Making History: Eliminating Viral Hepatitis Disparities in the African American Community

February 10, 2012

By J. Nadine Gracia, MD, MSCE, Acting Director, Office of Minority Health, U.S. Department of Health and Human Services

Dr. J. Nadine Gracia

During February’s observance of African American History Month, please join us in working to end the unfortunate history of viral hepatitis’ disproportionate impact on the African American community. This Administration is working hard to reduce and eliminate health disparities and achieve health equity.

Unfortunately, viral hepatitis is a health problem that is often overlooked by the public as well as healthcare providers. This, despite the fact that viral hepatitis is a leading infectious cause of death, claiming the lives of 12,000–15,000 Americans each year. As many as 5.3 million Americans are living with viral hepatitis, though most do not know that they are infected. This places them at greater risk for severe, even fatal, complications from the disease and increases the likelihood that they will spread the virus to others.

What Is Hepatitis?
“Hepatitis” means inflammation of the liver. It is most often caused by a virus. In the U.S., the most common types are hepatitis A, hepatitis B, and hepatitis C. All of these viruses cause acute, or short-term, viral hepatitis. But the hepatitis B and C viruses (HBV and HCV) can also cause chronic hepatitis, in which the infection is prolonged, sometimes lifelong. Chronic hepatitis can lead to cirrhosis, liver failure, and liver cancer. In fact, viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation.

Viral Hepatitis Disparities
Within the African American community, significant hepatitis-related health disparities exist. For example:

Hepatitis B

• Hepatitis B can be prevented by a vaccine; however, African American children have lower HBV vaccination rates than non-Hispanic white children.
• Since 2004, rates of hepatitis B have remained steady among all racial/ethnic populations. However, new infections of hepatitis B remain the highest among African Americans, with 2.3 cases per 100,000 people.

Hepatitis C

• African Americans are twice as likely to be infected with hepatitis C when compared with the general U.S. population and chronic liver disease, often hepatitis C-related, is a leading cause of death among African Americans ages 45-64.
• While African Americans represent only 12% of the U.S. population, they make up about 22% of the chronic hepatitis C cases. In fact, African Americans have a substantially higher rate of chronic hepatitis C infection than do Caucasians and other ethnic groups.

Viral Hepatitis Action Plan
My Federal colleagues and I are committed to ensuring that new cases of viral hepatitis are prevented and that persons who are already infected are tested; informed about their infection; and provided with counseling, care, and treatment. In fact, last year we issued Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis (PDF 672KB), which outlined robust and dynamic steps that are now underway across the government to increase viral hepatitis awareness and knowledge among health care providers and communities, and improve access to quality prevention, care, and treatment services for viral hepatitis. (Read more about the Action Plan.)

In addition, the Viral Hepatitis Action Plan is both supported by and complements several other initiatives unfolding within HHS and across the Federal government, including the:

• The National HIV/AIDS Strategy, which helps us address the significant rates of HIV-HCV coinfection;
• The National Prevention Strategy, which calls for us to enhance early detection of HIV, viral hepatitis, and other sexually transmitted infections and improve linkage to care;
• The U.S. National Vaccine Plan, which will help us reduce the incidence of vaccine-preventable hepatitis A and B;
• The HHS Action Plan to Reduce Racial and Ethnic Health Disparities; and
• The infectious disease and immunization objectives of Healthy People 2020, which specifically seek to reduce new hepatitis A, B, and C infections and increase viral hepatitis awareness among infected persons.

Your Help Is Essential
These are all part of our response to the silent epidemic of viral hepatitis. But we need your help, too. So, during African American History Month, please help by learning more about viral hepatitis, educating family and friends about this silent killer in the African American community, and encouraging conversations with healthcare providers about vaccinations for hepatitis A and B and screening for hepatitis C for those who may have been exposed.

Together, we can make viral hepatitis history.

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Tenofovir: Q&A for Patients and Providers

February 10, 2012

Scientists at the San Francisco VA Medical Center and the University of California, San Francisco have published a study showing that one of the most effective and commonly prescribed antiretroviral medications for HIV/AIDS, tenofovir, is associated with a significant risk of kidney damage and chronic kidney disease that increases over time. See accompanying news release, Tenofovir, Leading HIV Medication, Linked with Risk of Kidney Damage.

What is the new finding about HIV/AIDS drugs and associated kidney problems?

Tenofovir, an anti-retroviral drug used to treat HIV, was associated with an increased risk of kidney disease in an observational study of 10,841 HIV-infected veterans who were new users of antiretroviral therapy between 1997 and 2007. The study found that tenofovir is associated with an elevated risk of kidney disease, even in persons without pre-existing risk factors for kidney disease, and that this toxicity to the kidney may not be reversible.

The study showed that for each year that a person uses tenofovir, there is a 34 percent higher risk of developing protein in the urine, which is an important sign of kidney damage; an 11% higher risk of rapidly declining kidney function, and a 33% higher risk of developing chronic kidney disease. These risks are all independent of the other factors that cause kidney disease, such as age, diabetes, hypertension, smoking, hepatitis C infection and HIV-related factors.

How much extra risk is this?

Overall in the study, the differences in risk between users and non-users of tenofovir each year were: 13% vs. 8% for protein in urine, which is an important marker of kidney damage 9% vs. 5% for rapidly declining kidney function; and 2% vs. 1% for developing chronic kidney disease. However, these numbers are based on the average risks in the study population, and patients with more risk factors for kidney disease would be put at proportionately higher risk when they use tenofovir.

Which drugs are we talking about?

In the study, the risk appeared to be unique to tenofovir. Other antiretroviral drugs showed weaker or inconsistent associations with kidney disease events, and none was associated with higher risk for even two of these three adverse kidney disease outcomes.

Should I stop taking these drugs if I am already taking them now?

This decision should be made on an individual basis, in consultation with your physician. The decision should involve weighing the risks/benefits and discussion of alternative treatment options. Tenofovir is an important component of effective antiretroviral therapy that you may need to control your viral load. If you remain on tenofovir, you may need more frequent monitoring of your kidney function and your level of urine protein. You are likely at increased risk of kidney disease if you have diabetes, high blood pressure, cardiovascular disease or hepatitis C. African Americans, Hispanics, Pacific Islanders, Native Americans and older adults are also at increased risk.

What are the symptoms of kidney problems? Should I be taking tests to monitor my kidney function?

Most people do not have any symptoms until their kidney disease is advanced. So, kidney disease is typically detected by screening tests of blood and urine.

Moving forward, what questions should I ask my doctors?

You should ask your doctor about whether you need routine monitoring of blood and urine samples to measure the following: serum creatinine, proteinuria, and microalbuminuria. You should also ask your doctor to calculate your estimated glomerular filtration rate (eGFR). You may want to have a discussion about alternative treatment options.

What about the prophylactic use of these drugs to prevent HIV progression and transmission?

A study of HIV pre-exposure prophylaxis (PrEP) using once-daily oral tenofovir was presented at the XVIII International Conference on AIDS (AIDS 2010), which included 323 men. This study found no indication of significant safety issues, including kidney problems or bone loss. However, this study may not have been large enough to detect increases in risk for kidney disease.

Where can I get more information?

You may get more information from HIV/AIDS websites such as Project Inform or HIV InSite. You can also contact your doctor if you have additional questions about your anti-retroviral medications or risk for kidney disease.

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How Reliable is Hepatitis B Vaccination in People Celiac Disease?

By Jefferson Adams Published 02/10/2012

Celiac.com 02/10/2012 - The HBV vaccine is usually effective against common hepatitis B virus (HBV) infection, with just 4-10% of vaccine recipients failing to respond to standard immunization. Some studies suggest that people with celiac disease may have high levels of resistance to the HBV vaccine, compared to the general population.

A team of researchers recently took a look at the issue of HBV vaccine reliability in people with celiac disease.

