Tuesday, February 28, 2017

TECHNIVIE (fixed-dose combination of ombitasvir, paritaprevir, and ritonavir) label was updated to expand the indication

On February 27, 2017 the TECHNIVIE  (fixed-dose combination of ombitasvir, paritaprevir, and ritonavir) label was updated to  expand the indication to patients with genotype 4 chronic hepatitis C virus infection (HCV) with compensated cirrhosis. Below is a summary of the major changes to the label based on the results of the AGATE-1 trial in HCV genotype 4 infected adults with compensated cirrhosis who are either treatment-naïve or pegylated interferon/ribavirin treatment experienced. Other minor revisions were made to the table including updates to section 8.1 Pregnancy and 8.2 Lactation.

Section 1: INDICATIONS AND USAGE
TECHNIVIE is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.

Section 2: DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with TECHNIVIE)].

Prior to initiation of TECHNIVIE, assess hepatic laboratory and clinical evidence of hepatic decompensation. Prior to initiation of ribavirin, assess for underlying cardiac disease and refer to the ribavirin prescribing information.

2.2 Recommended Dosage in Adults
Table 1 shows the recommended TECHNIVIE treatment regimen and duration for HCV genotype 4 patients without cirrhosis or with compensated cirrhosis.

Table 1. Treatment Regimen and Duration for Patients with HCV Genotype 4 without Cirrhosis or with Compensated Cirrhosis
Patient Population
Treatment
Duration
Genotype 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A)
TECHNIVIE + ribavirin*
12 weeks
*TECHNIVIE administered without RBV for 12 weeks may be considered for treatment-naïve patients without cirrhosis who cannot take or tolerate ribavirin







Section 5: WARNINGS AND PRECAUTIONS
5.2 Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
For patients with compensated cirrhosis:
  • Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage).
  • Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated.
  • Discontinue TECHNIVIE in patients who develop evidence of hepatic decompensation.
Section 6: ADVERSE REACTIONS
6.1 Clinical Trials Experience
  • Adverse Events in Subjects with Compensated Cirrhosis
  • AGATE-I was a study including 120 subjects with compensated cirrhosis who received TECHNIVIE once daily with ribavirin for a total of 12 weeks (n=60) or 16 weeks (n=60). Adverse events occurring up to and including 12 weeks of treatment (≤ 84 days) from both arms were included in the analysis of adverse events and are listed in Table 4.
Seven of 120 subjects (6%) experienced serious adverse events at or before 12 weeks of treatment. No adverse events led to the discontinuation of TECHNIVIE. Thirty-one subjects (26%) underwent ribavirin dose reductions; five discontinued ribavirin, three received transfusion and one received erythropoietin.

Table 4. Selected Adverse Events (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection with Compensated Cirrhosis Treated with TECHNIVIE and Ribavirin through 12 Weeks
 

AGATE-I
Compensated Cirrhosis
Adverse Events
TECHNIVIE + RBV
N=120
(%)
Fatigue
25
Asthenia
25
Headache
23
Musculoskeletal Pain/Changes1
17
Pruritus
16
Insomnia/Sleep Disorder2
14
Skin Reactions3
13
Dyspnea4
11
Mood Disorders5
11
Nausea
11
Dizziness
11
Cardiac Events6
9
Abdominal Pain7
9
Cough
7
Clinical Liver or Bilirubin Related Events8
7
Edema9
6
Altered Mental Status10
6
Decreased Appetite
6
Vomiting
6
1Grouped term ‘musculoskeletal pain/changes’ includes the preferred terms arthralgia, arthritis, back pain, muscle injury, muscle spasms, muscular weakness, musculoskeletal chest pain, myalgia, neck pain, and pain in extremity.  
2Grouped term ‘insomnia/sleep disorder’ includes preferred terms insomnia and sleep disorder.
3Grouped term ‘skin reactions’ includes preferred terms dermatitis bullous, dermatitis psoriasiform, dry skin, eczema asteatotic, erythema, rash, skin exfoliation, skin lesion and skin toxicity.
4Grouped term ‘dyspnea’ includes preferred terms dyspnea and dyspnea exertional.
5Grouped term ‘mood disorders’ includes preferred terms affective disorder, agitation, anxiety, depressed mood, depression, irritability, mania and suicide attempt.
6Grouped term ‘cardiac events’ includes preferred terms acute coronary syndrome, angina pectoris, atrial fibrillation, chest pain, hypertension, hypotension and palpitations.
7Grouped term ‘abdominal Pain’ includes preferred terms abdominal discomfort, abdominal pain, abdominal pain lower and abdominal pain upper.
8Grouped term ‘clinical liver or bilirubin related events’ includes preferred terms ascites, hepatic encephalopathy, jaundice, ocular icterus, esophageal varices hemorrhage and portal vein thrombosis. 
9Grouped term ‘edema’ includes preferred terms edema and edema peripheral.
10Grouped term ‘altered mental status’ includes preferred terms disturbance in attention, memory impairment, psychomotor retardation and somnolence.

Serum Bilirubin Elevations/Hepatic Decompensation in Patients with Compensated Cirrhosis
Among the 120 subjects with compensated cirrhosis, mean total bilirubin and mean indirect bilirubin levels increased to approximately 3 fold from baseline on treatment. Mean direct bilirubin levels increased to approximately 2 fold on treatment. Mean bilirubin elevations occurred early, peaked by Week 1, remained elevated on treatment and normalized by post treatment week 4. Bilirubin elevations were generally not associated with serum ALT elevations.

Over 40% (50/120) of subjects across both arms experienced elevated direct bilirubin levels (>ULN) at or before 12 weeks of treatment. Twelve percent (6/50) of these subjects experienced clinical bilirubin or liver related events including jaundice, ocular icterus and portal vein thrombosis.
One subject who did not have direct bilirubin elevations also experienced liver related adverse events of esophageal varices and ascites.

Anemia/Decreased Hemoglobin in Patients with Compensated Cirrhosis
Across both treatment arms, 4/120 cirrhotic subjects (3%) had anemia (hemoglobin less than LLN) prior to initiation of treatment. However, 88/120 (73%) had anemia (hemoglobin less than LLN) and/or a hemoglobin decrease of ≥ 2g/dl at or before 12 weeks of treatment.One subject (1%) had a single hemoglobin value less than 8.0 g/dL on treatment at or before 12 weeks of treatment. Reductions in hemoglobin are most likely primarily related to ribavirin in this population.

