis B patients with hepatitis B virus DNA levels greater than 10,000 copies/mL, compared with non-coinfected patients.

A study in the Journal of Infectious Diseases found that Interferon Lambda (IFNL) genotypes were individually linked to higher rates of fibrosis in HIV–hepatitis C co-infection. Investigators said IFNL genotypes may be useful to target hepatitis C virus treatments to those who are at higher risk of liver disease.

A phase I study of a new NS3/4A protease inhibitor for treatment of chronic hepatitis C virus genotype 1-4 infection yielded positive tolerability, efficacy, and pharmacokinetic results, indicating further evaluation is warranted. The drug, GS-9857, produced by Gilead Sciences, achieved mean and median maximum reductions in HCV RNA of greater than or equal to 3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3, or 4 infection.

High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in hepatitis C-infected patients treated with sofosbuvir-containing regimens, according to a study in the Journal of Viral Hepatitis. Among 499 previously stable patients in the cohort, the incidence of decompensation/events was 4.5%, and the mortality rate was 0.6%.

A meta-analysis of national-level hepatitis C virus prevalence in the Arabian Gulf region found that it is comparable to global levels, although higher HCV prevalence is found in specific expatriate populations reflecting the prevalence in their countries of origin.

A resistance analysis of the drug GS-9190, a NS5B non-nucleoside analogue for the treatment of hepatitis C virus infection, found that the Y448H mutation was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Researchers concluded that Y448H confers reduced susceptibility to GS-9190 and other non-nucleoside inhibitors and persisted in most patients for months post-treatment.

A study published in the International Journal of Infectious Diseases found that hepatitis delta virus (HDV) patients in the Amazon region can be treated with a combination of Pegylated Interferon Alpha and Entecavir for 48 weeks, with good chances of negative HDV RNA at week 24. The results suggest that HDV-3 in the native population may be an “easy to treat” variant compared to HDV-1.

Development of acute hepatitis B virus disease in successfully vaccinated individuals is a rare event, affirmed a study of the Italian Surveillance System for Acute Viral Hepatitis (SEIEVA) from 1993 to 2014. Only 3.2% of acute hepatitis B cases had been vaccinated. Investigators said further efforts are needed to enhance the vaccine coverage rate in people at increased risk of infection, as hepatitis B is a vaccine-preventable disease.

Lab-made hepatocyte transplantation has therapeutic potential as a bridge or even alternative to whole organ liver transplantation, but researchers say deficiencies and uncertainties must be addressed in future studies aimed at developing liver cell therapies with such hepatocytes.

A major concern in potential liver transplant candidates is of unintended harm by achieving sustained viral response rates to direct-acting antiviral treatment, but without improvement in hepatic function to an extent where the patients might function well. A review essay in the Journal of Viral Hepatitis says there is a growing sentiment in some transplant quarters that those with decompensated liver disease awaiting liver transplant be treated for HCV after liver transplant instead of pre-transplant. The authors say it is essential that to develop robust predictors of improvement in liver function so patients can be carefully selected for therapy in the context of liver transplantation.

Treating mild-stage hepatitis C infection in people who inject drugs had virtually no impact on HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC) within 15 years, a recent study found, but the long timescale of liver disease means relatively few people who inject drugs reach cirrhosis before cessation of injecting. Investigators said strategies focusing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

AGA Resource

AGA offers a Hepatitis C Clinical Service Line to provide gastroenterologists with tools to support high-quality patient care.

[email protected]

On Twitter @richpizzi

Birth-cohort screening for hepatitis C virus according to U.S. Centers for Disease Control and Prevention guidelines may miss around one-quarter of infections, researchers said.

An 8-week seroprevalence survey in an urban emergency department tested excess blood samples from 4,713 patients for hepatitis C virus, finding an overall prevalence of 13.8%, of which 31.3% was undocumented infection.

Jezperklauzen/ThinkStock

According to a paper published in Clinical Infectious Diseases, among the 204 patients with undocumented HCV infection, 48.5% were born between 1945 and 1965 and therefore would have been included in birth-cohort testing, and 26.5% would have been picked up for risk-based testing.

But 25% of the patients found to be infected with HCV in the study would not have been tested based on birth cohort or risk (Clin Infect Dis. 2016 Feb 21. doi: 10.1093/cid/ciw074).

