Long-term follow-up of successful hepatitis C virus therapy: waning immune responses and disappearance of liver disease are consistent with cure

Long-term follow-up of successful hepatitis C virus therapy: waning immune responses and disappearance of liver disease are consistent with cure


Download full text article @ NATAP

Alimentary Pharmacology & Therapeutics March 2015

M. Hedenstierna*,, O. Weiland*,, A. Brass, D. Bankwitz, P. Behrendt, I. Uhnoo, S. Aleman**, K. Cardell,
A. Fryden, G. Norkrans, A. Eilard, H. Glaumann, T. Pietschmann, M. Sallberg & E. D. Brenndorfer
*Department of Infectious Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Department of Infectious Diseases, Akademiska University Hospital, Uppsala, Sweden.

**Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna and Huddinge, Stockholm, Sweden.

Department of Infectious Diseases, University Hospital, Linkoping, Sweden. Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden.

Clinical Pathology and Cytology, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Summary

Background

A sustained viral response (SVR) after interferon-based therapy of chronic hepatitis C virus (HCV) infection is regarded to represent a cure. Previous studies have used different markers to clarify whether an SVR truly represents a cure, but no study has combined a clinical work-up with highly sensitive HCV RNA detection, and the determination of immune responses.

Aim

To determine clinical, histological, virological and immunological markers 5-20 years after SVR.

Methods

In 54 patients, liver biochemistry, histology and elastography were evaluated. Liver biopsies, plasma and peripheral blood mononuclear cells (PBMCs) were tested for minute amounts of HCV RNA. HCV-specific T-cell responses were monitored by ELISpot and pentamer staining, and humoral responses by measuring HCV nonstructural (NS)3-specific antibodies and virus neutralisation.

Results

Liver disease regressed significantly in all patients, and 51 were HCV RNA-negative in all tissues tested. There was an inverse association between liver disease, HCV-specific T-cell responses and HCV antibody levels with time from SVR, supporting that the virus had been cleared. The three patients, who all lacked signs of liver disease, had HCV RNA in PBMCs 5-9 years after SVR. All three had HCV-specific T cells and NS3 antibodies, but no cross-neutralising antibodies.

Conclusions

Our combined data confirm that a SVR corresponds to a long-term clinical cure. The waning immune responses support the disappearance of the antigenic stimulus. Transient HCV RNA traces may be detected in some patients up to 9 years after SVR, but no marker associates this with an increased risk for liver disease.

Full Text Available @ NATAP

Hepatitis C Will Share Spotlight This Year at Liver Congress

Medscape Medical News > Conference News


Hepatitis C Will Share Spotlight This Year at Liver Congress
Miriam E. Tucker
April 17, 2015

Hepatitis C will again be a hot topic at this year's European Association for the Study of the Liver (EASL) International Liver Congress, but other subjects, such as nonalcoholic fatty liver disease, hepatocellular carcinoma, and noninvasive liver function assessment, will share more of the spotlight than they did previously.

There will also be a bit of a celebration in Vienna as EASL marks the fiftieth anniversary of the organization and the Congress, and the thirtieth anniversary of the Journal of Hepatology.

Hepatitis C dominated the agenda at last year's Congress, where phase 3 data from several manufacturers of oral interferon-free treatments were rolled out. But the issue has shifted from proving that the drugs work — in fact, sustained virologic response is now achieved in more than 90% of all hepatitis C patients — to the cost of treating patients in urgent need.

"Cost is now the main issue. We know we can cure almost everyone. Now we're focusing on the most severe patients, including those with liver transplants and decompensated patients who couldn't be cured before. And we'll be getting data on real-life cohorts," EASL vice-secretary Laurent Castera, MD, told Medscape Medical News.

A session will be devoted to the revised EASL hepatitis C treatment guidelines, which will be posted on the website shortly before the meeting and subsequently published in the Journal of Hepatology, according to EASL secretary-general Markus Peck-Radosavljevic, MD.

