December 7, 2011

Strong results from Biotron HCV trial

Nearly 90% of patients treated with Biotron's (ASX:BIT) Hepatitis C treatment candidate demonstrated a complete EVR at three month follow-up.

Dylan Bushell-Embling (Australian Life Scientist) 08 December, 2011 10:41

Sydney-based Biotron (ASX:BIT) has presented encouraging results from a trial of the use of its prospective Hepatitis C treatment, when coupled with existing therapies.

Patients treated in a phase IIa trial of Biotron's BIT225 drug candidate, combined with approved standard of care (SOC) treatments, mostly demonstrated improvement at three month follow-up.

Of the subjects to have been treated with BIT225, 87% showed a complete early viral response (EVR) – defined as virus levels in the blood below the level of detection.

This compares to 63% who received only SOC treatments interferon alfa-2b plus ribavirin, and backs up data from the four week point of the study showing significantly reduced levels of HCV virus in BIT225-treated patients.

The extent of virus reduction was dose-dependent, with the higher dose having the most effect.

Patients involved in the trial received either 200mg or 400mg doses of BIT225 for 28 days, and then remained on the SOC treatments for another 44 weeks.

Biotron CEO Dr Michelle Miller said the results of the trial were “extremely encouraging.” She said they also show that BIT225 was generally well-tolerated in patients, with the most common potential side effect being nausea, which may be solved by tweaks to the formulation.

Biotron is also in the middle of a phase 1b/IIa trial for BIT225 as a treatment for HIV.

Biotron (ASX:BIT) shares climbed 18.18% to a seven-month high of $0.130 after the results were released on Wednesday.

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Public release date: 1-Dec-2011

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

New research reveals that liver transplantation candidates want to be involved in decisions regarding quality of the donor organ, and many are reluctant to accept organs with a higher risk of failure. In fact, more than 42% of patients would choose to remain on the waiting list rather than accept a "lower quality" liver according to the study appearing in the December issue of Liver Transplantation, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

As of November 30, 2011, the Organ Procurement and Transplantation Network (OPTN) reports that 16,124 candidates are on the waiting list to receive a liver, with only 5,375 deceased donor organs recovered through August. Additionally, there is a large variation in quality of deceased donor livers, which is based on donor characteristics such as age, cause of death, and ischemia time. Previous research has shown that donor characteristics can make the difference between a 20% to 40% risk of graft failure by 3 years following transplantation.

"Organ quality is an important issue for all liver transplant candidates, increasingly so, given the aging donor pool and more frequent use of organs that carry a higher risk of failure," explains Dr. Michael Volk with the University of Michigan Health System in Ann Arbor. "The decision to accept or pass on an organ could mean the difference between life and death for patients with end-stage liver disease. Communication of the risks versus benefits of accepting a "lower quality" organ is critical, and understanding patient views on the subject is essential for physicians caring for transplant candidates."

For the current study, researchers tested presentation formats for communicating organ quality risks to patients, and factors that might influence patients' willingness to accept higher risk organs. First, the team conducted interviews with ten patients on the waiting list for liver transplantation to determine their knowledge of organ quality and preferences for accepting organs with greater risk of failure. Based on qualitative information obtained from interviews, the team created a web-based survey which 95 candidates completed.

The findings show that patients are reluctant to accept higher risk organs, wanting only the "best" organ. Of those completing the survey, 58% would only accept organs with a 25% (or less) risk of graft failure and 18% would only accept the lowest possible risk of 19% at 3 years following transplantation. Women were slightly more accepting of high risk organs than men. Researchers found that risk tolerance was increased by presenting organ quality as "average quality" rather than "best quality," and by providing feedback about the implications of these preferences on the likelihood of receiving a transplant. Additionally, 83% of candidates were found to prefer an equal or dominant role in deciding whether to accept a higher risk organ. This finding is striking given that, in most transplant centers, patient involvement in these decisions is minimal.

"Up until now, it has not been clear how much patients want to be involved in this complicated decision," says Dr. Volk. "Furthermore, explaining the intricacies of this topic to sick patients is easier said than done. Our findings offer transplant physicians some useful guidelines for how to council transplant candidates on issues of organ quality." The authors suggest future studies are needed to develop validated patient education tools that will enhance discussions between physicians and patients in need of liver transplantations.

