Hepatitis C Caring Ambassadors Program Newsletter

November 2006

In The News....................................................................................................1-10

Clinical Trials, Cohort Studies, Pilot Studies.................................... 11-16

Basic and Applied Science, Pre-Clinical Studies..................................17-21

HIV/HCV Coinfection..................................................................................21-23

Miscellaneous Works................................................. ...............................23-26

 

in the news

 

HIV/Hep C Cases Rising in Sudbury

http://www.northernlife.ca/News/Lifestyle/2006/12-01-06-aidsTOP.asp?NLStory=12-01-06-aidsTOP

Ecole Secondaire Macdonald-Cartier student Alex Vincent looked a little embarrassed when he was asked what he knows about HIV/AIDS or other sexually transmitted diseases.

“In Grades 7 and 8 we learned about AIDS, but not much since then,”  said the 17-year-old, who stopped to chat at a booth about sexual health outside his school’s cafeteria. “I don’t think we’re getting the right information about sexually transmitted diseases. That’s probably why you don’t see many students looking at the information.”

HIV/AIDS is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing the virus, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.  People can get the virus through anal, vaginal or oral sex, blood transfusions, contaminated hypodermic needles (often used by intravenous drug addicts), exchange between mother and baby during pregnancy, childbirth or breastfeeding, or exposure to bodily fluids.

Information about HIV/AIDS, sexually transmitted diseases and blood-borne diseases such as Hepatitis C, and how to prevent the spread of some diseases by using condoms was handed out at high schools and post-secondary students during AIDS Awareness Week, which ends today.

High school students tend to grab the information and laugh about it, but the point is  they’re learning something new, says Danielle Moncion, a child and youth worker student at Cambrian College who is on placement with Access AIDS.

“I think it’s extremely important because the majority of adults and youth don’t know their risk factors,” she says. “HIV is still, per capital, worse in Sudbury than it is in Toronto. Hepatitis C is also on the rise in Sudbury as well.”

Moncion wasn’t allowed to hand out condoms at high schools although they were distributed with AIDS information to post-secondary students.  “The majority of high schools have nurse practitioners, and they want the students to go to the nurse practitioners and get information,” she says.  “I don’t personally think that’s a good idea because I think they’re too embarrassed to go and see the nurse practitioner. They have to do this in front of their teachers, which is uncomfortable for them.”

 

 

China's Hepatitis C Prevalent Population is Ten Times that of the United States

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/12-05-2006/0004485476&EDATE=
Decision Resources, one of the world's leading research and advisory firms focusing on pharmaceutical and healthcare issues, estimates that China's hepatitis C virus (HCV) prevalent population is ten times that of the United States. This large prevalent population, combined with the country's rapid economic growth, makes it an important region of expansion for companies with HCV products.
"Nearly 45 million people in China have chronic HCV, a population ten times the size of that in the United States," said Aaron Woolsey, Ph.D., analyst at Decision Resources. "Although diagnosis rates and drug-treatment rates are currently quite low, small increases in these rates will have a significant impact on the overall market, and substantial increases in diagnosis or drug-treatment of this underdiagnosed and undertreated population would result in phenomenal expansion of this relatively sleepy market." The new Hepatitis C in China report also finds that China's therapeutic markets for HCV will remain a heavily cash-based economy and that new insurance schemes will not adequately cover therapies that cost more than five times the annual per capita income. Paradoxically, price cuts - implemented by the government or drug manufacturers - could expand the HCV market.  
"Price cuts to the more expensive regimens could help position these drugs in a more affordable price range for a large percentage of urban patients who are currently forced to accept a less-effective, cheaper therapeutic because the high cost of the best treatment regimens are beyond their means," continued Dr. Woolsey. [truncated] 
 

SAARC Nations Unprepared for Liver Disease Epidemic

http://www.thenews.com.pk/daily_detail.asp?id=34419

KARACHI: The people of South Asia, especially Pakistan, are unprepared for an epidemic of deadly liver diseases as there is not even a single liver transplantation centre in the country, warn medical experts.  During the annual meeting it was decided that a Liver Society of Saarc Countries should be formed to continue conducting awareness workshops and training programmes for post-graduate students.  The main focus of the society would be to set up working groups to conduct data gathering and collaborative research activities in the Saarc region and to utilise all expertise available towards betterment of patients with liver diseases. 

Speaking on the occasion, Prof. Wasim Jafri of the Aga Khan University Hospital (AKUH), President of Saarc Liver Society (SLS), said that prevalence rate of Hepatitis B and E in Pakistan was 4 to 5 percent while it was up to 7 percent for Hepatitis C. “This means that about 7.8 million people are vulnerable to hepatitis B and about 15 million to hepatitis C in Pakistan,” he noted. Liver diseases, including cirrhosis and cancer of liver, fatty liver disease, alcoholic liver disease and hepatitis co-infections were growing as a result of the junk food culture and contaminated water.

Prof. Jafri said it was the government’s responsibility to provide everyone with basic health facilities and that could only be possible if honest efforts were carried out. He informed that it was expected that liver transplantation facility would be available in AKUH in two to three years’ time. 

Prof. Y.K Chawla from PGMI, Chandigarh, said the primary objective of establishing the SLC was to halt the process of following Western recommendations and carry out research keeping the local needs and conditions in mind. He deplored the fact that even though morbidity and mortality rate on account of liver diseases was equivalent to that of heart attacks, it was not being given due attention. Experts concurred that the emphasis should be on vaccination, saying that Hepatitis B could be completely cured by vaccination. However, they said there was no treatment available right now for hepatitis C. As such, they said, the stress should be on preventive measures.  They also called for legislation of cadaver organ transplantation in the country. “One cadaver can save up to 12 human lives if organ transplantation is allowed,” they concluded. Dr. Saeed S. Hamid of AKUH and general secretary of SLC and Prof Zainul Abbas also spoke. 

The 3rd Liver Meeting of Saarc countries was held in Karachi from 1st to 3rd December 2006, in conjunction with the 6th Annual meeting of the Pakistan Society of Hepatology at the local hotel.  A group comprising foreign and local delegates also met Dr Ishratul Ibad, Governor of Sindh, to apprise him of the enormity of liver diseases in Pakistan and the region, and the difficulties in dealing with these issues effectively.

 

Closing Prison TattooParlours Can Only Cause Infectious Diseases to Spread Beyond Jails, Warns Leon Mar

http://www.thestar.com/NASApp/cs/ContentServer?pagename=thestar/Layout/Article_Type1&c=Article&cid=1164922265416&call_pageid=970599119419

Public Safety Minister Stockwell Day is facing a crucial and controversial decision on prison tattoo parlours that could reduce the rate of infectious diseases (like HIV and hepatitis C) not only among prisoners, but among the public at large. Evidence and experts suggest his choice is clear: Safer tattooing programs save money and lives and should be implemented in all prisons in Canada. But political decisions are rarely based on evidence alone.

Will this majority-seeking minority government let ideology get in the way? And will voters, who often do not see the link between prisoners' health and public health, let it happen?  In almost every country, HIV is more prevalent among prisoners than in the general population. In Canada, it's no different: People in prison are 30 times more likely to be infected with hepatitis C (HCV) and seven to 10 times more likely to be infected with HIV than people on the outside.

The lack of sterile tattooing equipment is partly to blame. As early as 1994, the federal Expert Committee on AIDS and Prisons (a Correctional Service Canada committee) recommended establishing safer tattooing programs to address this problem. Sadly, successive governments ignored both this and other recommendations aimed at stemming the alarming spread of blood-borne diseases in Canadian prisons.

Finally, in September 2005, CSC started a one-year pilot program for safer prison tattoo parlours, funded by the Public Health Agency of Canada. Tattoo shops were set up in six federal prisons, including a women's prison. The shops were run by prisoners and supervised by staff. Tattoos weren't allowed above the collarbone, below the wrists, or on the skull, and gang tattoos were forbidden.

Prisoners working in the shops received training in infection prevention and control practices, and were taught to be peer health educators. Now, the prison tattoo shops are closed; it's up to Ottawa to decide whether they're closed for good. Why, some may ask, can't we just stop tattooing from happening in prisons? Because prohibition has never worked, it's simply driven tattooing underground. As a result, prison tattooing is done secretly and quickly, often in unhygienic environments with makeshift inks and needles, such as sewing needles, paper clips and twist ties. Such practices increase the risk of HIV and HCV transmission and the spread of other blood-borne diseases, within the prison system.

This isn't just a problem for prisoners; it's also a problem for the public. When prisoners return to the community, the diseases they've acquired in prison come with them and are spread through sex, drug use and other behaviours. It follows that tattooing can and should be done safely, regardless of whether it's done in a downtown parlour or in a prison. It's a matter of public health.

Some will say it's fiscally irresponsible for governments to spend taxpayer dollars to pay for prisoners' tattoos. But the fact is, we'll either pay now or we'll pay later.  Each of the six safer prison tattoo pilot sites cost just more than $100,000 per year. But each case of HIV infection costs roughly $20,000 per year to treat; for each hepatitis C infection, it's $25,000. If even just five infections were prevented at each of the six sites, the pilot program will have paid for itself. The lesson here is: Safer prison tattoo programs now make sound economic sense by preventing much costlier public health expenses later.

What of the claim that putting more needles in prisons puts guards and other prison staff at risk? As Jim Motherall, a former prisoner turned prisoner-advocate, points out, if inmates really wanted to use needles as weapons, they could use the makeshift needles they have now, most of which are likely contaminated.

Besides, the fear of needle attacks is statistically unfounded. Between 1997 and 2002, Corrections Canada staff reported just 45 incidents of puncture injuries from prohibited, often improvised tattooing needles. All were accidental.

By eliminating the need to hide tattooing equipment, safer tattoo parlours arguably reduce the likelihood of such accidents. In doing so, the parlours prevent HIV or HCV transmission from prisoners to each other, to prison staff and, eventually, to the public. Prisoners are sentenced to serve time; they are not sentenced to be infected with fatal, transmissible diseases. The government has a chance to do the right thing, and Canadians should support it.

 

Licensing deal coup:  DRUG maker Biota will boost the size of its research team after signing a $102 million licensing deal yesterday for a possible treatment for hepatitis C.

http://www.news.com.au/couriermail/story/0,23739,20833516-3122,00.html

German pharmaceutical giant Boehringer Ingelheim bought into the early-stage drug deal knowing that it will reap huge rewards should it get a breakthrough treatment for the virus.

Hepatitis C has infected 4.1 million Americans where between 1-5 per cent of sufferers die from the complaint, according to figures produced by the US Centre for Disease Control.

Yesterday, Biota managing director Peter Cook said the agreement validated the company's ability to consistently deliver candidate drugs to major pharmaceutical companies.  As a result of the deal, Biota will add more than a dozen employees to its team of scientists working on Hepatitis C research.  A joint statement by both companies said Biota will get an up-front technology access fee as well as continuing research support. 

As a result of yesterday's sign-off, Biota and Boehringer Ingelheim will jointly develop and market an antiviral nucleoside.  Early research indicates the drug may inhibit the growth of an enzyme that replicates the Hepatitis C virus. 

The latest deal comes on top of a recent turnaround in Biota's fortunes.  Biota shares closed up 8¢ to $1.445 yesterday.

 

Arrow Therapeutics HCV Compound Enters Phase I

http://www.earthtimes.org/articles/show/news_press_release,26236.shtml

Arrow Therapeutics, the London based antiviral drug discovery and development company, has announced that it has initiated a Phase I study of A-831, a small molecule antiviral inhibitor of Hepatitis C infection. The study will evaluate the safety, tolerability and pharmacokinetics of single escalating doses of A-831 in healthy volunteers in the UK.  A-831 targets the NS5a protein, a novel mechanism of action, and is the first NS5a inhibitor to enter the clinic. Originating from Arrow's focused chemical library and optimised in-house, A-831 showed good safety and pharmacokinetics in preclinical studies and excellent potency in the replicon assay. A-831 is the first compound from Arrow's broad approach to the NS5a target. A further Arrow compound, also targeting the NS5a protein but of a completely different chemical structure, is expected to enter preclinical development shortly.

The urgent need for novel Hepatitis C inhibitors has been well documented, with an estimated 170 million sufferers worldwide. The current Standard of Care treatment (Pegylated Interferon + ribavirin) has a poor side effect profile and is only effective in around 50% of patients. As with HIV/AIDS, multiple drugs in combination therapy are likely to be needed to overcome drug resistance. The value of the Hepatitis C market was approximately US$ 2.2 billion in 2005 and is forecast to grow substantially to US$ 4.4 billion in 2010 and US$ 8.8 billion in 2015.

"The start of the first clinical trial for a compound from our Hepatitis C programme is a significant milestone for the company", said Ken Powell, CEO of Arrow. "From the inception of Arrow we have been committed to producing potent, innovative inhibitors of Hepatitis C and believe that compounds such as A-831 will bring us a step closer to successfully treating the huge number of patients suffering from the virus worldwide. Preclinical results for A-831 have been extremely encouraging and we look forward to this next stage of development for the compound, as well as the advancement of other compounds within our Hepatitis C programmes".