Of 64 subjects with a history of cardiovascular disease or diabetes mellitus, 9 (14%) experienced cardiac adverse events at or before 12 weeks of treatment. These 9 subjects had a mean hemoglobin decrease of 3.9 g/dL (range 1.1 to 5.3 g/dL) from baseline and experienced cardiac events including acute coronary syndrome, angina pectoris, chest pain, atrial fibrillation, palpitations, hypotension and hypertension. Among 56 subjects without a prior history of cardiovascular disease or diabetes, 2 (4%) experienced a cardiac event (mild or moderate hypertension).

12.4 Microbiology
The presence of NS5A L30S and Y93H polymorphisms in a genotype 4b clinical isolate was associated with approximately 200-fold reduced activity of ombitasvir.
In Clinical Studies

In the clinical study AGATE-I, one subject experienced on-treatment virologic failure and a second subject experienced virologic relapse at the Post-Treatment Week 24 timepoint. Treatment-emergent resistance-associated substitutions detected in these subjects included NS3 substitutions A156K or D168V, and NS5A substitutions K24Q, L28I/M, M31I or Y93H.

Phylogenetic analysis of HCV nucleotide sequences from subjects who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 weeks in the clinical study AGATE-I, identified 11 HCV genotype 4 subtypes (4a, 4c, 4d, 4e, 4f,  4k,  4n,  4p, 4q, 4r, 4t). Most subjects were infected with either subtype 4a (58%) or 4d (20%); 1 to 2 subjects were infected with each of the other genotype 4 subtypes. Two subjects who experienced virologic failure in AGATE-I were infected with HCV subtype 4a or 4d.

Baseline HCV polymorphisms are not expected to impact the likelihood of achieving SVR when TECHNIVIE is used as recommended to treat HCV genotype 4 infected patients, based on the low virologic failure rrates observed in PEARL-I and AGATE-I, although limited data are available for genotype 4 subtypes other than 4a and 4d.

Section 14: Description of Clinical Studies
14.3 Clinical Trial Results in Adults with Chronic GT4 HCV Infection with Compensated Cirrhosis
AGATE-I was a global multicenter, open-label trial in 120 HCV genotype 4 infected adults with compensated cirrhosis who were either treatment-naïve or pegIFN/RBV treatment-experienced and were treated for 12 weeks (n=59) or 16 weeks (n=61) with TECHNIVIE given once daily with weight based RBV. TECHNIVIE was administered as coformulated ombitasvir, paritaprevir, ritonavir tablets.

Of the 59 subjects in the 12 week arm, median age was 56 years (range: 43 to 81); 51% were treatment-naïve, 29% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 12% were prior pegIFN/RBV relapsers; 76% were male; 17% were Black; 29% had a body mass index of at least 30 kg/m2; 76% had baseline HCV RNA levels of at least 800,000 IU per mL; 86% had IL28B (rs12979860) non‑CC genotype; 12% had platelet counts of less than 90 x 109 per L; and 5% had albumin less than 3.5 mg per dL.

Table 11 presents the SVR12 rates for HCV genotype 4 infected subjects with compensated cirrhosis treated with TECHNIVIE with RBV for 12 weeks. Treatment with 16 weeks was not shown to increase SVR12 rates therefore, TECHNIVIE with RBV for 16 week arm is not presented in Table 11.
Table 11. AGATE-I: SVR12 for HCV Genotype 4-Infected Subjects with Compensated Cirrhosis
Treatment outcome
TECHNIVIE
with RBV for 12 Weeks
% (n/N)
SVR12, % (n/N)
97% (57/59)
Outcome for subjects without SVR12
      On-treatment VFa
2% (1/59)
      Relapseb
0 (0/57)
      Otherc
2% (1/59)
a.    On-treatment virologic failure (VF) was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed increase from nadir in HCV RNA > 1 log10 IU/mL during treatment, or HCV RNA ≥ 25 IU/mL persistently during treatment with at least 6 weeks of treatment.
b.    Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA less than 25 IU/mL at last observation during at least 11 weeks of treatment.
c.    Other includes subjects not achieving SVR12 but not experiencing on-treatment virologic failure or relapse (i.e premature discontinuation due to noncompliance).

You will be able to view the updated labels at drugs@fda or dailymed.
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
For more information about the Hepatitis Liaison Program visit the FDA Patient Network

Sovaldi/Harvoni/ Epclusa - How Gilead’s Revenue Trended in 2016

Thought this was interesting..

Investment Commentary @ Market Realist

How Gilead’s Liver Disease Drugs Portfolio Performed
By Mike Benson | Feb 28, 2017 5:54 pm EST

How Gilead’s Revenue Trended in 2016
Part 4

Epclusa
Epclusa is a new drug for the treatment of chronic Hepatitis C infection of Genotype-1 to Genotype-6 with or without cirrhosis. For patients who have advanced cirrhosis, the drug is used in combination with Ribavirin. Epclusa will be a new blockbuster drug for the treatment of patients with Hepatitis C infections. The drug reported revenues of $1.8 billion for 2016.

So what about Sovaldi and Harvoni, find out here...

Complete article; Why Gilead’s Valuation Is Low Compared to Peers

In Case You Missed It
Hepatitis C Virus Drug Costs Likely to Fall
Laurie Toich, Assistant Editor
Publish Date: Tuesday, February 07, 2017

The high cost of hepatitis C virus (HCV) drugs has caused significant financial strain for patients and the health care system. These drugs cost as much as $95,000 for a 12-week treatment, but carry a 90% or better cure rate, which many believe justifies the cost.

While some insurers have implemented cost containment strategies to prevent early stage patients from receiving the treatment, lawsuits have been filed challenging the ethics of these practices.

Lawmakers are now struggling to create legislation that will provide these patients with the treatments they need, but a majority of proposals do not gain traction, according to a report published by Mediware.

Continue reading, page 1, page 2...

Updates - February 2017
The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Liver Tumor Growth in Mice Slowed with New Chemo-Immunotherapy Treatment

Liver Tumor Growth in Mice Slowed with New Chemo-Immunotherapy Treatment
Researchers explore improved treatment strategies for hepatocellular cancer
Article ID: 670287
Released: 28-Feb-2017 1:05 PM EST
Source Newsroom: University of Missouri Health

Newswise — COLUMBIA, Mo. (Feb. 28, 2017) ― Hepatocellular carcinoma is the most common form of liver cancer, but treatment options are limited and many patients are diagnosed in late stages when the disease can’t be treated. Now, University of Missouri School of Medicine researchers have developed a new treatment that combines chemotherapy and immunotherapy to significantly slow tumor growth in mice. The researchers believe that with more research, the strategy could be translated to benefit patients with the disease.