New Hep C Guidelines

"We think we will have better discussions if people have already had a chance to go through them," Dr Peck-Radosavljevic told Medscape Medical News.

More public health sessions have been added this year. "We already had a public health track, but we re-enforced that, so there's more this year," he reported. "I think that is needed, especially in viral hepatitis, because the interest has now shifted from finding the best cure — of which there are now several — to how we can get this cure out to all the people who need it. For that reason, public health is occupying a larger part of the meeting."

Although the focus is on treating the sickest patients for now, the field is "slowly moving toward treating all patients. Of course, ultimately that's the goal. The cost is coming down everywhere, and it will come down further with the competition," he added

Several of the top studies presented will focus on nonalcoholic fatty liver disease, an increasing problem as rates of obesity continue to climb. "Now that hepatitis C will be controlled and cured, there's increasing awareness of fatty liver disease. This will be the future of hepatology," Dr Castera predicted.

"This is becoming an interesting issue, with clinical trials describing not only epidemiology and pathophysiology, but also moving into treatment," said Dr Peck-Radosavljevic. One of the trials that will be presented is a phase 2 trial of the diabetes drug liraglutide, for which "the data are good," he added.

Three of the four postgraduate courses will be devoted to fatty liver disease; the fourth is on liver transplantation. And three basic science seminars will address hepatocellular carcinoma.

Europeans are leading the way in the noninvasive assessment of liver disease, including hepatitis, cirrhosis, fatty liver disease, and hepatocellular carcinoma, according to Dr Castera, who was involved in the development of a set of guidelines on the topic that will be released in conjunction with the meeting.

Noninvasive Assessment

Despite a decade of work in the area, these will be the first-ever guidelines on noninvasive methods. They will address, among other things, ultrasound and blood tests for the diagnosis and monitoring of liver disease.

"This has really been a major revolution, particularly in Europe. It will really change the field, especially for hepatitis C patients," said Dr Castera, pointing out that there will be a recommendation to use noninvasive methods in the first line to determine the degree of fibrosis in every patient with hepatitis C.

But, he added, noninvasive diagnostic and monitoring techniques are also important in other liver diseases, such hepatocellular carcinoma, and for the characterization of fatty liver disease.

"Noninvasive assessment has generated a lot of interest for more than 10 years. It allows you to get information a lot more readily from your patients, both at diagnosis and as disease progresses," Dr Peck-Radosavljevic told Medscape Medical News. "We thought the data were good enough to write a guideline."

Anniversaries and Celebrations

In addition to a ceremony to commemorate the anniversary of EASL and the publication of an anniversary issue of the Journal of Hepatology to coincide with the meeting, there will be an acknowledgment that the journal "has reached an impact factor above 10," Dr Castera told Medscape Medical News.

Dr Peck-Radosavljevic will say a few words about the anniversary during his opening address and show some old photos, but "we won't do too much on the history," he said. "To be honest, we need the time for other things in the opening. We're doing so many things that it's important for people to know what's happening right now."

Dr Castera has served on the speaker's bureau for Echosens, which manufactures a FibroScan elastography device. Dr Peck-Radosavljevic has financial relationships with AbbVie, ArQule, Bayer, BMS, Gilead, Lilly MSD, Boehringer-Ingelheim, and Roche.

Medscape Medical News from the
European Association for the Study of the Liver (EASL) International Liver Congress 2015

FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions;

Related
March 21 - FDA Update - Important safety information: Harvoni and Sovaldi‏


FDA approved changes to the Olysio (simeprevir) package insert to include two new Warnings and Precautions;