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This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Full citation: Patient Decision Making about Organ Quality in Liver Transplantation." Michael L. Volk, Rachel S. Tocco, Shawn J. Pelletier, Brian J. Zikmund-Fisher and Anna S. F. Lok. Liver Transplantation; Published Online: November 29, 2011 (DOI: 10.1002/lt.22437) Print Issue Date: December 2011. http://onlinelibrary.wiley.com/doi/10.1002/lt.22437/abstract.

Author Contact:To arrange an interview with Dr. Volk, please contact Mary Masson with the University of Michigan at mfmasson@med.umich.edu .

About the Journal

Liver Transplantation is published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society . Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AALSD and the ILTS, Liver Transplantation. delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit Liver Transplantation.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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Public release date: 7-Dec-2011

Contact: Lisa Chensvold
lisa_chensvold@med.unc.edu
919-843-5719
University of North Carolina School of Medicine

CHAPEL HILL, N.C. -- New research from the University of North Carolina at Chapel Hill schools of medicine and pharmacy may help explain the failure of some recent clinical trials of prevention of HIV infection, compared to the success of others that used the same drugs.

The study published online December 7, 2011 in the journal Science Translational Medicine, also suggests how to improve the chances for success, even before the research begins. These suggestions are reinforced in an editorial by several of the UNC authors writing in The Lancet, also published online December 7, 2011.

Over the past two years, results from several clinical trials involving pre-exposure prophylaxis (PrEP) for HIV infection have been a mixed bag of successful prevention and futility. Reports described varying degrees of successful HIV infection prevention in four trials and failure in two others. In all the PrEP trials, the drugs used were tenofovir (TFV) and emtricitabine (FTC) in daily oral and/or gel combinations.

These drugs have been shown to be protective against HIV infection in animal PrEP studies and are now being used clinically, and tenofovir is considered the backbone of HIV therapy, both used orally and topically.

The new UNC study looked at drug concentrations in the mucus membrane tissues that are most susceptible to HIV infection: the tissue lining the vagina, cervix and rectum. The study was led by Angela D.M. Kashuba, PharmD, professor in the UNC Eshelman School of Pharmacy and director of the UNC Center for AIDS Research Clinical Pharmacology and Analytic Chemistry Core. She also is a member of the UNC Institute for Global Health & Infectious Diseases.

"We did this study to understand how much drug got into these tissues and how long they lasted over two weeks," Kashuba said. And after giving normal, healthy volunteers a single pill combination of TFV/FTC, "What we found over the next 14 days was somewhat surprising. When a person takes a drug, it doesn't end up in the same concentration in different tissues."

Indeed, concentrations of tenofovir were 100 times higher in rectal tissue than in vaginal or cervical tissue. "And FTC achieved concentrations 10 to 15 times higher in vaginal and cervical tissue than they were in rectal tissue," Kashuba said. "And this raised some questions: because of these discrepancies can the two drugs be used equally well in both populations – women at risk for HIV infection and men at risk for HIV infection? And are the concentrations achieved even after a single dose high enough to prevent HIV infections?"

According to Kashuba, it's clear from the recent clinical studies that drug concentration in tissue may make a difference in effectiveness. For example, in one of the placebo-controlled PrEP clinical trials involving men who have sex with men, the combination of these drugs provided about 44 percent effectiveness overall.

But the half the men given the active form of the drugs had no detectable drug in their system when they were sampled during the study and, therefore, were not taking it consistently every day. Thus, the high tenofovir concentrations in rectal tissue could explain the relatively high efficacy of 44 percent.

Results of a PrEP clinical trial (VOICE) conducted in heterosexual women in Uganda, South Africa and Zimbabwe, also paralleled the UNC findings. The daily tenofovir arm was stopped because no protection was seen for the drug taken daily. "If these women did not take the drug every single day, we think our study supports the fact there would not be good efficacy because tenofovir drug concentrations in the vagina and cervix are so much lower than what we see in rectal tissue, Kashuba said."

The authors of the study and the editorial say adherence to taking the drug as prescribed is crucial. They lament that the only prospective means of measuring adherence now available is what the patient reports. "And so if you ask someone did you take all your doses, most will say yes," Kashuba said "People want to be considered good study participants, and sometimes they just can't remember how many doses they took last week, or in the last month, be it almost all of the doses or half of them."