“The current drug approved by the U.S. Food and Drug Administration to treat hepatocellular carcinoma only increases the average survival of patients by about three months,” said Kevin Staveley-O’Carroll, M.D., Ph.D., chair of the MU School of Medicine’s Hugh E. Stephenson Jr., M.D., Department of Surgery and director of Ellis Fischel Cancer Center. “While any extension of life is valuable, our research team is developing a new therapeutic strategy that might extend and improve the quality of life for these patients.”

Immunotherapy boosts the body’s natural defenses to fight off cancer. The therapy has been used to help treat several cancers, such as melanoma and lung cancer. However, little research exists on combining immunotherapy with chemotherapy.

During the study, one group of mice was treated with the chemotherapy agent sunitinib and another group was treated with an immunotherapy antibody known as anti-PD-1. Over a period of four weeks, tumors in mice treated with sunitinib grew 25 times larger. Tumors in mice treated with immunotherapy grew at a slower rate and were 15 times larger. However, a third group of mice treated with a combination of chemotherapy and immunotherapy experienced even slower tumor growth at a size that was only 11 times larger.

“Our results show that a combined chemo-immunotherapeutic approach can slow tumor growth in mice more effectively than either individual treatment,” said Guangfu Li, Ph.D., D.V.M., assistant professor in the MU Department of Surgery. “This innovative combination promotes an anti-tumor immune response and better suppresses growth of the cancer. Our findings support the need for a clinical trial to test whether this could become a cost-effective treatment that could help improve the lives of patients with liver cancer.”

The study, “Successful Chemo-immunotherapy against Hepatocellular Cancer in a Novel Murine Model,” was published in the January issue of the Journal of Hepatology. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (1 R01 CA164335-01A1 and R01-CA-025000) and the National Institute of Diabetes and Digestive Kidney Diseases of the National Institutes of Health (R01DK 057830). The researchers have no conflicts of interest to declare related to this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Monday, February 27, 2017

NeuroVive appoints recognized scientific advisors and enters research agreements in NASH and hepatocellular carcinoma

NeuroVive appoints recognized scientific advisors and enters research agreements in NASH and hepatocellular carcinoma

The aim of the agreements is to further explore NeuroVive’s new drug compounds in development for the treatment of NASH and hepatocellular carcinoma (HCC).

Lund, Sweden, February 22, 2017 - NeuroVive Pharmaceutical AB (Nasdaq Stockholm: NVP, OTCQX: NEVPF), the mitochondrial medicine company, today announced two new research agreements and the appointment of Professor Philippe Gallay, PhD, and Professor Massimo Pinzani, MD, PhD, FRCP, as scientific advisors. The aim of the agreements is to further explore NeuroVive’s new drug compounds in development for the treatment of NASH and hepatocellular carcinoma (HCC).

In the new collaboration with Philippe Gallay, the research teams will explore the mechanisms of action of the potent anti-cancer effects of NeuroVive’s novel sanglifehrin-based compounds. These studies will be an important part in NeuroVive’s HCC lead candidate selection process.

“I am enthusiastic about continuing the fruitful collaboration with the NeuroVive research team. NeuroVive’s potent drug compounds have unique and promising features that I am really excited in continuing to explore” said Prof. Philippe Gallay.

In the collaboration with Massimo Pinzani, the research groups at Engitix Ltd and NeuroVive will assess the anti-fibrotic properties of NV556 by using Engitix’ human liver 3D models. The models offer an important opportunity to evaluate and validate effects in appropriate pathophysiological conditions.

“Fibrosis is a critical part of the progression of several liver diseases including NASH, and I look forward to further study the anti-fibrotic effects of NeuroVive’s new drug compounds and how they may contribute to fill the unmet medical need in this area”, said Prof. Massimo Pinzani.

"I am very pleased that Philippe Gallay and Massimo Pinzani have joined our efforts in advancing the research and development of our NASH and HCC treatment opportunities" said Magnus Hansson, Chief Medical Officer at NeuroVive. "Their scientific guidance as experts in the field of liver disease mechanisms and clinical management will be most valuable in the continued development of our project pipeline, as well as in the ultimate positioning of our candidate drugs in the future treatment landscape.”

Philippe Gallay is Professor of Immunology at the Department of Immunology and Microbiology at the well esteemed Scripps Research Institute in California, US. Phillipe Gallay and NeuroVive has previously worked together with the company’s cyclophilin inhibitor platform, a research effort that focused on the most potent cyclophilin inhibitor so far developed, NV556.

Massimo Pinzani is Professor of Medicine, clinical hepatologist and Director of the University College London (UCL) Institute for Liver and Digestive Health, UK. He also holds the prestigious chair of the Sheila Sherlock Liver Centre at the Royal Free Hospital in London and he is the Chairman of Engitix Ltd.
http://publish.ne.cision.com/v2.0/Release/ViewReleaseHtml/78290AF4AC1073FC

Vitamin D decreases HCV cell replication, aids virologic response

Vitamin D decreases HCV cell replication, aids virologic response

Huang JF, et al. Hepatol Res. 2017;doi:10.1111/hepr.12878.

February 27, 2017
Vitamin D decreased hepatitis C cell replication and appeared significantly associated with rapid virologic response in anti-viral therapy, according to study results published in Hepatology Research.

“Liver has long been regarded as the key player manipulating complex biochemical metabolism, which is essential to maintenance of homeostasis,” the researchers wrote. “[Vitamin] D, the secosteroid hormone with pleiotropic effects, is an important physiological regulator contributed into various biological, immunological and metabolic functions in liver diseases. These non-skeletal effects are relevant in the pathogenesis of many causes of chronic liver disease.”
Continue Reading @ Healio

Related On This Blog
A collection of research articles investigating a possible role of vitamin D in hepatitis C.

