Showing posts with label Liver Fibrosis. Show all posts
Showing posts with label Liver Fibrosis. Show all posts

Tuesday, December 31, 2019

Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients

Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients
Lybeck, Charlottea; Brenndörfer, Erwin D.c; Sällberg, Mattic; Montgomery, Scott M.b,d,g; Aleman, Sooe,f; Duberg, Ann-Sofia
SVR is associated with clinical cure and regression of liver fibrosis in most patients after 10 years of FU. However, occult HCV infection can be detected in some patients many years after achievement of SVR; this may have a negative effect on the regression of liver fibrosis, but more studies are needed. Future studies are planned to determine whether the viable virus can be recovered from PBMC. If so, this raises the question of whether those repetitively positive for HCV in PBMC should be retreated. Further, the risk of HCC is not eliminated in all noncirrhotic patients with SVR. Studies of the long-term outcome more than 10 years after IFN therapy and eventually after DAA therapy are needed.
Full-text available online...

On This Blog
Read All Posts With The Label Liver Cancer
Review a collection of current research articles extracted from peer-reviewed journals, liver meetings/conferences, and learning activities investigating the natural history of liver cancer, approved therapies, risk factors associated with chronic viral hepatitis, cancer-prevention, including diet, nutrition and physical activity, and trends associated with the rising rate of hepatocellular carcinoma in the U.S.
Begin, here.....

Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase? Research is saying no, check out an index of articles here..... 

Wednesday, February 20, 2019

Intercept - Phase 3 REGENERATE Study of Obeticholic Acid in Patients with Liver Fibrosis Due to NASH

Recommended Reading
February 19, 2019
The beginning of 2019 has already seen several significant advancements for the field of nonalcoholic steatohepatitis, from the inaugural NASH-TAG meeting to the recently announced positive results from the phase 3 study of Ocaliva.
Healio Gastroenterology and Liver Disease presents the following reports including trial results for Ocaliva (obeticholic acid, Intercept Pharma), a take-home report from NASH-TAG, and an update for this year’s International NASH Day.

February 5, 2019
Nonalcoholic steatohepatitis may soon supplant chronic hepatitis C as the leading cause of hepatocellular carcinoma among patients awaiting liver transplantation, according to the findings of a national longitudinal registry study

Press Release
Intercept Announces Positive Topline Results from Pivotal Phase 3 REGENERATE Study of Obeticholic Acid in Patients with Liver Fibrosis Due to NASH

First and largest successful pivotal Phase 3 study in patients with liver fibrosis due to NASH

OCA achieves primary endpoint demonstrating statistically significant improvement in liver fibrosis without worsening of NASH at 18 months (p=0.0002)

Intercept intends to file for regulatory approval in the U.S. and Europe in the second half of 2019

Results to be presented at European Association for the Study of the Liver 2019 International Liver Congress

The International Liver CongressTM
Every year in April, scientific and medical experts from a broad range of fields including hepatology, gastroenterology, internal medicine, cell biology, transplant surgery, infectious diseases, microbiology and virology, pharmacology, pathology and radiology and imaging come together from around the world to learn about the latest in liver research. Specialists share recent data, present studies and findings, and discuss the hottest topics on liver disease. The annual Congress attracts around 10,000 delegates and 250 media representatives from all over the world making this a truly international networking opportunity!

The International Liver CongressTM 2019 #ILC2019 will take place 10-14 April 2019 at the Reed Messe Wien Exhibition & Congress Center, Vienna, Austria.

Intercept Press Release
NEW YORK, Feb. 19, 2019 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc. (Nasdaq:ICPT), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, today announced positive results from its pivotal Phase 3 REGENERATE study of obeticholic acid (OCA) in patients with liver fibrosis due to nonalcoholic steatohepatitis (NASH). In the primary efficacy analysis, once-daily OCA 25 mg met the primary endpoint of fibrosis improvement (≥1 stage) with no worsening of NASH at the planned 18-month interim analysis (p=0.0002 vs. placebo). In the primary efficacy analysis, a numerically greater proportion of patients in both OCA treatment arms compared to placebo achieved the primary endpoint of NASH resolution with no worsening of liver fibrosis, but this did not reach statistical significance. As agreed with the U.S. Food and Drug Administration (FDA), in order for the primary objective to be met, the study was required to achieve one of the two primary endpoints.

“We are thrilled to report the first positive registrational Phase 3 study results in patients with NASH, a devastating disease that is on track to become a leading cause of liver transplant in coming years,” said Mark Pruzanski, M.D., President and Chief Executive Officer of Intercept. “The topline REGENERATE data we are reporting today support our belief that OCA will become the first approved medicine for those living with liver fibrosis due to NASH. We are deeply grateful to the patients, investigators and study staff whose ongoing participation in REGENERATE has brought us one step closer to delivering a much-needed therapeutic option to address the enormous unmet medical need in this population.”

Based on these results, Intercept intends to file for approval in the U.S. and Europe in the second half of 2019. OCA remains the only investigational drug to have received Breakthrough Therapy designation from the FDA for NASH with fibrosis. REGENERATE results will be presented at the European Association for the Study of the Liver (EASL): The International Liver CongressTM 2019.

“Patients with significant fibrosis due to NASH are at the greatest risk of progression to severe liver-related complications, such as liver failure and death, and fibrosis is considered the strongest predictor of liver-related mortality in this population,” said Zobair M. Younossi, M.D., Professor and Chairman of the Department of Medicine at Inova Fairfax Medical Campus, Professor of Medicine at Virginia Commonwealth University, Inova Campus and the Chair of the REGENERATE Steering Committee. “I am very encouraged by these results that demonstrate OCA’s ability to significantly improve fibrosis in patients with advanced disease. As the first successful pivotal trial in NASH, REGENERATE is an important advancement for the liver community.”

