Wednesday, November 2, 2011

Hepatitis News Ticker; Introduction to Drug Resistance

New On The Blog

AASLD-Jennerex to Present Final Survival Data From Randomized Phase 2 Clinical Trial of JX-594 in Advanced Liver Cancer
TMC435 Phase IIb ASPIRE (C206) Study-Final Results
Hepatitis C Genotype-4 Infection: Role of Insulin Resistance in Hepatocellular Carcinoma
Hepatitis C- Pharmasset All-Oral Therapy By 2013?

Pharmasset Phase 3 Plan Announced: Slides Presented This Morning on Pharmasset Conference Call

Predicting clinical outcomes in patients with advanced chronic Hep C
The most recent issue of Hepatology predicts clinical outcomes using baseline and follow-up laboratory data from the hepatitis C long-term treatment against cirrhosis trial.

Predicting clinical outcomes in patients with chronic hepatitis C is challenging.
Dr Marc Ghany and colleagues from Maryland used the hepatitis C long-term treatment against cirrhosis (HALT-C) trial database to develop two models.
The team used baseline values of routinely available laboratory tests together with changes in these values during follow-up to predict clinical decompensation, and liver-related death/liver transplant in patients with advanced hepatitis C.

Patients randomized to no treatment and who had a 2-year follow-up without a clinical outcome were included in the analysis.

The team evaluated 4 variables, including platelet count, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, total bilirubin, and albumin.

Baseline values of all 4 variables were predictive of decompensation
In addition, the team assessed 3 categories of change, involving stable, mild, or severe, over 2 years.

Cumulative incidence of clinical outcome was determined by Kaplan-Meier analysis and Cox regression was used to evaluate predictors of clinical outcome.

In all, 470 patients with 60 events were used to develop models to predict clinical decompensation.

Baseline values of all 4 variables were predictive of decompensation.

There was a general trend of increasing outcomes with more marked worsening of laboratory values over 2 years, particularly for patients with abnormal baseline values.

A model that included baseline platelet count, AST/ALT ratio, bilirubin, and severe worsening of platelet count, bilirubin, and albumin was the best predictor of clinical decompensation.

The research team used a total of 483 patients with 79 events to evaluate predictors of liver-related death or liver transplant.

A model that included baseline platelet count and albumin as well as severe worsening of AST/ALT ratio and albumin was the best predictor of liver-related outcomes.

Dr Ghany's team concluded, "Both the baseline value and the rapidity in change of the value of routine laboratory variables were shown to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C."

Hepatology 2011: 54(5): 1527–1537
02 November 2011


Resistance in Hepatitis C

Join Stephane Chevaliez, PharmD, PhD; Paul J. Pockros, MD; and Stefan Zeuzem, MD, as they review and discuss key principles of HCV resistance with currently approved direct-acting antiviral agents, the latest resistance data on agents in development, and important considerations for potential future anti-HCV regimens. These expert faculty members also provide practical strategies for clinical challenges with the newly approved direct-acting agents through a case-based analysis.

Roundtable, 3 Expert Viewpoints, IVP, Slides

Topics covered include:

  • Introduction to Drug Resistance in Hepatitis C Virus
  • Key Resistance Principles for Currently Approved Direct-Acting Antiviral Agents
  • Considerations for Retreatment of Previous Peginterferon/Ribavirin Null Responders and Potential Consequences of Protease Inhibitor Resistance
  • Genotype and Resistance Testing
  • Case 1: Previous Null Responder
  • Case 2: Stopping Rules
  • Case 3: Boceprevir Resistance–Associated Variant
  • Future Regimens
  • Future Protease Inhibitors
  • Nucleos(t)ide Polymerase Inhibitors
  • Nonnucleos(t)ide Polymerase Inhibitors
  • NS5A Inhibitors
  • Cyclophilin Inhibitors
  • Summary: Important Considerations to Avoid Resistance-Associated Variants
  • Appendix: Principles of HCV Resistance

Free Registration Required

Effects of Anti-Viral Therapy and HCV Clearance on Cerebral Metabolism and Cognition

BACKGROUND/AIMS: Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism and neuropsychological performance.