AbbVie Receives CHMP Positive Opinion for eight-week regimen of VIEKIRAX + EXVIERA for HCV genotype 1b

AbbVie Receives CHMP Positive Opinion for Eight-Week Treatment Option with VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) for Patients with Genotype 1b Chronic Hepatitis C

Feb 27, 2017

- CHMP opinion brings AbbVie one step closer to approval of an eight-week regimen of VIEKIRAX + EXVIERA for previously untreated genotype 1b (GT1b) chronic hepatitis C virus (HCV) patients with minimal to moderate fibrosis*
- AbbVie's EMA label expansion is supported by 98 percent cure rate in the dedicated Phase 3b GARNET study[1]
- GT1b is the most common subtype globally and accounts for 47 percent of the nine million people infected with chronic HCV in Europe[2],[3],[4]

NORTH CHICAGO, Ill., Feb. 27, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced today that the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted a positive opinion for a shorter, eight-week treatment of VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) as an option for previously untreated adult patients with genotype 1b (GT1b) chronic hepatitis C virus (HCV) and minimal to moderate fibrosis*.

VIEKIRAX + EXVIERA is currently approved in the European Union for use as a 12-week treatment for GT1b chronic HCV-infected patients without cirrhosis or with compensated cirrhosis.

"AbbVie continuously strives to expand the utility of our HCV treatments, including investigating a shorter path to virologic cure for people living with HCV," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "With this positive CHMP opinion, we will bring an eight-week treatment option for the many HCV patients with GT1b."

Approximately 160 million people worldwide are infected with HCV, with GT1b being the most common subtype globally.2,5 In Europe, this subtype accounts for 47 percent of the nine million people infected with chronic HCV across the continent.3,4

"Nearly half of the people living with chronic hepatitis C in Europe are infected with genotype 1b," said Dr. Tania Mara Welzel, M.H.Sc., study author and Medical Lead of the Clinical Study Center at the Department of Medicine at J.W. Goethe University in Frankfurt, Germany. "VIEKIRAX + EXVIERA has demonstrated high cure rates with only eight weeks of treatment in GT1b patients with minimal to moderate fibrosis."

The CHMP positive opinion is supported by data from the dedicated Phase 3b GARNET study. Results showed that with eight weeks of treatment with VIEKIRAX + EXVIERA, 98 percent (n=160/163) of previously untreated GT1b chronic HCV infected patients without cirrhosis achieved sustained virologic response at 12 weeks post-treatment (SVR12).1 The most commonly reported adverse events, occurring at rate equal to or greater than 5 percent, were headache (21 percent), fatigue (17 percent), nasopharyngitis (8 percent), pruritus (8 percent), nausea (6 percent) and asthenia (5 percent).

* When assessing severity of liver disease using non-invasive methods, additional blood tests improve accuracy and should be undertaken prior to 8-week treatment in all patients with moderate fibrosis.

About the GARNET Study1
The Phase 3b GARNET study is a multicenter, open-label, single-arm study investigating the safety and efficacy of eight weeks of treatment with VIEKIRAX + EXVIERA without ribavirin in treatment-naïve patients with GT1b chronic HCV infection without cirrhosis.1 The study enrolled 166 patients across 20 sites around the world. Of the 166 patients enrolled, 163 patients had GT1b chronic HCV infection without cirrhosis and three patients with other HCV genotypes were excluded from the efficacy analysis. The primary endpoint is the percentage of patients who achieved SVR12.

Two patients experienced post-treatment relapse and one discontinued due to noncompliance. Less than one percent of patients experienced serious adverse events or clinically significant (Grade ?3) laboratory abnormalities. One patient discontinued treatment on Day 45 due to an adverse event but achieved SVR12.

Additional information about the GARNET study can be found on www.clinicaltrials.gov.

VIEKIRAX® + EXVIERA®
VIEKIRAX + EXVIERA is approved in the European Union for the treatment of genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including patients with compensated cirrhosis. VIEKIRAX is approved in the European Union for the treatment of genotype 4 (GT4) chronic HCV infection.

VIEKIRAX tablets consist of the fixed-dose combination of paritaprevir 150mg (NS3/4A protease inhibitor) and ritonavir 100mg with ombitasvir 25mg (NS5A inhibitor), dosed once daily. EXVIERA tablets consist of dasabuvir 250mg (non-nucleoside NS5B polymerase inhibitor) dosed twice daily. VIEKIRAX + EXVIERA is taken with or without ribavirin (RBV), dosed twice daily based on patient type. VIEKIRAX + EXVIERA is taken for 12 weeks with or without RBV, except in genotype 1a patients with compensated cirrhosis (Child-Pugh A), who should take it for 24 weeks with RBV.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C 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 chronic hepatitis C.

Additional information about AbbVie's hepatitis C development program can be found on www.clinicaltrials.gov.

EU Indication
VIEKIRAX is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults. EXVIERA is indicated in combination with other medicinal products for the treatment of CHC in adults.

Important EU Safety Information
Contraindications:
VIEKIRAX + EXVIERA are contraindicated in patients with severe hepatic impairment (Child-Pugh C). Patients taking ethinyl estradiol-containing medicinal products must discontinue them and switch to an alternative method of contraception prior to initiating VIEKIRAX + EXVIERA. Do not give VIEKIRAX with certain drugs that are sensitive CYP3A substrates or strong inhibitors of CYP3A. Do not give VIEKIRAX and EXVIERA with strong or moderate enzyme inducers. Do not give EXVIERA with certain drugs that are strong inhibitors of CYP2C8.

Special warnings and precautions for use:
VIEKIRAX and EXVIERA are not recommended as monotherapy and should be used in combination with other medicinal products for the treatment of hepatitis C infection.

Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
VIEKIRAX and EXVIERA are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Patients with cirrhosis should be monitored for signs and symptoms of hepatic decompensation, including hepatic laboratory testing at baseline and during treatment.

ALT elevations
Transient elevations of ALT to >5x ULN without concomitant elevations of bilirubin occurred in clinical trials with VIEKIRAX + EXVIERA and were more frequent in a subgroup who were using ethinyl estradiol-containing contraceptives.

Pregnancy and concomitant use with ribavirin
Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when VIEKIRAX with or without EXVIERA is taken in combination with ribavirin, see section 4.6 and refer to the Summary of Product Characteristics for ribavirin for additional information.

Use with concomitant medicinal products
Use caution when administering VIEKIRAX with fluticasone or other glucocorticoids that are metabolized by CYP3A4. A reduction in colchicine dosage or interruption in colchicine is recommended in patients with normal renal or hepatic function. VIEKIRAX with or without EXVIERA is expected to increase exposure of statins so certain statins need to be discontinued or dosages reduced. Low dose ritonavir, which is part of VIEKIRAX, may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with VIEKIRAX.