Efficacy Results
The primary efficacy analysis (Intent-to-Treat or ITT) assessed efficacy at 18 months in 931 patients with stage 2 or 3 liver fibrosis due to NASH. Overall study discontinuations in the primary efficacy analysis population were balanced across treatment arms: 16% in placebo, 17% in OCA 10 mg and 15% in OCA 25 mg.

An additional pre-specified full efficacy analysis at 18 months added an exploratory cohort of 287 NASH patients with stage 1 liver fibrosis and additional risk factors who were at increased risk of progression to cirrhosis (N=1,218).

Patients with biopsy proven NASH with fibrosis were randomized 1:1:1 to receive placebo, OCA 10 mg or OCA 25 mg once daily. A repeat biopsy was conducted after 18 months for histologic endpoint assessment. Patients without a repeat biopsy due to study discontinuation or other reason were treated as non-responders in the primary and full efficacy analyses. 

Click On Image To Enlarge

Fibrosis Improvement at Month 18

NASH Resolution at Month 18

Safety and Tolerability
The safety population in this planned 18-month analysis of REGENERATE included 1,968 randomized patients who received at least one dose of investigational product (OCA or placebo).

Adverse events were generally mild to moderate in severity and the most common were consistent with the known profile of OCA. The frequency of serious adverse events was similar across treatment arms (11% in placebo, 11% in OCA 10 mg and 14% in OCA 25 mg) and no serious adverse event occurred in >1% of patients in any treatment arm. There were 3 deaths in the study (2 in placebo: bone cancer and cardiac arrest, 1 in OCA 25 mg: glioblastoma) and none were considered related to treatment.

The most common adverse event reported was dose-related pruritus (19% in placebo, 28% in OCA 10 mg and 51% in OCA 25 mg). The large majority of pruritus events were mild to moderate, with severe pruritus occurring in a small number of patients (<1% in placebo, <1% in OCA 10 mg and 5% in OCA 25 mg). A higher incidence of pruritus associated treatment discontinuation was observed for OCA 25 mg (<1% in placebo, <1% in OCA 10 mg and 9% in OCA 25 mg). According to the clinical study protocol, investigator assessed severe pruritus mandated treatment discontinuation.

Consistent with observations from previous NASH studies, OCA treatment was associated with an increase in LDL cholesterol, with a peak increase of 22.6 mg/dL at 4 weeks and subsequently reversing and approaching baseline at month 18 (4.0 mg/dL increase from baseline). Triglycerides rapidly and continually decreased in the OCA treatment arms through month 18. There were few and varied serious cardiovascular events and incidence was balanced across the three treatment arms (2% in placebo, 1% in OCA 10 mg and 2% in OCA 25 mg).

With respect to hepatobiliary events, more patients (3%) on OCA 25 mg experienced gallstones or cholecystitis compared to <1% on placebo and 1% on OCA 10 mg. While numerically higher in the OCA 25 mg treatment arm, serious hepatic adverse events were uncommon with <1% incidence in each of the
Source - Download PDF

There are no approved treatments for NASH, or nonalcoholic steatohepatitis, a serious liver disease caused by fat accumulation in the liver that can result in chronic inflammation and scarring, or fibrosis. Eventually, the disease can lead to liver failure, cancer and death. 
Intercept’s treatment, obeticholic acid (OCA), is meant to treat patients with liver fibrosis due to NASH. The Phase 3 trial enrolled 931 patients with liver fibrosis who were randomly assigned to be treated with a placebo drug or one of two doses of OCA. 

Wednesday, February 6, 2019

2019 Hepatitis C - Testing, Treatment Options, Stages of fibrosis and Care

Caring for patients with chronic hepatitis C infection
Basic information about hepatitis C, published Jan 31, 2019 in: Nursing2019 - Ahead of Print, available in PDF format only.

Who is at risk?
How HCV infection progresses
Extrahepatic complications of HCV infection
Testing for HCV
Stages of fibrosis
Treatment options
Removing treatment barriers
Promising future

Nursing. 2019 Jan 31. doi: 10.1097/01.NURSE.0000553271.39804.a4. [Epub ahead of print]
Caring for patients with chronic hepatitis C infection
Chaney, Amanda, DNP, APRN, FNP-BC, FAANP
Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the US. This article discusses the pathophysiology of HCV infection, new treatment options, and nursing care and patient teaching for patients with chronic HCV infection.
Begin, here..….

For Patients On This Site
2019 February Hepatitis Newsletters: Finding Support 

Wednesday, January 30, 2019

Fibrosis Markers Tied to Mortality After Liver Cancer Surgery

Fibrosis Markers Tied to Mortality After Liver Cancer Surgery
By David Douglas

NEW YORK (Reuters Health) - Noninvasive markers of fibrosis are associated with perioperative mortality and survival after liver resection for hepatocellular carcinoma, a retrospective study suggests.

Such markers can improve selection criteria, Dr. Felipe B. Maegawa told Reuters Health by email. Moreover, "Resection remains as the preferred therapy for this disease, but it can be associated with significant morbidity and mortality if offered to the wrong patient. Tumor ablation and transplant are excellent curative alternatives."
Read more:

Wednesday, December 19, 2018

December Newsletters: Curing Hep C May Dial Back Liver Damage

Hi folks, over the next few weeks I'll be taking a holiday break to spend time with the family. Can't wait to start my Christmas shopping, trick out my tree, and bake some millennial sugar cookies. Using Pillsbury ready to make slice-and-bake cookies, add sprinkles after baking. Bad Nana!

In any event, here's your list of December newsletters with blog updates from across the web.

News & Review 
Catch up on what you missed this week by reading one of two HCV week in review publications:
The Weekly Bull is published by the Canadian non-profit organization HepCBC, the second publication by Caring Ambassadors Program, is filled with news as well, in addition to a monthly review of relevant HCV research published on PubMed.