The UNC researcher points to lessons learned: "Before delving into a clinical trial, we need to keep in mind that when someone takes a pill, you can't assume that the drug gets in all places at the same amount. And before we can select the drugs and the right doses for a clinical trial, we need to know what concentrations in tissue prevent HIV infection. They could be different."

And along with the above, the authors emphasize the need to develop ways to objectively measure drug-taking behavior in clinical studies so that the research can be designed and interpreted correctly.

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The study was funded in part from the National Institutes of Health, the UNC Center for AIDS Research, the UNC TraCS Clinical Translational Research Center, and the Gilead Sciences Investigator Initiated Research Program.

Along with Kashuba, UNC study co-authors from the School of Medicine are Kristine B. Patterson, Heather A. Prince, Nicholas J. Shaheen, and Myron S. Cohen. From the UNC Eshelman School of Pharmacy are Eric Kraft and Amanda J. Jenkins. And from Gilead Sciences, James F. Rooney. Co-authors of the editorial were Kashuba, Patterson, Cohen, and Julie B. Dumond of UNC Eshelman School of Pharmacy.

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Enoxaparin May Prevent Portal Vein Thrombosis in Advanced Cirrhosis

By: M. ALEXANDER OTTO, Internal Medicine News Digital Network

SAN FRANCISCO – The anticoagulant enoxaparin appears to prevent portal vein thrombosis in patients with advanced cirrhosis, based on a small Italian study presented at the annual meeting of the American Association for the Study of Liver Diseases.

In this trial, 6 of 36 patients (17%) randomized to placebo developed partial or complete portal vein thrombosis (PVT) within a year, whereas none of the 34 patients (0%) randomized to 4,000 IU daily of the low-molecular-weight heparin developed PVT.

The analysis indicated that enoxaparin had a significant protective effect (HR 0.218; 95% CI, 0.048-0.994, P = .049) in these patients with advanced cirrhosis.

At enrollment, none of the patients had PVT. The treatment and placebo groups had no significant differences in terms of biochemical or demographic factors at the outset of the trial, which was the first to prospectively investigate whether anticoagulation prevents PVT.

At the meeting, lead investigator Dr. Erica Villa, professor of gastroenterology at the University of Modena and Reggio Emilia in Modena, Italy, said that the results need to be confirmed in larger studies.

All of the subjects had cirrhosis classified as Child-Pugh B7 to C10. The mean age in both groups was 57 years, and the mean MELD (Model for End-Stage Liver Disease) score was approximately 14. Men made up more than 60% of both arms.

Enoxaparin appeared to provide significant protection against decompensation – defined as new-onset ascites, hepatic encephalopathy, or variceal bleeding – and death. Four enoxaparin patients (12%) decompensated during treatment, whereas 22 (61%) in the placebo arm decompensated. The difference persisted even after treatment with enoxaparin ended at 12 months.

Similarly, although 10 patients died in the enoxaparin group – 4 from sepsis, 2 from progressive liver failure, 3 from hepatocellular carcinoma, and 1 from variceal bleeding – 16 died in the placebo group. These deaths were due to sepsis in seven patients, progressive liver failure in another seven, hepatocellular carcinoma in one, and variceal bleeding in one.

There were no hemorrhagic or other treatment-related adverse events in the enoxaparin group, although asymptomatic thrombocytopenia led to the withdrawal of one patient 3 months into the trial. Three enoxaparin patients had liver transplants while on the drug, and Dr. Villa noted that they did not need extra blood transfusions.

Dr. Villa said she had no disclosures. She said the study was funded internally, and not by a company that makes enoxaparin.

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A Possible Sea Change in Cirrhosis Treatment

Enoxaparin "could certainly become a treatment for people who are at high risk for portal vein thrombosis. We don’t know enough about this; there may be side effects just like with other drugs, but [the findings are] exciting," said Dr. Jake Liang.

If this approach holds up to additional testing, it would signal "a sea change" in the treatment of advanced cirrhosis. "We treat thousands of people with cirrhosis; this would advocate that you should put them on this very expensive medicine" even if there’s no evidence of PVT, said Dr. Willscott Naugler.