METHODS: Fifteen non-cirrhotic HCV positive subjects underwent (1)H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12 weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing.

RESULTS: Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment.

CONCLUSIONS: HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function, and is, an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.


HCV Advocate;

November 2011 HCV Advocate

Download printable version

In This Issue:

Galectin Therapeutics Announces Formation of Liver Fibrosis Clinical Trials Advisory Board

Galectin TherapeuticsInc. (OTC: GALT) (“the Company”), the leader in developing carbohydrate-based therapeutic compounds to inhibit galectin receptors, today announced the formation of its Liver Fibrosis Clinical Trials Advisory Board comprised of key opinion leaders from Emory Hospital and School of Medicine, Massachusetts General Hospital and Harvard School of Medicine, University of Michigan Hospital and School of Medicine, Mount Sinai Hospital and School of Medicine, and University of Wisconsin Hospital and School of Medicine. The Company expects to file an Investigational New Drug application to treat liver fibrosis with the U.S. Food and Drug Administration and plans to initiate a clinical trial next year.

“Galectin Therapeutics has assembled an outstanding group of investigators and clinicians to help guide our clinical strategy and clinical trial design in liver fibrosis and additionally serve as principle investigators on clinical trials,” said Dr. Peter Traber, President, Chief Executive Officer and Chief Medical Officer, Galectin Therapeutics, Inc. “Our most advanced programs, the GM and GR series of compounds, have demonstrated the ability to arrest and reverse liver fibrosis in pre-clinical studies. There are currently no treatment options for liver fibrosis except liver transplantation. Our goal is to develop the first therapy for liver fibrosis and we expect to advance a lead candidate into clinical trials in 2012.”

Principal Investigators named to the Liver Fibrosis Clinical Trials Advisory Board include:

  • Dr. Ram Subramanian, Emory Hospital and School of Medicine: Dr. Subramanian is Assistant Professor of Medicine and specializes in gastroenterology, transplant hepatology, pulmonary medicine and critical care. Areas of interest include acute liver failure, decompensated cirrhosis, hepatic critical care and pre and post liver transplant care.
  • Dr. Raymond T. Chung, Massachusetts General Hospital and Harvard School of Medicine: Dr. Chung is Professor of Medicine and Vice Chief of Gastroenterology, Director of Hepatology, and Medical Director, Liver Transplant Program. His interests are viral hepatitis, liver cancer, and liver transplantation.
  • Dr. Robert J. Fontana, University of Michigan and School of Medicine: Dr. Fontana is Professor of Medicine and the Medical Director, Liver Transplant Program. His clinical and research interests include drug-induced liver disease, viral hepatitis, and acute liver failure.
  • Dr. Thomas D. Schiano, Mount Sinai Hospital and School of Medicine: Dr. Schiano is Professor of Medicine with specialty in liver disease and has a clinical background in hepatology, gastroenterology and clinical nutrition. He has expertise in the management of persons with cirrhosis and other acute/chronic liver diseases, and in caring for patients prior to and after liver transplantation.
  • Dr. Michael R. Lucey, University of Wisconsin Hospital and School of Medicine: Dr. Lucey is Professor of Medicine and Chief, Gastroenterology and Hepatology. His clinical interests are hepatology and liver transplant medicine. His research interests include alcoholic liver disease, viral hepatitis, and care of patients before and after liver transplantation.