The CDC added the recommendation for one-time testing of individuals born between 1945 and 1965 to its existing advice on risk-based screening in 2012, and this was backed by the U.S. Preventive Services Task Force in 2013.

“Since the CDC’s revised HIV testing recommendations for the health care settings were released, many EDs have had great success in implementing routine HIV testing to the population they serve over the past decade,” wrote Dr. Yu-Hsiang Hsieh of Johns Hopkins University, Baltimore, and coauthors. “This coupled with the availability of effective therapeutics makes EDs a key and strategic component of the national plan to expand HCV testing.”

At the same time, a second study, also in an urban emergency department, tested samples from 924 individuals enrolled in an HIV prevalence survey.

In this study, published in the same issue of Clinical Infectious Diseases, researchers found HCV antibodies in samples from 128 patients (14%); 34% of whom self-reported a history of HCV or hepatitis and 81% of whom were RNA positive.

The researchers noted, however, that, had they only implemented birth-cohort or risk-based screening, they would have missed 28% of individuals with antibodies and 25% of individuals with replicative HCV.

In this study, individuals with HCV infection were more likely to report injection drug use and high-risk sexual behavior, even among individuals reporting neither of these risk factors, but the prevalence of HCV infection was 7% (Clin Infect Dis. 2016 Feb 21. doi: 10.1093/cid/ciw073).

“We also cannot compare our results with the epidemiology of the surrounding population not using the ED, but suggest that as is the case with HIV, EDs are likely to provide a uniquely high level of access to populations with undiagnosed HCV who are in need of treatment,” wrote Dr. Michael S. Lyons and colleagues from the University of Cincinnati.

The authors, however, suggested that their survey may have underestimated the current prevalence of HCV because of an increase in heroin use in the area in more recent years.

Dr. Hsieh and colleagues suggested there was a need to revise the CDC recommendations and expand the age cut-off to all individuals aged 18 years or over.

The first study was supported by the National Institutes of Health and the authors declared no conflicts of interest. The second study was partly supported by Gilead Sciences, the National Institutes of Health, and Bristol-Myers Squibb. Four of the seven authors reported support, research grants, consultancies, or advisory board positions with pharmaceutical companies including Gilead and Bristol-Myers Squibb.

Birth-cohort screening for hepatitis C virus according to U.S. Centers for Disease Control and Prevention guidelines may miss around one-quarter of infections, researchers said.

An 8-week seroprevalence survey in an urban emergency department tested excess blood samples from 4,713 patients for hepatitis C virus, finding an overall prevalence of 13.8%, of which 31.3% was undocumented infection.

Jezperklauzen/ThinkStock

According to a paper published in Clinical Infectious Diseases, among the 204 patients with undocumented HCV infection, 48.5% were born between 1945 and 1965 and therefore would have been included in birth-cohort testing, and 26.5% would have been picked up for risk-based testing.

But 25% of the patients found to be infected with HCV in the study would not have been tested based on birth cohort or risk (Clin Infect Dis. 2016 Feb 21. doi: 10.1093/cid/ciw074).

The CDC added the recommendation for one-time testing of individuals born between 1945 and 1965 to its existing advice on risk-based screening in 2012, and this was backed by the U.S. Preventive Services Task Force in 2013.

“Since the CDC’s revised HIV testing recommendations for the health care settings were released, many EDs have had great success in implementing routine HIV testing to the population they serve over the past decade,” wrote Dr. Yu-Hsiang Hsieh of Johns Hopkins University, Baltimore, and coauthors. “This coupled with the availability of effective therapeutics makes EDs a key and strategic component of the national plan to expand HCV testing.”

At the same time, a second study, also in an urban emergency department, tested samples from 924 individuals enrolled in an HIV prevalence survey.

In this study, published in the same issue of Clinical Infectious Diseases, researchers found HCV antibodies in samples from 128 patients (14%); 34% of whom self-reported a history of HCV or hepatitis and 81% of whom were RNA positive.

The researchers noted, however, that, had they only implemented birth-cohort or risk-based screening, they would have missed 28% of individuals with antibodies and 25% of individuals with replicative HCV.

