Thursday, February 28, 2013

Hepatitis C - Did You Know?

Published on Feb 27, 2013
The CDC issued a recommendation that all Americans born from 1945-1965 get tested for hepatitis C. People in this age group are five times more likely to have hepatitis C, but most do not know they are infected. If you were born from 1945-1965, talk to your doctor about getting tested.
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Symposium summary: Swine cells could power artificial liver

Symposium summary: Swine cells could power artificial liver

Feb. 27, 2013 - Chronic or acute, liver failure can be deadly. Toxins take over, the skin turns yellow and higher brain function slows.

“There is no effective therapy at the moment to deal with the toxins that build up in your body,” said Neil Talbot, a Research Animal Scientist for the USDA Agricultural Research Service. “Their only option now is to transplant a liver.” 

Talbot thinks a line of special liver cells could change that. In an interview with the American Society of Animal Science, he discussed how a line of pig liver cells called PICM-19 could perform many of the same functions as a human liver.

In 1991, Talbot created PICM-19 from the cells of an 8-day-old pig embryo. The cell line is significant because it is “immortal,” meaning the cells can divide an infinite number of times. Many immortal cells lines continue dividing because they are derived from cancer cells; however, PICM-19 cells are derived from epiblast cells, the embryonic stem cells that form in the early stages of embryo development.

This immortal cell line has helped Talbot study how cells differentiate. Cells from the PICM-19 lines naturally differentiate into bile duct cells or hepatocytes. Hepatocytes do the bulk of the work in a liver. Hepatocytes form and secrete bile, store glycogen, control blood glucose, process vitamin D, and metabolize cholesterol and fat.

“The PICM- 19 cells are the cells that really do all the metabolic functions of the liver,” said Talbot.

Hepatocytes also “scrub” toxins from the blood. Talbot said PICM-19 cells could do the same thing inside an artificial liver. There have already been several in vitro tests of artificial liver devices, and the ARS scientists are working on ways to grow the PICM-19 cells without needing “feeder cells.” Feeder cells are mouse cells that hold PICM-19 cells in place and provide important molecules for PICM-19 cell growth and maintenance.

Artificial livers are still in development, but Talbot pointed out other applications for PICM-19 cells. Talbot and fellow scientists have used PICM-19 to study malaria, toxoplasmosis and hepatitis viruses. Researchers could also use the cells to study certain cancers of the liver or investigate the changes in the bile duct associated with cystic fibrosis.

Talbot recommends future studies on how PICM-19 cells respond to selective pressures. He said scientists could select for more efficient liver cells by exposing PICM-19 cells to toxins in culture.

“A lot of cells would die, but the survivors would really be tough,” Talbot said.

Those tougher cells could make artificial liver devices more effective. Scientists could also use genetic modification to prompt PICM-19 cells to behave like other cells in the body.

“Maybe we want to enable it to make insulin,” Talbot said. “It will be like a pancreas.” 

With PICM-19 cells filling in for livers or other organs, the transplant list could get a lot shorter.

Tom Caperna, an ARS Research Biologist and collaborator with Talbot, presented their work on PICM-19 during the Growth and Development Symposium at the 2012 Joint Annual Meeting. The full symposium summary is titled “Growth and Development Symposium: Development, characterization, and use of a porcine epiblast-derived stem cell line: ARS-PICM-19.” It can be read in full at

Scientific Contact:
Neil Talbot
USDA Agricultural Research Service
301-504-8216 /

Source -

Spring Bank Pharmaceuticals Closes $10.5 million Series A Financing to fund Phase 1 clinical trials in HCV-infected patients

Spring Bank Pharmaceuticals Closes $10.5 million Series A Financing to fund Phase I Clinical Trials in HCV-infected Patients

PRNewswirePRNewswireProvidence Journal

Published: 28 February 2013 12:01 PM

MILFORD, Mass., Feb. 28, 2013 /PRNewswire/ -- Spring Bank Pharmaceuticals, Inc., a biopharmaceutical company developing innovative medicines for the treatment of viral infections, today announced it has closed on a $10.5 million Series A financing. Proceeds will be used to fund Phase I clinical development of SB 9200, a novel, orally available treatment for Hepatitis C virus (HCV) infection and to further the preclinical pipeline. The Company plans to conduct a Phase I safety and antiviral efficacy study of SB 9200 in healthy, HCV-infected patients beginning in the first quarter of 2013. This financing was led by Brock Securities LLC with participation from Gilford Securities.

"This financing represents a major milestone for SBP," said Douglas Jensen, CEO and Co-founder of Spring Bank, "as it will enable us to move SB 9200 through an important Phase I clinical study that will provide both safety and early antiviral activity data. SB 9200 is an entirely new agent for the treatment of chronic HCV infections and is based on our proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology platform. We thank our investors for their enthusiastic support and together we look forward to the initiation of our first clinical program and the advancement of our strong pipeline of additional SMNH programs for Hepatitis B virus (HBV), Respiratory Syncytial Virus (RSV), Broad Spectrum Antiviral and COPD."

SB 9200 has a unique mechanism of antiviral action involving the selective activation of the host-immune response in HCV-infected cells. "Unlike other classes of drugs for HCV infection that act directly on the virus, SB 9200 targets host cytosolic sensor proteins, RIG-I and NOD2," states Dr. Kris Iyer, CSO and Co-founder of Spring Bank. "This leads to the selective activation of the host immune response in the presence of viral infection. By virtue of this novel mechanism of action, SB 9200 is ideally suited for combination with other classes of HCV antivirals. In preclinical studies, SB 9200 has shown synergistic antiviral activity when combined with other anti-HCV compounds and has demonstrated an excellent safety profile. Moreover, this novel mechanism of action suggests it could have pan-genotypic activity, as well as potentially a high barrier to resistance. These attributes could potentially lead to the use of SB 9200 as part of an Interferon-free, all-oral regimen for HCV therapy."