News Update
Jan 1, 2019
CDC: Could be a tough flu season based on early viruses, hospitalizations
By Anne-Gerard Flynn
The country could be in for another challenging flu season. There are already 11 pediatric deaths associated with the flu and hospitals rates among very young children are high, according to the Centers for Disease Control and Prevention.

Dec 19, 2018
NPR - Even in a setting with an identified risk factor in opioid-use disorder, too few youths are being screened for hepatitis C
As the number of people who inject drugs and share needles has soared, the rate of infection with Hep C has climbed too. Yet many drug treatment patients aren't tested for the liver-damaging virus.

Dec 17, 2018
Great news for New Zealanders pangenotypic regimen Maviret unrestricted access from Feb 2019 with $0 co-payment - PHARMAC funding decision gives Kiwis with hepatitis C access to a potential cure

December Newsletters
The aim of is to develop a high-quality online resource to increase awareness of viral hepatitis, its treatment, and the needs of people living with viral hepatitis in Europe. 
The December edition of the infohep bulletin is now online: 
Global trends in non-alcoholic fatty liver disease
NAFLD can occur in lean people too
Hepatitis C and the US opioid epidemic
Resistance testing for hepatitis C
Rwanda aims for hepatitis C elimination
Egypt hepatitis C elimination

Hep is an award-winning print and online brand for people living with and affected by viral hepatitis. Offering unparalleled editorial excellence since 2010, Hep and are the go-to source for educational and social support for people living with hepatitis.
Winter Issue 2018
Curing Hep C May Dial Back Liver Damage
Hep C Testing Slowly Rising Among Baby Boomers
People Who Inject Drugs Succeed With Hep C Treatment
and more....

The HCV Advocate newsletter is a valuable resource designed to provide the hepatitis C community with monthly updates on events, clinical research, and education.
In this month's newsletter coverage of the Liver Meeting continues; read easy to understand commentary on HCV-related topics that matter most to patients. In next month's issue notable research on liver cancer presented at the meeting will be featured as well.

On This Blog
After The Liver Meeting Summary: Viral Hepatitis & Fatty Liver Disease
For patients - An index of links provide an overview of the meeting with a focus on HCV; read expert analysis of key data, interviews with leading researchers and clinicians, or listen to live presentations, view slidesets and capsule summaries. Sit back and watch daily clips or a live symposium, finally review a webinar with all the notable Liver Meeting updates. 

HCV Action brings together hepatitis C health professionals from across the patient pathway with the pharmaceutical industry and patient representatives to share expertise and good practice.
Read the latest: HCV Action e-update

The World Hepatitis Alliance goal is to achieve a world free from viral hepatitis, World Hepatitis Alliance provides global leadership in awareness-raising, advocacy and in efforts to find the missing millions.
News & Headlines 
Click here to read our latest newsletter.

The New York City Hepatitis C Task Force is a city-wide network of service providers and advocates concerned with hepatitis C and related issues. The groups come together to learn, share information and resources, network, and identify hepatitis C related needs in the community. Committees form to
work on projects in order to meet needs identified by the community.
December Newsletter: Reminder: NYC Hep C Task Force Meeting. December 5 (3-5 PM) @ 132 West 32nd St.
NYC Hep C Task Force
All - Hep Free NYC Newsletters

Hepatitis NSW provides information, support, referral and advocacy for people affected by viral hepatitis in NSW. We also provide workforce development and education services both to prevent the transmission of viral hepatitis and to improve services for those affected by it.
News Updates

GI & Hepatology News covers the world of liver disease with breaking news, on-site medical meeting coverage, and expert perspectives both in print and online. 
View all updates here....

Hepatitis Victoria is the peak not-for-profit community organisation working across the state for people affected by or at risk of viral hepatitis.
View the Latest Newsletter, or relax and listen to a short podcasts interviewing health experts and practioners on topics related to viral hepatitis - have a listen!

The British Liver Trust is the leading UK liver disease charity for adults – we provide information and support; increase awareness of how liver disease can be prevented and promote early diagnosis; fund and champion research and campaign for better services. 
View Recent Newsletters, here.

The Hepatitis C Trust is run by patients with the goal of eliminating HCV in the United Kingdom. The Trust’s mission is to reverse the rapidly increasing death toll caused by hepatitis C in the UK until no-one dies from this preventable and treatable disease and, ultimately, it is all but eradicated in this country.

The National Viral Hepatitis Roundtable (NVHR) is national coalition working together to eliminate hepatitis B and C in the United States.
NVHR 2018 Year in Review
View all NVHR newsletters

Check out the latest National Institutes of Health Newsletter.
December Newsletter
Plan Your Plate - Shifting to a Healthy Eating Style

Blog Updates
Karen Hoyt is devoted to offering support and accurate information to people coping with the effects of hepatitis C.
Latest blog entry: Holiday and Health Problems
Find Karen on Facebook
YouTube Page

Lucinda K. Porter
Lucinda Porter is a nurse, speaker, advocate and patient devoted to increasing awareness about hepatitis C.
View all new blog updates, here....

Hep is an award-winning print and online brand for people living with and affected by viral hepatitis.
Latest blog updates: 
By Lucinda K. Porter, RN
By Connie M. Welch 
Hepatitis C Cure 
By Greg Jefferys
View all blog updates, here...

AGA Blog
Gastroenterology and Clinical Gastroenterology and Hepatology
View all blog updates, here...

Life Beyond Hep C is where faith, medical resources and patient support meet, helping Hep C patients and their families navigate through the entire journey of Hep C.
Latest blog entry: 5 Common Questions and Answers about Hepatitis C Treatment
View all updates, here...