 

Egypt Launches 5-Year National Campaign Against HIV/AIDS, Hepatitis C Among Children   

http://english.people.com.cn/200611/24/eng20061124_324692.html

Egypt Thursday launched a five-year campaign to help the Egyptian children fight against the HIV/AIDS and Hepatitis C diseases.  Under the theme of uniting for children against AIDS and hepatitis C, the campaign was cosponsored by the Egyptian Ministry of Health and Population, the United Nations International Children's Emergency Fund (UNICEF) and U.S. Coca-Cola North and West Africa. 

Egyptian Minister of Health and Population Hatem el-Gabali told the launching ceremony in a pre-recorded speech that raising awareness among the public on means how the HIV virus transits is the most important thing for Egypt.

He said that his ministry has taken many measures to fight the HIV/AIDS epidemic including setting up a dedicated hot line, establishing special medical care units and spreading common knowledge on HIV/AIDS through all-level governments in the country.

As for hepatitis C, Gabali said about eight percent of Egypt's total population was estimated to have infected with the virus, which makes Egypt one of the worst-hit nations in the world by the hepatitis C disease. For her part, UNICEF Deputy Executive Director Rima Salah said that the time had come to help children confront with the HIV/AIDS epidemic.

"Every minute of every day, somewhere in the world, a child dies because of AIDS. And every day, there are nearly 2,000 new infections among children under 15," said Salah.  She explained that the Egyptian campaign would aim to reduce the number of young people living with HIV/AIDS, prevent mother-to- child transmission of HIV virus and extend provision of pediatric AIDS treatment to children needing it.  

According to a press release issued by the organizers, HIV prevalence remains low in Egypt's general population, which amounted to some 74 million by the end of 2005.  However, the number of newly-reported HIV cases in Egypt is on the rise, they said.  

Since 1986 when Egypt reported the first case of HIV/AIDS, a cumulative number of 2,115 has been reported to the Egyptian Ministry of Health and Population.  But the World Health Organization estimates that some 12,000 people are living with the HIV virus in Egypt.

 

Free AIDS/HIV tests on World AIDS Day

 

 

http://www.greeleytrib.com/article/20061122/FAMHE
World AIDS Day will be Friday, Dec. 1. Established by the World Health Organization in 1988, World AIDS Day serves to focus global attention on the devastating impact of the HIV/AIDS epidemic.  Weld County has the fastest growing HIV rate in the eight-county service region of the Northern Colorado AIDS Project. As of June 30, there were 130 people living with HIV or AIDS in Weld County. 

In October the Centers for Disease Control and Prevention revised the recommendations for HIV testing for the general public. CDC believes that everyone should know whether or not they are infected with HIV because there are important health benefits to this knowledge. People who are HIV negative can take steps to stay that way and those who are infected with HIV can get treatment to improve health and extend life. They can also change their behaviors in order to reduce the chance of passing the virus on to others. 

For the second year the Weld County HIV Task Force is offering free HIV testing on World AIDS Day for people at high risk of HIV. The testing will take place Friday, Dec. 1 from 2-6 p.m. at the Island Grove Treatment Center, 1260 H St. in Greeley. Appointments are recommended, as only a limited number of people can be tested. Call (970) 313-1138 to schedule an appointment. 

HIV testing is recommended for people who engage in high-risk behaviors such as injecting drugs or steroids, having sex for money or drugs, men having sex with men, having sex with an HIV-infected person, and sexual partners of IV drug/vitamin/steroid users. 

Hepatitis C testing will also be offered because many people who have been infected with HIV are also infected with Hepatitis C. The HIV testing will be free, as will the Hepatitis C testing, for people who are at high risk for HIV and/or Hepatitis C. 

The Northern Colorado AIDS Project (NCAP) will also be offering free HIV testing at two Larimer County locations on World AIDS Day. [truncated]

 

Bayer Diagnostics and Innogenetics launch Versant HCV Genotype 2.0 assay (LiPA) for HCV genotyping

http://www.medadnews.com/News/Index.cfm?articleid=393787

November 21, 2006 –Bayer HealthCare, Diagnostics Division, a member of the Bayer Group and Innogenetics N.V. announced today that the VERSANT® HCV (Hepatitis C Virus) Genotype 2.0 Assay (LiPA) has been released for sale in Europe. This next generation hepatitis C assay is an upgrade of Bayer’s VERSANT® HCV Genotype 1.0 Assay (LiPA), which is considered to be the most widely used assay for HCV Genotyping. In addition to its ability to accurately classify all major HCV genotypes (genotypes 1 to 6), the assay now also provides accurate identification of genotypes 6c-l (formerly known as genotypes 7, 8, and 9) and improves the identification of genotype 1a and 1b. These additions will permit improved therapy management of hepatitis C-infected patients. 

It is now widely accepted by clinicians that HCV genotyping is a key element in HCV treatment management1. Knowing which genotype and subtype a patient has is extremely important to physicians since each genotype responds differently to treatment1. The launch of the VERSANT HCV Genotype 2.0 Assay (LiPA) now provides correct and broader identification of HCV genotypes with improved subtype accuracy that was not possible by commercial HCV genotyping products until now. 

The combined CE-marked reagents: the VERSANT HCV Amplification 2.0 Kit (LiPA), VERSANT HCV Genotype 2.0 Assay (LiPA), and LiPA-Scan HCV Software provide easy to use products that minimize hands-on time and maximize results. The system is completed by the release of plasma based run controls in the VERSANT HCV Control 2.0 Kit (LiPA). 

Based on Innogenetics’ important intellectual property assets with respect to HCV genotyping, the new test was developed through a joint development agreement. Bayer has the exclusive worldwide rights for the sales and marketing of Innogenetics’ LiPA HCV products, while Innogenetics is responsible for the manufacturing of this product.  

“Bayer has proven to be a solid and reliable partner for the sale and marketing of Innogenetics LiPA HCV products. They successfully kept this LiPA-based product as the most widely used assay for HCV genotyping,” said Frank Morich, CEO, Innogenetics. “Bayer’s decision to develop an updated version, based on our established LiPA platform, is a further validation of our technology and know-how. We are confident that this next generation product resulting from our corporate partnership will achieve the same success.”  

“Bayer recognizes there is a tremendous unmet need for a more accurate detection and diagnosis of the hepatitis C virus. The addition of the next generation VERSANT® HCV Genotype 2.0 Assay (LiPA) to our portfolio will help provide better treatment regimes for those infected with the virus,” said Tony Bihl, President, Bayer Diagnostics. [truncated]

 

Thousands Unknowingly Infected with Hepatitis C 

http://www.ksl.com/index.php?nid=148&sid=646083

Fifty to sixty thousand people in Utah have an infection and most - probably 90 percent - don't even know they have it. While many were infected as long as 30 years ago symptoms are just now showing up.  It's like reading an insidious mystery. Imagine trying to read that mystery. You check out the book only to find the pages at the end are missing. You never find out when it happened or who did it!  

Kathy Stay is in her 30's, only to find out she contracted a virus a long time ago. When and how, nobody knows for sure.  Doctors told Tim O'Rourke he had picked up the virus probably when he was only 18-years old. "I was devastated. I went back to work and closed my office door and cried."  The list goes on, including people like Mick Worthen and Bruce Hatch who need to see health care workers all the time.

"The problem with the disease is it sneaks up on you. Twenty or 30 years, you don't notice you are losing energy and that you're getting anemic and fatigued, when it's just one day at a time."  A lot of people some 30 years later are just finding out they have Hepatitis C, now considered the number one blood borne virus in the world. Amber Jarrett says symptoms are often vague and overlooked. "People tend to dismiss the symptoms as just stress or a busy life."  

Twenty five percent of those infected get rid of it on their own, but 75 percent don't.  Tim's not a smoker, nor a drinker, doesn't shoot drugs. He has a family and a good job, and yet, Hep C suddenly triggered inside his body, and he now needs a liver transplant to survive. He tires easily, often using the lunch hour to take a nap in his car. Like Bruce Hatch, the virus attacked without warning.  

Amber Jarrett, Salt Lake Valley Health Department: "It's not unusual for somebody to actually get diagnosed and already have cirrhosis and have no symptoms."

Where and when did all these folks get infected? Thirty years ago it could have been contaminated mass immunizations in the military. Bruce Hatch was in Vietnam.  "Kind of an assembly line injections that they would give you, kind of like cattle going down the chute."  Tim was also in Vietnam, during the cleanup at the end of the war.  "Every time we landed on a tarmac or any given base in Thailand or whatever, some medic would come up and wouldn't let us off the plane until we got all the series of injections."  

And for Kathy, it could have been when she was a baby.  "I had a transfusion as a baby, and Hep C can be dormant for approximately 30 years."  People you wouldn't consider high risk for Hep C have it and are getting sick. That's why support groups are calling for more widespread routine screening and testing.

 

Drug in New Hepatitis C Clinical Trial
http://biz.yahoo.com/prnews/061114/sftu184.html?.v=2

BRISBANE, Australia, Nov. 14 /PRNewswire/ -- Physicians at Brisbane's Princess Alexandra Hospital have treated the first two patients in a clinical trial designed to test a new strategy for defeating hepatitis C viral infection, one of the toughest infectious diseases in the modern world.

Implicit Bioscience's drug, oglufanide, which works as a regulator of the body's immune response, is being given to patients with chronic hepatitis viral infection.  "The drugs currently in use fail to control this disease in about one half of all patients," said Dr. Ian Frazer, Implicit's Chief Scientific Officer. "So there is a compelling need for new and better therapies, and we hope that oglufanide may control or reverse the suppression of the immune system which the hepatitis virus uses to defeat our normally healthy defences."

Dr. Elizabeth Powell, who is the Principal Investigator for the trial which will be recruiting patients into 2007, welcomed the opportunity to study the action of oglufanide in her busy liver diseases clinic at the Princess Alexandra Hospital. "It is an important opportunity for patients to be involved in a new trial such as this, in which new treatment prospects are explored."

Oglufanide was originally developed to treat severe infectious disease in Russia (where it is a registered pharmaceutical), and was extensively studied in cancer clinical trials in the United States before being acquired by the privately-owned Brisbane biotech company Implicit Bioscience Pty Ltd in 2005. Oglufanide regulates the body's innate immune response to defeat invading germs and cancer cells. The drug is also under development by Implicit for severe respiratory diseases such as influenza (including pandemic disease) and ovarian cancer. Oglufanide has US Investigative New Drug status and Orphan Drug designation for cancer.

 

Cookbook Sales Support Hep C Study:  Book's creator targets cure, treatment

http://www.mlive.com/features/aanews/index.ssf?/base/features-0/1163605563246680.xml&coll=2

If you're looking for a holiday gift idea that also raises funds for a worthy cause, "Cooking Around the World'' is ready for purchase. Created by Ann Arborite Debbie Green, the cookbook's proceeds help fund Hepatitis C research at the University of Michigan.

The book's 500 some recipes are nicely organized into courses, and within those, main ingredient, making it easy to find a main dish beef recipe, for example. There are handy charts for feeding a crowd and roasting meat, as well as plenty of places to keep notes.  "Cooking Around the World'' is $15 (shipping is $3), although amounts given over the cost of the book are tax deductible.

 

Prisons make unhealthy cuts on hepatitis testing

http://www.freep.com/apps/pbcs.dll/article?AID=/20061113/OPINION01/611130305/1068/opinion

Depending whether you believe the state or outside experts, Michigan prisons hold 7,000 to 18,000 inmates infected with hepatitis C. That's 14-40% -- and most of them don't even know they have the disease.

Contagious and potentially fatal, hepatitis C attacks the liver. The prison epidemic affects everyone. Practically all of those infected -- more than 95% -- will go home, carrying their infections and health problems with them, and in some cases spreading them. As a public health problem, the level of hepatitis C in the prison system demands the attention of not only the Department of Corrections but also the Department of Community Health and the Legislature.

Lawmakers, however, have made a bad problem even worse. They cut most of the $5.9 million that Gov. Jennifer Granholm requested in 2004 to test and treat hepatitis C in prisons, and this year whacked the funding altogether. By not routinely testing for hepatitis C, the state is failing to meet U.S. Centers for Disease Control guidelines.

"They don't test regularly enough to find people before they have a permanently damaged liver," said David Santacroce, a University of Michigan law professor who filed a class action suit in 2003 on behalf of infected inmates. "We're seeing more and more cases of people who are too sick to be treated, and they're going to die.  "It's a death sentence."

Up to 40% of the nation's prisoners have hepatitis C, compared to 2% of the general population. The infection is spread through blood, and can be passed by needles shared to inject drugs or in tattooing, through unprotected sex and, before blood screenings began in 1992, by transfusions.

Truth be told, prison administrators don't want to know everyone who has hepatitis C, because that would pressure them to treat more inmates. Drug therapies with interferon and ribavirin cost more than $10,000 for each patient, though not every infected prisoner needs them. Still, the number of inmates getting drug therapies in Michigan prisons is ridiculously low -- only 125 inmates enrolled this year. Hundreds, possibly thousands, more need it. Left untreated, the only option is a liver transplant, which costs about $250,000 and is not done in Michigan prisons. 

Prison officials say they treat everyone identified as needing it. The department regularly evaluates 2,500 inmates known to have hepatitis C, said spokesman Russ Marlan. Still, medical records and lawsuits show dozens of cases where inmates were denied testing or treatment or not even notified that they had the disease. 

In one case handled by Santacroce, inmate Jeffrey Muller, now dead, was taken off a liver transplant list in 2001, after he supposedly tested positive for marijuana. But law students tracked down Muller's urine sample and, using DNA, found that the sample was not Muller's. 