About Spring Bank Pharmaceuticals

Spring Bank Pharmaceuticals is engaged in the discovery and development of an entirely new class of safer and more effective medicines based on the Company's proprietary SMNH, "Small Molecule Nucleic Hybrid" technology program. SB 9200, a potential breakthrough drug for the treatment of HCV and HBV, is the Company's most advanced drug under development. The Company also has programs for the development of antivirals against Respiratory syncytial virus (RSV) infections; the development of a Broad spectrum antiviral; and therapies to treat Chronic obstructive pulmonary disease (COPD).

Contact: Douglas Jensen (508)-473-5993 x105

View more:

Profile of alisporivir and its potential in the treatment of hepatitis C

2013;7:105-15. doi: 10.2147/DDDT.S30946. Epub 2013 Feb 15.
Profile of alisporivir and its potential in the treatment of hepatitis C.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, One Kendall Square, Cambridge, MA, USA.

Full Text -
Dove Medical Press - PDF

Two classes of hepatitis C antiviral agents currently exist, ie, direct-acting antivirals and host-targeting antivirals. Direct-acting antivirals target viral proteins including NS3/NS4A protease, NS5B polymerase and NS5A protein, while host-targeting antivirals target various host proteins critical for replication of the hepatitis C virus (HCV). Alisporivir is the most advanced host-targeting antiviral in clinical development. Alisporivir blocks HCV replication by neutralizing the peptidyl-prolyl isomerase activity of the abundant host cytosolic protein, cyclophilin A. Due to its unique mechanism of antiviral action, alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals. Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that alisporivir causes a dramatic reduction in viral loads in HCV-infected patients. Alisporivir was shown to be highly potent in treatment-naïve and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with alisporivir in combination with pegylated interferon-alpha and ribavirin were similar to those associated with pegylated interferon-alpha and ribavirin used alone. A laboratory abnormality observed in some patients receiving alisporivir is hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that alisporivir plus other direct-acting antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior interferon-alpha therapy and patients with cirrhosis.

In conclusion, alisporivir represents an attractive candidate component of future interferon-free regimens.

alisporivir, cyclophilin inhibitors, cyclophilins, hepatitis C virus, treatment
PMID:23440335[PubMed - in process] 
 Full Text Sources

Chronic HCV linked to hypertension, congestive heart failure

Chronic HCV linked to hypertension, congestive heart failure
Younossi ZM. Aliment Pharmacol Ther. 2013;37:647-652.

February 27, 2013
Patients with chronic hepatitis C are more likely to have hypertension, in addition to insulin resistance and diabetes, and also are at elevated risk for congestive heart failure, according to recent results.

Researchers evaluated data from 19,741 participants in the National Health and Nutrition Examination Survey between 1999 and 2010. The cohort included 173 patients with chronic HCV, with the remaining 19,568 classified as controls.
Full Story »

Midodrine, clonidine improve ascites control in patients with cirrhosis
Singh V. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.9.

February 26, 2013
Patients with cirrhosis and ascites treated with standard care and midodrine, clonidine or both therapies experienced improvement to hemodynamics and ascites control compared with standard care alone in a recent pilot study.
More »

Wonder drug warning: Health Canada describes deaths from Hep C pills

Wonder drug warning: Health Canada describes deaths from Hep C pills

Serious skin reactions to Incivek in chronic Hepatitis C patients a sign they should seek “urgent” medical care, Health Canada says.

News reporter, Published on Thu Feb 28 2013

A chronic Hepatitis C wonder drug that has caused death and serious skin reactions has been hit with a serious warning and alert by Health Canada, two months after the same urgent message in the U.S.

The Incivek capsules are the flagship product of Vertex Inc., a Massachusetts pharmaceutical company with a branch in Laval, Que.

Health Canada warned people to seek “urgent” medical treatment if they develop a serious skin reaction while taking Incivek, the trademark name of the drug teleprevir produced by Vertex Pharmaceuticals Canada Inc.

Deaths have occurred in people with “progressive rash and systemic symptoms” who kept using the drug, Health Canada said Wednesday.

The U.S. parent company announced the “black box” warnings, the highest cautionary level, in December. The drug was approved in the U.S. and Canada in 2011.

Health Canada’s longer process for issuing such warnings caused the extra two-month lag in announcing the complications, Vertex U.S. spokeswoman Erin Emlock told the Star.

“We had to work through that process” with Health Canada, she said.

“There are a limited group of physicians who prescribe the drug in Canada. There are many, many more patients in the U.S.,” she said.

In December, the U.S. Federal Drug Administration said there had been two deaths and 112 serious skin reactions.

Emlock said she didn’t know if any of those were in Canada.

Ontario doctors last fall questioned why it was taking the province so long to approve the drug.

“The medication can dramatically shorten the treatment time for hep C, limiting the impact of side effects like anemia and rashes, and it has been shown to cure the condition in a majority of new cases,” the Star’s Rob Ferguson reported.

Provincial drug plans in Quebec, Nova Scotia, New Brunswick, Alberta, B.C. and the Yukon and private insurers were paying for the $35,000 cost of a standard 12-week treatment, Ferguson reported.

Health Canada advised patients to talk to their doctors before they stop using the medication.

“Fatal and non-fatal serious skin reactions, including Toxic Epidermal Necrolysis (TEN), Stevens Johnson Syndrome (SJS), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported in patients receiving Incivek combination treatment,” Health Canada said.

Incivek is used only in combination with peginterferon alfa and ribavirin.

At the time of the Health Canada approval, Canadian Incivek investigator Dr. Eric Yoshida of the University of British Columbia said, “Incivek has been shown to help clear the virus for nearly four out of five patients new to treatment.”

Vertex chief medical officer Robert Kauffman said a quarter of a million Canadians suffered from Hepatitis C.

The drug is used to treat genotype 1 chronic hepatitis C in adult patients with compensated liver disease.