The study team included Mohammad Rostami Nejad, Kamran Rostami, and Mohammad Reza Zali. They are variously affiliated with the Research Center for Gastroenterology and Liver Disease at Shahid Beheshti University of Medical Sciences in Tehran, Iran, and with Acute Medicine at Dudley Group of Hospital in Dudley, UK. Together, they reviewed data from previous studies.

The ability to respond to recombinant HBV vaccine is associated with certain gene sites. At those sites, certain HLA haplotypes, such as B8, DR3, and DQ2 are common genetic markers among non-responders.

Since HLA genotypes play an important role in unresponsiveness to the HBV vaccine, and since 90-95% of people with celiac disease have HLA-DQ2, celiac disease may be a factor in this failure to respond to the HBV vaccine.

For one study, Ertekin et al., a research team gave HBV vaccinations, according to a standard immunization schedule, to 52 children with celiac disease, and another twenty matched for age and sex.

The average age of the celiac disease patients was 10.7 ± 4 years (range, 4-18 years). Anti-HBs titers were positive in 32 (61.5%) patients and negative in 20 (38.5%) patients, while they were positive in 18 (90%) of the children in the control group (P < 0.05).

The review team found statistically significant differences between negative anti-HBs titers, clinical presentation of CD, and dietary compliance in patients with CD (P < 0.05).
In all, 32 of the 52 children with celiac disease responded favorably to HBV vaccination. This was a substantially lower percentage that the 18 of 20 control subjects responded (P < 0.05).

Ertekin et al. concluded that a significantly higher percentage of children with celiac disease failed to respond to hepatitis B vaccination, as compared with the control group.

They concluded that response to the HBV vaccine in children with celiac disease should be investigated, and a different immunization schedule should be developed for them. They suggested that celiac children who follow a gluten-free diet may have a better immune response to the HBV vaccine.

The data fits with previous studies that confirm the findings that children with celiac disease fail to respond to the HBV vaccine at significantly higher rates than do healthy children.

In fact, the researchers point out a similar study on adults, Noh et al., revealed that, of 23 adults with celiac disease who had completed a full course of HBV vaccination, 19 tested positive for HBsAb and 13 failed to acquire proper long-term immunity.

Another study, by Stachowski et al., further cemented this connection between HLA and non-responsiveness to HBV vaccine. In that study, 34 out of 153 patients with end-stage renal disease failed to respond to HBV vaccine, and HLA-DQ2 was found almost exclusively in the non-responder group.

Long stretches of time between vaccination and antibody testing might be one reason even celiac disease patients who follow a gluten-free diet have significantly reduced post-vaccination levels of HBV antibody. Therefore, current guidelines recommend revaccinating celiac patients once they have established a reliable gluten-free diet.

This study was not designed to assess the presence of HLA-DQ2 and HLA-DQ8 in the groups. Therefore, future studies assessing HLA haplotypes in celiac disease should seek to describe the role of HLA typing in response to HBV vaccination.

The evidence indicates that early diagnosis of celiac disease, and treatment with a gluten-free diet may increase the overall percentage of patients responding favorably to the HBV vaccine.

Treatment of celiac disease with a strict, gluten-free diet seems to play a positive role in the development of antibody memory.

The review team points out that the high prevalence of celiac disease in the general population and a lack of response to HBV vaccine in untreated patients, invites routine assessment in patients with celiac disease receiving the HBV vaccine.

Lastly, the review team notes that non-responsiveness to HBV vaccine may indicate undiagnosed celiac disease or noncompliance with gluten-free diet.

SOURCE:
Hepat Mon. 2011 August 1; 11(8): 597–598.
doi: 10.5812/kowsar.1735143X.761

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New Molecule Has Potential to Help Treat Genetic Diseases and HIV

Chemists at The University of Texas at Austin have synthesized a molecule that can entangle itself in a specific sequence of DNA and stay attached for 16 days, longer than any other molecule reported.

Feb. 10, 2012

AUSTIN, Texas — Chemists at The University of Texas at Austin have created a molecule that's so good at tangling itself inside the double helix of a DNA sequence that it can stay there for up to 16 days before the DNA liberates itself, much longer than any other molecule reported.

It's an important step along the path to someday creating drugs that can go after rogue DNA directly. Such drugs would be revolutionary in the treatment of genetic diseases, cancer or retroviruses such as HIV, which incorporate viral DNA directly into the body's DNA.

"If you think of DNA as a spiral staircase," says Brent Iverson, professor of chemistry and chair of the department of chemistry and biochemistry, "imagine sliding something between the steps. That's what our molecule does. It can be visualized as binding to DNA in the same way a snake might climb a ladder. It goes back and forth through the central staircase with sections of it between the steps. Once in, it takes a long time to get loose."

Iverson says the goal is to be able to directly turn on or off a particular sequence of genes.

"Take HIV, for example," he says. "We want to be able to track it to wherever it is in the chromosome and just sit on it and keep it quiet. Right now we treat HIV at a much later stage with drugs such as the protease inhibitors, but at the end of the day, the HIV DNA is still there. This would be a way to silence that stuff at its source."

Iverson, whose results were published in September in Nature Chemistry, strongly cautions that there are numerous obstacles to overcome before such treatments could become available.

The hypothetical drug would have to be able to get into cells and hunt down a long and specific DNA sequence in the right region of our genome. It would have to be able to bind to that sequence and stay there long enough to be therapeutically meaningful.

"Those are the big hurdles, but we jumped over two of them," says Iverson. "I'll give presentations in which I begin by asking: Can DNA be a highly specific drug target? When I start, a lot of the scientists in the audience think it's a ridiculous question. By the time I'm done, and I've shown them what we can do, it's not so ridiculous anymore."

In order to synthesize their binding molecule, Iverson and his colleagues begin with the base molecule naphthalenetetracarboxylic diimide (NDI). It's a molecule that Iverson's lab has been studying for more than a decade.

They then piece NDI units together like a chain of tinker toys.

"It's pretty simple for us to make," says Amy Rhoden Smith, a doctoral student in Iverson's lab and co-author on the paper. "We are able to grow the chain of NDIs from special resin beads. We run reactions right on the beads, attach pieces in the proper order and keep growing the molecules until we are ready to cleave them off. It's mostly automated at this point."

Rhoden Smith says that the modular nature of these NDI chains, and the ease of assembly, should help enormously as they work toward developing molecules that bind to longer and more biologically significant DNA sequences.

"The larger molecule is composed of little pieces that bind to short segments of DNA, kind of like the way Legos fit together," she says. "The little pieces can bind different sequences, and we can put them together in different ways. We can put the Legos in a different arrangement. Then we scan for sequences that they'll bind."

Iverson and Rhoden Smith's co-authors on the paper were Maha Zewail-Foote, a visiting scientist in Iverson's lab who's now an associate professor and chairman of chemistry at Southwestern University in Georgetown; Garen Holman, another former doctoral student of Iverson's who did most of the experimental work before obtaining his Ph.D.; and Kenneth Johnson, the Roger J. Williams Centennial Professor in Biochemistry at The University of Texas at Austin.

For more information, contact: Daniel Oppenheimer, College of Natural Sciences, 512 232 0682; Brent Iverson, 512-471-5053

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FDA sets draft rules for biotech drug copies

By Deena Beasley

Thu Feb 9, 2012 4:46pm EST

(Reuters) - The Food and Drug Administration's long-awaited guidelines for the sale of lower-cost versions of biotechnology drugs leave open the possibility that some products might not need to be tested in humans.

The proposed rules, issued on Thursday, require studies showing that the generic copies are "highly similar" to the originals, but there are several ways that might be proven.

Because of their complexity, generic copies of biotech drugs - first introduced in the 1980s - are known as "biosimilars."

"We're trying to send the signal that it's not one-size-fits-all. It's product-by-product," Rachel Sherman, director of the FDA's office of medical policy, said during a conference call with reporters.