Canadian Liver Foundation
We strive to improve prevention and the quality of life of those living with liver disease by advocating for better screening, access to treatment, and patient care.
Latest blog entry: Tips for a struggling caregiver
View all updates, here...

The Hepatitis B Foundation is a national nonprofit organization dedicated to finding a cure and improving the quality of life for those affected by hepatitis B worldwide.
Latest blog entry: My partner has been diagnosed with hepatitis B. Can transmission be prevented by vaccination?
 Ask An Expert: Managing Hepatitis Delta During Pregnancy
View all updates, here....

ADRLF (Al D. Rodriguez Liver Foundation)
Al D. Rodriguez Liver Foundation is a non-profit organization that provides resources, education and information related to screening, the prevention of and treatment for the Hepatitis Virus and Liver Cancer.
View all updates, here....

At we empower patients and caregivers to take control of Hepatitis C by providing a platform to learn, educate, and connect with peers and healthcare professionals.
Part 1: Doctors and Dragons: The Adventure Continues - By Rick Nash
View all updates, here....

Kevin Pho is a practicing physician and most known for his blog KevinMD. Thousands of authors contribute to his blog: primary care doctors, surgeons, specialist physicians, nurses, medical students, policy experts. And of course, patients, who need the medical profession to hear their voices.
View latest blog entry, here... 

Harvard Health Blog
The goal of our publications is to bring people around the world the most current health information that is authoritative, trustworthy, and accessible, drawing on the expertise of the 10,000+ faculty physicians at Harvard Medical School.
Latest blog entry: Alcohol use disorder: When is drinking a problem?
Benefits of a healthy diet — with or without weight loss
Safe and effective use of insulin requires proper storage

University of Michigan - Lab Blog
Providing physicians with virtual access to specialists can be lifesaving to liver disease patients.
View all updates: Lab Blog

In Case You Missed It
Dec 13, 2018
New HCV Clinical Advances
Sit back and watch a live symposium from the November 2018 Liver Meeting featuring table discussions with leading physicians discussing viral hepatitis, launched by Chronic Liver Disease Foundation (CLDF) on December 13, 2018.

December 21, 2018
During 2013 to 2016, what proportion of adults were living with hepatitis C virus (HCV) infection in each US state?
Regions with long-standing HCV epidemics, and those with newly emergent ones partly driven by the opioid crisis, face substantial HCV prevalence.
Prevalence of Hepatitis C Virus Infection in US States and the District of Columbia, 2013 to 2016
Prevalence of HCV infection varies widely in the United States. Highest rates are frequently in states deeply affected by the opioid crisis or with a history of increased levels of injection drug use and chronic HCV infection, particularly in the West. Progress toward hepatitis C elimination is theoretically possible with the right investments in prevention, diagnosis, and cure. The urgency for action and the resources necessary will vary by jurisdiction.

JAMA In The News: Hepatitis C Cases Cluster in States Hit Hard by Opioids
FRIDAY, Dec. 21, 2018 (HealthDay News) -- More than half of Americans with hepatitis C are living in just nine U.S. states -- five of those in a region hit hard by the opioid epidemic, a new study shows.

JAMA Patient Page
This JAMA Patient Page describes recent advancements in hepatitis C treatment.
December 4, 2018
Treating Hepatitis C
From a medical point of view, almost all patients with hepatitis C should be treated.

See you soon!

Friday, November 30, 2018

Combination interventions for Hepatitis C and Cirrhosis reduction among people who inject drugs: An agent-based, networked population simulation experiment

Combination interventions for Hepatitis C and Cirrhosis reduction among people who inject drugs: An agent-based, networked population simulation experiment
Bilal Khan, Ian Duncan, Mohamad Saad, Daniel Schaefer, Ashly Jordan, Daniel Smith, Alan eaigus,
Don Des Jarlais, Holly Hagan, Kirk Dombrowski 

Published: November 29, 2018

Fig 1. Finite state diagram of the HCV model used in the experiments.
Once infected, agents face a series of stochastic and enforced progressions through a series of ever worsening liver function. Throughout the simulation, infected agents who have reached a chronic state (non-acute HCV infected agents) face a small but regular chance of moving directly to cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma. In addition, their Metavir fibrosis level is incremented yearly, moving them gradually from early stage fibrosis to cirrhosis. Once in any of the three severe liver stages, agents face an increasing probability of death due to HCV infection, incremented on a five year basis.

Full-text article:

Hepatitis C virus (HCV) infection is endemic in people who inject drugs (PWID), with prevalence estimates above 60% for PWID in the United States. Previous modeling studies suggest that direct acting antiviral (DAA) treatment can lower overall prevalence in this population, but treatment is often delayed until the onset of advanced liver disease (fibrosis stage 3 or later) due to cost. Lower cost interventions featuring syringe access (SA) and medically assisted treatment (MAT) have shown mixed results in lowering HCV rates below current levels. However. little is known about the potential cumulative effects of combining DAA and MAT treatment. While simulation experiments can reveal likely long-term effects, most prior simulations have been performed on closed populations of model agents—a scenario quite different from the open, mobile populations known to most health agencies. This paper uses data from the Centers for Disease Control’s National HIV Behavioral Surveillance project, IDU round 3, collected in New York City in 2012 to parameterize simulations of open populations. To test the effect of combining DAA treatment with SA/MAT participation, multiple, scaled implementations of the two intervention strategies were simulated. Our results show that, in an open population, SA/MAT by itself has only small effects on HCV prevalence, while DAA treatment by itself can lower both HCV and HCV-related advanced liver disease prevalence. More importantly, the simulation experiments suggest that combinations of the two strategies can, when implemented together and at sufficient levels, dramatically reduce HCV incidence. We conclude that adopting SA/MAT implementations alongside DAA interventions can play a critical role in reducing the long-term consequences of ongoing HCV infection.