Tuesday, February 26, 2013

Hepatitis C Research and Clinical Trial updates

Updates @ NATAP

This study is currently recruiting participants

 Dose Ranging of NS5A GSK2336805 (vs telaprevir) in Combination Therapy 
GSK2336805 is a novel hepatitis C virus (HCV) non-structural 5A (NS5A) inhibitor being developed for the treatment of chronic HCV infection. This Phase II, multicenter, parallel-group, randomized, dose-ranging study will assess the safety and tolerability, antiviral activity, and pharmacokinetics of GSK2336805 at 2 dose levels (40 and 60 mg) in combination with pegylated interferon alfa-2a (PEG) and ribavirin (RIBA) in approximately 100 treatment-naïve subjects with chronic genotype 1 HCV infection.....

NS5A Review - Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein 
"NS5A-targeting molecules are probably the most potent antiviral molecules ever discovered"

"At least 4 NS5A-targeting molecules are being evaluated in combination with pegIFN/RBV: BMS-790052, GS-5885, ABT-267, and GSK23368005 (Table 1 and Table 2)."

"BMS-790052 serves as the prototype molecule for this class of HCV inhibitor; defined by exquisite low picomolar EC50 values for HCV genotype 1 (Table 1.). These molecules are over a 1000-fold more potent than the current licensed HCV protease inhibitors in cell culture-based HCV replicon assays ( Flint et al., 2009, Gao et al., 2010 and Lin et al., 2006); they are probably the most potent antiviral molecules ever discovered."

"Both Achillion's and Merck's NS5A inhibitors (ACH-3102 and MK-8742, respectively) retain substantial levels of in vitro potency against NS5A resistance polymorphisms that plague early NS5A inhibitors, such as BMS-790052 and GS-5885 ( Liu et al., 2012 and Yang et al., 2012). Accordingly, they can be viewed as 'second generation' NS5A inhibitors and time will tell whether these favorable preclinical profiles will also translate to superior clinical efficacy." -Updated in the last 30 days

Efficacy and Safety Evaluation of a Treatment Consisting of Peg Interferon Alfa + Ribavirin + Daclatasvir in HCV Genotype 1 and 4 Treatment naïve Patients
‎Thursday, ‎February ‎21, ‎2013, ‏‎12:00:00 PM
Condition: Hepatitis C
Interventions: Drug: Peginterferon alfa 2a; Drug: Ribavirin; Drug: Placebo matching Daclatasvir; Drug: Daclatasvir
Sponsors: Bristol-Myers Squibb; Bristol-Myers Squibb
Not yet recruiting - verified February 2013
‎Monday, ‎February ‎11, ‎2013, ‏‎12:00:00 PMGo to full article
Condition: Chronic Hepatitis C
Interventions: Drug: VX-135; Drug: Ribavirin
Sponsors: Alios Biopharma Inc.; Alios Biopharma Inc.; Vertex Pharmaceuticals Incorporated
Recruiting - verified February 2013
‎Wednesday, ‎January ‎23, ‎2013, ‏‎12:00:00 PMGo to full article
Condition: Post-transplant Recurrent Hepatitis C
Intervention: Drug: Sofosbuvir + RIbavirin +/- Pegylated Interferon
Sponsors: Gilead Sciences; Gilead Sciences
Available - verified January 2013

Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period

"Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period"

Dr. Zoe Mariño discusses her article "Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period"

Abstract -

Editorial - Silibinin: An old drug in the high tech era of liver transplantation

Healio-Chronic acetaminophen exposure worsened outcomes for pediatric acute liver failure

FDA requires additional safety data before approving HBV vaccine Heplisav
February 25, 2013
The FDA will not approve hepatitis B vaccine Heplisav for its proposed indication without further safety data, according to a press release.
The drug (Dynavax) is a recombinant vaccine consisting of hepatitis B surface antigen and a Toll-like receptor 9 agonist developed to increase immune response. The company had sought approval for its use in adult patients aged 18 to 70 years.
Full Story »

Chronic acetaminophen exposure worsened outcomes for pediatric acute liver failure
February 25, 2013
Patients with pediatric acute liver failure had worse outcomes when exposed to chronic acetaminophen compared with those with single-dose exposure in a recent study.
More »

Fibromyalgia pain treatment moves to ‘high-definition’
February 25, 2013
More precise brain stimulation credited with less perceived pain.
High-definition transcranial direct current stimulation was well tolerated and produced a significant reduction in overall perceived pain in patients with fibromyalgia, according to recent study results.
Read more.

Daclatasvir/Sofosbuvir: Should Gilead Sciences’ profitability trump doing what is right?

Murphy: Hepatitis and the pharmacology of greed
Posted: February 25, 2013 - 10:35pm | Updated: February 26, 2013 - 12:06am
I was eight years old, making rounds at the hospital with my father, when I first met the Yellow Man.
His eyes were an astonishing saffron color. His skin was also striking — an iridescent bilious hue.

My father sat poring over the Yellow Man’s voluminous chart in the nurses’ station, reading glasses perched on the end of his nose, while I tried my best to stay quiet.

Ultimately, I couldn’t.

“Why is he that color?” I asked my dad in a whisper.

“He has hepatitis,” my father said matter-of-factly, never looking up.

I nodded. I was fascinated. I even talked to my third-grade class about the Yellow Man later that week in Show and Tell. But I had no clue what my father was talking about when he told me that the Yellow Man had “hepatitis.”

Today, I do.

You see, I am a gastroenterologist. In my medical specialty, we deal with Yellow Men (and Yellow Women) just about every day. And many of them have various forms of hepatitis, or inflammation of the liver.

Some get it from alcohol; some, from medication. But an emerging variable in the growing liver disease population is hepatitis C — a viral illness that is now the leading cause for liver transplants in this country.

Over 170 million people worldwide have hepatitis C. More than 4 million of those people are in the United States. A lot of those folks acquired hepatitis C through blood transfusions (there was no blood test for the virus before 1989); some got it through IV drug use, or through tattoos and body piercings. A shocking 30 percent have no risk factors for it, and have no idea how they became infected.

So why is hepatitis C a problem?