Inmate Lionel Stewart, 54, serving 35-75 years for armed robbery, is another example of the oke-doke inmates say they get when trying to get treated. A college graduate, Stewart never made it to law school because he got hooked on heroin and robbed to feed his habit. He's up for parole in two years. 

Stewart said that his levels of ALT -- an enzyme produced in higher amounts when the liver is inflamed -- were high enough early this year to qualify for drug therapies, but then the department stopped testing him. Another prison doctor, he said, is trying to get him in treatment.  "She said that, if I don't get it, I'll die," Stewart told me last week in the visiting room of Deerfield Correctional Facility in Ionia. 

Another Ionia inmate, Randy Rodgers, 46, who's serving 7 to 20 years for home invasion and breaking and entering, said doctors predict he will die in two years from hepatitis C, which he may have contracted from injecting drugs or tattooing more than 20 years ago. Rodgers has been in and out of jail and prison six times, all for nonviolent offenses related to alcohol and drug abuse.  Rodgers has undergone two unsuccessful treatments in Michigan prisons for hepatitis C and wants to try a low-dosage drug therapy, but he said prison administrators wouldn't permit it.  "I've got nothing to lose," Rodgers said. "If I die, I die."  Rodgers is also trying to get a medical parole and ought to get it, especially considering his nonviolent record. 

No doubt, prison medical administrators have a tough job, trying to contain an epidemic without enough money. Still, Michigan's prison system should at least routinely test all high-risk inmates, especially injection drug users, and treat those with life-threatening symptoms. Blood tests for hepatitis C cost only $35. 

"Thousands of people in prisons are left to die without treatment," said Dr. Bennett Cecil of Louisville, Ky., a national expert on hepatitis C in prisons. "Cirrhosis of the liver is just as deadly as breast cancer, and we don't say we're not going to pay for that." 

The prison system could be the spot where the state starts to get a handle on hepatitis C by testing and treating inmates before they get out and return to their communities. But that's not going to happen with policies that are more focused on hiding than healing. 

 

Reinfection with Hepatitis C Stopped in drug users

http://www.medindia.net/news/view_news_main.asp?x=15614

Drug users, once infected with hepatitis C and battled off the infection appear to be shielded from future infections of the liver-killing virus according to a Canadian study.  WebMD.com said that Drug users in Vancouver, British Columbia were tested by University of British Columbia researchers for presence of Hepatitis C antibodies indicating presence of past infection. Drug users contract hepatitis C mainly through their habit of sharing needles during injection drug use.  WebMD.com said that further testing on the 658 hepatitis C-positive drug users showed that 506 had persistent infection and 152 had rid themselves of active virus.

According to the researchers if treatment-related clearance works similar to spontaneous clearance, future infection might be prevented, leading to big changes in treatment policy.  Although Canadian doctors hesitate to prescribe the treatment to active drug users, the Web site said that if drug users continue to drive the hepatitis C epidemic in developed countries, efforts to control it must include a strategy that addresses this particular population segment.

 

Vertex May Beat Roche, Merck on Drug for Hepatitis C

http://www.bloomberg.com/apps/news?pid=20601109&sid=alXXDRUwcAfE&refer=home

Vertex Pharmaceuticals Inc., a biotechnology company founded in 1989, may beat drugmakers from Roche Holding AG to Merck & Co. to produce the first medicine in a decade to treat hepatitis C, the main cause of liver cancer.  Vertex's drug, which the company plans to seek approval for in 2008, is one of several treatments in patient testing. The experimental medicines target the biological machinery the hepatitis C virus uses to thrive and draws on advances in gene science employed in the discovery of AIDS drugs. Researchers say the competing medicines may be combined someday, much as AIDS is treated by a so-called cocktail of drugs. 

Hepatitis C, identified only 17 years ago, infects as many as 200 million people worldwide and about 1 percent of the U.S. population. Symptoms of the blood-borne virus can take 20 years to emerge, and existing drugs help only about half of patients, doctors say. More effective treatments from Vertex, Merck, Roche, Novartis AG, Pfizer Inc. and Schering-Plough Corp. may generate $10 billion in annual sales, analysts say.

``We're at the dawn of a new era of advances in the field of hepatitis C,'' said Ira Jacobson, chief of gastroenterology and hepatology at Weill Medical College of Cornell University in New York. ``Several drugs may be the breakthroughs we are hoping for.''  

A hepatitis C health crisis is emerging worldwide as people progress to more severe stages of the disease since its discovery in 1989, doctors say. In poor countries, unscreened blood transfusions and re-use of needles that haven't been properly sterilized remain a main cause of infection. About 10,000 people die from hepatitis C each year in the U.S., approaching the 15,000 annual deaths from AIDS.

Human Genome Sciences Inc., Vertex, Roche, Novartis and Pfizer are among companies that reported results of experimental hepatitis C drugs this week at a meeting in Boston of the American Association for the Study of Liver Diseases.  Vertex may have the most potent treatment in a compound called telaprevir, researchers and analysts say. The shares gained 18 percent on Oct. 27 when the Cambridge, Massachusetts- based company announced study results at the start of the medical conference.  Shares of Vertex gained 43 percent this year before today on positive research data on the pill. The stock slipped 10 cents to $39.56 at 4:30 p.m. New York time in Nasdaq Stock Market composite trading.

The study showed that the pill, taken in combination with standard therapy, helped cut the virus to undetectable levels in half the time of standard therapy alone. Twelve weeks after ending treatment, five out of six patients still had undetectable levels of the virus.  ``The news is extraordinarily exciting,'' Geoffrey Porges, an analyst with Sanford C. Bernstein in New York, said in a telephone interview. ``It suggests the company has a drug that can transform the outlook for millions of patients with hepatitis C.''  Porges estimates Vertex's telaprevir can reach the market by 2009 and generate annual sales of $2 billion by 2011.

… The current standard of care for hepatitis C involves a yearlong course of injections with one of two interferon drugs, Schering-Plough Corp.'s Peg-Intron or Roche's Pegasys, combined with an older pill called ribavirin. Interferon is a natural human protein that can boost the immune system while ribavirin can reduce virus in the blood.  Injections are given weekly and can cause flu-like symptoms. Other side effects include depression, anemia and fatigue. The two interferon products generated a combined $2 billion in sales last year.

The most promising experimental medicines target the hepatitis C virus similar to ways AIDS drugs attack HIV, by blocking proteins the virus uses to reproduce inside the body.  Vertex's telaprevir blocks the protease enzyme the virus needs to reproduce. Schering-Plough, based in Kenilworth, New Jersey, is working on a similar drug known as SCH 503034. Both medicines are in the second of three stages of human testing needed for U.S. Food and Drug Administration approval. 

A drug from Basel, Switzerland-based Roche, called R1626, is from a class that inhibits polymerase, another key protein the virus uses to multiply. An early-stage study presented at the liver conference in Boston found it reduced the virus in hard-to- treat patients.  Novartis, also based in Basel, and Idenix Pharmaceuticals Inc., a Cambridge, Massachusetts-based biotechnology company, are testing a polymerase inhibitor called valopicitabine in the second of three phases of human trials. A study at this week's meeting found the drug combined with interferon lowered virus in the blood to undetectable levels after 24 weeks.  

Pfizer, based in New York, is working on a new drug called a pancaspase inhibitor that, instead of targeting the virus, is designed to protect the liver against damage from the infection.  Other companies developing new treatments for hepatitis C include Wyeth, ViroPharma Inc., InterMune Inc. and Abbott Laboratories, all based in the U.S.

``A cure for hepatitis C is what we're after, and it's a very robust environment right now,'' John M. Vierling, chief of hepatology at Baylor College of Medicine in Houston, said in an interview at the Boston meeting.

Better drugs may increase the market to $10 billion to $20 billion in sales annually, according to Ding Ding, an analyst with Maxim Group in New York. ``This is a race and there are a lot of companies involved,'' Ding said in an interview.

 

Patients Who Recover From Hepatitis C Have Lower Risk of Reinfection

http://www.docguide.com/news/content.nsf/news/852571020057CCF68525721A004CB12D

HOBOKEN, NJ -- November 2, 2006 -- A new study found that individuals who had tested positive for hepatitis C (HCV) but later tested negative for the virus were significantly less likely to become infected again compared to those who had never been infected, even though they had the same exposure risks.  The results of this study appear in the November 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). 

… Through a collaborative effort between Jason Grebely and Brian Conway of the University of British Columbia, Mark Tyndall of the BC Centre for Excellence in HIV/AIDS, the BC Centre for Disease Control, and Vancouver Coastal Health in Vancouver, a large community-based study was conducted comparing 926 individuals who tested negative for HCV during the recruitment period of the study between January 2003 and June 2004 with 506 individuals who had HCV, 152 of whom had spontaneous clearance of the virus. Clearance was considered to be the presence of HCV antibodies followed by at least one negative test for HCV. Using medical records, they then looked at the incidence of HCV infection between 1992 and 2005 in those who had antibodies but no detectable virus and those who tested negative in order to evaluate the effect of previous infection on reinfection rates. 

Although the two groups were similar in terms of the proportion of individuals engaging in illicit drug use, those previously infected were more likely to be engaged in frequent illicit drug use and IDU. Individuals who had tested positive for HCV, but subsequently tested negative were followed for an average of five years, compared to almost three years for those without previous HCV infection. 

The results showed that those with previous HCV infection and viral clearance were four times less likely to develop infection again than those infected for the first time, despite the fact that they had higher rates of HIV coinfection, illicit drug use and injection drug use. In fact, 90 percent of those reinfected continued to engage in illicit drug use, including 50 percent who reported IDU. 

"Our data lend support to the hypothesis that previous exposure to HCV may be protective, possibly on an immunologic basis, despite repeated exposure to HCV," the authors state. They propose two potential explanations for their results: those with HCV clearance are genetically predisposed to resist HCV infection and reinfection, or those previously exposed to HCV may be more experienced and have safer injection routines, which would have some protective value. 

The authors acknowledge some limitations in their study, such as the fact that HCV antibody tests have become more sensitive in recent years compared to the period from which the study looked at results and the fact that the study was retrospective, with testing being performed only by physician request, not systematically. However, they note that these limitations could easily be addressed in future prospective studies with systematic testing for HCV. 

The authors point out that treatment for HCV infection is often withheld from IDUs because of the supposed high risk of reinfection. "However, our data suggest that spontaneous clearance may confer some protection against re-infection," they write. "If protection against HCV infection extends to those who have cleared their viremia following antiviral therapy, it could provide a stronger rationale for expanding treatment programs for IDUs, including those who continue to be at risk for HCV exposure." Although further research is required, the present study indicates that since IDUs play such an important role in HCV transmission, strategies that address this group could have a significant impact on the HCV epidemic. 

REFERENCE:  "Hepatitis C Virus Reinfection in Injection Drug Users," Jason Grebely, Brian Conway, Jesse D. Raffa, Calvin Lai, Mel Krajden, Mark W. Tyndall, Hepatology; November 2006 (DOI: 10.1002/hep.21376).

 

Students at Unusual Risk of Contracting Hepatitis C, study says

http://www.statehornet.com/vnews/display.v/ART/2006/11/03/454b61b6319f1   

(WASHINGTON) - The next time you consider getting a tattoo or borrowing a roommate's toothbrush, you may want to think twice. Such behaviors put college students at risk for contracting Hepatitis C, according to a new study from Eastern Michigan University. 

The study also shows that students are unaware that many of their behaviors put them at especially high risk of contracting Hepatitis C, a disease of the liver that has no cure and can lead to chronic liver disease, cirrhosis and death.

Activities that can spread the disease include sharing needles during drug use, sexual contact, sharing earrings or having blood-to-blood contact with any object, like a toothbrush, carrying the blood of an infected person.  Symptoms of the disease include jaundice, fatigue, loss of appetite, nausea and vomiting.  

Although almost 4 million Americans have Hepatitis C, almost four times the number infected with HIV, most college students know very little about the disease.  Many university health service programs do not focus on Hepatitis C specifically because the disease is contracted in many of the same ways as HIV, said Pat Johnston, adviser for the Student Health Advisory Committee at the University of Maryland.

"Hepatitis C is a co-occurring disease with HIV," Johnston said. "Hepatitis C fits in with many of the same behaviors associated with contracting HIV."  University health programs respond to health concerns based on the demands of the student body, said Alli Matson, the Coordinator of Sexual Health Education Programs at the University of Maryland at College Park.

"There hasn't been a lot of demand for information on Hepatitis C," said Matson. "However, this department is a resource for all student health concerns."  

Some universities, including the University of Maryland, have taken steps to educate the student body on all types of diseases, including Hepatitis C.  After-hours hotlines, peer education groups, pamphlets, and open-door policies provide students with all types of health information and assistance.  Other universities have little to no information available on Hepatitis C, instead choosing to focus on diseases and conditions more well-known to the student body.

 

 

Clinical Trials, Cohort Studies, and Pilot Studies

 

Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial.  Everson GT, et al.  Hepatology. 2006 Dec;44(6):1675-84.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17133499&query_hl=8&itool=pubmed_DocSum

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon +/- RBV and had Ishak fibrosis scores >/= 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm(3) (n = 559); (B) bridging fibrosis with platelet counts </=125,000/mm(3) (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm(3) (n = 198); and (D) cirrhosis with platelet counts </=125,000/mm(3) (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these "difficult-to-cure" patients.