  1. serious symptomatic bradycardia when co-administered with sofosbuvir and amiodarone
  2. hepatic decompensation and hepatic failure.
Additional changes to the Indication and Usage, Dosage and Administration, Adverse Reactions, Drug Interactions, Use in Specific Populations and Pharmacokinetic sections of the label were made based on these Warnings and Precautions and are summarized below.
Summary of new WARNINGS AND PRECAUTIONS
5              WARNINGS AND PRECAUTIONS
5.1          Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown.
Co administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co administered OLYSIO and sofosbuvir:
  • Counsel patients about the risk of serious symptomatic bradycardia
  • Cardiac monitoring in an in-patient setting for the first 48 hours of co administration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Patients who are taking sofosbuvir in combination with OLYSIO who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone’s long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see Adverse Reactions (6.2) and Drug Interactions (7.3)].
5.2          Hepatic Decompensation and Hepatic Failure
Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO in combination with peginterferon alfa and ribavirin or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO and these events has not been established [see Adverse Reactions (6.2)].
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Dosage and Administration (2.5) and Use in Specific Populations (8.8)].
In clinical trials of OLYSIO, modest increases in bilirubin levels were observed without impacting hepatic function [see Adverse Reactions (6.1)]. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:
  • Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
  • Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.
Additional Changes
The Indications and Usage section was updated to state:
Limitations of Use:
  • OLYSIO is not recommended in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.8) and Clinical Pharmacology (12.3)].
The Dosage and Administration section was updated as follows:
2              DOSAGE AND ADMINISTRATION
2.1          OLYSIO Combination Treatment
Administer OLYSIO in combination with other antiviral drugs for the treatment of CHC infection. Monitor liver chemistry tests before and during OLYSIO combination therapy [see Warnings and Precautions (5.2)]. OLYSIO monotherapy is not recommended. For specific dosing recommendations for the antiviral drugs used in combination with OLYSIO, refer to their respective prescribing information.
2.5          Hepatic Impairment
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Use in Specific Populations (8.8)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) [see Clinical Pharmacology (12.3)].
In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].
OLYSIO in combination with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment) [see Peg IFN alfa prescribing information].
The Adverse Reactions section was updated as follows:
6              ADVERSE REACTIONS
Laboratory abnormalities
Elevations in bilirubin were predominately mild to moderate (Grade 1 or 2) in severity, and included elevation of both direct and indirect bilirubin. Elevations in bilirubin occurred early after treatment initiation, peaking by study Week 2, and were rapidly reversible upon cessation of OLYSIO. Bilirubin elevations were generally not associated with elevations in liver transaminases. The frequency of elevated bilirubin was higher in subjects with higher simeprevir exposures.
6.2          Postmarketing Experience
The following adverse reactions have been reported during post approval use of OLYSIO. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship between drug exposure and these adverse reactions.
Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].
Hepatobiliary Ddisorders: hepatic decompensation, hepatic failure [see Warnings and Precautions (5.2)].
Section 7 Drug Interactions was updated to include revisions to the antiarrhythmic section.
Table 6:                Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug
Class
Drug Name
Effect on Concentration of Simeprevir orConcomitant Drug
Clinical Comment
Antiarrhythmics
Amiodarone
Effect on amiodarone, simeprevir, and sofosbuvir concentrations unknown

Co‑administration of amiodarone with OLYSIO in combination with sofosbuvir is not recommended because it may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. If co‑administration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.1), Adverse Reactions (6.2)].
amiodarone
Caution is warranted and therapeutic drug monitoring of amiodarone, if available, is recommended for concomitant use of amiodarone with an OLYSIO-containing regimen that does not contain sofosbuvir.
Concomitant use of OLYSIO with amiodarone when given orally may result in mild increases in amiodarone concentrations due to intestinal CYP3A4 inhibition by simeprevir.