Because it is a stealth epidemic.

You see, most people with this disease are not “yellow.” In fact, most of them have no symptoms at all. None, that is, until they develop cirrhosis and liver failure — or worse still, liver cancer. Hepatitis C is now the leading cause of liver cancer in the United States, and is the most rapidly increasing cause of cancer death in this country.

Hepatitis C kills more people every year than AIDS.

Let that sink in for a moment.

Traditionally, hepatitis C has been treated with a combination of an injectable drug called interferon and another orally-administered medicine called ribavirin. It’s a grueling regimen, resulting in nausea, malaise, weight loss, skin and hair changes, anemia, thyroid problems and depression in many patients.

Moreover, the cure rate (technically called “sustained virologic response,” or SVR) for this regimen is less than 40 percent after 48 weeks of treatment. Many people cannot complete the full course of therapy because of the horrendous side effects.
Now, to the punchline.

At a recent national medical meeting of liver specialists, Dr. Mark Sulkowski of Johns Hopkins University Medical Center described a Phase II research protocol using a combination of two new oral medications, daclatasvir and sofosbuvir. This medication combination has almost no side effects.

The gist of Dr. Sulkowski’s presentation is this: After a mere 12 weeks of treatment with this new regimen, the “cure” (SVR) rate for hepatitis C was an astonishing 93 percent.

When I read this, I literally stood up and whooped.

Hepatitis C patients have been waiting for a treatment regimen like daclatasvir and sofosbuvir for decades. It’s a true rarity in medicine — an honest-to-goodness game-changer, a phenomenally effective regimen for a serious, life-threatening disease that is also safe and well-tolerated.

The only problem? The two drugs are owned by different companies — daclatasvir is a Bristol-Myers-Squibb drug, while sofosbuvir is made by Gilead Sciences.

For reasons that are almost certainly financial in nature, Gilead has refused to do further work on this drug combination with Bristol-Myers Squibb, so there will be no further study of the regimen. With no Phase III trials, that means that the daclatasvir/sofosbuvir combination regimen will likely not be approved for use by the FDA.

Gilead has issued no formal commentary about why it does not wish to pursue further development of the new regimen, although there is speculation that it is altering its focus to produce single-tablet combination regimens — a product line that has been highly successful for the company in the treatment of HIV.

In fact, Gilead is doing quite well financially. It is a company with over $4 billion in annual revenues and over 4,000 employees. Its average margin of profitability over the last five years has been a whopping 34 percent.

Moreover, the total return to its shareholders on Gilead’s stock has been nearly 95 percent over the past year.

Still, the salient question is this: Should Gilead Sciences’ profitability trump doing what is right?
Since Dr. Sulkowski’s data presentation at the AASLD meeting in Boston this past November, over 200,000 hepatitis C patients worldwide have died of complications of their disease. Meanwhile, Gilead, a tremendously profitable corporation, refuses to consider the development of a drug regimen that could have cured most of those individuals in the pursuit of even greater profits.

I find that unconscionable. In fact, I find it patently offensive.

In short, it’s just plain wrong.
Mark Murphy, M.D., is a Savannah physician and writer.

Monday, February 25, 2013

OHSU scientists first to grow liver stem cells in culture, demonstrate therapeutic benefit

OHSU scientists first to grow liver stem cells in culture, demonstrate therapeutic benefit

PORTLAND, Ore. — For decades scientists around the world have attempted to regenerate primary liver cells known as hepatocytes because of their numerous biomedical applications, including hepatitis research, drug metabolism and toxicity studies, as well as transplantation for cirrhosis and other chronic liver conditions. But no lab in the world has been successful in identifying and growing liver stem cells in culture -- using any available technique – until now.

In the journal Nature, physician-scientists in the Papé Family Pediatric Research Institute at Oregon Health & Science University Doernbecher Children's Hospital, Portland, Ore., along with investigators at the Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, Netherlands, describe a new method through which they were able to infinitely expand liver stem cells from a mouse in a dish.

"This study raises the hope that the human equivalent of these mouse liver stem cells can be grown in a similar way and efficiently converted into functional liver cells," said Markus Grompe, M.D., study co-author, director of the Papé Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital; and professor of pediatrics, and molecular and medical genetics in the OHSU School of Medicine.

In a previous Nature study, investigators at the Hubrecht Institute, led by Hans Clever, M.D, Ph.D., were the first to identify stem cells in the small intestine and colon by observing the expression of the adult stem cell marker Lgr5 and growth in response to a growth factor called Wnt. They also hypothesized that the unique expression pattern of Lgr5 could mark stem cells in other adult tissues, including the liver, an organ for which stem cell identification remained elusive.

In the current Nature study, Grompe and colleagues in the Papé Family Pediatric Research Institute at OHSU Doernbecher used a modified version of the Clever method and discovered that Wnt-induced Lgr5 expression not only marks stem cell production in the liver, but it also defines a class of stem cells that become active when the liver is damaged.

The scientists were able to grow these liver stem cells exponentially in a dish – an accomplishment never before achieved – and then transplant them in a specially designed mouse model of liver disease, where they continued to grow and show a modest therapeutic effect.

"We were able to massively expand the liver cells and subsequently convert them to hepatocytes at a modest percentage. Going forward, we will enlist other growth factors and conditions to improve that percentage. Liver stem cell therapy for chronic liver disease in humans is coming," said Grompe.

Hepatitis C-Moderate, excessive or heavy alcohol consumption: each is significantly associated with increased mortality

Moderate, excessive or heavy alcohol consumption: each is significantly associated with increased mortality in patients with chronic hepatitis C

Z. M. Younossi1,2,*, L. Zheng1,2, M. Stepanova2, C. Venkatesan1, H. M. Mir1

Article first published online: 24 FEB 2013
DOI: 10.1111/apt.12265 © 2013 Blackwell Publishing Ltd

Alimentary Pharmacology & Therapeutics
The impact of moderate alcohol consumption on long-term outcomes of chronic hepatitis C (CH-C) infected patients remains controversial.