The worldwide market for copies of biotech medicines will grow to $3.7 billion by 2015, from just $243 million in 2010, as more than 30 branded biologics with sales of $51 billion lose patent exclusivity, according to market analysis firm Datamonitor.

The FDA rules would set "an abbreviated pathway" to approval that would consider factors including a product's complexity, formulation and stability, the agency said.

The proposal "reads largely as we expected, although a few points read as slightly more friendly to the generics industry," ISI Group analyst Mark Schoenebaum said in a note to clients.

The FDA said it would decide on the "extent and scope of animal and clinical studies" needed for approval once it has considered other analytical data. The agency said it has yet to receive an application for a biosimilar drug, but nine applications have been filed for clinical trials.

Manufacturers will have the option of asking the FDA to deem their copies "interchangeable" with a brand-name drug, but the `agency said that would require additional clinical studies.

Makers of branded biotech drugs have argued that full-scale human trials need to be conducted before a rival version of an existing biologic drug should be allowed on the market.

Despite such qualms, biotech drug makers including Amgen Inc, Merck & Co and Biogen Idec are working to produce rival versions of biotech drugs made by competitors.

"While the documents provide a roadmap, they are sufficiently vague as to give FDA leeway for case by case assessments of each proposed biosimilar along their respective development paths," said Wells Fargo analyst Brian Abrahams.

The Congressional Budget Office has estimated that the United States could save $25 billion from the use of biosimilars over 10 years.

European regulators have already approved cheaper versions of some biotech drugs.

The FDA said advances in science and manufacturing may facilitate fingerprint-like analysis of therapeutic protein products, which may allow for a more selective approach to any animal or human studies.

Unlike conventional, easy-to-replicate, chemical-based drug compounds, biotech drugs are derived from living organisms, such as proteins, and are often produced using recombinant DNA technologies.

Once a traditional pill loses patent protection, there is a quick regulatory pathway for generic drugmakers to sell much cheaper versions of the branded medicine. Similar U.S. guidelines for biotech drugs have been under negotiation for several years.

Biosimilar drugs are expected to sell at discounts of 25 to 45 percent to branded rivals, compared with generic versions of traditional pills that often sell for one-tenth the price of the branded product.

Under the U.S. healthcare reform law passed in 2010, brand-name biotech drugs - ranging from relatively simple molecules like insulin to complex antibodies used to treat cancer - were granted a 12-year period of market exclusivity, after which generic versions can be sold.

Opposing trade groups - the Biotechnology Industry Organization and the Generic Pharmaceutical Association - said they are reviewing the proposed rules.

The generic drugs group said it was pleased with the FDA's action, which it called "an important step in getting these affordable, lifesaving medicines into the hands of doctors and patients."

The FDA will require that biosimilar manufacturers provide a post-marketing safety monitoring program, which in some cases may include long-term clinical studies.

The agency is accepting public comment on the draft guidance documents for the next 60 days.

(Reporting by Deena Beasley in Los Angeles, Additional reporting by Bill Berkrot in New York and Anna Yukhananov in Washington; Editing by Gerald E. McCormick, John Wallace and Matthew Lewis)

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New mental health manual is "dangerous" say experts

By Kate Kelland, Health and Science Correspondent

LONDON | Thu Feb 9, 2012 2:24pm EST

LONDON (Reuters) - Millions of healthy people - including shy or defiant children, grieving relatives and people with fetishes - may be wrongly labeled mentally ill by a new international diagnostic manual, specialists said on Thursday.

In a damning analysis of an upcoming revision of the influential Diagnostic and Statistical Manual of Mental Disorders (DSM), psychologists, psychiatrists and other experts said new categories of mental illness identified in the book were at best "silly" and at worst "worrying and dangerous."

"Many people who are shy, bereaved, eccentric, or have unconventional romantic lives will suddenly find themselves labeled as mentally ill," said Peter Kinderman, head of Liverpool University's Institute of Psychology at a briefing in London about widespread concerns over the manual.

"It's not humane, it's not scientific, and it won't help decide what help a person needs."

The DSM is published by the American Psychiatric Association (APA) and has symptoms and other criteria for diagnosing mental disorders. It is used internationally and seen as the diagnostic "bible" for mental health medicine.

No one from the APA was immediately available for comment.

More than 11,000 health professionals have already signed a petition (at dsm5-reform.com) calling for the development of the fifth edition of the manual to be halted and re-thought.

Some diagnoses - for conditions like "oppositional defiant disorder" and "apathy syndrome" - risk devaluing the seriousness of mental illness and medical zing behaviors most people would consider normal or just mildly eccentric, the experts said.

At the other end of the spectrum, the new DSM, due out next year, could give medical diagnoses for serial rapists and sex abusers - under labels like "paraphilic coercive disorder" - and may allow offenders to escape prison by providing what could be seen as an excuse for their behavior, they added.

RADICAL, RECKLESS, AND INHUMANE

Simon Wessely of the Institute of Psychiatry at King's College London said a look back at history should make health experts ask themselves: "Do we need all these labels?"

He said the 1840 Census of the United States included just one category for mental disorder, but by 1917 the APA was already recognizing 59. That rose to 128 in 1959, to 227 in 1980, and again to around 350 disorders in the fastest revisions of DSM in 1994 and 2000.

Allen Frances of Duke University and chair of the committee that oversaw the previous DSM revision, said DSM-5 would "radically and recklessly expand the boundaries of psychiatry" and result in the "lexicalization of normality, individual difference, and criminality."

David Pilgrim of Britain's University of Central Lancashire said it was "hard to avoid the conclusion that DSM-5 will help the interests of the drug companies."

"Madness and misery exist but they come in many shapes and sizes," he said. "We risk treating the experience and conduct of people as if they are botanical specimens waiting to be identified and categorized in rigid boxes.

"That would itself be a form of collective madness for all those complicit in the continuing pseudo-scientific exercise."

Nick Craddock of Cardiff University's department of psychological medicine and neurology, who also spoke at the London briefing, cited depression as a key example of where DSM's broad categories were going wrong.

Whereas in previous editions, a person who had recently lost a loved one and was suffering low moods would be seen as experiencing a normal human reaction to bereavement, the new DSM criteria would ignore the death, look only at the symptoms, and class the person as having a depressive illness.

Other examples of diagnoses cited by experts as problematic included "gambling disorder," "internet addiction disorder" and "oppositional defiant disorder" - a condition in which a child "actively refuses to comply with majority's requests" and "performs deliberate actions to annoy others."

"That basically means children who say 'no' to their parents more than a certain number of times," Kinderman said. "On that criteria, many of us would have to say our children are mentally ill."

(Editing by Andrew Heavens)

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The trials of creating a hepatitis C vaccine

Oxford Clinical Trials

New research from the University of Oxford is using cutting-edge science to solve the problems associated with creating a hepatitis C vaccine

Hepatitis C is a problematic disease, for patient and clinician alike. In the UK, up to 500,000 people may be infected with the virus, and globally the World Health Organization believes the figure could be as high as 170 million people. Particularly troubling is the fact that the virus can go unnoticed for years, but during that time is capable of causing considerable liver damage.

But weight of numbers isn’t the only difficulty. In fact, perhaps the biggest barrier to creating an effective hepatitis C vaccine is the fact that the virus changes its appearance, making it hard to find a point to target in order to defeat it. “One of the big issues is the variability of the virus,” explains Dr Ellie Barnes form the Jenner Institute. “In fact, it’s ten times more variable than HIV.”

A team at the Jenner Institute led by Dr Barnes have, however, been working to create a vaccine that manages to target the small part of the virus that never changes. To do that, they captured roughly two thirds of the hepatitis C genome, and then attached it to rare adenoviruses -- essentially, strains of the common cold. By using rare adenoviruses, one of which was derived from chimpanzees, itself a world-first, the team could be sure that patients had never been exposed to them before -- a fundamental requirement for the vaccine to work.