In this study, individuals with HCV infection were more likely to report injection drug use and high-risk sexual behavior, even among individuals reporting neither of these risk factors, but the prevalence of HCV infection was 7% (Clin Infect Dis. 2016 Feb 21. doi: 10.1093/cid/ciw073).

“We also cannot compare our results with the epidemiology of the surrounding population not using the ED, but suggest that as is the case with HIV, EDs are likely to provide a uniquely high level of access to populations with undiagnosed HCV who are in need of treatment,” wrote Dr. Michael S. Lyons and colleagues from the University of Cincinnati.

The authors, however, suggested that their survey may have underestimated the current prevalence of HCV because of an increase in heroin use in the area in more recent years.

Dr. Hsieh and colleagues suggested there was a need to revise the CDC recommendations and expand the age cut-off to all individuals aged 18 years or over.

The first study was supported by the National Institutes of Health and the authors declared no conflicts of interest. The second study was partly supported by Gilead Sciences, the National Institutes of Health, and Bristol-Myers Squibb. Four of the seven authors reported support, research grants, consultancies, or advisory board positions with pharmaceutical companies including Gilead and Bristol-Myers Squibb.

Birth-cohort screening for hepatitis C virus according to U.S. Centers for Disease Control and Prevention guidelines may miss around one-quarter of infections, researchers said.

An 8-week seroprevalence survey in an urban emergency department tested excess blood samples from 4,713 patients for hepatitis C virus, finding an overall prevalence of 13.8%, of which 31.3% was undocumented infection.

Jezperklauzen/ThinkStock

According to a paper published in Clinical Infectious Diseases, among the 204 patients with undocumented HCV infection, 48.5% were born between 1945 and 1965 and therefore would have been included in birth-cohort testing, and 26.5% would have been picked up for risk-based testing.

But 25% of the patients found to be infected with HCV in the study would not have been tested based on birth cohort or risk (Clin Infect Dis. 2016 Feb 21. doi: 10.1093/cid/ciw074).

The CDC added the recommendation for one-time testing of individuals born between 1945 and 1965 to its existing advice on risk-based screening in 2012, and this was backed by the U.S. Preventive Services Task Force in 2013.

“Since the CDC’s revised HIV testing recommendations for the health care settings were released, many EDs have had great success in implementing routine HIV testing to the population they serve over the past decade,” wrote Dr. Yu-Hsiang Hsieh of Johns Hopkins University, Baltimore, and coauthors. “This coupled with the availability of effective therapeutics makes EDs a key and strategic component of the national plan to expand HCV testing.”

At the same time, a second study, also in an urban emergency department, tested samples from 924 individuals enrolled in an HIV prevalence survey.

In this study, published in the same issue of Clinical Infectious Diseases, researchers found HCV antibodies in samples from 128 patients (14%); 34% of whom self-reported a history of HCV or hepatitis and 81% of whom were RNA positive.

The researchers noted, however, that, had they only implemented birth-cohort or risk-based screening, they would have missed 28% of individuals with antibodies and 25% of individuals with replicative HCV.

In this study, individuals with HCV infection were more likely to report injection drug use and high-risk sexual behavior, even among individuals reporting neither of these risk factors, but the prevalence of HCV infection was 7% (Clin Infect Dis. 2016 Feb 21. doi: 10.1093/cid/ciw073).

“We also cannot compare our results with the epidemiology of the surrounding population not using the ED, but suggest that as is the case with HIV, EDs are likely to provide a uniquely high level of access to populations with undiagnosed HCV who are in need of treatment,” wrote Dr. Michael S. Lyons and colleagues from the University of Cincinnati.

The authors, however, suggested that their survey may have underestimated the current prevalence of HCV because of an increase in heroin use in the area in more recent years.

Dr. Hsieh and colleagues suggested there was a need to revise the CDC recommendations and expand the age cut-off to all individuals aged 18 years or over.

The first study was supported by the National Institutes of Health and the authors declared no conflicts of interest. The second study was partly supported by Gilead Sciences, the National Institutes of Health, and Bristol-Myers Squibb. Four of the seven authors reported support, research grants, consultancies, or advisory board positions with pharmaceutical companies including Gilead and Bristol-Myers Squibb.

Portal inflammation in children with nonalcoholic fatty liver disease is associated with more than a threefold greater risk of more advanced fibrosis, according to a paper published in Hepatology.