To assess the impact of moderate alcohol consumption on long-term outcomes of CH-C patients using population-based data.

Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES III)-mortality linked files. Alcohol consumption was estimated as grams/day. Multivariate Cox proportional hazards model was utilized to assess the effects of CH-C and alcohol consumption on mortality (all causes, cardiovascular disease, and liver disease).

A total of 8985 participants were included as the study cohort. Of these, 218 had CH-C. The follow-up time was 162.95 months for CH-C and 178.27 months for controls. CH-C patients had increased risk for both overall mortality and liver-related mortality. CH-C patients with excessive alcohol consumption had even higher risks for overall mortality and liver-related mortality. The risk of overall mortality associated with CH-C increased with moderate alcohol consumption of 1–19 g/day and heavy alcohol consumption ≥30 g/day.

Although chronic hepatitis C is associated with increased risks for overall and liver-related mortality, these risks are even higher for patients consuming moderate and excessive amounts of alcohol.

Chronic hepatitis C (CH-C) is a major cause of chronic liver disease, cirrhosis and hepatocelluar carcinoma (HCC). CH-C is associated with tremendous burden on the health and the well-being of the population.[1, 2] Although the incidence of new cases of hepatitis C virus (HCV) infection has fallen,[3] over the next few decades, a large cohort of actively infected CH-C patients is expected to be responsible for a significant rise in the number of cases of HCC and decompensated cirrhosis.[4, 5] In this context, CH-C will continue to increase its clinical and economic burden and will overtake other important chronic infectious diseases, including HIV in terms of mortality.[6]
Despite this projected threat from HCV, not all patients progress to cirrhosis and develop HCV-related complications.[1, 3] There are a number of factors that affect progression of liver disease in patients with CH-C.[7] Of these, excessive alcohol consumption has been recognized as an important factor.[8, 9] The impact of moderate alcohol consumption in patients chronically infected with HCV has not been fully understood. The aim of this study was to assess the impact of excessive and moderate alcohol consumption on the overall, liver-related and cardiovascular mortality of patients with CH-C.

To assess the impact of alcohol consumption on CH-C mortality, we used the Third National Health and Nutrition Examination Survey (NHANES III) and the NHANES III linked mortality file.[10] The survey was conducted from 1988 through 1994 using a complex, multi-stage, stratified, clustered sample design to obtain a representative sample of the total civilian, non-institutionalized US population. It includes an in-home interview for demographic and basic health information, a health examination in a mobile examination center, and laboratory/imaging tests (including ultrasonography of the gallbladder and liver). Public use data files were obtained from the NHANES Website ( The study was approved by the Inova Institutional Review Board.

Study population
During NHANES III, 33 994 participants were interviewed in their homes, in which standardized questionnaires were used to obtain self-reported data on age, gender, race or ethnicity, smoking, and prevalent medical conditions.[10] The present study was restricted to adult participants (aged 20–74 years at the time of the examination). Age was categorized into four groups: 20–44, 45–54, 55–64, and 65–74. Four major race/ethnic groups were reported including non-Hispanic white, non-Hispanic black, Mexican American and ‘Other,’ which included all Hispanics who were not Mexican American and also all non-Hispanics from racial groups other than white and black. A positive smoking history was defined as ongoing smoking or smoked at least 100 cigarettes in life. For participants who underwent health examinations, blood and urine specimens were obtained, and a number of body measurements and tests were performed including height, weight, waist circumference, systolic and diastolic blood pressure, glucose tolerance tests, diabetes tests, general biochemistry tests, HCV antibody tests, and ultrasonography. Analysis was restricted to persons with complete data on demographics (age, gender, race/ethnicity), history of smoking and alcohol consumption, history of type II diabetes, body mass index, waist circumference, blood pressure measured at the time of examination, as well as gradable hepatic ultrasound video images for hepatic steatosis assessment. The following tests also were required for all individuals in this study: serum glucose, triglyceride, high-density lipoprotein, aspartate aminotransferase, alanine transaminase, transferrin saturation levels, and viral hepatitis serologies for hepatitis B virus (HBV) and hepatitis C virus (HCV).

Chronic hepatitis C (CH-C)
All serum from participants was tested for antibody to hepatitis C virus (anti-HCV) and positive anti-HCV tests were confirmed using HCV RNA by polymerase chain reaction (PCR). Participants with positive HCV RNA were considered to have chronic hepatitis C (CH-C). In the current study, only patients with established CH-C in absence of CH-B or iron overload were included. The unexposed group (Controls) consisted of individuals without CH-C, CH-B, NAFLD, iron overload, or elevated liver enzymes.

Exposure to alcohol consumption
Alcohol consumption was assessed during the alcohol and drug assessment component of the NHANES III medical examination.[10] Participants were asked if they had at least 12 drinks of alcohol in the past 12 months as well as life time. Persons who reported no alcohol drinking in their entire lives were considered to be ‘never drinkers’. Historical drinkers were defined as persons who reported drinking at least 12 drinks of alcohol in entire life, but none in the past 12 months. Current drinkers were defined as persons who reported at least 12 drinks of alcohol in the past 12 months. The amount of current alcohol consumption was determined from self-reported number of days with alcohol drinking and the average number of drinks per day when they drank alcohol in the past 12 months. As defined by NHANES, one drink which was equivalent to 10 g ethanol represented 12-oz of beer, 4-oz of wine or 1-oz of liquor. Average daily alcohol consumption was estimated by: the number of drinks on a drinking day × 10 g × the number of drinking days over the past 12 months/365.
Moderate alcohol consumption was defined as 1–19 g of alcohol consumption per day and excessive alcohol consumption was defined as average daily alcohol consumption of 20 g or greater.[11] A sub-category of excessive alcohol consumption was considered as heavy alcohol consumption, which was defined as 30 g or more of alcohol consumption per day.
Participants who did not answer the alcohol consumption questions and those who reported drinking alcohol in the past 12 months but did not report the frequency or amount of alcohol consumption were excluded from this study.

