November 15, 2010

Journal of Gastroenterology and Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)
Anna Suk-Fong Lok MD, FRCP
DOI: 10.1111/j.1440-1746.2010.06576.x
© 2010 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd

Author Information
 
University of Michigan, Ann Arbor, MI, USA

* Correspondence: Anna SF Lok, MD Division of Gastroenterology University of Michigan Health System 3912 Taubman Center, SPC 5362 Ann Arbor, MI 48109 USA Fax: 734-936-7024 Email: aslok@med.umich.edu

Publication History
Accepted manuscript online: 11 NOV 2010 08:21AM EST
Accepted: 25 October 2010

Abstract
 
Approximately 75% to 80% of hepatocellular carcinomas (HCC) worldwide are attributed to chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection. Thus, effective prevention of HBV and HCV infection and progression from acute HBV and HCV infection to chronic hepatitis, cirrhosis and HCC might prevent as many as 450,000 deaths from HCC each year. The most effective approach to preventing HCC is to prevent HBV and HCV infection through vaccination. Indeed HBV vaccine is the first vaccine demonstrated to prevent cancers. However, a vaccine for HCV is not available and for persons who are chronically infected with HBV or HCV, antiviral therapy is the only option for preventing HCC. Direct evidence supporting a benefit of antiviral therapy on the prevention of HCC has been shown in a few randomized controlled trials. There is abundant evidence that antiviral therapy, in patients with long-term virological response, can improve liver histology providing indirect support that antiviral therapy may prevent HCC by slowing progression of liver disease and possibly even reversing liver damage. Nevertheless, the risk of HCC remains in patients with chronic HBV or chronic HCV infection if treatment is initiated after cirrhosis is established. These data indicate that treatment might be of greater benefit if instituted earlier in the course of chronic hepatitis B or C. Safer, more effective, and more affordable antiviral therapies are needed for both hepatitis B and hepatitis C so more patients can benefit from treatment and more HCCs can be prevented.

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The Journal of Infectious Diseases 2010;202:000–000
© 2010 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2010/20212-00XX$15.00
DOI: 10.1086/657317

MAJOR ARTICLE

Jennifer A.Smith, 1 Judith H. Aberle, 4 Vicki M. Fleming, 2 Peter Ferenci, 5 Emma C. Thomson, 3 Peter Karayiannis, 3 Angela R. McLean, 1 Heidemarie Holzmann, 4 and Paul Klenerman 2

1 Institute for Emerging Infections and 2 Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, and 3 Department of Hepatology, Imperial College, London, United Kingdom; 4 Institute of Virology and 5 Department of Internal Medicine, Gastroenterology, and Hepatology, Medical University of Vienna, Vienna, Austria

Introduction.Acute hepatitis C virus (HCV) infection is rarely studied, but virus sequence evolution and host‐virus dynamics during this early stage may influence the outcome of infection. Hypervariable region 1 (HVR1) is genetically diverse and under selective pressure from the host immune response. We analyzed HVR1 evolution by frequent sampling of an acutely infected HCV cohort.

Methods.Three or more pretreatment samples were obtained from each of 10 acutely infected subjects. Polymerase chain reaction amplification was performed with multiple primer combinations to identify the full range of sequences present. Positive samples were cloned and sequenced. Phylogenetic analyses were used to assess viral diversity.

Results.Eight of the 10 subjects were coinfected with at least 2 HCV subtypes. Multiple subtypes were detected in individual samples, and their relative proportions changed through acute infection. The subjects with the most complex subtype structure also had a dynamic viral load; however, changes in viral load were not directly linked to changes in subtype.

Conclusions.This well‐sampled cohort with acute HCV infection was characterized by dynamic coinfection with multiple viral subtypes, representing a highly complex virologic landscape extremely early in infection.

Received 18 January 2010; accepted 19 July 2010; electronically published 10 November 2010.

(See the editorial commentary by Irving and Brown, on pages XXX–XXX.)

Reprints or correspondence: Prof Paul Klenerman, Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford OX1 3SY, United Kingdom (paul.klenerman@ndm.ox.ac.uk).

Potential conflicts of interest: none reported.

Presented in part: Epidemics Conference, Monterey, California, 1–3 December 2008 (oral presentation).

Financial support: Wellcome Trust; Medical Research Council; James Martin 21st Century School, Oxford; US National Institutes of Health (grant U19 AI082630); UK National Institute for Health Research Biomedical Research Centre Programme, Oxford.