Section 8 Use in Specific Populations was updated as follows:
8              USE IN SPECIFIC POPULATIONS
8.8          Hepatic Impairment
No dose adjustment of OLYSIO is required in patients with mild hepatic impairment (Child Pugh Class A) [see Clinical Pharmacology (12.3)].
The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).
OLYSIO is not recommended for patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5)]. There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO combination therapy [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Clinical Pharmacology (12.3)]. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].
Refer to the prescribing information for the antiviral drug(s) used in combination with OLYSIO regarding their use in patients with hepatic impairment. The combination of OLYSIO with Peg IFN alfa and RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment).
Section 12.3 Pharmacokinetics included the following updates:
12.3        Pharmacokinetics
Specific Populations
Hepatic Impairment
Simeprevir is primarily metabolized by the liver. Compared to HCV uninfected subjects with normal hepatic function, the mean steady state AUC of simeprevir was 2.4 fold higher in HCV uninfected subjects with moderate hepatic impairment (Child Pugh Class B) and 5.2 fold higher in HCV uninfected subjects with severe hepatic impairment (Child Pugh Class C).
No dose adjustment of OLYSIO is necessary in patients with mild hepatic impairment (Child Pugh Class A).
The safety and efficacy of OLYSIO have not been established in HCV infected patients with moderate or severe hepatic impairment (Child Pugh Class B or C).
OLYSIO is not recommended for use in patients with moderate or severe hepatic impairment (Child Pugh Class B or C) [see Dosage and Administration (2.5), Warnings and Precautions (5.2) and Use in Specific Populations (8.8)].
In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity [see Adverse Reactions (6.1)].
Based on a population pharmacokinetic analysis of HCV infected subjects with mild hepatic impairment (Child-Pugh Class A) treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.
Refer to the prescribing information for the antiviral drugs used in combination with OLYSIO regarding their use in patients with hepatic impairment.
Drug Interactions
[See also Warnings and Precautions (5.67) and Drug Interactions (7)]
In vitro studies indicated that simeprevir is a substrate and mild inhibitor of CYP3A. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo. Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. In vivo, simeprevir mildly inhibits the CYP1A2 activity and intestinal CYP3A4 activity, while it does not affect hepatic CYP3A4 activity. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.
In vitro, simeprevir is a substrate for P gp, MRP2, BCRP, OATP1B1/3 and OATP2B1; simeprevir inhibits the uptake transporters OATP1B1/3 and NTCP and the efflux transporters P gp/MDR1, MRP2 and BSEP. The inhibitory effects of simeprevir on the bilirubin transporters OATP1B1/3 and MRP2 likely contribute to clinical observations of elevated bilirubin [see Adverse Reactions (6.1)].
The updated product label will be available soon at DailyMed or at Drugs@FDA.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

AbbVie's Investigational Chronic Hepatitis C Treatment Granted Priority Review in Japan

AbbVie's Investigational Chronic Hepatitis C Treatment Granted Priority Review in Japan

- AbbVie's investigational, interferon and ribavirin-free treatment in Japan consists of a 12-week, two direct-acting antiviral, fixed-dosed combination of paritaprevir/ritonavir with ombitasvir, dosed once daily-


New Drug Application, based on the Phase 3 GIFT-I study results in Japanese patients with genotype 1b hepatitis C virus (HCV) infection, was submitted in February 2015-

GIFT-I met its primary endpoint, achieving 95 percent sustained virologic response rate at 12 weeks post-treatment (SVR12); two patients (0.9 percent) discontinued treatment due to adverse events-

Approximately 1.5 to 2 million people are living with hepatitis C in Japan(1); genotype 1 is most common, accounting for 60 to 70 percent of all patients infected with HCV(2)

NORTH CHICAGO, Ill., April 15, 2015 /PRNewswire/ -- AbbVie ABBV, +0.50% today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted priority review for its investigational, two direct-acting antiviral treatment of ombitasvir/paritaprevir/ritonavir. This all-oral treatment is interferon (IFN) and ribavirin (RBV)-free and will be dosed once daily. The MHLW grants priority review to certain medicines on the basis of clinical usefulness and severity of the disease, including diseases like hepatitis C, which affects approximately 1.5 to 2 million people in Japan.1 AbbVie's investigational hepatitis C treatment was submitted for marketing approval in Japan in February 2015. The New Drug Application is for the treatment of patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection and is supported by the Phase 3 GIFT-I study in Japanese genotype 1b (GT1b) HCV patients.