Study definitions
  1. Diabetes mellitus type 2 (DM) was defined as a fasting glucose value of 126 mg/dL or greater or the use of oral hypoglycemics and/or insulin.
  2. Insulin resistance (IR) was evaluated using the homeostasis of model assessment score (HOMA), which was calculated using the formula: fasting serum insulin (μU/mL) × fasting plasma glucose (mmol/L)/22.5.[12] HOMA-IR was defined as a HOMA score of 3.0 or greater. DM and IR were combined as one variable DM/IR in our data analysis.
  3. Hypertension was defined as a systolic blood pressure of 140 mmHg or greater, diastolic blood pressure of 90 mmHg or greater, or being on oral antihypertensive medications.
  4. Obesity was defined as a body mass index greater than 30 or a waist circumference more than 102 cm in men and more than 88 cm in women.
  5. All serum was tested for core antibody to hepatitis B virus (anti-HBC). Serum testing positive for anti-HBC were tested further for the hepatitis B surface antigen (HBsAg). Chronic Hepatitis B (CH-B) was presumed in individuals with positive HBsAg.
  6. Elevated serum transferrin saturation is a commonly used indicator for a predisposition of iron overload. Potential iron overload is defined as serum transferrin saturation greater than 50%.
  7. Elevated liver enzyme was defined as serum alanine aminotransferase level greater than 40 U/L or aspartate aminotransferase level greater than 37 U/L in men and alanine aminotransferase or aspartate aminotransferase level greater than 31 U/L in women.
  8. Between 2009 and 2010, the hepatic steatosis (fatty liver) was assessed by reviewing ultrasound video images originally obtained in NHANES III between 1988 and 1994.[13] Nonalcoholic fatty liver disease (NAFLD) was defined as presence of moderate-to-severe hepatic steatosis from the ultrasound examination in the absence of any other evidence of chronic liver disease such as ALD, CH-B, CH-C and iron overload.
Follow-up for mortality
The main outcomes in this study were all-cause mortality, liver-related mortality and cardiovascular mortality. The NHANES III Linked Mortality File provides mortality follow-up data from the date of NHANES III survey participation (1988–1994) through 31 December 2006.[10, 14] Mortality ascertainment is based on the results from a probabilistic match between NHANES III and the National Death Index (NDI) death certificate records. In addition to mortality status, the linked file contains months of follow-up from examination date as well as the Underlying Cause of Death 113 (UCOD_113) code to recode all deaths according to ICD-9 and ICD-10 criteria.[14] Liver-related mortality (UCOD_113 15, 24, 93–95) included causes of death such as viral hepatitis, hepatocellular carcinoma, alcoholic liver disease, and other chronic liver disease and cirrhosis. Cardiovascular mortality (UCOD_113 58–63, 67, 70–74) covered causes of death such as ischaemic heart diseases, heart failure, atherosclerosis, cerebrovascular diseases, aortic aneurysm and other diseases of arteries, arterioles and capillaries. As HIV screening results were not released in NHANES III data for public use, to separate the effects of co-infection of HCV and HIV, individuals who died of human immunodeficiency virus (HIV) (UCOD_113 16) were presumed to have HIV infection and were excluded. Individuals without available mortality follow-up data were also excluded from the study.

Statistical analysis
We compared the baseline characteristics of participants by the status of CH-C using χ2-test for independence. Periods of risk of death were defined in months for each participant between NHANES III examination date and the date of death or the end of follow-up (31 December 2006). If an individual did not die or died from causes other than the event of interest, his survival time was censored.
Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals for deaths from all causes, cardiovascular disease and liver disease by status of CH-C. To examine the amount of alcohol consumption on the survival of persons with CH-C, stratified analyses by levels of alcohol consumption were conducted Each model was adjusted for major demographic and clinical confounders including age, gender, race/ethnicity, smoking history, obesity, diabetes/insulin resistance and hypertension. Statistical significance was set at P < 0.05.
NHANES III is based on a complex multistage probability sample design. The sampling weights incorporate the differential probabilities of selection and include adjustments for noncoverage and nonresponse. Sample weights together with stratification and clustering were incorporated into our analysis to estimate variances and test for statistical significance.[10] All analyses were performed using standalone SUDAAN 10.0 (RTI International, Research Triangle Park, NC, USA).

After applying the exclusion criteria, a total of 8985 participants remained in the analytical sample.

Table 1 summarizes the characteristics of participants according to their diagnosis.
Table 1. Characteristics of study participants by hepatitis C status from NHANES III (1988–1994)
CharacteristicsCH-C (n = 218) Percent ± S.E.No CH-Ca (n = 8767) Percent ± S.E.P-valueb
  1. a
    No CH-C was the control group for the CH-C cohort, which included persons without CH-C, CH-B, NAFLD, elevated liver enzyme, or iron overload.
  2. b
    Participants with CH-C were compared with their controls using χ2-test.
  3. c
    Excessive alcohol consumption was defined as self-reported average daily drinking of ≥20 g of pure alcohol during the past 12 months.
Excessive alcohol consumptionc28.35 ± 5.487.29 ± 0.470.0075
20–4479.25 ± 4.9763.05 ± 1.09
45–5415.06 ± 4.6914.56 ± 0.62
55–641.63 ± 0.4912.02 ± 0.59
65–744.07 ± 1.5210.36 ± 0.65
Male67.37 ± 4.9246.41 ± 0.680.0042
Non-Hispanic white63.33 ± 5.5977.56 ± 2.14
Non-Hispanic black21.80 ± 3.5210.55 ± 1.16
Mexican American6.61 ± 1.924.70 ± 0.78
Other8.26 ± 3.707.20 ± 1.15
Smoking83.19 ± 4.9654.27 ± 1.320.0007
Obesity33.22 ± 4.8231.36 ± 0.900.7001
Diabetes or insulin resistance36.13 ± 4.1516.84 ± 0.830.0013
Hypertension18.42 ± 4.4617.21 ± 0.710.7859

Compared with participants without CH-C, participants with CH-C were more likely to have excessive alcohol consumption, smoke cigarettes, to be male, younger than 45 years, non-Hispanic black, and have diabetes or insulin resistance. Previous studies have shown that participants' age, gender, race/ethnicity, smoking status and disease conditions including obesity, DM/IR and hypertension were associated with mortality (7). Therefore, multivariate Cox proportional hazards model was utilized to evaluate the independent effect of each diagnosis on all-cause mortality and cause-specific mortality while adjusting for possible confounding effects of these variables. Exploratory analyses revealed that the effect of obesity on mortality varied across age groups; therefore, an interaction between age and obesity was included in the multivariate model.