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Therapeutic HIV Vaccine Promising in Early Study

By Michael Smith, North American Correspondent, MedPage Today
Published: November 13, 2010
Reviewed by Barry S. Zingman, MD; Professor of Clinical Medicine, Albert Einstein College of Medicine, Bronx, NY.
 
A therapeutic HIV vaccine appears to reverse some of the immune dysfunction caused by the virus, researchers reported.

According to preliminary data from a randomized phase II trial, a vaccine against the HIV protein Tat was both safe and immunogenic, according to Barbara Ensoli, MD, PhD, of the National AIDS Center of the Istituto Superiore di Sanità in Rome, and colleagues.

But in patients with fully suppressed HIV replication, the vaccine also appeared to improve a range of markers of immune function, Ensoli and colleagues reported online in PLoS One.

Even when highly active anti-retroviral therapy (HAART) slows HIV replication, there is often enough growth to cause continued immune activation in patients, Ensoli and colleagues noted, and immune homeostasis is impaired.

The Tat protein is essential for HIV replication, so Ensoli and colleagues are testing several doses and vaccination schedules of a recombinant protein in a phase II randomized trial, designed to determine immunogenicity and safety.

But a secondary goal is to see what effect the vaccine has on immune parameters, including such things as the number of B cells, CD4-positive T cells, and CD8-positive T cells.

For this analysis -- described as "ad hoc and exploratory" -- Ensoli and colleagues analyzed results from 87 volunteers and compared them with patients taking part in a separate, prospective observational trial that is examining the effect of naturally-occurring Tat immunity.

The 87 volunteers in the trial had no antibodies to Tat, but had undetectable HIV on a range of HAART regimens. They were given either 7.5 or 30 micrograms intradermally, either three or five times.

Overall, Ensoli and her colleagues found, 79% of the volunteers responded to the vaccine by producing antibodies to Tat.

Although 59% of the volunteers had at least one adverse event, they were mostly the usual side effects associated with HIV infection, the researchers said. Of those that were linked to the Tat vaccine most were local, related to the injection, and mild.

The researchers reported seven serious adverse events, but only one -- a severe case of disarthria and paresthesia -- was regarded as possibly related to the drug. It resolved after the vaccine was stopped.

The researchers also found that responders had:

• Significant increases in interleukin-2, interferon-gamma, and interleukin-4, as well as Tat-specific CD4 and CD8 T cells

• Improvements in the in vitro viability of peripheral blood mononuclear cells, which is lessened in HIV infection, that continued to increase for up to 48 weeks and were significant at that point at P<0.0001

• Increases in the number of CD4 T cells, ranging on average from 48 to 69 cells/mL of blood, depending on dose

• Increases in the number of B cells that ranged on average from 25 to 66 cells/mL of blood

• An increased proportion of CD4 T cells and B cells, but a decrease in the proportion of CD8 T cells and natural killer cells -- a marker of immune activation

The responses, in general, were better with the larger dose, the researchers reported.

The results, Ensoli said in a statement, "suggest that therapeutic vaccination with the Tat vaccine, combined with HAART, can significantly improve the recovery of the immune system in patients with HIV."

The study was supported by the Italian health ministry.
The researchers said they had no disclosures.

Primary source: PLoS One

Source reference:
Ensoli B, et al. "Therapeutic Immunization with HIV-1 Tat Reduces Immune Activation and Loss of Regulatory T-Cells and Improves Immune Function in Subjects on HAART." PLoS ONE 5(11): e13540.

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Alcohol harms not only liver but other parts of the body too

by Shrabani Mukherjee    2010-11-15

Taking alcohol and beverages on a daily basis is becoming the order of the day. In the new lifestyle which people are leading everyday, taking alcohol after a hard day’s work or savoring new cock tails in some party are very common these days. People know the side effects of alcohol consumption but what they don’t know is that in a new study it has been found out that alcohol is not only damaging to the liver but also to the other parts of the body.

Researchers in the Loyola Institute have found out the other harmful effects of alcohol consumption. Alcohol actually weakens the immune system of the body, it can increase the risk of HIV, affects the bones of the body and decreases recovery of the bones, burns and bleeding in the body.

A group of 50 members had participated in the test of the alcohol which gave the result that alcohol actually harms other body parts apart from the liver. The researchers are hoping that after this study might actually open the eyes of the people to the harmful effects of alcohol drinking.

The Director of Alcohol Research Program and Associate Director of Burn and Shock Trauma Institute, Loyola University, Elizabeth J. Kovacs when asked said that the best way to take care of one’s body and prevent any long damage is to not drink alcohol at all. It is high time that people understand that alcohol should not be made a part and parcel of life as it kills the body, slowly an surely.