Tuesday, November 13, 2018

DAA Treatment and Hepatic Fibrosis Improvement in HCV: What's the Link?

Presented at AASLD The Liver Meeting 2018. Study number 0603.
Kommineni VT et al.

Factors Associated with Lack of Improvement in Fibrosis Following HCV Treatment.

Monthly Prescribing Reference
DAA Treatment and Hepatic Fibrosis Improvement in HCV: What's the Link?
According to the results of a prospective cohort study, 57% of patients with hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) showed no improvement in hepatic fibrosis. The study, which took place at a tertiary liver center, aimed to determine whether direct-acting antiviral (DAA) therapy reduced fibrosis and assessed whether any predictors of treatment failure existed at 1-year follow-up. A total of 193 patients were divided into 2 groups: those who achieved SVR (N=143) and those who failed treatment or did not receive it (N=50). 

Conference Articles
By Cassandra Pardini, PharmD November 13, 2018 

Sunday, November 11, 2018

Glucose Metabolism Changes in Patients with Chronic Hepatitis C Treated with Direct Acting Antivirals

In Case You Missed It

Can J Gastroenterol Hepatol. 2018 Oct 3;2018:6095097. doi: 10.1155/2018/6095097. eCollection 2018.

Glucose Metabolism Changes in Patients with Chronic Hepatitis C Treated with Direct Acting Antivirals.
Drazilova S1, Janicko M2, Skladany L3, Kristian P4, Oltman M5, Szantova M6, Krkoska D7, Mazuchova E7, Piesecka L8, Vahalova V8, Rac M9, Schreter I4, Virag L4, Koller T10, Liptakova A11, Ondrasova M12, Jarcuska P2.

This retrospective study confirmed that the prevalence of either type 2 diabetes mellitus ( T2DM ) or impaired fasting glucose (IFG) increases in chronic hepatitis C patients with the degree of fibrosis; patients with F4 fibrosis had 27.1% prevalence of IFG and 31.8% of T2DM. The predictive factors for T2DM had besides F4 fibrosis also higher age and BMI. Significant decrease of fasting glycemia at the end of treatment and 12 weeks after that was observed in the whole cohort and in subgroups of patients with type 2 diabetes mellitus, impaired fasting glucose, Child-Pugh A cirrhotic patients, treatment experienced patients, and treatment experienced cirrhotics. Long term follow-up may further show if the achievement of SVR after DAA treatment will reduce the risk of future T2DM development similarly to SVR after interferon treatment and if the improvement of glycemic control in patients with T2DM decreases the risk of chronic complications and improves survival.

Open Access

Background and Aims
Chronic hepatitis C is a systemic disease and type 2 diabetes mellitus (T2DM) belongs to more common extrahepatic. The aim of this study was to (i) explore the prevalence of impaired fasting glucose (IFG) and T2DM in patients with chronic hepatitis C, (ii) explore the effect of direct acting antivirals (DAA) treatment on the glycemia, and (iii) explore the factors that modulate the effect of DAA treatment on glycemia in patients with chronic hepatitis C.

We performed a longitudinal retrospective observational study focused on the patients undergoing DAA treatment of chronic hepatitis C. Data about glycemia, history of diabetes, hepatitis C virus, treatment, and liver status, including elastography, were obtained at baseline (before treatment start), at the end of treatment and 12 weeks after the end of treatment. Patients were treated with various regimens of direct acting antivirals.

We included 370 patients; 45.9% had F4 fibrosis. At baseline, the prevalence of T2DM increased with the degree of fibrosis (F0-F2 14.4%, F3 21.3%, and F4 31.8%, p=0.004). Fasting glycemia also increased with the degree of fibrosis (F0-F2 5.75±0.18 F3 5.84±0.17, and F4 6.69±0.2 mmol/L, p=0.001). We saw significant decrease of glycemia after treatment in all patients, but patients without T2DM or IFG from 6.21±0.12 to 6.08±0.15 mmol/L (p=0.002). The decrease was also visible in treatment experienced patients and patients with Child-Pugh A cirrhosis.

We confirmed that the prevalence of either T2DM or IFG increases in chronic hepatitis C patients with the degree of fibrosis. The predictive factors for T2DM were, besides F4, fibrosis also higher age and BMI. Significant decrease of fasting glycemia after the DAA treatment was observed in the whole cohort and in subgroups of patients with T2DM, IFG, cirrhotic, and treatment experienced patients.

30402450 PMCID:
PMC6192081 DOI: 10.1155/2018/6095097

Friday, November 9, 2018

Gilead Presents Data From Nonalcoholic Steatohepatitis (NASH) Development Program for Advanced Fibrosis at The Liver Meeting® 2018

Meeting Coverage @ Healio
Nov 27, 2018
SAN FRANCISCO — In this exclusive video perspective from The Liver Meeting 2018, Rob Myers, MD, senior director of the liver diseases therapeutic area at Gilead…

View all updates on this blog (LINK), recommended coverage elsewhere (LINK). 

Gilead Press Release
November 09, 2018
Gilead Presents Data From Nonalcoholic Steatohepatitis (NASH) Development Program for Advanced Fibrosis at The Liver Meeting® 2018

-- Phase 2 Data Presented on Investigational FXR Agonist GS-9674 in NASH --
-- Enrollment Complete in Phase 2 ATLAS Combination Trial of Three Investigational Therapies Targeting Distinct Mechanisms of the Disease --

SAN FRANCISCO--(BUSINESS WIRE)--Nov. 9, 2018-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced new data from the company’s clinical development program for advanced fibrosis due to nonalcoholic steatohepatitis (NASH). Data presented support the ongoing development of the company’s investigational compounds, evaluate the utility of noninvasive tests for the identification of patients with advanced fibrosis, and demonstrate the significant burden of disease in affected patients. The data presented across 24 abstracts are being shared at The Liver Meeting® 2018 in San Francisco this week.