The impact of chronic hepatitis C on mortality
The median follow-up was 162.95 months for patients with CH-C, and 175.49 months for controls. A total of 1320 (11.37%) participants died at the end of the follow-up, including 415 (3.39%) deaths due to cardiovascular diseases and 32 (0.27%) deaths due to liver diseases.
For CH-C patients, the cumulative mortality rate was 19.09% (54 deaths) for all-cause death, 1.66% (5 deaths) for cardiovascular death and 6.37% (11 deaths) for liver-related death. In comparison, the cumulative mortality rate for controls was 11.22% (1266 deaths) for all-cause death, 3.43% (410 deaths) for cardiovascular death, and 0.15% (21 deaths) for liver-related death.
The unadjusted analyses showed that compared with controls, patients with CH-C had significantly higher risk for all-cause mortality (HR: 1.91, 95% CI: 1.16–3.15, P = 0.01) and liver-related mortality (HR: 49.52, 95% CI: 12.37–198.26, P < 0.01), but not cardiovascular mortality (HR: 0.53, 95% CI: 0.17–1.67, P = 0.28).

The impact of excessive alcohol consumption and chronic hepatitis C on mortality
The combined effects of CH-C and excessive alcohol consumption on mortality outcomes were evaluated by including an interaction term of these two factors in the multivariate Cox proportional hazard model, the results are summarized in Table 2.
Table 2. Hazard ratios (HR) and 95 confidence intervals (CI) of all-cause and cause-specific mortality, by hepatitis C status and alcoholic consumption and other risk factors at baseline, NHANES III (1988–1994)
CharacteristicsAll-cause mortalityCardiovascular mortalityLiver-related mortality
  1. Values in bold are statistically significant.
  2. a
    Excessive alcohol consumption was defined as self-reported average daily drinking of ≥20 g pure alcohol during the past 12 months.
  3. b
    No excessive alcohol consumption was defined as self-reported no alcohol drinking in entire life or in the past 12 months, or average daily drinking of <20 g pure alcohol during the past 12 months.
CH-C: Excessive alcohol consumptiona 5.12 (1.97–13.28) 3.34 (0.55–20.50)183.74 (15.98–infinity)
CH-C: No excessive alcohol consumptionb 2.44 (1.59–3.75) 0.71 (0.23–2.21) 74.25 (19.62–280.92)
Excessive alcohol consumption0.80 (0.60–1.07)0.57 (0.27–1.20)0.28 (0.04–2.17)
45–54 3.04 (2.03–4.54) 3.56 (1.44–8.84) 1.31 (0.18–9.77)
55–64 7.16 (4.95–10.35) 6.87 (3.23–14.61) 7.82 (0.66–92.92)
65–74 22.90 (16.15–32.48) 33.61 (16.40–68.90) 30.92 (4.47–214.16)
Male 1.33 (1.12–1.57) 1.72 (1.24–2.37) 1.70 (0.45–6.49)
Non-Hispanic white1.001.001.00
Non-Hispanic black 1.26 (1.05–1.52) 1.18 (0.89–1.56)0.79 (0.29–2.18)
Mexican American0.94 (0.76–1.16)0.96 (0.67–1.39)1.01 (0.29–3.63)
Other0.80 (0.51–1.25)0.39 (0.15–1.05)0.27 (0.02–3.38)
Smoking 2.08 (1.72–2.52) 1.56 (1.15–2.11) 1.36 (0.45–4.12)
Obesity: Age 20–441.30 (0.84–2.03)1.34 (0.46–3.90)8.85 (1.3359.04)
Obesity: Age 45–54 1.63 (1.01–2.61) 1.28 (0.50–3.24)6.14 (0.80–47.30)
Obesity: Age 55–640.98 (0.74–1.31)1.11 (0.63–1.98)0.49 (0.05–4.94)
Obesity: Age 65–740.67 (0.53–0.86)0.60 (0.39–0.93)0.63 (0.09–4.54)
DM/IR 1.66 (1.35–2.03) 1.74 (1.29–2.36) 0.76 (0.30–1.94)
Hypertension 1.47 (1.24–1.74) 2.50 (1.72–3.64) 2.64 (0.94–7.42)

For participant without excessive alcohol consumption, having CH-C was associated with increased risk of all-cause mortality (HR: 2.44, 95% CI: 1.59–3.75, P < 0.01) and liver-related mortality (HR: 74.25, 95% CI: 19.62–280.92, P < 0.01). Similar to the unadjusted results; CH-C without excessive alcohol use was not associated with cardiovascular mortality (HR: 0.71, 95% CI: 0.23–2.21, P = 0.55).
On the other hand, for participants with excessive alcohol use, having CH-C dramatically increased the risk of all-cause mortality (HR: 5.12, 95% CI: 1.97–13.28, P < 0.01), liver-related mortality (HR: 183.74, 95% CI: 15.98–infinity, P < 0.01), as well as a trend in increasing the risk of cardiovascular mortality (HR: 3.34, 95% CI: 0.55–20.50, P = 0.19) (Table 2).