Principal Consultants for the Liver Fibrosis Clinical Trials Advisory Board include:

  • Dr. Scott L. Friedman, Mount Sinai Hospital and School of Medicine: Dr. Friedman is Professor of Medicine and Director of the Section of Liver Disease. Dr. Friedman has performed pioneering research into the underlying causes of scarring, or fibrosis, associated with chronic liver disease, which affects millions worldwide. He was the first to isolate and characterize the hepatic stellate cell, which is the key cell type responsible for scar production in liver.
  • Dr. Maria Isabel Fiel, Mount Sinai Hospital and School of Medicine: Dr. Fiel is a Professor of Pathology. Dr. Fiel’s specialties include Anatomic pathology, Cytopathology and Clinical pathology. Having finished two fellowships in Liver & Transplant Pathology and Cytopathology, her main clinical interests include Liver Pathology and Gastrointestinal Pathology, and she has published extensively in the areas of viral hepatitis, alcoholic liver disease, non-cirrhotic portal hypertension, liver cancer and liver fibrosis. In addition, Dr. Fiel is Director of the Mount Sinai Alcohol Liver Disease Research Center.

About Galectin Therapeutics

Galectin Therapeutics (OTC: GALT) is developing promising carbohydrate-based therapies for fibrotic liver disease and cancer based on the Company’s unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at

Forward Looking Statements

This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as “may,” “estimate,” “could,” “expect” and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others: incurrence of operating losses since our inception, uncertainty as to adequate financing of our operations, extensive and costly regulatory oversight that could restrict or prevent product commercialization, inability to achieve commercial product acceptance, inability to protect our intellectual property, dependence on strategic partnerships, product competition, and others stated in risk factors contained in our SEC filings. We cannot assure that we have identified all risks or that others may emerge which we do not anticipate. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements


OSHA Most Frequently Cites ASCs for Bloodborne Pathogen Violations

In fact, in the last decade, more than 130,000 U.S. patients served at ASCs were notified of potential exposure to HBV, HCV and HIV due to unsafe injection practices and lapses in infection control.

Although more than half of the surgeries in the U.S. are performed in
ambulatory care centers, ambulatory surgery center (ASC) resources and safety oversight may lag significantly behind those of their hospital counterparts.

In the past four years, the Occupational Safety and Health Administration(OSHA) has increased medical facility inspections. As a result, agents are citing more ASCs and physician offices for Bloodborne Pathogen Standard violations. In fact, such violations make up the majority of OSHA medical facility citations in recent years.

According to a two-part series of articles published in October and November editions of the AORN Journal, the most frequent causes of bloodborne pathogen violations were outdated or nonexistent exposure control plans, poor documentation, the failure to use safety devices and the lack of free training
during working hours. The violations that merited the largest fines dealt with failure to immediately remove personal protective equipment (PPE) penetrated with body fluids; failure to use safety devices; and the failure to provide workers with a free hepatitis B vaccination and follow up.

“Compliance with the Bloodborne Pathogen Standard may seem complex; however, it is the key to providing a safe workplace for both the healthcare employee and patient,” writes Pamela Dembski Hart, BS, MT(ASCP), CHSP, principal of Healthcare Accreditation Resources of Boston, in the two-part series,
“Complying With the Bloodborne Pathogen Standard: Protecting Health Care Workers and Patients,” and “Compliance: the Key to Bloodborne Pathogen Safety.”

OSHA adopted the mandatory Bloodborne Pathogen Standard approximately 20 years ago in order to protect healthcare workers from exposure to blood, body fluids and infectious material. These infectious liquids and materials may contain bloodborne pathogens, particularly hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV. While protecting workers from disease, safe practices also guard against patient violations. In fact, in the last decade, more than 130,000 U.S. patients served at ASCs were notified of potential exposure to HBV, HCV and HIV due to unsafe injection practices and lapses in infection control.
Hart describes how healthcare facilities can avoid frequent and costly OSHA violations. Facilities should develop and exposure control plans that determine safety risks and describe work practice controls. Facility managers should also solicit input from all employees to prevent needle sticks and sharps contamination and identify employees’ exposure risks. Issues related to mandatory vaccinations are also discussed.

Healthy You

When the fat comes out of food, what goes in?

When fat, sugar and gluten come out of salad dressings, sauces, cookies, beverages, and other foods with the new genre of package labels shouting what's not there, what goes into "light" or "-free" versions of products to make them taste like the original version? The answers appear in the cover story in the current edition of Chemical & Engineering News, ACS' weekly newsmagazine.