Data from a Phase 2 randomized, placebo-controlled trial of the investigational, selective, non-steroidal farnesoid X receptor (FXR) agonist GS-9674 will be presented. In this study, 140 NASH patients were treated with GS-9674 100 mg, GS-9674 30 mg or placebo orally once daily for 24 weeks. A decline of at least 30 percent in hepatic fat measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was observed in 38.9 percent of patients treated with GS-9674 100 mg (p=0.011 vs placebo), 14 percent treated with GS-9674 30 mg (p=0.87), and 12.5 percent with placebo. Improvements in liver biochemistry tests (serum GGT) and markers of reduced bile acid synthesis (serum C4 and bile acids) were observed in the 30 mg and 100 mg arms of GS-9674-treated patients.

GS-9674 was generally well tolerated; moderate to severe pruritus, or itching, occurred in 14 percent of patients in the GS-9674 100 mg arm compared to four percent in the GS-9674 30 mg and placebo arms. Changes in lipid profile and glycemic parameters did not differ between GS-9674 and placebo-treated patients. The most common adverse events in patients treated with GS-9674 were pruritus, upper respiratory tract infection, headache and fatigue. Treatment was discontinued due to adverse events in one patient treated with GS-9674 100 mg (two percent), five patients treated with GS-9674 30 mg (nine percent), and two patients with placebo (seven percent).

A separate Phase 2 study (ATLAS) is investigating treatment with GS-9674, the investigational apoptosis signal-regulating kinase 1 (ASK-1) inhibitor selonsertib, and the investigational acetyl-CoA carboxylase (ACC) inhibitor GS-0976 alone or in combination, in patients with advanced fibrosis due to NASH. This randomized, double-blind 52-week study will assess improvement in fibrosis without worsening of NASH, adverse events and laboratory abnormalities in approximately 350 patients.

“We believe our development program is well positioned to address the unmet need for effective therapies for people living with advanced fibrosis due to NASH. We are pleased to share that the Phase 2 ATLAS combination trial of experimental GS-9674, selonsertib, and GS-0976 has completed enrollment ahead of schedule,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead Sciences. “We also continue to support the liver community in the study of noninvasive tests to help overcome the risks and limitations of liver biopsies in the diagnosis of advanced fibrosis due to NASH.”

Noninvasive Tests
In a late-breaker session, Gilead will present an analysis of baseline data from its Phase 3 STELLAR trials of selonsertib suggesting that the use of currently available noninvasive tests (NITs) can accurately identify patients with advanced fibrosis (F3-F4) due to NASH and potentially reduce the need for liver biopsy. The use of the Fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test and liver stiffness measurement by FibroScan® (FS) each demonstrated good sensitivity and specificity for the discrimination of advanced fibrosis due to NASH when compared to liver biopsy. When used sequentially, FIB-4 followed by FS or the ELF test accurately identified advanced fibrosis in 76-81 percent of patients while reducing the frequency of indeterminate results to as low as 13 percent.

“There is a major need for accurate and readily available tests to diagnose patients with advanced fibrosis due to NASH, a disease which affects many aspects of patients’ lives,” said Zobair Younossi, MD, MPH, FACP, FACG, AGAF, FAASLD, lead study author and Chairman and Professor, Department of Medicine, Inova Fairfax Hospital. “These findings from the STELLAR program indicate that currently available noninvasive tools, when used alone or sequentially, can identify these patients with advanced fibrosis due to NASH rather accurately, providing a potentially simple option for physicians to use in clinical practice.

Burden of Disease
Baseline data from patients enrolled in the STELLAR Phase 3 program presented in a poster session at The Liver Meeting® 2018 demonstrate the significant burden of disease among people with advanced fibrosis due to NASH. In 1,660 patients enrolled in the STELLAR trials, patient-reported outcome measures (PROs) were assessed prior to treatment initiation and compared with population norms. The data demonstrate that physical health-related PRO scores of NASH patients were significantly lower than population norms. In addition, patients with cirrhosis had lower PRO scores than those with bridging fibrosis in areas including bodily pain, social functioning, and all but one domain of the disease-specific Chronic Liver Disease Questionnaire (CLDQ) for nonalcoholic fatty liver disease (NAFLD) and NASH.

In another analysis of patients enrolled in the STELLAR Phase 3 study presented during a poster session, elevated values of the ELF test and NAFLD fibrosis score were associated with impairment in PROs, especially physical health-related scores and the scores captured by the disease-specific CLDQ-NAFLD/NASH. These data extend prior observations that noninvasive fibrosis markers may predict fibrosis stage and adverse clinical outcomes, and now, impairments in health-related quality of life, in patients with NASH.

GS-9674, selonsertib and GS-0976 are investigational compounds and are not approved by the U.S. Food & Drug Administration (FDA) or any other regulatory authority. Their safety and efficacy have not been established.

About Gilead’s Clinical Programs in NASH
NASH is a chronic and progressive liver disease characterized by fat accumulation and inflammation in the liver, which can lead to scarring, or fibrosis, that impairs liver function. Individuals with advanced fibrosis, defined as bridging fibrosis (F3) or cirrhosis (F4), are at a significantly higher risk of liver-related mortality.

Gilead is advancing multiple novel investigational compounds for the treatment of advanced fibrosis due to NASH, evaluating single-agent and combination therapy approaches against the core pathways associated with NASH – hepatocyte lipotoxicity, inflammation and fibrosis. Investigational compounds in development include the ASK1 inhibitor selonsertib, the selective, non-steroidal FXR agonist GS-9674 and the ACC inhibitor GS-0976. The STELLAR Phase 3 trial program evaluating selonsertib among NASH patients with bridging fibrosis (F3) or cirrhosis (F4) is ongoing. GS-9674 and GS-0976 are currently in Phase 2 studies in NASH.