As the team report in Science Translational Medicine, they have so far conducted a phase 1 trial in 41 patients, and the results are promising. In fact, the vaccine has been shown to produce a very strong immune response, which lasted a year, and had no major side-effects.

Prof Paul Klenerman, also of the Jenner Institute said: "The immune responses we've seen are exciting and we are beginning the next stage of trials. While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C."

The next step is to move the research forward into phase 2 trials, testing whether the vaccine can protect people who are at risk of contracting hepatitis C. In fact, those trials are already under development in the US, funded by the NIHR, and are due to commence in late 2012.

Read more in Science Translational Medicine

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New website: NIH Clinical Research Trials and You

For Immediate Release
Monday, February 6, 2012

Contact:
NIH Office of Communications
301-496-5787

Agency-wide resource provides important information for the public and health care providers

The National Institutes of Health has created a new website, NIH Clinical Research Trials and You to help people learn more about clinical trials, why they matter, and how to participate. From the first cure of a solid tumor with chemotherapy to the use of nitroglycerin in response to heart attacks, clinical research trials — or research studies involving people — have played a vital role in improving health and quality of life for people around the globe.

Clinical trials are essential for identifying and understanding ways to prevent, diagnose, and treat disease. Research has shown that among the greatest challenges to recruitment of volunteers is the lack of general knowledge about what trials involve, where they are carried out, and who may participate.

"The ability to recruit the necessary number of volunteers is vital to carrying out clinical research that leads to health and medical advances," said NIH Director Francis S. Collins, M.D., Ph.D. "This new, centralized resource will make it much easier for the public and health professionals to learn about clinical trials and how people can participate in them."

Visitors to the website will find information about:

• The basics of clinical trial participation
• First hand experiences from actual clinical trial volunteers
• Explanations from researchers
• Links on how to search for a trial or enroll in a research matching program

In addition, health care professionals can read about evidence-based strategies for talking with patients about trials, print audience-tested posters to help promote trials in clinics and offices, and find other educational materials.

NIH supports clinical research trials across the country and throughout the world. NIH’s ongoing effort to raise awareness about clinical research and educate potential clinical trial participants about the option of a clinical trial is vital to developing public support and understanding for how clinical research drives medical discovery and improves health outcomes.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Low-protein diets for hepatic encephalopathy debunked: let them eat steak

Nutr Clin Pract. 2011 Apr;26(2):155-9.

Cabral CM, Burns DL.

Gastroenterology, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805, USA. Chad.M.Cabral@Lahey.org

Abstract

Hepatic encephalopathy (HE) is an incompletely understood phenomenon and serves as a poor prognosis in patients with cirrhosis. Confusion from HE can affect the ability to eat adequately. Despite the prevalence of malnutrition in cirrhotic patients in the 1950s, it was reported that bouts of overt HE were controlled with low protein intake. This largely uncontrolled observation led to restriction of protein intake in cirrhotic patients with or without HE and was an accepted standard of care for many decades to follow. Published in 2004, the pivotal article "Normal Protein Diet for Episodic Hepatic Encephalopathy: Results of a Randomized Study" by Cordoba and colleagues was the first controlled study randomizing cirrhotic patients with HE to receive different amounts of dietary protein. At the completion of the study, the authors concluded that a normal-protein diet was safe and did not exacerbate HE. The Cordoba study suggests that low-protein diets should be abandoned. In light of this evidence, nutrition guidelines have proposed that protein restriction should be avoided in patients with HE as protein requirements are increased in cirrhosis. Despite the advice of experts in the field, it has been shown in recent years that some physicians still believe that protein restriction is needed in patients with HE. This belief has not been substantiated in controlled studies, and societal recommendations have changed. There is no real evidence documenting the advantages of protein restriction in HE. On the contrary, Cordoba and colleagues' article has shown that there are disadvantages to restricting protein in HE.

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Merck says hepatitis pill hampers HIV Drugs

By Ransdell Pierson

Thu Feb 9, 2012 2:37pm EST

(Reuters) - Merck & Co's recently approved Victrelis treatment for hepatitis C considerably lessens the effectiveness of some widely used medicines against the virus that causes AIDS, Merck and U.S. regulators said in separate reports.

"These drug interactions may be clinically significant for patients infected with both chronic hepatitis C virus and HIV by potentially reducing the effectiveness of these medicines when co-administered," Merck said in a February 6 letter to healthcare professionals.

Victrelis, approved last May, attacks the hepatitis C virus that over decades can lead to cirrhosis and liver failure. A significant percentage of hepatitis patients are also infected with the human immunodeficiency virus, or HIV, which weakens the immune system and is fatal without treatment.

The drug interactions were seen in a study among healthy volunteers who took Victrelis and the widely used HIV treatment Norvir in combination with one of three other anti-HIV pills: Reyataz (atazanavir), Prezista (darunavir) and Kaletra (lopinavir/ritonavir). All of the HIV drugs work by blocking protease, an enzyme the virus requires to replicate.

Victrelis reduced concentrations in the blood of Reyataz, Prezista and Kaletra by an average 49 percent, 59 percent and 43 percent, respectively.

Further, levels of Victrelis itself were reduced by 45 percent among volunteers who took it with Kaletra, and 32 percent among those who took it with a combination of Norvir and Prezista.

ISI Group analyst Mark Schoenebaum said 10 percent to 15 percent of patients with hepatitis C are co-infected with HIV, and the findings could crimp Victrelis sales by as much as 25 percent. But he said the setback would have little impact on Merck's earnings this year or in 2013.

The reduced prospects for Victrelis come even as its sales are being dwarfed by Vertex Pharmaceuticals Inc's Incivek, a rival protease inhibitor that was also approved last May.

The U.S. Food and Drug Administration, in an announcement of the findings that appeared on the agency's website on Wednesday, said patients should not stop taking any of their medicines without talking to healthcare professionals.

Drug interactions had previously been found between Victrelis and another HIV treatment called Sustiva (efavirenz). Sustiva belongs to a family of HIV drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Merck said it was conducting drug-interaction studies of Victrelis with other HIV drugs. They include Intelence (etravirine), which is also a NNRTI, and Isentress (raltegravir), which belongs to a class of drugs called HIV integrase inhibitors,

Merck shares slid 14 cents to $38.28 in afternoon trading on the New York Stock Exchange.

(Reporting By Ransdell Pierson; editing by John Wallace and Maureen Bavdek)

Source

Also See: Victrelis (boceprevir) and Ritonavir-Boosted Human Immunodeficiency Virus (HIV) Protease Inhibitor Drugs: Drug Safety Communication - Drug Interactions

When Will We Have Interferon-Free Treatment for Hepatitis C?

From Medscape Gastroenterology > Ask the Experts

William F. Balistreri, MD

Authors and Disclosures

Posted: 02/09/2012

Question:

Is it true that we are close to treatment of patients with chronic hepatitis C virus (HCV) infection with an interferon-free regimen?

Response from William F. Balistreri, MD
Professor of Medicine, University of Cincinnati College of Medicine; Staff Physician, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

A New Era of Therapy

Combination therapy with pegylated interferon (PEG-IFN) and ribavirin long stood as the standard of care for chronic hepatitis C virus (HCV) infection. Although effective in achieving high rates of sustained virologic response (SVR), this combination regimen was associated with troublesome side effects.^[1] Therefore, the development of 2 effective protease inhibitors -- telaprevir and boceprevir -- was hailed as a new era of therapy for patients with HCV genotype 1 infection.^[2] These direct-acting antiviral agents act at specific steps in the viral lifecycle and allow more effective treatment with a shorter duration.