Tags: alcohol HARMFUL effects body, alcohol and liver harmful effects, alcohol and immune system

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Author: Shrabani Mukherjee
Contact shrabanimukherjee29@gmail.com for more information

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Weighing Risk, Benefit Of Live-Donor Transplant

by The Associated Press

November 15, 2010 Live-donor liver transplantation is a lifesaving option for many suffering from end-stage liver disease but also a controversial procedure that raises questions about when it's appropriate to put a healthy person at risk to save another.

The procedure, in which a segment of the liver is taken from a healthy donor and transplanted into the ailing recipient, is possible because of the liver's ability to regenerate. In weeks, both the old liver and the transplanted liver begin to grow back to a normal size, providing long-term function for both donor and patient.

The first such successful transplantations, beginning in 1989, involved taking liver grafts from adult donors for transplantation into sick children, a procedure with fewer risks to the donor because only about 25 percent of the liver is needed. As pediatric living-donor liver transplantation grew more widely accepted, the technique was modified for use in adult patients, with up to 60 percent of the donor's liver taken.

Through 1996, just six adult-to-adult live-donor liver transplants had been performed in the United States, according to the United Network for Organ Sharing (UNOS), which manages the nation's organ transplant system. Five years later, that number had grown to 412. Today, more than 2,800 adult-to-adult procedures have been performed in the United States.

In all of those, UNOS reports, four donors have died due to complications of the surgery or immediately following surgery. Though rare, these deaths raise the most serious question surrounding live-donor liver transplants: When is it OK to operate on an otherwise healthy person?

The death of donor Mike Hurewitz at New York's Mount Sinai Hospital in 2002 brought widespread scrutiny of adult live-donor liver transplants, resulting in risk-benefit studies and an examination of screening procedures for donors. Hurewitz developed a bacterial stomach infection and died three days after donating part of his liver to his brother. Reviews blamed poor post-surgical care, and the state temporarily halted the hospital's live donation program until corrective measures were put in place.

The other donor deaths were: in 1999 at the University of North Carolina at Chapel Hill hospital, where the donor suffered a series of complications, including kidney failure, pancreatitis, a bile leak and infection; this past May at the Lahey Clinic in Massachusetts, where the donor died during surgery after a vein was detached from the vena cava, causing an uncontrollable hemorrhage; and in August at the University of Colorado hospital, where the donor suffered cardiac arrest, possibly due to a combination of surgical stress and other factors.

UNOS provides transplant centers with guidelines to ensure donors are appropriately evaluated. Potential donors undergo a thorough medical and mental examination prior to signing a written consent agreement, and they must have an independent advocate to represent their interests alone.

Still, there are no standardized procedures, and actual tests to ensure the donor's mental and physical health may vary among transplant centers, said Dr. Connie Davis, chair of the living donor committee for UNOS who stressed that, ultimately, "Every donor, heaven forbid, they have the right to say no. They don't have to do this."

Katrina Bramstedt, a transplant ethicist who also serves as a donor advocate, said that while the ethical questions surrounding living donation are valid, risk-benefit analyses show that the procedure should continue. "Yes, occasionally something goes wrong, but that's going to happen in any surgical procedure," she said. "Generally, the donors are well-informed and very well-screened and they're healthy and ready to go."

After Hurewitz's death, the National Institutes of Health implemented a seven-year study of adult living-donor liver transplants to weigh risks to donors and benefits to recipients. Study results found a 20-25 percent chance of donors experiencing some type of complication, the most common being bile leaks, collection of fluid around the lung and infections. Most were considered minor, said Dr. Carl Berg, the director of hepatology at the University of Virginia, who served as a co-chair of the federal research team. The research found a 50 percent reduction in deaths among the sick patients receiving the live-donor livers, Berg said. Without the live-donor livers, those patients most likely would have remained on the cadaver transplant list — some growing more ill as they awaited a transplant, some dying before a transplant ever happened.

The back-to-back deaths in Colorado and Massachusetts this year shook the transplant community and prompted centers to re-examine their programs, Berg said. However, he added that so long as the benefits of the surgery outweigh the risks of death or complication — and until more Americans decide to become organ donors at death — adult living-donor liver transplants will continue.

"Is it safe?" he asked. "I would give half my liver to my brother in an instant, and I know as much as could be known about the risks. I would still gladly do that as opposed to having him wait for a deceased donor because I know the benefit is there, and I believe (for donors) that the quantified risk is small."

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