The Liver Meeting: Gilead making gains in NASH, PSC programs
New data from two mid-stage studies of Gilead Sciences Inc.'s farnesoid X receptor agonist (FXR) reported during the American Association for the Study of Liver Diseases meeting showcased the company's ongoing efforts to establish new strengths beyond viral hepatitis C, where time and competition have eroded its dominance. Though still active on the next frontier of the hepatitis battle, HBV, most of the company's liver disease pipeline today is focused on nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC).

Saturday, October 27, 2018

Researchers identify potential new target to inhibit the progression of liver disease

Interleukin IL-22, a new target to inhibit the progression of liver disease  

Montreal, October 26, 2018 - Naglaa Shoukry, Ph. D., and her team have made a significant breakthrough in their research aiming to limit the progression of liver disease. They have characterized the mechanisms of action of type 3 inflammatory cytokines that are produced by the cells of the immune system, which result in a progression of hepatic scarring known as fibrosis. These research efforts have identified new potential targets to inhibit the progression of liver disease and prevent cancer.

Researchers from the liver immunology research unit of the University of Montreal Hospital Research Center (CRCHUM) have discovered how a protein called interleukin 22 (IL-22) accelerates fibrosis during episodes of chronic hepatitis by amplifying the signal of the fibrogenic cytokine TGF-β. The fibrogenic nature of IL-22 had been unknown up to now. The new finding allows us to understand its interaction when combined with TGF-β, a cytokine that is produced during liver inflammation. Indeed, cases of advanced fibrosis confirm the pathogenic aspect of IL-22.

Another type 3 cytokine, namely interleukin 17A (IL-17A), had been known as an agent amplifying the inflammation and fibrosis leading to liver cirrhosis, which can cause cancer. The team has identified neutrophils and mast cells as the prime source of IL-17A in humans. Indeed, their number increases in inflammation induced by the immune system during liver disease.

It appears now that two type 3 cytokines, IL-17A and IL-22, can by independent mechanisms sensitize hepatic stellate cells (HSC) to the action of TGF-β. The HSCs, thus more sensitized to signals of proliferation and fibrosis, remodel the extracellular matrix leading to a deterioration of the architecture and function of the affected patient's liver.

Experiments successful in blocking the production of IL-17A and IL-22
The balance between the two cytokines IL-17A and IL-22 during different stages of liver disease and their combined roles remain unknown and further studies are needed. However, experiments in mice have determined that the inhibition, by small molecules, of programmes associated with production of IL-17A and IL-22 delays the development of hepatic fibrosis. These discoveries allow us to better characterize the pathogenic role of type 3 cytokines, and elucidate how to intervene to prevent the development of fibrosis as well as liver cancer.

The next steps
The next steps will make it possible to determine when cells producing IL-17A and IL-22 receive the signal to penetrate the liver, triggering a tissue-repair response. The objective will be to examine how the balance between the pro-inflammatory and anti-inflammatory signals is disrupted, since this is how fibrosis progression is influenced. Given that the replacement of healthy tissue by scar tissue favours the development of more serious pathologies, such as cirrhosis of the liver and liver cancer, it is vital to learn how to block inflammatory cells from entering, which over the course of time may induce cancer. The various types of treatment, as well as frequency and intensity of doses that would make it possible to block the effects of type 3 responses, must be pursued in preclinical mouse models prior to being ultimately tested in humans. Medications already developed for the treatment of psoriasis in humans, successfully target type 3 cytokines such as IL-17 and IL-22. This avenue appears promising.

Prevalence of liver disease in Canada and Quebec
An estimated eight million Canadians may be affected by liver disease, an illness that exhibits few or no symptoms, and that can affect anyone. Chronic liver disease can lead to fibrosis, cirrhosis, and cancer of the liver. An increase in the risk of liver disease, including non-alcoholic hepatic steatosis (NASH) (known as fatty liver disease), chronic hepatitis B and C, and liver cancer, is the reason that, in just 10 years, the number of Canadians affected by liver disease has increase from 1 in 10 to 1 in 4. Our nutrition, sedentary behaviour, and lifestyle are key causes. This scientific breakthrough may make it possible to develop strategies whose goal is to limit the development and progression of fibrosis.

Naglaa Shoukry and her team's research interests
Naglaa Shoukry, Ph. D., and her team's research involves investigating the immune response against hepatitis C virus (HCV), an infection that affects approximately 71 million individuals worldwide, and is a major cause of chronic liver disease including cancer. The team is also interested in understanding the role of immune regulation in the progression of hepatic fibrosis and the development of liver cancer. In particular, it examines the complementary and at times opposing roles of IL-17 and IL-22 in hepatic fibrosis and cancer, and the populations of inflammatory versus regulatory cells involved in this process.