The impact of different amounts of alcohol consumption on CH-C mortality
The impact of CH-C on the mortality outcomes stratified by levels of alcohol consumption is summarized in Table 3.
Table 3. Adjusted hazard ratios (HR) and 95 confidence intervals (CI) of all-cause mortality for persons with CH-C compared with persons without CH-Ca stratified by alcohol consumption, NHANES III (1988–1994)
CH-C and alcohol consumption (number of participants, N)All-cause MortalityP-valueb
  1. a
    Persons without CH-C were defined as persons who had no CH-C or any other liver diseases including CH-B, NAFLD, iron overload or elevated liver enzyme.
  2. b
    P-value of the Wald chi-squared test.
CH-C with a previous history of alcohol consumption (N = 60)2.33 (1.21–4.49)0.0116
CH-C without previous a history or current alcohol consumption (N = 14)2.52 (0.87–7.34)0.0887
CH-C with moderate current alcohol consumption <20 g/day (N = 99)2.29 (1.36–3.88)0.0023
CH-C with excessive current alcohol consumption 20–29 g/day (N = 23)7.63 (1.48–39.31)0.0157
CH-C with heavy current alcohol consumption ≥30 g/day (N = 22)3.50 (1.20–10.17)0.0219

Among participants with a history of alcohol consumption (but currently none), those with CH-C had over two-fold increased risk of overall mortality as compared with those without the disease (HR: 2.33, P = 0.01). For participants who actively consumed moderate amounts of alcohol (1–19 g/day), CH-C was also associated with two-fold increased risk of overall mortality [HR = 2.29 (1.36–3.88), P = 0.01]. However, CH-C was associated with over seven-fold increased risk of overall mortality for those individuals who were consuming 20–29 g of alcohol per day (HR = 7.63, P = 0.02), and a three-and-a-half-fold increased risk of overall mortality for those consuming ≥30 g of alcohol per day (HR = 3.50, P = 0.02) (Table 3).
It is important to note that for individuals with CH-C, liver disease was the top causes of death, accounting for 20.4% of all deaths. On the other hand, among participants without CH-C or any other liver diseases, the top cause of death was cardiovascular disease, which accounted for 32.5% of all deaths (Table 4).
Table 4. Causes of death in different cohorts
Top 3 causes of deatha
  1. a
    Based on the unweighted percentage of all deaths for each specific cause.
Controls without CH-CCardiovascular disease (32.4%), lung cancer (10.3%), pneumonia or other chronic lower respiratory disease (6.8%)
CH-C (the entire cohort)Liver diseases (20.4%), motor vehicle or poisoning accidents (16.7%), cardiovascular disease (9.3%)
CH-C with a history of alcohol consumptionLiver disease (29.4%), cardiovascular diseases (17.6%), diabetes (11.8%)
CH-C with excessive current alcohol consumptionMotor vehicle accidents (25.0%), liver disease (16.7%), suicide (16.7%)
This study uses the population data collected as a part of NHANES III surveys and the associated Mortality Linked Files to assess the impact of CH-C and the combination of CH-C with alcohol consumption on overall mortality and cause-specific mortality in US general population. Our data show that patients with CH-C are at increased risk for overall mortality and liver-related mortality. Although the increased risk of overall mortality in CH-C has been controversial, this study supports this increased risk.[15-17]
Additionally, our data confirm that CH-C is independently associated with increased risk for liver-related mortality at the population level. Given the estimated 4–5 million individuals infected with HCV in the United States and 130–140 million people infected with HCV worldwide,[1, 3, 18] these findings can have important national and global implications.[5]
In this study, we also assessed the interaction between CH-C and alcohol consumption. Previous studies have reported that excessive alcohol consumption can be associated with increased risk of liver-related mortality, but not with the increased risks of overall mortality or cardiovascular mortality.[19] Our study also shows that having CH-C in individuals who excessively consume alcohol can dramatically increase the risk of all-cause mortality, liver-related mortality and potentially, cardiovascular mortality. In fact, in patients with CH-C, this increased risk for overall mortality, and liver-related mortality was further amplified with increasing amounts of alcohol consumption. Although alcohol consumption in excess of 40–50 g/day has previously been associated with an increased risk of liver-related mortality,[20] this is the first study documenting the combined effects of alcohol consumption and CH-C on both overall mortality and liver-related mortality. This is especially important for CH-C patients who consume moderate amounts of alcohol (<20 g per day). Although the detrimental effect of ‘moderate alcohol use’ in CH-C patients has been clinically suspected,[21] this population-based study provides further evidence to support this association. In our study, moderate alcohol consumption in patients with CH-C does not seem to have a potential ‘cardio protective’ effect. On the contrary, the negative impact of alcohol consumption related to HCV-related liver disease may outweigh any potential cardiac benefits.
Despite its long-term follow-up and in-depth clinical and mortality data, our study does have some weaknesses. The most important weakness is the relative small sample size of patients with CH-C, which may have led to our inability to show some important potential associations as well as being responsible for the large confidence interval seen in some of the hazard ratios. Nevertheless, the in-depth nature of this population-based study and the long-term follow-up mortality data make this study quite unique and important. Future research can include the incorporation of similar epidemiological and natural history data of this same population in one comprehensive report. Additionally, a meta-analysis that will combine some of the similar studies assessing interaction between HCV, alcohol consumption and mortality will be important.
In summary, our study finds that patients with CH-C are at increased risks for both liver-related mortality and overall mortality. This risk increases in CH-C patients who consume alcohol excessively and potentially moderately. These results should inform clinicians to advocate complete alcohol abstinence in patients with CH-C. Additionally, our study should inform health care policy makers to address CH-C infection at the population level and recognize that CH-C will not only increase the risk for liver-related mortality but also the risk for overall mortality. This recognition of CH-C as an important cause of all-cause mortality at the population level should prompt the availability of resources to address this important public health issue both nationally and globally.

Guarantor of the article: Zobair M. Younossi.
Author contributions: All authors contributed to the design, data interpretation, editing of the manuscript and approved the final version of the manuscript.

Declaration of personal interests: None.
Declaration of funding interests: Internal funds only.

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