Adverse Reactions
Most common (>20 percent) adverse reactions for VIEKIRAX + EXVIERA with RBV were fatigue and nausea.

Full summary of product characteristics is available at www.ema.europa.eu

Sunday, February 26, 2017

Probiotics for people with hepatic encephalopathy

Cochrane Database Of Systematic Reviews

Probiotics for people with hepatic encephalopathy
Rohan Dalal, Richard G McGee, Stephen M Riordan, Angela C Webster
First published: 23 February 2017 Editorial Group: Cochrane Hepato-Biliary Group
DOI: 10.1002/14651858.CD008716.pub3

Plain language summary

Why the review is important
Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when administered in adequate amounts may confer a health benefit on the host. We searched and summarised randomised trials about the benefits and harms of any probiotic in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy.

Main findings
The evidence is current to June 2016. Of the 21 included trials including 1420 participants, 14 trials compared a probiotic with placebo or no treatment and seven trials compared a probiotic with lactulose. The treatment duration of the trials ranged from 10 days to 180 days.

Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but may lead to little or no difference in mortality. Probiotics may slightly improve quality of life when compared with no intervention; however, this conclusion is based on three trials with low-quality evidence. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence was very low. There were no reports of septicaemia attributable to probiotic in any trial. There was no evidence of more adverse events with probiotics when compared to placebo or lactulose.

Funding
Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source.

Limitations of the review
Many of the included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality.

Conclusions
Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence was very low. High-quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.

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Hepatitis C infected patients need vitamin D3 supplementation in the era of direct acting antivirals treatment 

Useful Link
Vitamin D2 and/or Vitamin D3
Vitamin D: A Rapid Review
Vitamin D2 is the form of D that is found in fortified foods like milk, juices or cereals, and D3 is the form that is synthesized by the skin when it's exposed to the sun or (ultraviolet light/UVB). 
UVB light from the sun strikes the skin, and humans synthesize vitamin D3, so it is the most "natural" form. Human beings do not make vitamin D2, and most healthy fish contain vitamin D3.

On This Blog
Is There A Natural Way To Improve Liver Fibrosis?
On this page the goal is to explore published data on natural alternatives and dietary supplements to fight or curtail liver damage.  

Hepatitis C infected patients need vitamin D3 supplementation in the era of direct acting antivirals treatment 
Yasuteru Kondo

World J Gastroenterol. Feb 28, 2017; 23(8): 1325-1327
Published online Feb 28, 2017. doi: 10.3748/WJG.v23.i8.1325

Abstract
It has been reported that the serum level of vitamin D3 (VitD3) could affect the natural course of chronic hepatitis C (CH-C) and the response to treatment with pegylated interferon (Peg-IFN) and ribavirin. Although several mechanisms for the favorable effects of VitD3 supplementation were reported, the total effect of VitD3 supplementation remains unclear. Previously, we reported that supplementation with 1(OH)VitD3 could enhance the Th1 response inducing not only a favorable immune response for viral eradication but also HCC control. Recently, the main treatment of CH-C should be direct acting antivirals (DAAs) without Peg-IFN. Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients with severe fibrosis lacking sufficient amounts of VitD3.


Core tip: Although several mechanisms for the favorable effects of vitamin D3 (VitD3) supplementation were reported, the total effect of VitD3 supplementation remains unclear. Recently, the main treatment of chronic hepatitis C should be direct acting antivirals (DAAs) without pegylated interferon (Peg-IFN). Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients with severe fibrosis lacking sufficient amounts of VitD3.

INTRODUCTION
It has been reported that the serum level of vitamin D3 (VitD3) could affect the natural course of chronic hepatitis C (CH-C) and the response to treatment with pegylated interferon (Peg-IFN) and ribavirin (RBV)[1,2]. Although several mechanisms for the favorable effects of VitD3 supplementation were reported, the total effect of VitD3 supplementation remains unclear. It has been reported that VitD3, as synthesized in the skin by photolysis from 7-dehydrocholesterol, is transported in the blood to the liver where it is hydroxylated at the C-25-position. Then, it is hydroxylated at the C-1α-position to form the active metabolite 1,25(OH)2VitD3 in the kidney. 1,25(OH)2VitD3 is known to regulate calcium and phosphorus metabolism in skeletal homeostasis. Moreover, 1,25(OH)2VitD3 could affect various kinds of immune cells via vitamin D receptor[3,4]. Several groups reported that the amount of 25(OH)VitD3 affects the progression of CH-C and response to Peg-IFN/RBV treatment. Moreover several mechanisms for the favorable effects of VitD3 supplementation in CH-C patients have been reported[5]. Dr. Azza reported that the serum level of 25(OH)VitD3 in CH-C children was significantly lower than that in healthy children. In addition to the treatment response, the deficiency of VitD3 could affect bone density. Therefore, we should consider supplementation with VitD3 for CH-C patients even in the era of direct acting antivirals (DAAs).

DISCUSSION
After a sustained virological response, the risk of hepatocarcinogenesis remains. Previously, we reported that supplementation with 1(OH)VitD3 could enhance the Th1 response inducing not only a favorable immune response for viral eradication but also HCC control[5]. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients lacking sufficient amounts of VitD3. Another group reported that 1,25(OH)2VitD3 could inhibit HCC development through reducing secretion of inflammatory cytokines from immune-related cells[6]. Moreover, it has been reported that reduced 25(OH)VitD3 serum levels were found to be associated with HCV-related HCC[7]. In addition to the risk of HCC development, 25(OH)VitD3 deficiency could be associated with advanced stages of HCC and it could be a prognostic indicator for a poor outcome[8]. In Japan, hepatocarcinogenesis after achieving SVR is an important issue since many CH-C patients are old and have severe fibrosis. Especially, CH-C patients with severe fibrosis might not have sufficient VitD3 since hepatocytes are necessary to metabolize VitD3. Moreover, it has been reported that there might be a relationship between carcinogenesis and insufficient VitD3[6,9]. Therefore, we should analyze the effect of VitD3 supplementation on hepatocarcinogenesis after achieving SVR[7]. Additionally, the immunological effect of VitD3 might differ between DAAs with and without Peg-IFN.

CONCLUSION
Recently, the main treatment of CH-C should be DAAs without Peg-IFN. Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN.