 

Relationship between the severity of hepatitis C virus-related liver disease and the presence of Helicobacter species in the liver: A prospective study.  Castera L, et al.  World J Gastroenterol. 2006 Dec 7;12(45):7278-84.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17143941&query_hl=8&itool=pubmed_docsum  

AIM: To determine the presence of Helicobacter species DNA in the liver of chronic hepatitis C (CHC) patients with and without cirrhosis as compared to controls, and to identify the bacterial species involved. METHODS: Seventy-nine consecutive patients (HBV and HIV negative) with a liver sample obtained after liver biopsy or hepatic resection were studied: 41 with CHC without cirrhosis, 12 with CHC and cirrhosis, and 26 controls (HCV negative). Polymerase chain reactions (PCRs) targeting Helicobacter 16S rDNA and species-specific were performed on DNA extracted from the liver. A gastric infection with H pylori was determined by serology and confirmed by (13)C-urea breath test. RESULTS: Overall, Helicobacter 16S rDNA was found in 16 patients (20.2%). Although positive cases tended to be higher in CHC patients with cirrhosis (41.6%) than in those without cirrhosis (17.0%) or in controls (15.4%), the difference was not statistically significant (P = 0.08). H pylori-like DNA was identified in 12 cases and H. pullorum DNA in 2, while 2 cases remained unidenti-fied. Gastric infection with H pylori was found in only 2 of these patients. CONCLUSION: Our results do not confirm the associ-ation of Helicobacter species DNA in the liver of CHC patients with advanced liver disease. The lack of correlation between positive H pylori serology and the presence of H pylori-like DNA in the liver may indicate the presence of a variant of this species.

 

Clinical significance of organ- and non-organ-specific autoantibodies on the response to anti-viral treatment of patients with chronic hepatitis C.  Gatselis NK, et al.  Aliment Pharmacol Ther. 2006 Nov 10; [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17094775&query_hl=8&itool=pubmed_DocSum

Background Development of organ- and non-organ-specific autoantibodies has been reported in hepatitis C virus patients treated with interferon-alpha plus/minus ribavirin. Aims To address whether prevalence and the titre of gastric parietal autoantibodies and non-organ-specific autoantibody in hepatitis C virus-treated patients were affected by therapy, and if the development of these antibodies carries any clinical significance on the response to treatment, as few studies in adults have been strictly designed to address the above hypothesis. Methods Samples at three time-points (baseline, end of treatment, end of follow-up) from 102 hepatitis C virus patients (39 sustained responders, 26 relapsers, 33 non-responders; four lost in follow-up) were studied for gastric parietal autoantibodies and/or non-organ-specific autoantibody by indirect immunofluorescence, commercial and in-house enzyme-linked immunosorbent assays. Results Sustained virological and biochemical response was associated with antinuclear antibody absence (end of treatment or end of follow-up), decrease of smooth-muscle antibody titres during therapy and gastric parietal autoantibodies negativity at baseline. However, after multivariate analysis only antinuclear antibody positivity at the end of treatment and increase of smooth-muscle antibody titres were associated with worst treatment response, independently of known factors of worst treatment outcome. Conclusions We were able to demonstrate a negative correlation between the efficacy of anti-viral treatment for hepatitis C virus and the presence of antinuclear antibody and smooth-muscle antibody before treatment, or their increase during therapy.

 

Differences in viral kinetics between genotypes 1 and 3 of hepatitis C virus and between cirrhotic and non-cirrhotic patients during antiviral therapy.  Medeiros-Filho JE, et al.  World J Gastroenterol. 2006 Dec 7;12(45):7271-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17143940&query_hl=8&itool=pubmed_docsum

AIM: To evaluate the impact of hepatitis C virus (HCV) infection with genotype 1 or 3 and the presence or absence of liver cirrhosis (LC) in the early viral kinetics response to treatment. METHODS: Naive patients (n = 46) treated with interferon-alpha (IFN-alpha) and ribavirin and followed up with frequent early HCV-RNA determinations were analysed. Patients were infected with genotype 1 (n = 28, 7 with LC) or 3 (n = 18, 5 with LC). RESULTS: The first phase decline was larger in genotype 3 patients than in genotype 1 patients (1.72 vs 0.95 log IU/mL, P < 0.001). The second phase slope decline was also larger in genotype 3 patients than in genotype 1 patients (0.87 vs 0.15 log/wk, P < 0.001). Differences were found in both cirrhotic and non-cirrhotic patients. Genotype 1 cirrhotic patients had a slower 2nd phase slope than non-cirrhotic patients (0.06 vs 0.18 log/wk, P < 0.02). None of genotype 1 cirrhotic patients had a 1st phase decline larger than 1 log (non-cirrhotic patients: 55%, P < 0.02). A similar trend toward a slower 2nd phase slope was observed in genotype 3 cirrhotic patients but the 1st phase slope decline was not different. Sustained viral response was higher in genotype 3 patients than in genotype 1 patients (72% vs 14%, P < 0.001) and in genotype 1 non-cirrhotic patients than in genotype 1 cirrhotic patients (19% vs 0%). A second phase decline slower than 0.3 log/wk was predictive of non-response in all groups. CONCLUSION: Genotype 3 has faster early viral decline than genotype 1. Cirrhosis correlates with a slower 2nd phase decline and possibly with a lower 1st phase slope decline in genotype 1 patients.

 

The prevalence and risk factors associated with esophageal varices in subjects with hepatitis C and advanced fibrosis.  Sanyal AJ, et al.  Gastrointest Endosc. 2006 Dec;64(6):855-864.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17140886&query_hl=8&itool=pubmed_docsum

BACKGROUND: The factors predictive of the presence or the absence of esophageal varices in hepatitis C virus (HCV) and advanced fibrosis have not been defined. OBJECTIVES: To define the prevalence of esophageal varices and the factors that are positively and negatively with such varices in hepatitis C and advanced fibrosis. DESIGN: A prospective study of esophageal varices and associated risk factors in subjects with hepatitis C and advanced fibrosis. SETTING: Prerandomization data from the HALT-C (hepatitis C long-term antiviral treatment against cirrhosis) clinical trial. PATIENTS AND INTERVENTION: Subjects with bridging fibrosis or cirrhosis, who were virologic nonresponders to treatment with pegylated interferon alpha 2a and ribavirin, underwent endoscopy. RESULTS: Sixteen percent of subjects with bridging fibrosis (95/598) and 39% of subjects with cirrhosis (164/418) had varices (P < .0001); 2% of subjects with bridging fibrosis (13/598) and 11% of those with cirrhosis (48/418) had medium or large varices. Subjects with bridging fibrosis and varices had a significantly lower platelet count and higher bilirubin and international normalized ratio (INR) compared with those without varices, suggesting that the biopsy may have underestimated the severity of fibrosis. A platelet count >150,000/mm(3) was associated with a negative predictive value of 99% for esophageal varices. By logistic regression modeling, African American race and female sex were protective, whereas a lower platelet count and higher bilirubin and INR predicted varices (c statistic, 0.758). CONCLUSIONS: The risk of having varices increases with decreasing platelet counts, increasing bilirubin, and INR. The probability of having medium or large varices at platelet counts >150,000/mm(3) is negligible in this population.

 

Heterozygous {beta} -globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis c.  Sartori M, et al.  Gut. 2006 Nov 29 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17135308&query_hl=8&itool=pubmed_DocSum

BACKGROUND: Iron accumulation is a well known risk factor for the progression of chronic hepatitis C (CHC) to fibrosis. However, the pro-fibrogenic role of the genes controlling iron homeostasis is still controversial. In this work we have evaluated the relative role of HFE, ferroportin, and beta-globin genes mutations in promoting iron accumulation and fibrosis in patients with CHC. METHODS: Genetic analysis was performed together with the assessment of hepatic iron content and histology in 100 consecutive HIV-Ab, HBsAg negative patients with biopsy-proven CHC. RESULTS: Among the patients investigated, 12 were heterozygous for various beta-globin gene mutations (39[C-->T], IVS1.1[G-->A], 22 7bp deletion and IVS1.6[T-->C]) and 29 carried HFE (C282Y, H63D and S65C) gene mutations. One further patient was heterozygous for both HFE (H63D) and beta-globin (39[C-->T]) variants, while 58 had the wild-type alleles of both the genes. Hepatic iron concentration and hepatic stainable iron were significantly higher (p<0.05) in CHC patients carrying beta-globin mutations than in those with HFE mutations or the wild-type alleles. Multivariate analysis confirmed that the presence of beta-globin mutations was independently associated with both hepatic iron concentration (p=0.008) and hepatic stainable iron (OR 6.11; 95%CI 1.56-23.92; p=0.009). Moderate/severe fibrosis or cirrhosis (Ishak's score>2) was observed in 48/100 patients. Logistic regression demonstrated that age (OR 1.05; 95%CI 1.02-1.09; p<0.005) and beta-globin mutations (OR 4.99; 95%CI. 1.22-20.3; p=0.025) were independent predictors of the severity of fibrosis. CONCLUSIONS: Heterozygosis for beta-globin mutations is a novel risk factor for both hepatic iron accumulation and the progression to fibrosis in CHC patients.

 

Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis.  Mazzaferro V, et al.  Hepatology. 2006 Dec;44(6):1543-54.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17133492&query_hl=8&itool=pubmed_DocSum

Tumor recurrence after resection of hepatocellular carcinoma (HCC) can occur early (<2 years) or late (>2 years) as metastases or de novo tumors. Interferon (IFN) has the potential for chemoprevention against hepatitis C virus (HCV)-related cirrhosis. A predetermined group of 150 HCV RNA-positive patients undergoing resection of early- to intermediate-stage HCC was stratified into 80 HCV-pure (hepatitis B anticore antibody [anti-HBc]-negative) and 70 mixed HCV+hepatitis B virus (HBV) (anti-HBc-positive) groups, then randomized to IFN-alpha (3 million units 3 times every week for 48 weeks [n = 76]) versus control (n = 74). The primary end point was recurrence-free survival (RFS); secondary end points were disease-specific and overall survival. Intention-to-treat and subgroup analysis on adherent patients were conducted. Treatment effects on early/late recurrences were assessed using multiple Cox regression analysis. No patient experienced life-threatening adverse events. There were 28 adherent patients (37%). After 45 months of median follow-up, overall survival was 58.5%, and no significant difference in RFS was detectable between the two study arms (24.3% vs. 5.8%; P = .49). HCC recurred in 100 patients (48 IFN-treated, 52 controls), with a 50% reduction in late recurrence rate in the treatment arm. HCC multiplicity and vascular invasion were significantly related to recurrence (P = .01 and .0003). After viral status stratification, while no treatment effect was apparent in the mixed HCV+HBV population and on early recurrences (72 events), there was a significant benefit on late recurrences (28 events) in HCV-pure patients adherent to treatment (HR: 0.3; 95% CI: 0.09-0.9; P = .04). In conclusion, IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV-pure patients receiving effective treatment.

 

Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosis.  Bugianesi E, et al.  Hepatology. 2006 Dec;44(6):1648-55.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17133473&query_hl=8&itool=pubmed_DocSum

Hepatic steatosis has been associated with fibrosis, but it is unknown whether the latter is independent of the etiology of fat infiltration. We analyzed the relationship between clinical characteristics, insulin resistance (HOMA-R) and histological parameters in 132 patients with "viral" steatosis caused by genotype 3 chronic hepatitis C (CHC-3) and 132 patients with "metabolic" steatosis caused by nonalcoholic fatty liver disease (NAFLD), matched by age, BMI, and degree of liver fat accumulation. Tests of liver function were comparable in the two study populations. The prevalence of features of insulin resistance was higher in NAFLD, as was HOMA-R (P = .008). Logistic regression analysis confirmed that steatosis was associated with a high viral load and low serum cholesterol in CHC-3, and with high aminotransferase, glucose, ferritin and hypertriglyceridemia in NAFLD. At univariate analysis, advanced fibrosis was associated with steatosis in NAFLD, but not in CHC-3. Other parameters related to fibrosis severity were HOMA-R and a low platelet count in CHC-3, and high aminotransferases, HOMA-R, ferritin and low HDL-cholesterol in NAFLD. On multivariate analysis, only low platelet count (OR = 0.78; 95% CI, 0.67-0.92) and HOMA-R (OR = 2.98; 1.13-7.89) were independent predictors of advanced fibrosis in CHC-3. In NAFLD, severe fibrosis was predicted by fat grading (OR = 3.03; 1.41-6.53), ferritin (OR = 1.13; 1.03-1.25) and HOMA-R (OR = 1.16; 1.02-1.31). In conclusion, insulin resistance is an independent predictor of advanced fibrosis in both NAFLD and CHC-3, but the extent of steatosis contributes to advanced disease only in NAFLD. Virus-induced hepatic steatosis as seen in CHC-3 does not contribute significantly to liver fibrosis.