Telaprevir and boceprevir, linear inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease, were approved by the US Food and Drug Administration for HCV treatment in May 2011. However, the recent American Association for the Study of Liver Diseases (AASLD) recommendations indicate that these direct-acting antiviral agents must be used in combination with PEG-IFN and ribavirin.^[1] This is far from the ideal regimen; because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until an IFN-free regimen is available.

An Ideal Strategy for HCV

It is true that an IFN-free regimen is "no longer a dream."^[3] It is now viewed as part of a larger goal: the development and validation of an ideal strategy to treat HCV infection. The long sought-after therapeutic objective is to define a strategy that would be highly effective against allHCV genotypes, simple (oral drugs only, low pill burden, and short duration), and safe and tolerable, with low rates of resistance emergence. The recommended strategy would also assess each potential treatment candidate for interleukin 28B genotype, which is a robust pretreatment predictor of SVR to therapy in patients with genotype 1 chronic HCV infection.^[1]

How close are we? Various compounds, encompassing at least 5 distinct drug classes, are currently under development for the treatment of chronic HCV infection, and the results of trials of several investigational agents were recently published.^[3-5] Many other drug trials were presented at The Liver Meeting 2011: The AASLD 62nd Annual Meeting. These drugs bring us one step closer to the long sought-after ideal: the ability to delete noisome IFN injections from treatment strategies.

Promising Preliminary Results

Let me illustrate by focusing on phase 2 studies presented by 2 groups who reported exciting preliminary results of an investigational agent (PSI-7977) even in the absence of IFN coadministration.^[6,7] PSI-7977, a uridine nucleotide analog polymerase inhibitor, is administered orally once daily and has strong antiviral activity against HCV genotype 1 when used in combination with PEG-IFN and ribavirin. A double-blind placebo-controlled dose-ranging study of PSI-7977 in patients with HCV genotype 1 documented a rapid virologic response (RVR) in 98% of patients, with an end-of-treatment response at 24 weeks in 91%.^[6] The RVR in the placebo group was 19%, and the end-of-treatment response was 50%. Of specific note, all patients with the difficult-to-treat interleukin 28B single-nucleotide polymorphism T/T mutation had an RVR -- all became HCV-negative by week 3, and 100% went on to achieve an SVR.

In another phase 2 study, this investigational compound allowed all patients to achieve an RVR. More than 80% of the treatment group had nondetectable HCV RNA at 2 weeks, and all patients had undetectable levels at 3 weeks.^[7] All patients achieved normalization of serum alanine aminotransferase levels. No serious adverse events were attributable to PSI-7977, and as expected, safety and tolerability were greatest in the IFN-free treatment group.

Thus, PSI-7977 exhibits high-potency antiviral activity against a broad range of HCV genotypes, has a high barrier to resistance, and has a reassuring safety profile. This drug also allowed a shorter duration of therapy for viral clearance. These studies support the continued exploration of this drug and related compounds -- alone, with other direct-acting antiviral agents, or with shorter duration of IFN therapy in patients with all HCV genotypes. Further studies will hopefully confirm the initial excitement and optimism and, of note, will document the spectrum of potential adverse effects.

Getting to IFN-Free Regimens

Within the next 5 years, IFN-free regimens may be a reality and available in the clinic. As Sharma and Lok^[3] stated, "[I]t is possible that some of these regimens will also be ribavirin free. This will be good news for patients who wish to be treated but have to defer treatment because of contraindications to use of PEG-IFN or ribavirin, or out of concerns about their ability to tolerate these medications." The ideal strategy is on the horizon.

References

1. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. Abstract
2. Jensen DM. A new era of hepatitis C therapy begins. N Engl J Med. 2011;364:1272-1274. Abstract
3. Sharma P, Lok AS. Interferon-free treatment regimens for hepatitis C: are we there yet? Gastroenterology. 2011;141:1963-1967.
4. Gane EJ, Roberts SK, Stedman CA, et al. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010;376:1467-1475. Abstract
5. Zuezem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology. 2011;141:2047-2055. Abstract
6. Lawitz E, Lalezar JP, Hassanein T, et al. Once-daily PSI-7977 plus PEG/RBV in treatment-naive patients with HCV GT1: robust end of treatment response rates are sustained post-treatment. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, Massachusetts. Abstract 225.
7. Gane EJ, Stedman CA, Hyland RH, et al. Once daily PSI-7977 plus RBV: pegylated interferon-alfa not required for complete rapid viral response in treatment-naive patients with HCV GT2 or GT3. Program and abstracts of The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting; November 9-13, 2011; Boston, Massachusetts. Abstract 34.

Source

Tocotrienols Reach Organs, Impart Clinical Benefits

EDISON, NJ— A recently published human study reported orally supplemented tocotrienols (as Tocomin SupraBio®, from Carotech) are distributed to various tissues and vital organs and produce significant clinical benefits. Half of end-stage liver disease patients given the supplement for 12 weeks had a reduced Model for End Stage Liver Disease (MELD) score, while only 20 percent of patients taking tocopherols (the regular vitamin E) had similar score reductions.

The trial was conducted by Chandan K. Sen, Ph.D., and his team from the Ohio State University Medical Center and registered at NIH's ClinicalTirals.gov website. The study was designed to determine the levels of vitamin E isomers in human tissues and vital organs following oral supplementation with Tocomin SupraBio, a patented and bioenhanced natural full spectrum palm tocotrienol softgel.

Among the 80 total study subjects, one group of healthy participants had blood and skin tests and were then given 400 mg/d Tocomin for 12 weeks, while another group of surgical patients provided tissue samples of cardiac muscle, liver, abdominal adipose tissues, and brain tissues, and were randomized to either 400 mg/d tocotrienols (Tocomin) or tocopherols for a mean supplement duration of 20 weeks (range: one to 96 weeks).

The researchers found the healthy subjects had negligible levels of tocotrienols in both blood and skin prior to tocotrienols supplementation; after 12 weeks of supplementation, blood and skin levels of tocotrienols increased. In addition, the observed alpha-tocotrienol concentration in blood was 20-fold higher than the amount required to provide neuroprotection. Further, the adipose tissue in tocotrienol supplemented patients contained approximately 10-times the tocotrienol levels, compared to controls. Tocotrienol supplementation also significantly increased alpha, gamma, and delta-tocotrienol levels in the human brain. According to the researchers, alpha-tocotrienol was transported to human brain at a concentration reported to be neuroprotective in earlier studies. In both heart muscle and liver, alpha, gamma, and delta-tocotrienol levels were significantly higher in tocotrienol supplemented patients as compared to subjects receiving tocopherol alone.

As far as health benefits, the researchers utilized the MELD scoring system, which is clinically used to assess the severity of chronic liver disease—the higher the MELD score, the more severe the condition and increased urgency for liver transplantation. They noted MELD score is a reliable marker for mortality in end-stage liver disease. Over the period of the study the researchers noticed that tocotrienols supplemented end stage liver disease patients experienced a reduction in their MELD scores. Among subjects supplemented with tocopherol alone, only 20 percent (one out of five) experienced reduced MELD score, while 50 percent (seven out of 14) of the tocotrienol supplemented subjects showed MELD score improvement.

In fact, MELD score reduction associated with tocotrienol supplementation was most evident in patients with viral hepatic cirrhosis: four out of six patients (67 percent) with hepatitis C and one single hepatitis B patient had reduced MELD score. Researchers noted standard of care therapy is available for viral hepatitis, but it is poorly tolerated due to its toxicity and side effects.

“It is very exciting to learn from this human study that oral supplementation of bioenhanced palm tocotrienol complex that Tocomin SupraBio, improves accumulation of tocotrienols in the blood, skin, adipose, brain, heart and liver," said WH Leong, VP of Carotech. "The study also shows that Tocomin SupraBio® significantly lowered the MELD score in end stage liver disease patients. and may therefore be an exciting oral supplement with potential to benefit these patients. Tocopherol again did not show the same level of efficacy." He further stated this human study also proved tocotrienols are absorbed and accumulated in vital human organs even in the presence of tocopherol, thereby unequivocally dispelling claims that tocopherol prevents the absorption of tocotrienols.