References
1. Petta S, Cammà C, Scazzone C, Tripodo C, Di Marco V, Bono A, Cabibi D, Licata G, Porcasi R, Marchesini G. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51:1158-1167.  [PubMed]  [DOI]
2. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011;17:5184-5190.  [PubMed]  [DOI]
3. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol. 2014;5:151.  [PubMed]  [DOI]
4. Ryynänen J, Carlberg C. Primary 1,25-dihydroxyvitamin D3 response of the interleukin 8 gene cluster in human monocyte- and macrophage-like cells. PLoS One. 2013;8:e78170.  [PubMed]  [DOI]
5. Kondo Y, Kato T, Kimura O, Iwata T, Ninomiya M, Kakazu E, Miura M, Akahane T, Miyazaki Y, Kobayashi T. 1(OH) vitamin D3 supplementation improves the sensitivity of the immune-response during Peg-IFN/RBV therapy in chronic hepatitis C patients-case controlled trial. PLoS One. 2013;8:e63672.  [PubMed]  [DOI]
6. Guo J, Ma Z, Ma Q, Wu Z, Fan P, Zhou X, Chen L, Zhou S, Goltzman D, Miao D. 1, 25(OH)2D3 inhibits hepatocellular carcinoma development through reducing secretion of inflammatory cytokines from immunocytes. Curr Med Chem. 2013;20:4131-4141.  [PubMed]  [DOI]
7. Lange CM, Miki D, Ochi H, Nischalke HD, Bojunga J, Bibert S, Morikawa K, Gouttenoire J, Cerny A, Dufour JF. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. PLoS One. 2013;8:e64053.  [PubMed]  [DOI]
8. Finkelmeier F, Kronenberger B, Köberle V, Bojunga J, Zeuzem S, Trojan J, Piiper A, Waidmann O. Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma - a prospective cohort study. Aliment Pharmacol Ther. 2014;39:1204-1212.  [PubMed]  [DOI]
9. Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, Trepo E, Tjønneland A, Olsen A, Overvad K. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology. 2014;60:1222-1230.  [PubMed]  [DOI]

Saturday, February 25, 2017

Hepatitis C - Big Pharma Quietly Enlists Leading Professors to Justify $1,000-Per-Day Drugs

Big Pharma Quietly Enlists Leading Professors to Justify $1,000-Per-Day Drugs
by Annie Waldman
ProPublica, Feb. 23, 2017, 8 a.m.

This story was co-published with Consumer Reports.

Over the last three years, pharmaceutical companies have mounted a public relations blitz to tout new cures for the hepatitis C virus and persuade insurers, including government programs such as Medicare and Medicaid, to cover the costs. That isn’t an easy sell, because the price of the treatments ranges from $40,000 to $94,000 — or, because the treatments take three months, as much as $1,000 per day.

To persuade payers and the public, the industry has deployed a potent new ally, a company whose marquee figures are leading economists and health care experts at the nation’s top universities. The company, Precision Health Economics, consults for three leading makers of new hepatitis C treatments: Gilead, Bristol-Myers Squibb, and AbbVie. When AbbVie funded a special issue of the American Journal of Managed Care on hepatitis C research, current or former associates of Precision Health Economics wrote half of the issue. A Stanford professor who had previously consulted for the firm served as guest editor-in-chief.

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Jet guns should be a recognized risk factor for hepatitis C

Jet guns should be a recognized risk factor for hepatitis C
By PAUL HARASIM
LAS VEGAS REVIEW-JOURNAL
When I watch the federal government’s current public service messages on TV urging baby boomers to get tested for hepatitis C, I can’t stop thinking about how my arm, and those of many men next to me, bled as we received jet gun vaccinations during our earliest days in the military.

Powerful air pressure from the jet gun forced a tiny stream of medication through our skin without a needle. Because the shot hurt, many of us flinched. Our skin broke, and as we started bleeding, the blood blew back on the jet gun.

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2017 - Management of extrahepatic manifestations of chronic hepatitis C virus infection

On This Blog;

Article in Press
To appear in: Journal of Hepatology
Received Date: 10 November 2016
Revised Date: 5 February 2017
Accepted Date: 6 February 2017

Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection
Manuel Ramos-Casals, Anna Linda Zignego, Clodoveo Ferri, Pilar Brito-Zerón, Soledad Retamozo, Milvia Casato, Peter Lamprecht, Alessandra Mangia, David Saadoun, Athanasios G Tzioufas, Zobair M Younossi, Patrice Cacoub

Full Text
Download Accepted Manuscript
DOI: http://dx.doi.org/10.1016/j.jhep.2017.02.010

Lay Summary
  • The current therapeutic armamentarium against HCV has been recently expanded with an explosion of new molecules (DAAs) with high virological efficacy
  • The objective of this international consensus is to provide therapeutic recommendations for HCV patients with extrahepatic manifestations (EHM).
  • The use of non-antiviral therapeutic approaches should be evaluated according to the type of EHM and severity of the clinical presentation
  • B cell depletion with rituximab is the established biologic approach to cryoglobulinaemic vasculitis (CV) employed to date.
  • The efficacy of therapies in EHM patients should be evaluated not only according to the virological response, but also according to the full impact of the other clinical and immunological responses achieved.
  • Clinical experience of the use of the new DAAs in EHM remains very limited, with less than 100 cases reported in the last 2 years (overwhelmingly in CV patients)



Friday, February 24, 2017

The Liver Loving Diet - A Must Read For People With HCV Or Liver Disease

The Liver Loving Diet

My admiration runs deep for a small group of bloggers who spend hours in front of a computer helping those suffering with HCV. What they accomplish is astounding, why do they do it?

So that no one with this disease ever feels alone.

HCV is a progressive liver disease that can be cured, although cirrhosis is usually irreversible and can potentially lead to life threating complications.

Karen Hoyt understands this only to well, she is devoted to offering support and accurate information to people coping with the effects of liver disease. Karen writes from a patients' perspective about living with and treating hepatitis C, cirrhosis, liver cancer and liver failure on her blog, "Your Best Friends Guide To Hepatitis C."

This compassionate author, HCV advocate, and survivor, once again is doing what she does best, keeping us informed and full of hope. Karen has recently announced her new book, "The Liver Loving Diet" is available to enjoy, a book that will help you learn to eat well during all phases of liver disease. For the cost of a few cups of liver friendly coffee - this book can be yours.

Purchase is now available through PayPal, click here to learn more.