Dr. Naugler is assistant professor of medicine at Oregon Health and Science University in Portland. Dr. Liang is president of the American Association for the Study of Liver Diseases and chief of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases

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Genes modify the risk of liver disease among alcoholics

Public release date: 6-Dec-2011

Contact: R Curtis Ellison
ellison@bu.edu
508-333-1256
Boston University Medical Center

It has been widely observed that only a small percentage of alcoholics develop cirrhosis of the liver, the most advanced form of alcoholic liver disease (ALD); the reason why all alcoholics do not develop such disease is not known. The present study from Spain, that includes original work and a meta-analysis, evaluates whether genetic polymorphisms that determine levels of glutathione-S-transferases (GST) relate to the risk of developing ALD among alcoholics. Alcoholics with certain genetic GST polymorphisms were found to be at significant excess risk for such liver disease in comparison with alcoholics without these polymorphisms.

As stated by the authors, the theory that these enzymes may affect risk is based on the ability of certain GST alleles to detoxify harmful ethanol metabolites in the liver by conjugating acetaldehyde and ROS to reduced glutathione. The specific polymorphisms that the authors found to be associated with increased liver disease are among those that would be expected to lower the activity of the corresponding GST enzymes; this would permit higher levels of toxic metabolites of alcohol and oxidative stress to be present for longer periods of time after excessive alcohol consumption.

Some Forum reviewers thought that while the study was well done, the authors were unclear how these data could directly lead to "potential therapeutic targets" for liver disease in alcoholics. Nevertheless, the original study and meta-analysis provide important data on how specific genetic factors relate to the development of liver disease among alcoholics and could theoretically lead to better strategies for the prevention and treatment of alcoholic liver disease.

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Reference: Marcos M, Pastor I, Chamorro A-J, Ciria-Abad S, González-Sarmiento R, Laso F-J. Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease. Aliment Pharmacol Ther 2011;34:1159.

Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Francesco Orlandi, MD, Dept. of Gastroenterology, UniversitĂ  degli Studi di Ancona, Italy

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Arne Svilaas, MD, PhD, General Practice & Lipidology, Oslo University Hospital, Oslo, Norway

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

For the detailed critique of this paper by the International Scientific Forum on Alcohol Research, go to http://www.bu.edu/alcohol-forum or http://www.bu.edu/alcohol-forum/critique-063-genes-modify-the-risk-of-liver-disease-among-alcoholics-5-december-2011/

The specialists who are members of the Forum are happy to respond to questions from Health Editors regarding emerging research on alcohol and health and will offer an independent opinion in context with other research on the subject

Helena Conibear co Director
The International Scientific Forum on Alcohol Research
helena@alcoholforum4profs.org

Professor R Curtis Ellison co Director
The International Scientific Forum on Alcohol Research
ellison@bu.edu
http://www.alcoholforum4profs.org
http://www.bu.edu/alcohol-forum
Tel UK: 44-1300-320869

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Nonalcoholic Fatty Liver Disease Not so Deadly

Jim Kling

December 6, 2011 — Nonalcoholic fatty liver disease is not associated with increased all-cause or cardiovascular mortality, according to a study published online November 18 in the British Medical Journal.

Nonalcoholic fatty liver disease is present in as much as 30% of the population and is a leading cause of chronic liver disease. It includes a number of conditions including steatosis, nonalcoholic steatohepatitis, fibrosis, and cirrhosis. It can also cause hepatocellular carcinoma and is associated with some cardiovascular risk factors.

Despite these trends, previous studies have shown inconsistent association between nonalcoholic fatty liver disease and mortality. The studies were small and either used highly selected patient populations or used liver enzyme measurements as surrogate markers for nonalcoholic fatty liver disease.

The researchers conducted a prospective cohort study using the US Third National Health and Nutrition Examination Survey (1988 - 1994), with follow-up to 2006. The study included 11,371 adults aged 20 to 74 years who were assessed for nonalcoholic fatty liver disease by the presence of moderate to severe steatosis (diagnosed by ultrasound) and normal levels of enzyme levels. Participants with steatosis and raised liver enzymes were classified as having nonalcoholic steatohepatitis. Mortality was categorized by all causes, cardiovascular disease, cancer, and liver disease.