Editor's Note: For more information on tocotrienols, check out INSIDER's On-Demand webinar entitled, "Partner Series—Natural Vitamin E Tocotrienol in Neuroprotection and Stroke Prevention," as well as the INSIDER Tocotrienols Solution Center , which includes slideshows and video from the recent SupplySide workshop on tocotrienols.

Source

Victrelis (boceprevir) and Ritonavir-Boosted Human Immunodeficiency Virus (HIV) Protease Inhibitor Drugs: Drug Safety Communication - Drug Interactions

[Posted 02/09/2012]

AUDIENCE: Infectious Disease, Pharmacy

ISSUE: FDA notified healthcare professionals and patients that drug interactions between the hepatitis C virus (HCV) protease inhibitor Victrelis (boceprevir) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (atazanavir, lopinavir, darunavir) can potentially reduce the effectiveness of these medicines when they are used together.

A drug interaction study showed that taking boceprevir (Victrelis) with ritonavir (Norvir) in combination with atazanavir (Reyataz) or darunavir (Prezista), or with Kaletra (lopinavir/ritonavir) reduced the blood levels of the HIV medicines and boceprevir in the body (see Data Summary below). FDA will be updating the Victrelis drug label to include information about these drug interactions.

BACKGROUND: Victrelis is a hepatitis C virus (HCV) protease inhibitor used with the medicines peginterferon alfa and ribavirin to treat chronic (long-lasting) hepatitis C infection in adults. HIV protease inhibitors are a class of anti-viral drugs used to treat HIV infection. Ritonavir is an HIV protease inhibitor used to “boost” other HIV protease inhibitors, increasing their levels in the blood and making them more effective.

RECOMMENDATION: Patients should not stop taking any of their medicines without talking to their healthcare professional. Patients should contact their healthcare professional if they have any questions or concerns.

Healthcare professionals who have started patients infected with both chronic HCV and HIV on Victrelis and antiretroviral therapy containing a ritonavir-boosted protease inhibitor should closely monitor patients for HCV treatment response and for potential HCV and HIV virologic rebound.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

[02/09/2012 - Drug Safety Communication - FDA]

[02/06/2012 - Dear Healthcare Professional Letter - Merck]

Source

Chronic Liver Disease Foundation Issues Statement in Support of Birth-Cohort Screening for Hepatitis C

PRESS RELEASE

Feb. 9, 2012, 12:00 p.m. EST

Recommendations Include Expanded Testing with Rapid Point-of-Care HCV Test

CLARK, N.J., Feb 9, 2012 (GlobeNewswire via COMTEX) -- The Chronic Liver Disease Foundation (CLDF), a leading educational organization dedicated to increasing awareness of the effect of chronic liver disease (CLD) in the United States, issued today a position paper in support of expanding screening for hepatitis C (HCV) in the United States.

The position paper, "Endorsement of Birth-Cohort Approach to Expand Screening for Hepatitis C," outlines the CLDF's recommendations for a more effective strategy to identify patients with HCV infection and link such patients to expert care and treatment.

HCV is the most common blood-borne chronic viral infection in the U.S., with more than four million Americans currently infected with the HCV virus. Of these, up to 75 percent are unaware of their infection. Individuals born between the years of 1945 and 1965 have an HCV prevalence level four times higher than those born outside the birth cohort.

While the CDC currently recommends HCV screening only for individuals found to be at risk for the HCV infection, it is currently evaluating the potential benefits of using a birth-cohort based approach to HCV screening to help increase identification of HCV-positive patients.

The CLDF issued the following recommendations in support of the expansion of HCV screening efforts:

• Routine screening for HCV among persons born between 1945 and 1965
• Use of the OraQuick HCV rapid point-of-care test to expand testing opportunities and facilitate immediate care
• Educational programs aimed at primary care providers to increase awareness of HCV risk factors
• Testing for HCV in primary care setting with established linkages to HCV
• Creative ways to increase access to HCV testing and care for injection-drug users and other underserved populations.

"Today, more than 4 million Americans are infected with hepatitis C and the vast majority does not know it," said Dr. Willis C. Maddrey, President of the Chronic Liver Disease Foundation. "Hepatitis C is a leading cause of chronic liver disease, cirrhosis and liver cancer. However, new therapies are now available that can effectively treat a high percentage of people with HCV infection, making expanded and accessible testing for HCV -- particularly among those born between 1945 and 1965 -- a critical step in fighting this epidemic." 

About the Chronic Liver Disease Foundation

Established in 2001, the Chronic Liver Disease Foundation is a nonprofit 501(c)(3) educational organization dedicated to providing hepatology related continuing medical education, news and information to healthcare professionals across the US. The CLDF is led by a Board of Trustees comprised of nationally renowned liver disease specialists. Furthermore, the CLDF believes that educational programs should be developed by the specialists who are actively involved in the research, treatment and management of a disease. As such, the CLDF has developed a network of 75 Centers of Educational Expertise and multiple Advisory Boards who are actively involved in program creation related to specific disease topics which include: hemochromatosis, hepatic encephalopathy, hepatitis B, hepatitis C, hepatocellular carcinoma, HIV co-infection, liver transplantation and NASH/NAFLD. The CLDF's educational opportunities are offered in a variety of formats including an interactive web site, live meetings, teleconferences, print pieces, webcasts and other electronic mediums. For more information, please visit www.chronicliverdisease.org .

This news release was distributed by GlobeNewswire, www.globenewswire.com 

SOURCE: Chronic Liver Disease Foundation

        CONTACT: CLDF Media Contact:
        mediarelations@chronicliverdisease.org 
        888-565-5321
        
Source

Effect of Maintenance Therapy With Low-dose Peginterferon for Recurrent Hepatitis C After Living Donor Liver Transplantation

From Journal of Viral Hepatitis

Y. Ueda; H. Marusawa; T. Kaido; Y. Ogura; F. Oike; A. Mori; K. Ogawa; A. Yoshizawa; E. Hatano; A. Miyagawa-Hayashino; H. Haga; H. Egawa; Y. Takada; S. Uemoto; T. Chiba

Authors and Disclosures

Posted: 02/07/2012; J Viral Hepat. 2012;19(1):32-38. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n = 17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were −0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

Introduction

Cirrhosis and hepatocellular carcinoma caused by hepatitis C virus (HCV) infection is the leading indication for liver transplantation in Japan, the United States and western Europe. However, liver allograft infection with HCV following liver transplantation is universal, and almost all patients develop recurrent liver injury.^[1–6] The progression of recurrent hepatitis C is often accelerated and, without appropriate antiviral therapy, 10–25% of patients develop cirrhosis within 5 years after transplantation, resulting in poorer prognosis for HCV-positive recipients than HCV-negative recipients.^[7]

To prevent the progression of hepatitis C after liver transplantation, a combined therapy of pegylated interferon plus ribavirin is commonly administered.^[8,9] However, the efficacy of this combination therapy is limited: The mean sustained virological response (SVR) rate among patients with recurrent hepatitis C after liver transplantation was only 30% (range, 8–50%).^[10] Effective management of the remaining 70% of the patients who are unable to achieve SVR has not been established.^[11]

We recently reported the change in liver histology after combination therapy with interferon plus ribavirin in patients who have recurrent hepatitis C after living donor liver transplantations (LDLT). Among patients who did not achieve SVR, activity grade was not improved and fibrosis stage deteriorated. On the other hand, SVR was associated with reduced hepatic inflammation and suppression of liver fibrosis progression.^[12] Because the histological progression of non-SVR patients occurred mainly after interferon therapy was discontinued, we hypothesized that long-term, continuous interferon administration might be effective in slowing the progression of liver damage in these patients. Therefore, after our previous study, we prescribed a low-dose peginterferon maintenance therapy for non-SVR patients. Here, we evaluated the efficacy of this treatment by investigating long-term histological changes in these patients, as well as comparing them to the changes observed in SVR patients and non-SVR patients who did not receive maintenance treatment.