 

Predicting sustained virological response and anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.  Snoeck E, et al.  Br J Clin Pharmacol. 2006 Dec;62(6):699-709.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17118125&query_hl=8&itool=pubmed_DocSum

Aim To assess the likelihood of a sustained virological response (SVR) vs. the likelihood of anaemia in patients with chronic hepatitis C. Methods Data from 1732 patients treated with peginterferon alfa-2a (40KD) plus ribavirin in two randomized, multinational studies were pooled. Probabilities of SVR and anaemia were modelled using the generalized additive logistic model, with numerous clinical variables considered for entry into the model. Baseline haemoglobin was only considered in the analysis for anaemia. Results The probability of anaemia increased from 6 to 16% as a function of the ribavirin dose kg(-1) (12-16 mg kg(-1)), whereas the relationship between SVR and ribavirin dose kg(-1) was influenced by hepatitis C virus (HCV) genotype. The probability of an SVR was not influenced by the ribavirin dose kg(-1) in patients with HCV genotype 2 or 3 infection, but increased as a function of ribavirin dose kg(-1) in patients with HCV genotype 1 infection (40-50% increase in probability of SVR for 12-16 mg kg(-1) dose ribavirin increase). The probability of an SVR in patients included with HCV genotype 1 decreased with increasing HCV RNA level to about 3 million copies ml(-1), but was relatively independent of increasing HCV RNA level thereafter. In addition, older age, a higher ribavirin apparent oral clearance and cirrhosis had a negative impact on achieving an SVR, but improved with increasing alanine aminotransferase (ALT) quotient. Sex and ribavirin dose kg(-1) were the most important prognostic factors for anaemia, followed by baseline haemoglobin, age, baseline ALT quotient and cirrhosis. Conclusion This study supports individualizing ribavirin dosages by HCV genotype and body weight, and highlights several clinical variables that influence the likelihood of an SVR compared with anaemia in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) plus ribavirin.

 

Peginterferon alpha-2b plus ribavirin for treatment of chronic hepatitis C with severe fibrosis: a multicentre randomized controlled trial comparing two doses of peginterferon alpha-2b.  Abergel A, et al.  J Viral Hepat. 2006 Dec;13(12):811-20.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109680&query_hl=8&itool=pubmed_DocSum

We compared sustained virological response (SVR) in chronic hepatitis C patients with severe fibrosis treated with pegylated interferon (Peg-IFN) alpha-2b 1.5 mug/kg/week or 0.75 mug/kg/week in combination with ribavirin 800 mg/day for 48 weeks. This was a multicentre randomized controlled study. SVR was observed in 44.5% (45/101) of patients treated with the standard dose of Peg-IFN and 37.2% (38/102) of patients treated with the low dose (NS). In patients with genotypes 1, 4 and 5, SVR was observed in 25.0% of patients who received the standard dose and 16.9% of patients who received the low dose of Peg-IFN (P = NS). In patients with genotypes 1, 4 and 5 and low viraemia, SVR was obtained in 27.3% of patients treated with the standard dose and 25.8% of patients treated with the low dose (P = NS). In the high-viraemia subgroup, SVR was obtained in 24.0% and 9.1% of patients, respectively. In patients with genotypes 2 and 3, SVR was similar in both groups (73.2%vs 73.0%). Thus, (1) patients with genotypes 2 and 3 and severe fibrosis can be treated with low dose of Peg-IFN and ribavirin, (2) this study suggests that patients with genotypes 1, 4 and 5 and high viraemia could receive a standard dose of Peg-IFN associated with ribavirin for 48 weeks, (3) side effects limit the efficacy of the treatment with standard dose of Peg-IFN in patients with genotypes 1, 4 and 5 and low viraemia, (4) more studies are needed for patients with genotype 2 or 3 to define the optimal duration (24 or 48 weeks) in patients with severe fibrosis.

 

Hepatis C virus transmission and its risk factors within families of patients infected with hepatitis C virus in southern Iran: Khuzestan.  Hajiani E, et al.  World J Gastroenterol. 2006 Nov 21;12(43):7025-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109499&query_hl=8&itool=pubmed_DocSum

AIM: To determine whether hepatitis C virus (HCV) infection of index cases increases intrafamilial transmission (sexual and nonsexual contacts) of HCV. METHODS: In a case-control descriptive study we enrolled 300-household contacts of 60 index cases (40 males and 20 females) of HCV infection and 360 pair-matched controls in Ahwaz JundiShapour University Hospitals from August 1, 1998 to September 1, 2003. The control group consisted of first time blood donors referred to the Regional Blood Transfusion Organization. Serum samples and demographic data and a medical history including the existence of risk factors for HCV (after a questionnaire on the risk factors for parenteral exposure) were obtained from each subject. Antibodies to HCV were detected employing a commercially available second-generation enzyme immunoassay (EIA, Abbott II). Positive serum specimens were retested using a second-generation recombinant immunoblot assay (RIBA-2) and a polymerase chain reaction for HCV RNA. Data analysis was carried out for intra-household clustering. RESULTS: Only 4 of 300 (1.33%) cases of household contacts without percutaneous risk factors were positive for HCV Ab while the remaining 296 family contacts were negative for anti-HCV. The mean age of the index cases was 28.4 (Std 15.22) years. The anti-HCV prevalences in parents, spouses, children of the index cases were 0.87% (1/115), 3.39% (2/59)) and 0.79% (1/126), respectively. Among couple partners negative for anti-HCV antibodies, the mean duration of the sexual relationship was 6 years. The two-couple partners positive for anti-HCV antibodies married the index cases for longer than 15 years. The prevalence of positive HCV Ab among household contacts (1.33%) was not significantly higher than that in the controls (1%) (P > 0.06). CONCLUSION: Intrafamilial transmission of HCV is not the significant transmission route and sexual transmission does not seem to play a role in the intrafamilial spread of HCV infection. Intrafamilial transmission of HCV is possible but occurs at a low rate.

 

Different doses of consensus interferon plus ribavirin in patients with hepatitis C virus genotype 1 relapsed after interferon monotherapy: A randomized controlled trial.  Alaimo G, et al.  World J Gastroenterol. 2006 Nov 14;12(42):6861-4.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17106937&query_hl=8&itool=pubmed_DocSum

AIM: To assess the efficacy of different schedules of consensus interferon (CIFN) plus ribavirin in retreating chronic hepatitis C patients who relapsed after recombinant interferon (rIFN) monotherapy. METHODS: Forty-five patients (34 males and 11 females) with chronic hepatitis due to hepatitis C virus (HCV) genotype 1 who relapsed after a previous course of rIFN monotherapy were randomized to receive 9 mug CIFN three times per week for 52 wk (group A, n = 22) or 18 mug CIFN three times per week for 52 wk (group B, n = 23) in combination with ribavirin 800 to 1200 mg daily for 52 wk (according to body weight). Virological response was evaluated at week 24 (EVR), at the end of treatment (ETR) and at 76 wk (SVR). RESULTS: By intention-to-treat analysis, subjects in group A had an EVR in 35% of cases, an ETR in 35% and a SVR in 27.3% of cases. Subjects in group B had an EVR in 32% of cases, an ETR in 35% and a SVR in 26.1% of cases. Treatment was stopped because of adverse effects (mostly intolerance) in 15 patients (6 in group A and 9 in group B). IFN dose reduction was needed in 2 patients (1 in group A and 1 in group B). Ribavirin dose was reduced in 2 patients in group A and 1 in group B respectively. Among the 15 subjects who received at least 80% of the intended schedule, the rate of SVR was 80% (6 in group A and 6 in group B). CONCLUSION: CIFN in combination with ribavirin when given to HCV genotype 1 relapsers after rIFN monotherapy obtains an unsatisfactory rate of sustained viral clearance independently of dosage of the drug. This may be due to its scarce tolerability.

 

Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C.  Yoshiji H, et al.  World J Gastroenterol. 2006 Nov 14;12(42):6786-91.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17106926&query_hl=8&itool=pubmed_DocSum

AIM: To evaluate the effect of combination treatment with the interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with refractory chronic hepatitis C (CHC). METHODS: Perindopril (an ACE-I; 4 mg/d) and/or natural IFN (3 MU/L; 3 times a week) were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed. RESULTS: ACE-I decreased the serum fibrosis markers, whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-I, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-beta was significantly attenuated almost in parallel with suppression of the serum fibrosis markers. CONCLUSION: The combination therapy of an ACE-I and IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

 

A 24-week course of high-dose interferon-alpha plus ribavirin for Taiwanese chronic hepatitis C patients with persistently normal or near-normal alanine aminotransferase levels.  Yu ML, et al.  Liver Int. 2006 Dec;26(10):1187-95.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17105583&query_hl=8&itool=pubmed_DocSum

We aimed to evaluate the efficacy, advantage, and safety of a 24-week regimen with high-dose interferon-alpha (INF-alpha; 6 million units thrice weekly) plus ribavirin (1000-1200 mg/day) combination therapy for 46 Taiwanese chronic hepatitis C (CHC) patients with persistently normal or near-normal alanine aminotransferase (PNALT) levels. Methods: Ninety-two age- and sex-matched CHC patients with elevated ALT levels (>2 times the upper limit of normal range) with a ratio of 1:2, treated with the same regimen, served as a control. Results: The sustained virologic response (SVR) rate was comparable between PNALT (67.4%) and elevated ALT (65.2%) groups (intention-to-treat analysis). The two groups had similar rates of discontinuation and incidence of adverse effects. Viral genotype 1b, baseline viral loads, body mass index, and age were significant factors negatively associated with SVR. Further decline of ALT levels throughout the follow-up period was observed in sustained responders of the PNALT group. None of the eight patients with ALT flares developed icteric hepatitis. The virologic efficacy was sustained in a 3-year extended follow-up period. Conclusion: high-dose INF-alpha with ribavirin combination therapy is effective, safe, and well tolerated in CHC patients with PNALT levels. The ALT assay might not be used as a single biochemical marker for determination of treatment consideration.

 

Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV.  Deterding K, et al.  J Hepatol. 2006 Dec;45(6):770-8. Epub 2006 Sep 22.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17034895&query_hl=8&itool=pubmed_DocSum

BACKGROUND/AIMS: The significance of hepatitis A virus (HAV) super-infection in patients with chronic hepatitis C had been a matter of debate. While some studies suggested an incidence of fulminant hepatitis A of up to 35%, this could not be confirmed by others. METHODS: We identified 17 anti-HCV-positive patients with acute hepatitis A from a cohort of 3170 anti-HCV-positive patients recruited at a single center over a period of 12 years. RESULTS: Importantly, none of the anti-HCV-positive patients had a fulminant course of hepatitis A. HCV-RNA was detected by PCR in 84% of the anti-HCV-positive/anti-HAV-IgM-negative patients but only in 65% of anti-HCV-positive patients with acute hepatitis A (p=0.03), indicating suppression of HCV replication during hepatitis A. Previous HAV infection had no effect on HCV replication. After recovery from hepatitis A, an increased HCV replication could be demonstrated for 6 out of 9 patients with serial quantitative HCV-RNA values available while 2 patients remained HCV-RNA negative after clearance of HAV throughout follow-up of at least 2 years. CONCLUSIONS: HAV super-infection is associated with decreased HCV-RNA replication which may lead to recovery from HCV in some individuals. Fulminant hepatitis A is not frequent in patients with chronic hepatitis C recruited at a tertiary referral center.

 

Direct and indirect evidence for the reversibility of cirrhosis.  Serpaggi J, et al.  Hum Pathol. 2006 Dec;37(12):1519-26. Epub 2006 Sep 25.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16997354&query_hl=8&itool=pubmed_DocSum

The aim of this study was to assess the reversibility of cirrhosis after therapy in a large series of patients with cirrhosis from various etiologies. We performed a retrospective study of 113 patients with biopsy-proven cirrhosis who underwent specific therapy and follow-up biopsies. Two pathologists performed blinded analyses of indirect biochemical and morphological signs of cirrhosis. Fourteen (12.4%) of the 113 cirrhotic patients had biopsy-proven disappearance of cirrhosis, defined as a decrease of 2 or greater in their METAVIR fibrosis score: 8 were related to hepatitis C virus, 3 to hepatitis B virus, and 3 to autoimmune cirrhosis. Necro-inflammatory activity decreased from 2.4 +/- 0.65 to 0.85 +/- 0.9 (P = .004), and fibrosis from 4 to 1.7 +/- 0.61 (P = .001). Prothrombin time (n = 1), platelet count (n = 2), serum albumin level (n = 2), and ultrasound abnormalities (n = 6) normalized in patients who had initial abnormalities. Hyaluronic acid and procollagen type III serum level decreased in all. In the 11 patients with regression of viral cirrhosis, 2 were nonresponders and 9 were responders, including 2 relapsers. The 3 patients with regressive autoimmune cirrhosis were complete responders to immunosupressive therapy. Using repeated liver biopsies, clinicobiochemical, radiologic, and endoscopic tests, we provide evidence for potential reversibility of cirrhosis after long-lasting suppression of the necro-inflammatory activity of liver disease.