Nonalcoholic steatohepatitis was present in 3.1% of the population, whereas nonalcoholic fatty liver disease was present in 16.4% of the participants. After adjustment for sex, race/ethnicity, education, smoking, alcohol consumption, physical activity, body mass index, hypertension, hypercholesterolemia, and diabetes, the researchers found that among participants with nonalcoholic fatty liver disease, the hazard ratio (compared with that of those patients without steatosis) for all-cause mortality was 0.92 (95% confidence interval [CI], 0.78 to 1.09). For cardiovascular disease, the ratio was 0.86 (95% CI, 0.67 - 1.12). The hazard ratio for cancer was 0.92 (95% CI, 0.67 - 1.27), and for liver disease it was 0.64 (95% CI, 0.12 - 3.59).

Participants with nonalcoholic steatohepatitis had the following adjusted hazard ratios compared with participants without stenosis: all-cause mortality, 0.80 (95% CI, 0.52 - 1.22); cardiovascular disease, 0.59 (95% CI, 0.29 - 1.20); cancer, 0.53 (95% CI, 0.26 - 1.10); and liver disease, 1.17 (95% CI, 0.15 - 8.93).

The study had several limitations, including the fact that it relied on raised liver enzymes in the presence of steatosis to define nonalcoholic fatty liver disease, rather than liver autopsies. There was no measure of change in nonalcoholic fatty liver disease over time, and some data were self-reported. In addition, follow-up time may not have been long enough to determine the association between nonalcoholic fatty liver disease and liver-related mortality.

The researchers recommend that the study be repeated in the general population, using improved, noninvasive assessment tools and finer staging of nonalcoholic fatty liver disease.

The authors have disclosed no relevant financial relationships.

BMJ. Published online November 18, 2011. Full text

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Fatty livers are in overdrive

Public release date: 6-Dec-2011

Contact: Elisabeth (Lisa) Lyons
elyons@cell.com
617-386-2121
Cell Press

When our livers become loaded with fat, it isn't because they are slacking. A new study of human patients in the December Cell Metabolism shows that fatty livers actually burn more fat, not less. All that "hard work" may be at the root of the organ damage that comes with nonalcoholic fatty liver disease (NAFLD), a condition associated with insulin resistance that affects about one in three in the U.S. population.

The findings represent a paradigm shift in the connection between metabolism and fatty liver disease, as it was previously thought that fatty livers burned less fat.

"Our overwhelming goal is to try to understand what happens in those with fatty liver," says Jeffrey Browning of the University of Texas Southwestern Medical Center. "By understanding what leads to the onset and progression of the disease, we hope we can come up with therapies that actually work."

Most studies of people with insulin resistance have focused on the more accessible skeletal muscle. Those studies show that the mitochondria that power skeletal muscle cells work at a slower pace in the context of metabolic syndrome, including insulin resistance and fatty liver. Browning and his colleague Shawn Burgess weren't so sure that muscle could tell you much about what might be happening in other organs, including the liver.

"Unless skeletal muscle is working, it doesn't have much of an energy requirement," Browning explained. "The liver is always working." The liver breaks down fat and makes glucose and ketone bodies that fuel the rest of our bodies, including our hearts and our brains.

In the new study, the researchers used a special method that allowed them to trace metabolic inputs and outputs in the human liver in people with low and high levels of triglyceride fats in their livers. Those studies show that people with fatty livers are breaking down lipids 50 percent faster and producing glucose 30 percent faster in comparison to those with healthy livers.

That increased demand on the liver suggests a link between fatty liver, oxidative stress, and liver damage. Browning says that means therapies including antioxidants like vitamin E might help protect the liver.

The researchers now hope to explore how metabolism shifts over the course of the disease. One day the tracer technique they have developed might even help to identify those patients at the greatest risk of progressing to the point of liver transplantation.

"A third of the population has fatty liver, and it is difficult to look at them and tell anything without a liver biopsy," Browning says. The trouble is all those biopsies would simply overwhelm the health care system.

Perhaps most important, the findings show that researchers need to rethink what insulin resistance means for the functioning of mitochondria throughout the body. "Skeletal muscle is very different from the liver," he says.

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