"AbbVie is pleased that the Japanese MHLW has granted priority review for our interferon and ribavirin-free, 12-week, two direct-acting antiviral treatment regimen. This marks another important advancement in our HCV clinical development program as we aim to provide our HCV treatment to patients across the world," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "If approved, AbbVie's HCV treatment holds the potential to be a promising new treatment option for patients living with this chronic infection in Japan."

AbbVie studied a two direct-acting antiviral treatment regimen without RBV in Japan due to patient and viral characteristics specific to the Japanese population, including high prevalence of GT1b. In Japan, GT1 is the most common HCV genotype and accounts for 60 to 70 percent of all patients infected with HCV.2 Of those patients, about 95 percent are infected with the GT1b sub-type.2

Additional information about AbbVie's GIFT-I study can be found onwww.clinicaltrials.gov.

About AbbVie's Investigational Two Direct-Acting Antiviral HCV Treatment For the treatment of genotype 1 chronic hepatitis C virus (HCV) infection in Japan, AbbVie's investigational, two direct-acting antiviral treatment consists of the fixed-dosed combination of paritaprevir/ritonavir (150/100 mg) with ombitasvir (25 mg), dosed once daily.

AbbVie's chronic HCV treatment combines two direct-acting antivirals, each with a distinct mechanism of action that targets and inhibits specific HCV proteins of the viral replication process.

About AbbVie's HCV Clinical Development Program in JapanAbbVie's HCV clinical development program in Japan focuses on its investigational, two direct-acting antiviral treatment and is designed to achieve high SVR rates in chronic HCV infected patients, including additional genotypes and patients with compensated cirrhosis.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals ENTA, -1.66% for HCV protease inhibitors and regimens that include protease inhibitors. Paritaprevir has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

Ombitasvir/paritaprevir/ritonavir is an investigational product and its safety and efficacy have not been established in Japan.

About AbbVie AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs more than 26,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visitwww.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook orLinkedIn page.

Forward-Looking Statements Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2014 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

1 Kohnodai Hospital. National Center for Global Health and Medicine [cited 20 February 2013]. Available from:http://www.ncgm.go.jp/center/forpatient_hcv.html

2 Hajarizadeh B et al. Nat Rev Gastroenterol Hepatol 2013; 10: 553-562. http://www.nature.com/nrgastro/journal/v10/n9/fig_tab/nrgastro.2013.107_F1.html. Accessed December 2014

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/abbvies-investigational-chronic-hepatitis-c-treatment-granted-priority-review-in-japan-300066794.html

SOURCE AbbVie

Copyright (C) 2015 PR Newswire. All rights reserved

Caffeinated drinks associated with decreased risk of liver scarring

Caffeinated drinks associated with decreased risk of liver scarring

Modest daily consumption of caffeinated drinks is associated with less advanced liver scarring in people with hepatitis C, according to a recent study by Baylor College of Medicine researchers that appears online in the journal Clinical Gastroenterology and Hepatology.

Dr. Hashem El-Serag, chief of gastroenterology and hepatology at Baylor and at the Michael E. DeBakey Veterans Affairs Medical Center and lead author of the study, said the results showed that the risk of liver scarring in hepatitis C patients was decreased when individuals regularly consumed caffeinated coffee, and to a lesser extent tea and soda.

“We found that participants who drank caffeinated coffee daily had the best results,” he said. “This is most likely do to the fact that one coffee drink has more caffeine than tea or sodas.”

He said the researchers saw no benefit to patients who drank decaffeinated coffee, tea and soda.

This cross-sectional study consisted of 910 participants aged 18 to 70 years of age with confirmed hepatitis C who were not receiving antiviral therapy.