Methods

Eighty patients who had previously received the combination therapy with interferon and ribavirin (n = 40) or peginterferon and ribavirin (n = 40) for recurrent hepatitis C after LDLT at Kyoto University between January 2001 and April 2007 were retrospectively analysed.

Patients

Between March 1999 and December 2006, 141 patients with HCV-related liver diseases underwent LDLT at Kyoto University. Of these, 100 patients had been followed up for more than 6 months after LDLT in our hospital. Antiviral therapy was given to 80 patients with recurrent hepatitis C between January 2001 and April 2007. The remaining 20 patients did not receive the antiviral therapy because of no histological recurrence of hepatitis C in the follow-up period. To evaluate the histological progression caused by hepatitis C, patients who were diagnosed as having other causes of liver injury, such as biliary complications, chronic rejection, and de novo autoimmune hepatitis (AIH), were excluded. Patients who discontinued the treatment within 3 months because of worsening of liver function caused by hepatitis C were also excluded, because the rapid progression of these patients is not comparable to the long-term progression and inclusion of these patients would have led to overestimation of the progression in the patients who discontinued treatment. Patients were also excluded if they did not have a liver biopsy more than 2 years after the initiation of treatment, because this prevented an analysis of long-term histological changes.

Treatment Protocol and Definition of Responses to Treatment

After liver transplantation, patients with recurrent HCV liver disease underwent treatment with interferon–α–2b (3 or 6 mega units thrice weekly) plus ribavirin (400–800 mg/day orally) for the first 6 months. This was followed by interferon monotherapy for 6 months.^[12] This treatment protocol was employed between January 2001 through April 2004 inclusive. From May 2004 to April 2007, patients underwent combination antiviral therapy comprising peginterferon–α–2b (1.5 μg/kg body weight, weekly) and ribavirin (400–800 mg/day orally).^[13] Patients who became negative for serum HCV RNA within 12 months after initiating the treatment continued to receive the full (initial) dose for 8–22 months to achieve SVR; then, the treatment ended. Patients who were negative for serum HCV RNA for more than 6 months after completion of interferon therapy were defined as achieving SVR.

Patients who did not become negative for serum HCV RNA within 12 months of initiating the combination therapy, as well as patients who experienced a relapse after transient discontinuation of the treatment, continued to receive a low-dose peginterferon maintenance therapy (0.5–0.75 μg/kg of peginterferon-α-2b with or without ribavirin at 200 mg/day). Treatments occurred during the study period, May 2005–December 2009. During this time, the therapy was discontinued in patients with severe adverse events. Additionally, peginterferon treatments were discontinued when neutrophil and platelet counts fell below 500 and 30 000/μL, respectively, and ribavirin was discontinued when haemoglobin levels fell below 8 g/dL.

Histological Assessment

Liver biopsies were performed when patients' alanine aminotransferase (ALT) levels were more than twice the upper limit of normal, or at yearly intervals, with informed consent. Biopsy specimens were evaluated by two pathologists (H.H. and A.M.) with extensive experience in the pathology of liver transplantation. Necroinflammatory activity (A0–A3) and fibrosis stage (F0–F4) were assessed using METAVIR scores.^[14,15] Grading was defined as A0 (no activity), A1 (mild activity), A2 (moderate activity) or A3 (severe activity); staging was defined as F0 (no fibrosis), F1 (mild fibrosis), F2 (moderate fibrosis), F3 (severe fibrosis) or F4 (cirrhosis).^[14,15]

The following equations were used to analyse the histological changes:

1. Changes in activity grade = grade at final biopsy − grade at pretreatment biopsy, and
2. Changes in fibrosis stage = stage at final biopsy − stage at pretreatment biopsy.

Immunosuppression

Tacrolimus and low-dose steroid therapies were administered to induce immunosuppression.^[12,13,16] The lower limit of the target for whole blood tacrolimus level was 10–15 ng/mL during the first 2 weeks, 10 ng/mL during weeks 2–8 and 5–8 ng/mL thereafter. Four patients received cyclosporine microemulsions, rather than tacrolimus, to induce immunosuppression (Table 1). Steroid therapy was initiated at a dose of 10 mg/kg before graft reperfusion and then tapered from 1 mg/kg per day on the first day to 0.3 mg/kg per day until the end of the first month, followed by 0.1 mg/kg per day until the end of the third month. After that, steroid administration was terminated. Mycophenolate mofetil (MMF) was administered to patients who experienced refractory rejection or required reduction in tacrolimus or cyclosporine doses because of adverse events.

Virological Assays

Hepatitis C virus genotype was determined using a genotyping system based on polymerase chain reaction (PCR) of the core region using genotype-specific PCR primers.^[17] Serum HCV RNA load was evaluated once a month during treatment and 24 weeks after treatment, using PCR and an Amplicor HCV assay (Cobas Amplicor HCV Monitor; Roche Molecular Systems, Pleasanton, CA, USA).

Statistical Analysis

Wilcoxon and Kruskal–Wallis tests, chi-square tests and t-tests were used to analyse the continuous variables, categorical variables and histological changes, respectively. The Kaplan–Meier method was used to estimate the rates of patients who showed a progression of fibrosis to stage F3 or F4 after the initiation of the interferon therapy; log-rank tests were used to compare these rates among groups. Significance was defined as P < 0.05.

Results

Characteristics of Patients

Hepatitis C virus RNA concentrations and histological evidence were used to diagnose 80 patients with recurrent hepatitis C after LDLT. These patients were given one of two combination therapies: interferon and ribavirin (n = 40) or peginterferon and ribavirin (n = 40) at Kyoto University between January 2001 and April 2007. Thirty-one of the 80 patients who received the combination therapy achieved SVR (Fig. 1). Among the remaining 49 non-SVR patients, 23 (47%) received the low-dose peginterferon maintenance therapy, while 26 (53%) discontinued treatment within 12 months and did not receive low-dose peginterferon maintenance therapy as this was the patients' wish (n = 4), because of general fatigue (n = 4), recurrent hepatocellular carcinoma (n = 4), worsening of liver function (n = 3), biliary complications (n = 3), heart failure (n = 2), brain haemorrhage (n = 1), dementia (n = 1), sinusitis (n = 1), anaemia (n = 1), neutropenia (n = 1), and haemosputum (n = 1).

Figure 1. Flow diagram showing the outcome of interferon therapy for patients with recurrent hepatitis C after living donor liver transplantation and indicating the classification of patients in this study.

Of the 31 SVR patients, five were excluded because of chronic rejection (n = 3), biliary complications (n = 1) and de novo AIH (n = 1). Fifteen patients did not have liver biopsies more than 2 years after the initiation of the interferon therapy, mainly because liver function tests were normal. The remaining 11 patients were classified as the SVR group for analysis in this study. Among the 23 patients who received maintenance therapy, one patient with biliary complications and five patients who did not have liver biopsy more than 2 years after the initiation of therapy were excluded from the study. The remaining 17 patients were classified into the non-SVR-IFN group. Among the 26 patients who discontinued treatment within 12 months, three patients who initially experienced worsening of liver function were excluded because of the rapid progression of HCV; an additional three patients were excluded because of biliary complications. Eight patients were excluded because they had no liver biopsies taken more than 2 years after the initiation of the treatment. The remaining 12 patients were classified into the non-SVR-Withdrawal group. Cumulatively, we analysed the long-term histological changes of 40 patients: 11 in the SVR group (27.5% of the total), 17 in the non-SVR-IFN group (42.5% of the total) and 12 in the non-SVR-Withdrawal group (30% of the total).