 

Basic and Applied Science, Pre-Clinical Studies

 

Serendipitous identification of natural intergenotypic recombinants of hepatitis C in Ireland.  Moreau I, et al.  Virol J. 2006 Nov 15;3:95.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17107614&query_hl=8&itool=pubmed_DocSum

BACKGROUND: Recombination between hepatitis C single stranded RNA viruses is a rare event. Natural viable intragenotypic and intergenotypic recombinants between 1b-1a, 1a-1c and 2k-1b, 2i-6p, respectively, have been reported. Diagnostically recombinants represent an intriguing challenge. Hepatitis C genotype is defined by interrogation of the sequence composition of the 5' untranslated region [5'UTR]. Occasionally, ambiguous specimens require further investigation of the genome, usually by interrogation of the NS5B region. The original purpose of this study was to confirm the existence of a suspected mixed genotype infection of genotypes 2 and 4 by clonal analysis at the NS5B region of the genome in two specimens from two separate individuals. This initial identification of genotype was based on analysis of the 5'UTR of the genome by reverse line probe hybridisation [RLPH]. RESULTS: The original diagnosis of a mixed genotype infection was not confirmed by clonal analysis of the NS5B region of the genome. The phylogenetic analysis indicated that both specimens were natural intergenotypic recombinant forms of HCV. The recombination was between genotypes 2k and 1b for both specimens. The recombination break point was identified as occurring within the NS2 region of the genome. CONCLUSION: The viral recombinants identified here resemble the recombinant form originally identified in Russia. The RLPH pattern observed in this study may be a signature indicative of this particular type of intergenotype recombinant of hepatitis C meriting clonal analysis of NS2.

 

Small interfering RNA targeted to stem-loop II of the 5 untranslated region effectively inhibits expression of six HCV genotypes.  Prabhu R, et al.  Virol J. 2006 Nov 27;3(1):100 [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17129382&query_hl=8&itool=pubmed_DocSum

BACKGROUND: The antiviral action of interferon alpha targets the 5 untranslated region (UTR) used by hepatitis C virus (HCV) to translate protein by an internal ribosome entry site (IRES) mechanism. Although this sequence is highly conserved among different clinical strains, approximately half of chronically infected hepatitis C patients do not respond to interferon therapy. Therefore, development of small interfering RNA (siRNA) targeted to the 5UTR to inhibit IRES mediated translation may represent an alternative approach that could circumvent the problem of interferon resistance. RESULTS: Four different plasmid constructs were prepared for intracellular delivery of siRNAs targeting the stem loop II-III of HCV 5 UTR. The effect of siRNA production on IRES mediated translation was investigated using chimeric clones between the gene for green fluorescence protein (GFP) and IRES sequences of six different HCV genotypes. The siRNA targeted to stem loop II effectively mediated degradation of HCV IRES mRNA and inhibited GFP expression in the case of six different HCV genotypes, where as siRNAs targeted to stem loop III did not. Furthermore, intracytoplasmic expression of siRNA into transfected Huh-7 cells efficiently degraded HCV genomic RNA and inhibited core protein expression from infectious full-length infectious clones HCV 1a and HCV 1b strains. CONCLUSION: These in vitro studies suggest that siRNA targeted to stem-loop II is highly effective inhibiting IRES mediated translation of the major genotypes of HCV. Stem-loop II siRNA may be a good target for developing an intracellular immunization strategy based antiviral therapy to inhibit hepatitis C virus strains that are not inhibited by interferon.

 

Hepatitis C virus genotype 1b chimeric replicon containing genotype 3 NS5A domain.  Lanford RE, et al.  Virology. 2006 Nov 25;355(2):192-202. Epub 2006 Aug 21.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16919701&query_hl=8&itool=pubmed_DocSum

Infections with hepatitis C virus (HCV) genotype 3 exhibit differences in clinical phenotype including an increase in response to interferon therapy and development of steatosis. To initiate studies on genotype 3, we created a chimeric genotype 1b replicon containing a genotype 3a NS5A domain. The chimera was capable of efficient colony formation after the selection of a novel dominant adaptive mutation. Thus, domains from highly different strains can interact to form a functional replicase. A new genotype 1a replicon was constructed as well. Genotype specific influence on interferon sensitivity was examined using genotype 1a, 1b and chimeric 1b-3a replicons. The genotype 3a NS5A domain did not increase the sensitivity of the chimeric replicon to IFNalpha. The results suggest that NS5A is not sufficient to convey the increased IFNalpha response by genotype 3 or the replicon model is not capable of mimicking the events involved in increased sustained viral response.

 

Modulation of the immune response induced by gene electrotransfer of a hepatitis C virus DNA vaccine in nonhuman primates.  Capone S, et al.   J Immunol. 2006 Nov 15;177(10):7462-71.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17082666&query_hl=8&itool=pubmed_DocSum

Induction of multispecific, functional CD4(+) and CD8(+) T cells is the immunological hallmark of acute self-limiting hepatitis C virus (HCV) infection in humans. In the present study, we showed that gene electrotransfer (GET) of a novel candidate DNA vaccine encoding an optimized version of the nonstructural region of HCV (from NS3 to NS5B) induced substantially more potent, broad, and long-lasting CD4(+) and CD8(+) cellular immunity than naked DNA injection in mice and in rhesus macaques as measured by a combination of assays, including IFN-gamma ELISPOT, intracellular cytokine staining, and cytotoxic T cell assays. A protocol based on three injections of DNA with GET induced a substantially higher CD4(+) T cell response than an adenovirus 6-based viral vector encoding the same Ag. To better evaluate the immunological potency and probability of success of this vaccine, we have immunized two chimpanzees and have compared vaccine-induced cell-mediated immunity to that measured in acute self-limiting infection in humans. GET of the candidate HCV vaccine led to vigorous, multispecific IFN-gamma(+)CD8(+) and CD4(+) T lymphocyte responses in chimpanzees, which were comparable to those measured in five individuals that cleared spontaneously HCV infection. These data support the hypothesis that T cell responses elicited by the present strategy could be beneficial in prophylactic vaccine approaches against HCV.

 

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-{alpha} and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection.  Dolganiuc A, et al.  J Immunol. 2006 Nov 15;177(10):6758-68.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17082589&query_hl=8&itool=pubmed_DocSum

IFN-alpha production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-alpha-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-alpha production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-alpha production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-alpha and increased TNF-alpha and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-alpha and IL-10 induced apoptosis and inhibited IFN-alpha production in PDCs. Neutralization of TNF-alpha and/or IL-10 prevented HCV core-induced inhibition of IFN-alpha production. We identified CD14(+) monocytes as the source of TNF-alpha and IL-10 in the HCV core-induced inhibition of PDC IFN-alpha production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-alpha production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-alpha production. These mechanisms are likely to contribute to HCV viral escape from immune responses.

 

Equal amounts of intracellular and virion-enclosed hepatitis C virus RNA are associated with peripheral-blood mononuclear cells in vivo.  Kaiser P, et al.  J Infect Dis. 2006 Dec 15;194(12):1713-23. Epub 2006 Nov 13.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109344&query_hl=8&itool=pubmed_DocSum

Background. Hepatitis C virus (HCV) replicating in peripheral-blood mononuclear cells (PBMCs) may represent an extrahepatic viral reservoir. Quantitation of HCV RNA with regard to its subcellular distribution and longitudinal course is needed for better understanding of the largely unexplored in vivo dynamics and potential pathogenetic significance of HCV in PBMCs.Methods. Plasma and PBMCs from 30 patients coinfected with HCV and human immunodeficiency virus were evaluated in cross-sectional and longitudinal analyses, for up to 40 months. Differential extraction of virion-enclosed HCV RNA associated with cells was performed in parallel with extraction of total cellular HCV RNA. HCV RNA of either orientation was quantified by real-time polymerase chain reaction.Results. HCV RNA was detected only in PBMCs from patients with viremia and at relatively stable quantities over time. Intracellular HCV RNA corresponding to ~60% of total cellular HCV RNA was strongly correlated with virion-enclosed HCV RNA but was only weakly associated with viral loads in plasma. In contrast, the ratio of HCV RNA load in PBMCs versus that in plasma was patient specific and stable over time.Conclusions. The substantial and patient-specific amounts of intracellular HCV RNA found by the present study support a concept of low-level replication in PBMCs. There was no evidence for persistent HCV infection in PBMCs after clearance of viremia in plasma.

 

Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors.  Ikegashira K,  et al.  J Med Chem. 2006 Nov 30;49(24):6950-6953.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17125247&query_hl=8&itool=pubmed_DocSum

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo&lsqb;5,6&rsqb;&lsqb;1,4&rsqb;diazepino&lsqb;7,1-a&rsqb;indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.

 

Distinct cellular responses differentiating alcohol- and hepatitis C virus-induced liver cirrhosis.  Lederer SL, et al.  Virol J. 2006 Nov 22;3:98.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17121680&query_hl=8&itool=pubmed_DocSum

BACKGROUND: Little is known at the molecular level concerning the differences and/or similarities between alcohol and hepatitis C virus induced liver disease. Global transcriptional profiling using oligonucleotide microarrays was therefore performed on liver biopsies from patients with cirrhosis caused by either chronic alcohol consumption or chronic hepatitis C virus (HCV). RESULTS: Global gene expression patterns varied significantly depending upon etiology of liver disease, with a greater number of differentially regulated genes seen in HCV-infected patients. Many of the gene expression changes specifically observed in HCV-infected cirrhotic livers were expectedly associated with activation of the innate antiviral immune response. We also compared severity (CTP class) of cirrhosis for each etiology and identified gene expression patterns that differentiated ethanol-induced cirrhosis by class. CTP class A ethanol-cirrhotic livers showed unique expression patterns for genes implicated in the inflammatory response, including those related to macrophage activation and migration, as well as lipid metabolism and oxidative stress genes. CONCLUSION: Stages of liver cirrhosis could be differentiated based on gene expression patterns in ethanol-induced, but not HCV-induced, disease. In addition to genes specifically regulating the innate antiviral immune response, mechanisms responsible for differentiating chronic liver damage due to HCV or ethanol may be closely related to regulation of lipid metabolism and to effects of macrophage activation on deposition of extracellular matrix components.

 

Elicitation of strong immune responses by a DNA vaccine expressing a secreted form of hepatitis C virus envelope protein E2 in murine and porcine animal models.  Li YP, et al.  World J Gastroenterol. 2006 Nov 28;12(44):7126-35.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17131474&query_hl=8&itool=pubmed_DocSum

AIM: To characterize the immunogenicity of a hepatitis C virus (HCV) E2 DNA vaccine alone or with a protein vaccine boost in murine and porcine animal models. METHODS: A DNA vaccine expressing a secreted form of HCV E2 protein was constructed and used to vaccinate mice and piglets with or without boosting with a recombinant E2 protein vaccine formulated with CpG ODN and 10% Emulsigen. The immunogenicity of HCV E2 vaccines was analyzed by ELISA for antibody responses, MTT assay for lymphocyte proliferation, ELISPOT for the number of interferon-gamma secreting cells, and cytotoxic T lymphocyte assays. RESULTS: Intradermal injection of E2 DNA vaccine induced strong Th1-like immune responses in mice. In piglets, E2 DNA vaccine elicited moderate and more balanced immune responses. A DNA vaccine prime and protein boost vaccination strategy induced significantly higher E2-specific antibody levels and shifted the immune response towards Th2-like ones in piglets. CONCLUSION: A DNA vaccine expressing a secreted form of HCV E2 protein elicited E2-specific immune responses in mice and piglets. Recombinant E2 protein vaccination following DNA immunization significantly increased the antibody response in piglets. These HCV E2 vaccines may represent promising hepatitis C vaccine candidates for further investigations.

 

Genetic vaccination with Flt3-L and GM-CSF as adjuvants: Enhancement of cellular and humoral immune responses that results in protective immunity in a murine model of hepatitis C virus infection.  Encke J, et al.  World J Gastroenterol. 2006 Nov 28;12(44):7118-25.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17131473&query_hl=8&itool=pubmed_DocSum

AIM: To investigate whether transfection of plasmid DNA encoding these cytokines enhances both humoral and cellular immune responses to hepatitis C virus (HCV) in a murine model. METHODS: We established a tumor model of HCV infection using syngenic mouse myeloma cells stably transfected with NS5. Co-vaccination of DNA encoding granulocyte macrophage colony-stimulating factor (GM-CSF) and Flt-3 ligand together with a plasmid encoding for the HCV NS5 protein was carried out. Mice were sacrificed 14 d after the last immunization event with collection of spleen cells and serum to determine humoral and cellular immune responses. RESULTS: Co-vaccination of DNA encoding GM-CSF and Flt-3 ligand together with a plasmid encoding for the HCV NS5 protein induced increased antibody responses and CD4+ T cell proliferation to this protein. Vaccination with DNA encoding GM-CSF and Flt-3L promoted protection against tumor formation and/or reduction in mice co-immunized with cytokine-encoding DNA constructs. This suggests this strategy is capable of generating cytotoxic T lymphocyte activity in vivo. Following inoculation with plasmid DNA encoding Flt-3L, no increase in spleen size or in dendritic cell (DC) and natural killer cell numbers was observed. This was in contrast to a dramatic increase of both cell types after administration of recombinant Flt3-L in vivo. This suggests that vaccination with plasmid DNA encoding cytokines that regulate DC generation and mobilization may not promote unwanted side effects, such as autoimmunity, splenic fibrosis or hematopoietic malignancies that may occur with administration of recombinant forms of these proteins. CONCLUSION: Our data support the view that plasmid DNA vaccination is a promising approach for HCV immunization, and may provide a general adjuvant vaccination strategy against malignancies and other pathogens.