From Karen

Low Sodium, Healthy Protein Plan
After my diagnosis with Hepatitis C and liver failure, I got busy putting together a low sodium, healthy protein plan for eating.

Here at Your Best Friends Guide, you all have blown me away with requests for an easy menu plan. I love the emails pouring in from you all sitting in hospitals, grocery stores, and at home. You’ve begged for recipes. Well, it’s taken some time (2 years), but I heard you and here it is!

Drumroll please….

The Liver Loving Diet Book is a big picture peek at liver disease that helps you understand how valuable it is to eat well during treatments, cures, setbacks, cancer, and transplant. My diet played a huge role in keeping me alive and active. Now I’m handing all that power to you in one tidy package – tied up with love and priced at $4.99. I worked extra hard to give you a simple book with over 300 pages of personal stories and recipes.

Visit Karen on Facebook or follow her on Twitter

Thursday, February 23, 2017

Hepatitis C virus infection and risk of thyroid cancer: A systematic review and meta-analysis

Systematic review

Hepatitis C virus infection and risk of thyroid cancer: A systematic review and meta-analysis
Peng Wanga, 1, Zhaohai Jingb, 1, Changjiang Liua, Meihua Xua, Pei Wanga, Xiao Wanga,
Yulei Yina, Ying Cuia, Dunlin Renc, Xiaopang Raoa, ,

Received 8 August 2016, Accepted 21 January 2017, Available online 20 February 2017
http://dx.doi.org/10.1016/j.ajg.2017.01.003

Abstract
Purpose
Several epidemiological studies investigated the relationship between hepatitis C virus (HCV) infection and risk of thyroid cancer, but the results were not consistent. A systematic review and meta-analysis was conducted to assess the impact of HCV infection on thyroid cancer risk.

Methods
The literature was searched up to March 15, 2016 for case-control or cohort studies on the association between HCV infection and thyroid cancer risk. The summary relative risks (RR) and 95% confidence intervals (CI) were calculated.

Results
Five studies (two case-control studies and three cohort studies) were included in the meta-analysis, with a total of 751,551 participants and 367 cases of thyroid cancer. Meta-analysis of those 5 studies found that there was no statistically significant association between HCV infection and thyroid cancer risk (summary RR = 2.09, 95%CI 0.78–5.64, p = 0.145; I2 = 81.2%). However, HCV infection was significantly associated with increased risk of thyroid cancer (summary RR = 2.86, 95%CI 1.63–5.03, p = 0.003; I2 = 24.9%) after adjusting the heterogeneity.

Conclusion
There is a possible association between HCV infection and increased risk of thyroid cancer, and more cohort studies are needed to validate the possible association.

Abbreviations
RR, relative risk;
CI, confidence interval;
NOS, Newcastle Ottawa scale;
HCV, hepatitis C virus

With hep C franchises languishing, Merck’s MK-3682 goes from blockbuster to bomb

With hep C franchises languishing, Merck’s MK-3682 goes from blockbuster to bomb
by John Carroll

A little less than three years after acquiring the hepatitis C drug MK-3682 (uprifosbuvir) in its $3.85 billion buyout of Idenix, Merck’s prospects in the field have cooled dramatically, and its once great hopes for the drug have been reduced to nearly nothing.

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Of Interest
MK-3682 + grazoprevir + elbasvir or MK-3682 + grazoprevir + MK-8408 There are two triplet therapies and at least one doublet regimen in development by Merck (Kenilworth, NJ) that include MK-3682 (a novel NS5b nucleotide polymerase inhibitor) with or without grazoprevir and with either elbasvir or MK-8408 (a novel NS5A inhibitor). MK-3682 was tested in 300 mg and 450 mg doses in the CREST 1 (for genotypes 1 and 2) and CREST 2 (for genotype 3) studies. The CREST 1 study showed mITT SVR24 of 91–100% for genotypes 1 (n = 93 with 46 GT1a and 47 GT1b) with either elbasvir or MK-8408 at both doses for MK-3682. However, only the MK-3682 (450 mg)/grazoprevir/MK-8408 regimen showed efficacy >90% in genotype 2 patients (n = 61). For genotype 3 patients, both the 300 mg and 450 mg doses of MK-3682 showed SVR24 rates >90% (n = 86).....

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Egypt Targets Spain, Belgium, Italy, Netherlands and the UK hepatitis C patients for medical tourism

Egypt targets hepatitis C patients for medical tourism

In mid 2016, Prime Pharma, a private Egyptian pharmaceutical company, launched Tour n’ Cure to revive therapeutic tourism in Egypt. The first target is hepatitis C patients from around the world. Countries targeted are Spain, Belgium, Italy, Netherlands and the UK.

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Chronic Hepatitis C Virus Infection and the Risk for Diabetes

Chronic Hepatitis C Virus Infection and the Risk for Diabetes
Does chronic hepatitis C infection increase diabetes risk?
February 23, 2017

Abstract
Background
The association between hepatitis C virus (HCV) infection and the occurrence of type II diabetes remains controversial. Prospective studies are needed to assess its causal temporality.

Methods
A cohort of 21 559 adults enrolled from seven townships in Taiwan during 1991–1992 and followed till the end of 2010. Incident diabetes over a study time period from 2000 to 2010 was ascertained through computerized linkage with the National Health Insurance database and the National Death Certification profiles. Cox's proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Antibodies against HCV (anti-HCV) were tested for all participants, and serum HCV RNA levels were measured for anti-HCV seropositives.

Results
During 180 244 person-years of follow-up, there were 1917 incident diabetes cases recorded. The cumulative risk for diabetes was 10.9% for anti-HCV seronegatives and 16.7% for anti-HCV seropositives respectively. The HR for diabetes of anti-HCV seropositivity was 1.53 (95% CI: 1.29–1.81) compared with anti-HCV seronegatives after adjustment for risk predictors. The adjusted HRs were 1.63 (1.31–2.02) for anti-HCV seropositives with positive HCV RNA compared to anti-HCV seronegatives (P<.001).

Conclusion
Chronic HCV infection was associated with an increased risk for diabetes after adjustment for other risk predictors.