There were no significant differences in the baseline characteristics among patients in the SVR, non-SVR-IFN, and non-SVR-Withdrawal groups (Table 1). The median age of patients at the beginning of therapy was 56.5 years (range, 15–70 years). The treatment started at a median of 9.5 months (range, 1.1–85.3 months) after LDLT. Thirty-five patients (88%) were infected with HCV genotype 1b. HCV genotypes of the remaining patients were 2a (n = 3), 2b (n = 1) and undetermined (n = 1). Median serum HCV RNA load was 2290 kIU/mL (range, 73.7–5000 kIU/mL); i.e. most patients had an extremely high viral load. Before the treatment, the necroinflammatory activity of all patients was A1 or greater, and 33 patients (83%) had a fibrosis score of F1 or greater. Among patients receiving tacrolimus for immunosuppression, the median serum trough level was 5.95 ng/mL (range, 3.3–10.9).

Effect of Maintenance Interferon Therapy on Liver Histology

To evaluate the efficacy of long-term peginterferon therapy on histological changes, we compared scores between final biopsy samples (median, 44.0 months; range, 24.0–81.3 months) and those taken prior to treatment. Five patients in the non-SVR-IFN group discontinued maintenance therapy between 26.5 and 53.1 months after the initiation of the treatment because of the adverse events. For these patients, the biopsies taken just before or within 3 months after discontinuation of the treatment were analysed as final biopsies. Despite the variation in time between pretreatment and final biopsy sample collection, there were no significant differences in the duration among the three groups (P = 0.547). Median duration from initiation of interferon therapy to final liver biopsy was 41.9 months (range, 24.0–81.3 months) in the SVR group, 41.7 months (range, 26.5–68.4 months) in the non-SVR-IFN group and 46.5 months (range, 30.4–79.6 months) in the non-SVR-Withdrawal group.

There were no significant differences in baseline activity grades or fibrosis stages of patients in the three treatment groups when they were first diagnosed with recurrent hepatitis C (Table 1). However, there were noticeable differences among the three groups by the end of treatment (Fig. 2a). The activity grade of all patients in the SVR and non-SVR-IFN groups improved or remained stable, whereas it deteriorated in 6 (50%) of 12 patients in the non-SVR-Withdrawal group. The fibrosis stage deteriorated in all patients in the non-SVR-Withdrawal group; nine of these patients (75%) deteriorated by more than one stage. In contrast, only four patients (24%) in the non-SVR-IFN group deteriorated, all by only a single stage. Furthermore, three patients actually improved. In the SVR group, fibrosis stage decreased or remained stable in 10 of 11 patients (91%).

Figure 2. Effect of maintenance interferon therapy on liver histology: (a) Changes in activity grade (upper) and fibrosis score (lower) of individual patients before interferon therapy (Pre) and at final biopsy (final). (b) Mean changes of liver activity grade (left) and fibrosis stage (right) between pretreatment liver biopsy and the final liver biopsy in each of the three treatment groups. The error bars represent 2 SEs. (c) Kaplan–Meier estimates of the progression rates among patients whose fibrosis advanced to F3 or F4. The dashed line indicates the sustained virological response (SVR) group, the solid line indicates the non-SVR-IFN group and the dotted line indicates the non-SVR-Withdrawal group

In patients in the SVR and non-SVR-IFN groups, the mean activity grade was markedly reduced in the final biopsy, compared to the pretreatment biopsy (Fig. 2b). In contrast, patients in the non-SVR-Withdrawal group experienced an increase in activity grade. The differences between the non-SVR-Withdrawal group and both the SVR and the non-SVR-IFN groups were statistically significant (P <0.001). The mean changes in fibrosis stage in the SVR and non-SVR-IFN groups were −0.18 and +0.06, respectively, suggesting that fibrosis did not change during the follow-up period. However, there was an obvious increase (+2.2) among patients in the non-SVR-Withdrawal group, indicating marked progression of fibrosis.

The Kaplan–Meier analysis allowed us to investigate whether patients in the three treatment groups experienced different progression rates to late-stage fibrosis (Fig. 2c). No patient in the SVR group and only 1 patient (6%) in the non-SVR-IFN group developed fibrosis stage F3 or F4, whereas nine patients (75%) in the non-SVR-Withdrawal group progressed to these stages. The rates of fibrosis progression were significantly higher in the non-SVR-Withdrawal group than in the non-SVR-IFN and SVR groups (P = 0.0049 and P = 0.0086, respectively). There was no significant difference between the SVR group and the non-SVR-IFN group (P = 0.3980). Five-year progression rates to F3 or F4 were 0% in the SVR group, 14% in the non-SVR-IFN group and 54% in the non-SVR-Withdrawal group.

Safety and Tolerability of Maintenance Interferon Therapy

Five of 17 patients (29%) who received low-dose maintenance peginterferon treatment discontinued interferon therapy because of biliary complications (n = 2), neutropenia (n = 1), anaemia (n = 1) and de novo AIH (n = 1), between 26.5 and 53.1 months after its initiation. The biliary complications were not related to interferon therapy. Patients with neutropenia and anaemia recovered after discontinuing interferon therapy and were able to resume therapy within months (3 and 10, respectively). Steroid therapy alleviated the de novo AIH, but the patients did not resume interferon therapy.

Discussion

Studies have repeatedly shown the benefits of achieving SVR via interferon therapy after liver transplantation. For instance, the durability of the SVR is associated with improvements in hepatic inflammation and histological regression of fibrosis over the long-term.^[18–23] In contrast, efficacy of interferon therapy for non-SVR patients after liver transplantation had not previously been investigated. Here, we have demonstrated that long-term peginterferon maintenance therapy suppresses histological progression of recurrent hepatitis C after LDLT.

Maintenance interferon therapy was recently shown to have no influence on either histological or clinical outcomes in patients with nontransplant hepatitis C.^[24] This conclusion was drawn after observing that the rate of fibrosis progression was similar between treatment and control groups following a 3.5-year randomized controlled trial of low-dose peginterferon. As a large number of patients with advanced fibrosis were enrolled in the randomized controlled trial, it is difficult to compare with our study in which the number of patients studied is much smaller and patients with advanced fibrosis were not enrolled. In the current study after liver transplantation, however, we demonstrated that low-dose maintenance interferon therapy reduced necroinflammatory activity and fibrosis scores in non-SVR patients to levels similar to those in SVR patients. Furthermore, we found that non-SVR patients who discontinued treatment had significantly worse scores once no longer receiving therapy.

Although these results clearly suggest that low-dose peginterferon maintenance therapy is beneficial for non-SVR patients with recurrent hepatitis C after liver transplantation, the mechanism behind this positive response is unknown. Progression of hepatitis C and development of fibrosis after discontinuation of interferon treatment has been shown to proceed more rapidly in patients who have undergone liver transplantation.^[20,21] Our results, indicating that activity grade and fibrosis stage markedly deteriorated in non-SVR patients who discontinued maintenance treatment, support these previous findings. Thus, such a rapid progression of recurrent hepatitis C in patients who discontinued interferon therapy may have highlighted the beneficial effect of the low-dose peginterferon maintenance therapy.

Another issue is the tolerability and safety of long-term peginterferon maintenance treatment. In this study, five patients (29%) discontinued the treatment during the peginterferon maintenance treatment, but only three did so for reasons directly related to the treatment. While two of these patients recovered simply by discontinuing the treatment, the third did require steroid pulse therapy to treat de novo AIH. Overall, however, the maintenance therapy did not result in the incidence of major adverse events, suggesting that it is both a tolerable and a safe treatment method.

Our work shows that long-term, low-dose peginterferon administration is an effective method for inhibiting the progression of liver damage for recurrent hepatitis C after liver transplantation. Unfortunately, this was not a randomized control study, and only a small number of patients were eligible for research. Therefore, we recommend further work to more fully explore the effects of this treatment and to improve the outcomes for patients who do not achieve SVR.

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