“We specifically chose to study hepatitis C patients because they are at an increased risk for hepatic fibrosis (liver scarring), and there is limited data on the effects of coffee or caffeine on the progression of scarring within this patient population,” said El-Serag, also a member of the Dan L. Duncan Cancer Center at Baylor.

Liver scarring can lead to cirrhosis of the liver, liver failure and liver cancer, and may require liver transplantation.

Of the participant study population, 37.6 percent of them had advanced liver scarring while 62.4 percent had milder scarring. Participants with advanced fibrosis were significantly older, more likely to have type 2 diabetes and were more likely to be overweight or obese.

“Most participants reported drinking caffeinated coffee, and about half of those drank one or more cups of coffee per day,” El-Serag said. “Patients with milder liver scarring had a higher average daily intake of caffeinated coffee compared to those with more advanced cases.”

“An estimated 100 milligrams of caffeine from coffee, tea or soda was associated with approximately one-third reduction of advanced scarring, and higher consumption didn’t produce an additional benefit,” he said.

Others who took part in this study include Natalia Khalaf, Donna White, Fasiha Kanwal, David Ramsey, Sahil Mittal, Shahriar Tavakoli-Tabasi and Jill Kuzniarek, all of Baylor.

This research was funded in part by a VA Clinical Research and Development Merit Award (H-22934, PI: El-Serag) and the National Institute of Diabetes Digestive and Kidney Diseases (R03 DK095082, PI: White). The efforts of White and El-Serag effort were supported in part by the National Institute of Diabetes Digestive and Kidney Diseases (K24 DK04-107 and K01 DK081736, respectively) and the Houston VA Health Services Research and Development Center of Excellence (HFP90-020).

Abstract:
Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C

Natalia Khalaf, Donna White, Fasiha Kanwal, David Ramsey, Sahil Mittal, Shahriar Tavakoli-Tabasi,
Jill Kuzniarek,Hashem B. El-Serag

Published Online: March 14, 2015

DOI: http://dx.doi.org/10.1016/j.cgh.2015.01.030
Publication stage: In Press Uncorrected Proof

Abstract
Background & Aims
Coffee or caffeine has been proposed to protect against hepatic fibrosis, but few data are available on their effects in patients with chronic hepatitis C virus (HCV) infection.
Methods

We conducted a cross-sectional study of veterans with chronic HCV infection to evaluate the association between daily intake of caffeinated and decaffeinated coffee, tea, and soda, and level of hepatic fibrosis, based on the FibroSURE test (F0–F3, mild [controls] vs F3/F4–F4, advanced). Models were adjusted for multiple potential confounders including age, alcohol abuse, and obesity.

Results
Among 910 patients with chronic HCV infection, 98% were male and 38% had advanced hepatic fibrosis. Daily intake of caffeinated coffee was higher among controls than patients with advanced fibrosis (1.37 vs 1.05 cups/d; P = .038). In contrast, daily intake of caffeinated tea (0.61 vs 0.56 cups/d; P = .651) or soda (1.14 vs 0.95 cans/d; P = .106) did not differ between the groups. A higher percentage of controls (66.0%) than patients with advanced fibrosis (57.9%) consumed 100 mg or more of caffeine daily from all sources (P = .014); controls also received a larger proportion of their caffeine from coffee (50.2% vs 43.0%; P = .035). Hepatoprotective effects of an average daily intake of 100 mg or more of caffeine (adjusted odds ratio, 0.71; 95% confidence interval, 0.53–0.95; P = .020) and 1 cup or more of caffeinated tea by non–coffee drinkers (adjusted odds ratio, 0.56; 95% confidence interval, 0.34–0.94; P = .028) persisted after adjustment for confounders, including insulin resistance.

Conclusions
A modest daily caffeine intake (as little as 100 mg) may protect against advanced hepatic fibrosis in men with chronic HCV infection. Additional research is needed to confirm these findings in women and in people with other chronic liver diseases.