 

The protein kinase IKKepsilon can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers.  Vilasco M, et al.  Hepatology. 2006 Dec;44(6):1635-47.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17133498&query_hl=8&itool=pubmed_DocSum

During a viral infection, binding of viral double-stranded RNAs (dsRNAs) to the cytosolic RNA helicase RIG-1 leads to recruitment of the mitochondria-associated Cardif protein, involved in activation of the IRF3-phosphorylating IKKepsilon/TBK1 kinases, interferon (IFN) induction, and development of the innate immune response. The hepatitis C virus (HCV) NS3/4A protease cleaves Cardif and abrogates both IKKepsilon/TBK1 activation and IFN induction. By using an HCV replicon model, we previously showed that ectopic overexpression of IKKepsilon can inhibit HCV expression. Here, analysis of the IKKepsilon transcriptome profile in these HCV replicon cells showed induction of several genes associated with the antiviral action of IFN. Interestingly, IKKepsilon still inhibits HCV expression in the presence of neutralizing antibodies to IFN receptors or in the presence of a dominant negative STAT1alpha mutant. This suggests that good IKKepsilon expression levels are important for rapid activation of the cellular antiviral response in HCV-infected cells, in addition to provoking IFN induction. To determine the physiological importance of IKKepsilon in HCV infection, we then analyzed its expression levels in liver biopsy specimens from HCV-infected patients. This analysis also included genes of the IFN induction pathway (RIG-I, MDA5, LGP2, Cardif, TBK1), and three IKKepsilon-induced genes (IFN-beta, CCL3, and ISG15). The results show significant inhibition of expression of IKKepsilon and of the RNA helicases RIG-I/MDA5/LGP2 in the HCV-infected patients, whereas expression of TBK1 and Cardif was not significantly altered. In conclusion, given the antiviral potential of IKKepsilon and of the RNA helicases, these in vivo data strongly support an important role for these genes in the control of HCV infection.

 

In vitro antiviral activity of SCH446211 (SCH6), a novel inhibitor of the hepatitis C virus NS3 serine protease.  Liu R, et al.  J Antimicrob Chemother. 2006 Dec 5; [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17151003&query_hl=8&itool=pubmed_docsum

Background: Current hepatitis C virus (HCV) therapies may cure approximately 60% of infections. They are often contraindicated or poorly tolerated, underscoring the need for safer and more effective drugs. A novel, alpha-ketoamide-derived, substrate-based inhibitor of the HCV serine protease (SCH446211) was developed. Compared with earlier reported inhibitors of similar chemical class, it has a P1'-P2' extension which provides extended interaction with the protease active site. The aim of this study was to evaluate the in vitro antiviral activity of SCH446211. METHODS: Binding constant of SCH446211 to HCV NS3 protease was measured with the chromogenic substrate in vitro cleavage assay. Cell-based activity of SCH446211 was evaluated in replicon cells, which are Huh-7 hepatoma cells stably transfected with a subgenomic HCV RNA as reported previously. After 72 h of incubation with SCH446211, viral transcription and protein expression were measured by real-time RT-PCR (TaqMan), quantitative in situ hybridization, immunoblot and indirect immunofluorescence. RESULTS: The binding constant of SCH446211 to HCV NS3 protease was 3.8 +/- 0.4 nM. HCV replication and protein expression were inhibited by SCH446211 in replicon cells as consistently shown by four techniques. In particular, based on quantitative real-time RT-PCR measurements, the IC50 and IC90 of SCH446211 were estimated to be 40 +/- 20 and 100 +/- 20 nM (n = 17), respectively. Long-term culture of replicon cells with SCH446211 reduced replicon RNA to <0.1 copy per cell. SCH446211 did not show cellular toxicity at concentrations up to 50 microM. CONCLUSIONS: SCH446211 is a potent inhibitor of HCV protease in vitro. Its extended interaction with the HCV NS3 protease active site is associated with potent in vitro antiviral activity. This observation is potentially a useful guide for development of future potent inhibitors against HCV NS3 protease.

 

Modulation of the IL-12/IFN-{gamma} axis by IFN-{alpha} therapy for hepatitis C.  Byrnes AA, et al.  J Leukoc Biol. 2006 Dec 5; [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17148690&query_hl=8&itool=pubmed_docsum 

Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment of IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.

 

Involvement of PA28{gamma}-Dependent Pathway in Insulin Resistance Induced by Hepatitis C Virus Core Protein.  Miyamoto H, et al.  J Virol. 2006 Nov 29; [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17135326&query_hl=8&itool=pubmed_docsum

The hepatitis C virus (HCV) core protein is a component of nucleocapsids and a pathogenic factor for hepatitis C. Several epidemiological and experimental studies have suggested that HCV infection is associated with insulin resistance leading to type 2 diabetes. We have previously reported that HCV core gene-transgenic (PA28gamma(+/+)CoreTg) mice develop marked insulin resistance and that the HCV core protein is degraded in the nucleus through a PA28gamma-dependent pathway. In this study, we examined whether PA28gamma is required for HCV core-induced insulin resistance in vivo. HCV core gene-transgenic mice lacking the PA28gamma gene (PA28gamma(-/-)CoreTg) were prepared by mating of PA28gamma(+/+)CoreTg with PA28gamma-knockout mice. Although there was no significant difference in the glucose tolerance test results among the mice, the insulin sensitivity in PA28gamma(-/-)CoreTg mice was recovered to a normal level in the insulin tolerance test. Tyrosine phosphorylation of insulin receptor substrate (IRS)1, production of IRS2, and phosphorylation of Akt were suppressed in the livers of PA28gamma(+/+)CoreTg mice in response to insulin stimulation, whereas they were restored in the livers of PA28gamma(-/-)CoreTg mice. Furthermore, activation of the tumor necrosis factor alpha promoter in human liver cell lines or mice by HCV core protein was suppressed by knockdown or knockout of the PA28gamma gene. These results suggest that the HCV core protein suppresses insulin signaling through a PA28gamma-dependent pathway.

 

HIV/HCV Coinfection

 

Hepatitis C virus and non-Hodgkin's lymphoma: findings from the Swiss HIV Cohort Study.  Franceschi S, et al.  Br J Cancer. 2006 Dec 4;95(11):1598-602. Epub 2006 Nov 14.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17106439&query_hl=8&itool=pubmed_DocSum

Infections with hepatitis C virus (HCV) and, possibly, hepatitis B virus (HBV) are associated with an increased risk of non-Hodgkin's lymphoma (NHL) in the general population, but little information is available on the relationship between hepatitis viruses and NHL among people with HIV (PHIV). We conducted a matched case-control study nested in the Swiss HIV Cohort Study (SHCS). Two hundred and ninety-eight NHL cases and 889 control subjects were matched by SHCS centre, gender, age group, CD4+ count at enrolment, and length of follow-up. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using logistic regression to evaluate the association between NHL and seropositivity for antibodies against HCV (anti-HCV) and hepatitis B core antigen (anti-HBc), and for hepatitis B surface antigen (HBsAg). Anti-HCV was not associated with increased NHL risk overall (OR=1.05; 95% CI: 0.63-1.75), or in different strata of CD4+ count, age or gender. Only among men having sex with men was an association with anti-HCV found (OR=2.37; 95% CI: 1.03-5.43). No relationships between NHL risk and anti-HBc or HBsAg emerged. Coinfection with HIV and HCV or HBV did not increase NHL risk compared to HIV alone in the SHCS.

 

Negative-Strand Hepatitis C Virus (HCV) RNA in Peripheral Blood Mononuclear Cells from Anti-HCV-Positive/HIV-Infected Women.  Laskus T, et al.  J Infect Dis. 2007 Jan 1;195(1):124-133. Epub 2006 Nov 27.          

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17152016&query_hl=8&itool=pubmed_docsum

Background. Hepatitis C virus (HCV) has been reported to replicate in peripheral blood mononuclear cells (PBMCs), particularly in patients coinfected with HCV and human immunodeficiency virus (HIV). However, there are limited data regarding the prevalence of and the factors associated with extrahepatic replication. Methods. The presence of negative-strand HCV RNA in PBMCs was evaluated by a strand-specific assay for 144 anti-HCV-positive/HIV-infected women enrolled in the Women's Interagency HIV Study. One to 5 PBMC samples obtained from each woman were tested. Multivariate analyses were used to assess for associations with the clinical and demographic characteristics of the women. Results. Negative-strand HCV RNA was detected in 78 (25%) of 315 specimens, and, for 61 women (42%), >/=1 specimen was found to have positive results. The presence of negative-strand HCV RNA in PBMCs was significantly positively associated with an HCV RNA plasma level of >/=6.75 log copies/mL (P=.04) and consumption of >/=7 alcoholic drinks per week (P=.02). It was also negatively associated with injection drug use occurring in the past 6 months (P=.03). A negative association with a CD4(+)CD38(+)DR(+) cell percentage of >10% and a positive association with acquired immunodeficiency syndrome were borderline significant (P=.05). Conclusions. HCV replication in PBMCs is common among HIV-coinfected women and appears to be a dynamic process related to lifestyle, virologic, and immunologic factors.

 

Pretreatment assessment and predictors of hepatitis C virus treatment in US veterans coinfected with HIV and hepatitis C virus.  Backus LI, et al.  J Viral Hepat. 2006 Dec;13(12):799-810.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109679&query_hl=8&itool=pubmed_DocSum

The US Department of Veterans Affairs (VA) cares for many human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients. VA treatment recommendations indicate that all HIV/HCV-coinfected patients undergo evaluation for HCV treatment and list pretreatment assessment tests. We compared clinical practice with these recommendations. We identified 377 HIV/HCV-coinfected veterans who began HCV therapy with pegylated interferon and ribavirin and 4135 HIV/HCV-coinfected veterans who did not but were in VA care at the same facilities during the same period. We compared laboratory and clinical characteristics of the two groups and estimated multivariate logistic regression models of receipt of HCV treatment. Overall, patients had high rates of receipt of tests necessary for HCV pretreatment assessment. Patients starting HCV treatment had higher alanine aminotransferase (ALT), lower creatinine, higher CD4 counts and lower HIV viral loads than patients not starting HCV treatment. In the multivariate model, positive predictors of starting HCV treatment included being non-Hispanic whites, having higher ALTs, lower creatinines, higher HCV viral loads, higher CD4 counts, undetectable HIV viral loads and receiving HIV antiretrovirals. A history of chronic mental illness and a history of hard drug use were negative predictors. Most HIV/HCV-coinfected patients received the necessary HCV pretreatment assessments, although rates of screening for hepatitis A and B immunity can be improved. Having well-controlled HIV disease is by far the most important modifiable factor affecting the receipt of HCV treatment. More research is needed to determine if the observed racial differences in starting HCV treatment reflect biological differences, provider behaviour or patient preference.

 

Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic.  Mehta SH, et al.  AIDS. 2006 Nov 28;20(18):2361-9.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17117023&query_hl=8&itool=pubmed_DocSum

OBJECTIVE:: To evaluate predictors and trends of referral for hepatitis C virus (HCV) care, clinic attendance and treatment in an urban HIV clinic. DESIGN AND METHODS:: A retrospective cohort analysis in which 845 of 1318 co-infected adults who attended the Johns Hopkins HIV clinic between 1998 and 2003 after an on-site viral hepatitis clinic was opened, attended regularly (>/= 1 visit/year for >/= 2 years). Logistic regression was used to examine predictors of referral. RESULTS:: A total of 277 (33%) of 845 were referred for HCV care. Independent predictors of referral included percentage elevated alanine aminotransferase levels [adjusted odds ratio (AOR) for 10% increase,1.16; 95% confidence interval (CI), 1.10-1.22] and CD4 cell count > 350 cells/mul (AOR, 3.20; 95% CI, 2.10-4.90), while injection drug use was a barrier to referral (AOR, 0.26; 95% CI, 0.11-0.64). Overall referral rate increased from < 1% in 1998 to 28% in 2003; however, even in 2003, 65% of those with CD4 cell count > 200 cells/mul were not referred. One hundred and eighty-five (67%) of 277 referred kept their appointment, of whom 32% failed to complete a pre-treatment evaluation. Of the remaining 125, only 69 (55%) were medically eligible for treatment, and 29 (42%) underwent HCV treatment. Ninety percent of 29 were infected with genotype 1 and 70% were African American; six (21%) achieved sustained virologic response (SVR). Only 0.7% of the full cohort achieved SVR. CONCLUSIONS:: Although the potential for SVR and the recent marked increase in access to HCV care are encouraging, overall effectiveness of anti-HCV treatment in this urban, chiefly African American, HCV genotype 1 HIV clinic is extremely low. New therapies and treatment strategies are an urgent medical need.

 

Reduction in liver-related hospital admissions and deaths in HIV-infected patients since the year 2002.  Martin-Carbonero L, et al.  J Viral Hepat. 2006 Dec;13(12):851-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109686&query_hl=8&itool=pubmed_DocSum

Since the advent of highly active antiretroviral therapy (HAART), complications of chronic liver disease (CLD) have emerged as one of the leading causes of hospital admission and death among HIV-infected patients with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. The impact of CLD on hospital admissions and deaths in HIV-infected patients attended at one reference HIV hospital in Madrid during the last 9 years was analysed. All clinical charts from January 1996 to December 2004 were retrospectively examined. Demographics, discharge diagnosis, complications during inhospital stay and causes of death were recorded. A total of 2527 hospital admissions in 2008 distinct HIV-infected persons were recorded. Overall, 84% were iv drug users; mean age was 37 years and the mean CD4 count was 224 cells/muL. Both mean age and CD4 count significantly increased during the study period (P < 0.01). Overall, 42% of hospitalized patients were on antiretroviral therapy. Decompensated CLD was the cause of admission and/or developed during hospitalization in 345 patients (14%). Admissions caused by decompensated CLD increased significantly from 9.1% (30/329) in 1996 to 26% (78/294) in 2002. A significant steady decline occurred since then, being 11% (29/253) in the year 2004. Similarly, inhospital liver-related deaths were 9% (5/54) in 1996, peaked to 59% (10/17) in 2001 and declined to 20% (3/15) in the year 2004. Chronic hepatitis C was responsible for admissions and/or deaths in 73.5% of CLD cases. In conclusion, the rate of liver-related hospital admissions and deaths among HIV-infected patients peaked in the year 2002 and has steadily declined since then. A slower progression to liver cirrhosis in patients on HAART, avoidance of hepatotoxic antiretroviral drugs and more frequent use of anti-HCV therapy in HIV/HCV-coinfected patients could account for this benefit.