Discussion Only
Medscape - Full Text Article
Liver International
In this study, our data suggested that HCV infection brought significant increasing risk for the occurrence of diabetes after controlling several risk factors. Whereas the findings from NHANES were inconsistent, and their most recent report did not demonstrate an association of HCV infection with diabetes or with insulin resistance. NHANES is a large survey that consists of interviews, health examinations and laboratory data collected from a stratified, multistage probability cluster sample to obtain a nationally representative sample of the noninstitutionalized civilian US population. The first investigation using the NHANES data that evaluated the relationship between HCV infection and diabetes used the survey collected in the cycles of 1988–1994.[12] The investigators found that among individuals who were 40 years of age or older, those with HCV infection had an increased likelihood of having diabetes with the odds ratio of 3.8 (95% CI: 1.8–7.8) after controlling risk factors.[12] However, during the later study cycles (1999–2004 and 2005–2008), a statistically significant association was not found.[10] In the NHANES survey, the prevalence of obesity, insulin resistance and diabetes increased steadily over the same time period.[25] Thus, it is possible that estimates of the relationship between HCV infection and diabetes became attenuated in the presence of this epidemic of obesity and increased numbers of metabolic factors in recent decades. More recently, investigators using NHANES data have found that chronic hepatitis C patients, defined as anti-HCV seropositives with positive HCV RNA levels, had a two-fold risk for insulin resistance or diabetes,[9] suggesting that serum HCV RNA testing which enables the differentiation of past HCV infection with spontaneous clearance of HCV RNA (undetectable HCV RNA) and chronic HCV infection (detectable HCV RNA) might be important.

Finally, the most recent report from NHANES, using data from the 1999 through 2010 surveys failed to find an association between HCV infection and diabetes.[11] However, they did find a positive relationship between insulin resistance and elevated liver enzymes.[11] The elevated serum liver enzyme levels may be as result of either HCV infection or other conditions such as metabolic syndrome or steatohepatitis. It is difficult to disentangle the association of these factors and diabetes by cross-sectional study design in which participants were tested for their serum levels of liver enzymes and diabetes at the same time. Compared with the participants in NHANES, the participants in our study had lower educational levels, lower BMI and a lower percentage of cigarette smoking and alcohol drinking habits than the participants in NHANES. In other words, our study population seemed to have relatively fewer metabolic risk factors for diabetes. The major risk factor for HCV infection was illicit drug use in NHANES, whereas iatrogenic factors were the main transmission route for HCV infection in our population.[17,26] Thus, differences in the findings from our study from those in the NHANES study might be caused by differences in the characteristics of the study populations as well as in the study design.

Comparing to anti-HCV seronegatives, the adjusted HR was 1.39 for anti-HCV seropositives with seronegative HCV RNA, and 1.63 for anti-HCV seropositives with seropositive HCV RNA respectively. It showed a trend effect on the risk of diabetes for patients who had replication of HCV. Whereas, among anti-HCV seropositives, the risk of diabetes was only increased slightly when comparing to HCV RNA seronegatives and RNA seropositives, suggesting that the lipid profiles may be altered once individuals infected by HCV. However, the mechanisms still need to be further evaluated. Our study suggested that HCV infection has a major public health impact, not only for hepatic diseases but also for extrahepatic diseases.

Our cohort is recognized as a natural history cohort because most of the participants did not have the experience of antiviral treatment as a result of its high cost and adverse effects. Until October 2003, only patients with abnormal ALT levels (>82 U/L) and moderate fibrosis proven by liver biopsy could be reimbursed for treatment by the National Health Insurance. However, there are still huge gaps of self-awareness, referral and linking to care.[27] Although it is an important clue to compare the patients with or without antiviral treatment for further clarification of the associations between HCV infection and diabetes in the future.

In addition, we identified diabetes cases through a computerized data linkage with the National Health Insurance database, which provided coverage for 96% of the total population for Taiwan (23 million) in 2000, 98% in 2005 and 99.6% in 2009.[22] A limitation of our study is that we enrolled the participants and collected the questionnaires and blood samples during 1991–1992, whereas the index date for the linkage with the National Health Insurance database for the study described in this study was January 1, 2000 when the claims data were released. Life style and biochemical markers in the REVEAL-HCV enrolees might have changed over the period 1991–1992 to 2000. In particular, there might have been new infection with HCV during the 10 years of follow-up. However, establishing the incidence of HCV is very difficult because most infections are initially asymptomatic. In Taiwan the incidence of transfusion-associated hepatitis decreased as a result of the effectiveness of a series of donor screening intervention.[28] Also the presence of such cases would result in an underestimate of the effects of HCV on the incidence of diabetes. In this study, we defined the patients with diabetes with the stringent criteria: patients with at least one hospital admission code with diabetes diagnosis or with three or more outpatient visits code for diabetes,[21,22] which made the findings conservatively.

During the long-term follow-up, BMI may change when individuals change their life style, it is important to consider the follow-up changes on anthropometrical parameters. In our study, the anti-HCV seropositives were asked and invited for regular health examinations every 6–12 months. We obtained BMI data during their follow-up, and it showed similar results in the four models of multivariate analyses. The stratification analysis showed that chronic HCV infection may increase the risk for diabetes by comparing anti-HCV seronegatives. The changes in BMI during follow-up of each person were highly correlated (r=.84, P<.0001), and the correlation was even higher after grouping by <23 and ≥23 (r=.98, P<.0001). Another limitation of our study is that we did not measure blood glucose in our study. Thus, data of blood glucose are not available. However, serum level of triglycerides is highly correlated with blood glucose. We included triglyceride levels as an alternative marker for glucose levels in the analyses.

In a previous study, anti-HCV seropositives had increased mortality from diabetes (106.1 per 100 000 person-years) than anti-HCV seronegatives (60.8 per 100 000 person-years).[5] These results are consistent with the results from a database study of deaths in patients with diagnosed chronic hepatitis C infection which showed a 1.77 times increased risk of death from diabetes compared to the general population in the USA.[29] Although the evidence from these two studies of mortality provided an indication of a relationship between HCV and diabetes, it could not determine whether the infection increased the risk for the incidence of diabetes or worsened the prognosis for those with diabetes. The current longitudinal study has estimated the incidence of diabetes in those with and without anti-HCV seropositivity. Although data on steatosis in our study were lacking, we stratified by surrogate measures for steatosis including BMI, ALT and triglycerides.

In conclusion, our data suggested that HCV infection has increased risk for the occurrence of diabetes after controlling other risk factors. Chronic hepatitis C patients may benefit from antiviral treatment to decrease their risks for diabetes. More affordable prices of the effective drugs are required to increase the accessibility for the patients in need.
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