A cross-sectional study in 430 children with nonalcoholic fatty liver disease – 12% with type 1 disease, 22% with type 2, and 66% with an overlap of both – found that the presence of portal inflammation was associated with a significant independent association with stage 2-4 fibrosis (odds ratio, 3.70; 95% confidence interval, 1.40-5.21; P = .003), after adjustment for age and sex.

Courtesy of ICL2015

Stage 2-4 fibrosis was associated with a greater incidence of steatosis (OR, 1.81; P less than .0001), lobular inflammation (OR, 1.40; P less than .0001) and a twofold greater incidence of ballooning (P less than .0001).

While children with type 2 or overlap nonalcoholic fatty liver disease typically had lower alanine aminotransferase, aspartate aminotransferase, and bilirubin scores than those with type 1, they had a higher adjusted body mass index and waist circumference, lower HDL cholesterol and higher triglycerides (Hepatology. March 2016;63:745-53).

“Our data highlight that patients with type 2 and overlap NAFLD, in particular portal inflammation and high BMI or waist circumference, may be at increased risk of hepatic or metabolic complications,” wrote Dr. Jake P. Mann from the University of Cambridge, England, and his coauthors, suggesting that an elevated waist circumference could serve as a noninvasive indicator of risk of portal inflammation and fibrosis.

No conflicts of interest were declared.

Portal inflammation in children with nonalcoholic fatty liver disease is associated with more than a threefold greater risk of more advanced fibrosis, according to a paper published in Hepatology.

A cross-sectional study in 430 children with nonalcoholic fatty liver disease – 12% with type 1 disease, 22% with type 2, and 66% with an overlap of both – found that the presence of portal inflammation was associated with a significant independent association with stage 2-4 fibrosis (odds ratio, 3.70; 95% confidence interval, 1.40-5.21; P = .003), after adjustment for age and sex.

Courtesy of ICL2015

Stage 2-4 fibrosis was associated with a greater incidence of steatosis (OR, 1.81; P less than .0001), lobular inflammation (OR, 1.40; P less than .0001) and a twofold greater incidence of ballooning (P less than .0001).

While children with type 2 or overlap nonalcoholic fatty liver disease typically had lower alanine aminotransferase, aspartate aminotransferase, and bilirubin scores than those with type 1, they had a higher adjusted body mass index and waist circumference, lower HDL cholesterol and higher triglycerides (Hepatology. March 2016;63:745-53).

“Our data highlight that patients with type 2 and overlap NAFLD, in particular portal inflammation and high BMI or waist circumference, may be at increased risk of hepatic or metabolic complications,” wrote Dr. Jake P. Mann from the University of Cambridge, England, and his coauthors, suggesting that an elevated waist circumference could serve as a noninvasive indicator of risk of portal inflammation and fibrosis.

No conflicts of interest were declared.

Portal inflammation in children with nonalcoholic fatty liver disease is associated with more than a threefold greater risk of more advanced fibrosis, according to a paper published in Hepatology.

A cross-sectional study in 430 children with nonalcoholic fatty liver disease – 12% with type 1 disease, 22% with type 2, and 66% with an overlap of both – found that the presence of portal inflammation was associated with a significant independent association with stage 2-4 fibrosis (odds ratio, 3.70; 95% confidence interval, 1.40-5.21; P = .003), after adjustment for age and sex.

Courtesy of ICL2015

Stage 2-4 fibrosis was associated with a greater incidence of steatosis (OR, 1.81; P less than .0001), lobular inflammation (OR, 1.40; P less than .0001) and a twofold greater incidence of ballooning (P less than .0001).

While children with type 2 or overlap nonalcoholic fatty liver disease typically had lower alanine aminotransferase, aspartate aminotransferase, and bilirubin scores than those with type 1, they had a higher adjusted body mass index and waist circumference, lower HDL cholesterol and higher triglycerides (Hepatology. March 2016;63:745-53).

“Our data highlight that patients with type 2 and overlap NAFLD, in particular portal inflammation and high BMI or waist circumference, may be at increased risk of hepatic or metabolic complications,” wrote Dr. Jake P. Mann from the University of Cambridge, England, and his coauthors, suggesting that an elevated waist circumference could serve as a noninvasive indicator of risk of portal inflammation and fibrosis.

No conflicts of interest were declared.