The discovery, published today in Science Immunology, was the work of a multidisciplinary research team consisting of Thomas Fabre, Manuel Flores Molina (graduate students at the Université de Montréal), Geneviève Soucy (CHUM Pathology Department), Jean-Philippe Goulet (Caprion), Bernard Willems, Jean-Pierre Villeneuve, and Marc Bilodeau (CHUM Hepatology Department). For more information, see the study: 

University of Montreal Hospital Research Centre (CRCHUM)

Thursday, October 25, 2018

Cirius Therapeutics Reports On Phase 2b Trial in NASH Patients with Fibrosis

Cirius Therapeutics Reports Positive Data for MSDC-0602K in Interim Analysis of Phase 2b Clinical Trial in NASH Patients with Fibrosis

- Interim analysis showed statistically significant reductions in liver enzymes, including ALT and AST, measured from baseline at six months

- In two highest dose groups, at least 50% of patients with high baseline ALT or AST improved to normal range at six months

- Statistically significant reductions in HbA1c and other measures of glycemic control and insulin resistance were observed

- Overall adverse event rate was similar across placebo and all doses of MSDC-0602K

- Largest Phase2b clinical trial including paired biopsies conducted in NASH; biopsy data after 12 months of treatment expected to be reported in the second half of 2019

SAN DIEGO and KALAMAZOO, Mich., Oct. 25, 2018 /PRNewswire/ -- Cirius Therapeutics today announced positive results from an interim analysis of exploratory endpoints from its ongoing, fully enrolled Phase 2b clinical trial (the EMMINENCE trial) evaluating MSDC-0602K in 402 patients diagnosed with non-alcoholic steatohepatitis (NASH) with fibrosis. The interim analysis, which was conducted in the first 328 patients to reach their six-month follow-up visit, showed that patients treated with MSDC-0602K had significant improvements from baseline in measures of liver function and insulin resistance at six months. MSDC-0602K, a second-generation insulin sensitizer, is designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition, a major cause of NASH and other metabolic disorders.

The subjects included in this interim analysis had significant liver disease, as established by liver biopsy, with an average non-alcoholic fatty liver disease (NAFLD) activity score at baseline of 5.3. Almost sixty percent of these subjects had a baseline fibrosis score of 2 or 3 and approximately fifty percent also had a diagnosis of Type 2 diabetes at baseline. Overall, baseline characteristics were well-balanced across treatment groups.

Key findings from the interim analysis include improvements in liver enzymes, with placebo-corrected reductions at 6 months of 14.3 U/L (p<0.001) and 7.9 U/L (p=0.012) in ALT and AST, respectively, in the 125mg cohort, and 10.6 U/L (p=0.004) and 4.0 (NS) in ALT and AST, respectively, in the 250mg cohort. Placebo-corrected reductions, relative to baseline, were 25% and 18% in ALT and AST, respectively, in the 125mg cohort, and 19% and 9% in ALT and AST, respectively, in the 250mg cohort. Importantly, normalization of hepatic enzymes was observed across all three dose levels of MSDC-0602K. 

Percentage of patients with high baseline values who returned to normal range
*ALT normal range defined as 6-34 U/L and 6-43 U/L for women and men, respectively; AST normal range defined as 9-34 U/L and 11-36 U/L for women and men, respectively) 

"We believe these interim results around improved measures of liver function and glycemic control, together with the preliminary adverse event profile, support MSDC-0602K's potential to be used in the treatment of NASH with fibrosis, including for those patients with Type 2 diabetes, a group which represents approximately 50% of patients with NASH," said Cirius' chief medical officer Howard Dittrich, M.D. "These results support the view that therapies directed toward the MPC have the potential to achieve insulin sensitizing pharmacology with an improved profile over first generation insulin sensitizers. We look forward to presenting full data to the scientific community." 

In addition to the improvement in ALT and AST, observations included significant improvement at six months in fasting glucose, HbA1c, insulin levels and HOMA-IR at the 125mg and 250mg dose levels.  Significant improvement in HbA1c was also observed in subjects with a diagnosis of Type 2 diabetes in the 125mg and 250mg cohorts.  

In this interim analysis, the overall rate of treatment emergent adverse events was similar across placebo and all MSDC-0602K cohorts. There was a higher rate of treatment emergent adverse events reported in the 250mg dose compared to placebo in the musculoskeletal and connective tissue disorders category. Within this category, arthralgia and back pain were the most frequently reported individual adverse events across the pooled 328 subjects. A modest dose-dependent increase in body weight was seen in MSDC-0602K treated subjects, a finding seen with insulin and with other therapies that seek to improve insulin resistance. The rate of peripheral edema observed at six months was similar to that observed at baseline and was comparable across placebo and all MSDC-0602K cohorts. 

"The interim results from the EMMINENCE trial, the largest Phase 2b clinical trial to include paired biopsies ever conducted in NASH, are compelling," said Stephen Harrison, M.D., the principal investigator in the EMMINENCE trial. "The improvements in hepatic enzymes observed to date are impressive, especially when combined with the meaningful improvements in glycemic control." 

About the EMMINENCE Trial
The EMMINENCE trial is a 12-month, randomized, double-blind, placebo-controlled trial evaluating three oral dose levels of MSDC-0602K. Endpoints of the clinical trial include hepatic histological changes measured by biopsy after 12 months of treatment, changes in liver and metabolic function measured by the liver enzymes ALT and AST, markers of liver fibrosis, glycemic control and safety and tolerability. Not all of these endpoints were examined in this interim analysis; rather, in addition to the safety variables of incidence of treatment-emergent adverse events and  peripheral edema grades, changes from baseline relative to placebo for a number of endpoints, including liver functions tests such as ALT and AST, among others, biomarkers and indirect measures of apoptosis and fibrosis, circulating inflammatory markers and markers of bone metabolism, serum triglycerides and fasting cholesterol, markers of insulin sensitivity, and blood pressure, were examined in an exploratory manner. 

About Cirius Therapeutics
Cirius is a clinical-stage pharmaceutical company focused on the development and commercialization of innovative therapies for the treatment of liver and metabolic diseases. Our lead product candidate, MSDC- 0602K, is a novel small molecule being developed as a once-daily oral therapy to treat NASH with fibrosis. MSDC-0602K is designed to selectively modulate the MPC, which mediates at the cellular level the effects of overnutrition, a major cause of NASH and other metabolic disorders. We are conducting a Phase 2b clinical trial of MSDC-0602K, which we have fully enrolled with 402 patients diagnosed with NASH with fibrosis. We expect to report final data from this clinical trial in the second half of 2019.