 

Complementary and Alternative Therapies

No entries.

 

MISCELLANEOUS
 
Occult hepatitis C virus infection: A new form of hepatitis C.  Carreno V.  World J Gastroenterol. 2006 Nov 21;12(43):6922-5.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109511&query_hl=8&itool=pubmed_DocSum 
Occult hepatitis C virus (HCV) infection is a new recently characterized entity. This occult infection can be present in two different clinical situations: in anti-HCV negative, serum HCV-RNA negative patients with abnormal liver function tests and in anti-HCV positive subjects with normal values of liver enzymes and without serum HCV-RNA. This review describes recent studies of occult HCV infection in both kinds of patients.
 
A single alcohol ingestion does not affect serum hepatitis C virus RNA in patients with chronic hepatitis C.  Manolakopoulos S, et al.  Liver Int. 2006 Dec;26(10):1196-200.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17105584&query_hl=8&itool=pubmed_DocSum 
Background and aim: The safe level of alcohol ingestion in sporadic drinkers with hepatitis C is unknown. Our aim was to evaluate the effect of a single moderate alcohol intake on serum HCV RNA concentrations and hepatic function in patients with chronic HCV infection. Methods: Twenty-one patients with chronic hepatitis C were randomly assigned to consume 50 g alcohol (group 1) or a non-alcoholic beverage (group 2). In both groups, serum ethanol, serum HCV RNA, transaminase and gamma-glutamyltranspeptidase (gamma-GT) levels were measured just before alcohol intake and after 1, 2, 8, 24 h and 1 week's time. Results: The maximum concentration of ethanol in the blood was observed at the first hour after alcohol intake. No significant changes were observed in serum HCV RNA after alcohol intake. Repeated measurements of HCV RNA among the two groups revealed no difference (P=0.215). Similarly, no difference was observed in transaminase and gamma-GT levels at different time points in each group or among the groups [(ALT (P=0.082), AST (P=0.33), gamma-GT (P=0.538)]. Conclusions: In patients with chronic hepatitis C, a single intake of 50 g alcohol does not affect liver biochemistry and HCV RNA concentrations. Therefore, it is a matter of further research whether sporadic drinking of light or moderate amounts of alcohol should be avoided in patients with chronic hepatitis C.
 
The hepatitis C virus epidemic in Cameroon: Genetic evidence for rapid transmission between 1920 and 1960.  Njouom R, et al.  Infect Genet Evol. 2006 Nov 28; [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17137845&query_hl=8&itool=pubmed_docsum 
Hepatitis C virus (HCV) infection in Cameroon is characterized by widespread seropositivity and great virus genetic diversity (3 genotypes and over 10 subtypes). A total of 244 HCV NS5B sequences of 382-405bp long (95 type 1, 58 type 2, and 91 type 4) were phylogenetically analyzed to estimate the history of the HCV epidemic in Cameroon. The newly developed Bayesian coalescent approach was used to infer the history of each HCV type. The estimated dates of the most recent common ancestors (MRCA) for genotypes 1 (1500; 95% confidence interval (95% CI): 1300-1650) and 4 (1500; 95% CI: 1350-1700) were in the same range, while the date for genotype 2 MRCA (1600; 95% CI: 1400-1750) was slightly more recent. The mean genetic distance between HCV genotype 1 sequences was greater than that of HCV type 4 sequences, itself greater than that of HCV type 2 sequences. The initial infected populations of all three genotypes did not grow until recently, when they grew exponentially. The growth rate has now begun to slow, with a less steep exponential growth curve. The period of exponential growth of all the three genotypes was between 1920 and 1960. These results (i) confirm that HCV genotypes 1 and 4 have produced long-term endemics, (ii) suggest that genotype 2 was introduced into Cameroon more recently, and (iii) indicate that the exponential spread of the three genotypes between 1920 and 1960 coincided with the mass campaign against trypanosomiasis and mass vaccinations in Cameroon.
 
Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy.  Del Rio RA, et al.  Hepatology. 2006 Dec;44(6):1598-606.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17133490&query_hl=8&itool=pubmed_DocSum 
In hepatitis C virus (HCV)-infected patients who develop anemia during combination therapy, erythropoietic growth factors maintain higher drug treatment levels compared to ribavirin dose reduction, which may lead to an increase in treatment response rates. This study estimated the cost-effectiveness of growth factor therapy in maintaining anemic HCV-infected patients on target drug levels during combination therapy. A decision analysis using a Markov model was developed with 7 health states: Sustained viral response, chronic HCV, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Data sources included population-based studies of growth factor therapy, previously published estimates of costs and natural history of hepatitis C, and recent prospective studies. Our reference case was a 45-year-old Caucasian man with HCV infection (genotype 1, 2, or 3) who developed anemia while undergoing combination therapy with ribavirin and pegylated interferon. We compared growth factor injections (darbepoetin alpha or epoetin alpha) during combination therapy with standard ribavirin dose reduction. Compared to a ribavirin dose reduction strategy, the cost of darbepoetin per additional quality-adjusted life-year was $34,793 for genotype 1 and $33,832 for genotypes 2 or 3 versus $60,600 and $64,311 for epoetin. For all genotypes, the results were sensitive to changes in the cure rates of HCV therapy, the utility of chronic HCV, the costs of growth factors, and the age at which therapy is begun. In conclusion, use of erythropoietic growth factors, specifically darbepoetin, for patients with anemia occurring during HCV combination therapy appears to be cost-effective for genotypes 1, 2, or 3.
 
Hepatitis C in people with mental illness: how big is the problem and how do we respond?  Seccull A, et al.  Australas Psychiatry. 2006 Dec;14(4):374-8. 
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17116075&query_hl=8&itool=pubmed_DocSum 
Objective: To review the evidence available on best practice care of people with both hepatitis C and mental illness and its application in a mental health service. Methods: A literature search was conducted for publications dealing with screening, referral for specialist review and antiviral treatment for this population group. Results: A small number of studies was identified that specifically dealt with screening and treatment for hepatitis C in people with mental illness. Conclusions: Screening, referral and treatment for hepatitis C in people with mental illness is worthwhile and achievable.
 
Impaired health-related quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels.  von Wagner M, et al.  J Viral Hepat. 2006 Dec;13(12):828-34.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17109682&query_hl=8&itool=pubmed_DocSum 
A significant impact of hepatitis C virus (HCV) infection on health-related quality of life (HRQOL) has been previously described. However, comprehensive data on the quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels (PNAL) are currently not available. One hundred fifteen patients with chronic hepatitis C (45 with persistently normal aminotransferases and 70 with elevated aminotransferases) and 50 healthy subjects were enrolled. Emotional and psychological states were assessed by Profile of Mood States (POMS) scale and HRQOL was assessed by the 'Everyday Life' questionnaire (EDLQ), a validated questionnaire related to the SF-36 Health Survey. An impairment in HRQOL was observed in patients with chronic hepatitis C showing PNAL compared with healthy subjects with significant differences for the factor scores depression and anger in the POMS scale as well as for the items body, relationship to partner, self-confidence and zest of life in the EDLQ. No differences in any questionnaire were observed between patients with chronic hepatitis C showing PNAL or elevated aminotransferase levels except of a worse mean level for factor score anger in POMS scale in patients with persistently normal aminotransferases. No association of quality of life with severity of liver disease was found. Impairment of HRQOL by chronic infection with HCV is similar in patients with PNAL and those with elevated aminotransferase levels.
 
Follow-up for medical care among drug users with hepatitis C.  Reynolds GL, et al.  Eval Health Prof. 2006 Dec;29(4):355-66.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17102060&query_hl=8&itool=pubmed_DocSum 
Prevalence of hepatitis C (HCV) in injection drug users (IDUs) is high and once HCV has been detected, follow-up medical care is essential. Six hundred and one current and former IDUs who tested positive for HCV antibodies received referrals for medical care. Twenty-four percent (147) of participants returned to be interviewed regarding their medical follow-ups. Of these, only 42% (61) had sought additional medical care in the form of further liver or blood tests or liver ultrasound. Four variables predicted seeking medical care: (a) ever being in residential drug treatment, (b) ever trading sex for money, (c) self-reported homelessness, and (d) living in one's own apartment or house. Having income from a job was inversely associated with seeking medical care. Knowledge of HCV infection alone does not mean that IDUs will seek medical care. Additional education concerning medical care and treatment options are needed to address IDU needs.
 
Cost-utility analysis of different peg-interferon alpha-2b plus ribavirin treatment strategies as initial therapy for naive Chinese patients with chronic hepatitis C.  Lin WA, et al.  Aliment Pharmacol Ther. 2006 Nov 15;24(10):1483-93.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17081165&query_hl=8&itool=pubmed_DocSum 
BACKGROUND: Different peg-interferon alpha-2b plus ribavirin treatment strategies are more effective in treating hepatitis C. However, no cost-effectiveness data have been published using the clinical data from the peg-interferon alpha-2b and ribavirin in the treatment of patients with hepatitis C in Taiwan. AIM: To estimate the cost-effectiveness of different treatments with peg-interferon alpha-2b plus ribavirin for the initial treatment of patients with different genotype chronic hepatitis C. METHODS: Individual patient level data from a randomized clinical trial with peg-interferon plus ribavirin were applied to a Markov model to project lifelong clinical outcomes. Economic estimates and quality of life were based on published data and Taiwan patient data. We used a societal perspective and applied a 3% annual discount rate. RESULTS: Compared with different combination therapy strategies, peg-interferon alpha-2b plus weight-based dosing of ribavirin in all patients for 24 weeks is the most cost-effective treatment strategy. If the sustained virological response of peg-interferon plus ribavirin treatment for 48 weeks therapy in genotype 1 patients was higher than 67.8%, the best strategy of treating patients will be the peg-interferon plus weight-based dosing of ribavirin therapy for 48 weeks in genotype 1 patients and for 24 weeks in non-genotype 1 patients. CONCLUSIONS: Peg-interferon alpha-2b plus ribavirin combination for 24 weeks therapy in all genotype patients should reduce the incidence of liver complications, prolong life, improve quality of life and be cost-effective for the initial treatment of chronic hepatitis C.
 
Combined Hepatitis C Virus (HCV) Antigen-Antibody Detection Assay Does Not Improve Diagnosis for Seronegative Individuals with Occult HCV Infection.  Quiroga JA, et al.  J Clin Microbiol. 2006 Dec;44(12):4559-4560. Epub 2006 Oct 4.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17021056&query_hl=8&itool=pubmed_DocSum 
A combined hepatitis C virus (HCV) antigen-antibody assay was evaluated for 115 seronegative individuals with occult HCV infection. The assay was reactive in one patient and negative to weakly reactive in three others (all four gave indeterminate results by supplemental assay) but failed to detect HCV in the remaining patients. Despite increased sensitivity the combined assay does not improve serodiagnosis of occult HCV infection.
 
Illness-related stigma, mood and adjustment to illness in persons with hepatitis C.  Golden J, et al.  Soc Sci Med. 2006 Dec;63(12):3188-98. Epub 2006 Sep 28.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17010490&query_hl=8&itool=pubmed_DocSum 
We examined stigma in persons with hepatitis C and its relationship with mood and adjustment to illness. We studied 87 persons awaiting interferon treatment for hepatitis C at St James's Hospital, Dublin. Stigma was assessed using Fife's Experience of Illness scale. A structured clinical interview was used to establish DSM-IV diagnosis. The Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory (BDI) were also used as measures of mood. Factor analysis and clustering around latent variables analysis were used to assess scale structure and reliability. The stigma scale had an overall reliability of 0.94. A strong dimension of fear of disclosure emerged, from item analysis, together with dimensions of social isolation and social rejection. Stigma was higher in those in manual occupations and the unemployed than in those in non-manual occupation. There were high levels in those with disease associated with injecting drug use and iatrogenic disease caused by transfusion or anti-D blood products, and low levels in those who had been treated for haemophilia with contaminated products or whose hepatitis was of unknown origin. Adjusted for confounders, a 1-decile increase in stigma score had an odds ratio of 1.4 for DSM-IV depression and similar associations with depression on the HADS and BDI. Stigma was also associated with poorer work and social adjustment, lower acceptance of illness, higher subjective levels of symptoms and greater subjective impairment of memory and concentration. These associations were replicated in the non-depressed subsample. The results underline the strong link between stigma and well-being in hepatitis C. However, they also suggest that stigma is a complex construct that will require further research to elucidate.