In the article Melody Bombgardner, C&EN Senior Business Editor, explains that food processors usually face the problem of reproducing the texture or "mouth feel" of products that have cut back on fat, sugar and gluten. More and more of these products are appearing on supermarket shelves in response to changing preferences of health-conscious consumers. Food companies are in a quandary in selecting replacements, because of a parallel consumer backlash against products with long complicated lists of ingredients with the names of tongue-twisting chemical compounds.

The article describes how a host of ingredients derived from Mother Nature, are assuming increasingly important roles in giving those processed foods a satisfying taste. It includes a "mouth map" used to help formulate "light" foods so that they taste like the full-fat versions. The article also features one sidebar on natural food ingredients used to give processed foods a satisfying texture and another on food ingredients that do double-duty as ingredients in toothpastes, shampoo, skin creams, and even oil and gas drilling.

The American Chemical Society is a non-profit organization chartered by the U.S. Congress. With more than 163,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive news releases from the American Chemical Society contact

Dr. Pullen;

What Vitamins Should I Take?
I’ve been asked “What vitamins should I take?” by many patients over the years. I’ve usually answered that a store brand multiple vitamin is a good choice for most people, but recent evidence suggests that maybe the best answer to the question is that most people who have a reasonably healthy diet are best taking no vitamins at all. I know that answering the question, “What vitamin should I take?” with the answer that most vitamin supplements may cause more harm than good is not likely to be the answer patients want to hear, but as more evidence becomes available it is more clear that we just cannot get the healthy nutrients of a balanced diet in a pill, and that attempts to do so may actually be detrimental to our health.
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Complementary and Alternative Medicine

PLos Blogs

Contemplating Complementary Medicine

There is an old, familiar joke that goes something like this -

A tourist is walking through the New England countryside, trying to find his way to the nearest town. He stops a man to ask for help with directions to so-and-so. The local pauses to think about it. “Well,” he begins. “You go down this road for a bit. Then when you come to a barn, you go left. You walk through the field, and … no, wait, that’s not right.” He pauses for another moment. “What you do is this: you walk toward that hill over there, and when you come to the fence, go left. About a mile later, you’ll see a pond, where – no, wait, that’s not right.” He pauses to think about it some more, the tourist growing antsy and frustrated. Finally, the local speaks. “Well,” he says, “You can’t get there from here.”

And though I am probably going to regret poking this particular hornet’s nest, here goes. Some recent research, for this article about the alternative medicine approaches pursued by Steve Jobs following his diagnosis of a pancreatic neuroendocrine tumor, brought that joke to mind when I saw the vitriol flying around, on the one hand about so-called complementary medicine, and on the other hand, about that harsh judgment.

Complementary medicine typically refers to any approach to healthcare that a person chooses to pursue alongside modern medicine. That is, it complements the scientifically proven treatment. Complementary medicine usually includes some form of traditional Chinese medicine (or, as many refer to it, Traditional Chinese Medicine [TCM]), including acupuncture, herbal remedies, mushroom blends, and certain movement and breathing practices like Qi Gong and Tai Chi. When someone who is ill chooses to use only these approaches and no form of Western medicine, it’s usually called alternative, not complementary.

Many people are also aware that TCM has been increasingly incorporated into medical care—in cancer treatment, it’s called integrative oncology—and, albeit with less vigor than many would like, put to the test in scientific research. Scientific literature now supports the use of acupuncture as a way to reduce nausea among people receiving chemotherapy, for example.

There are many hurdles facing the use of complementary approaches in a way that modern medicine will support, but chief among them is a pervasive attitude that refers to complementary medicine as “woo” or “quackery.” And, when people who are interested in complementary medicine see it referred to thusly, the reaction that modern medicine doesn’t work and all anyone is trying to do is to get sick people to spend money on expensive drugs.

It’s difficult to subject things like dietary changes to the scientific method. It’s also questionable whether that’s the right approach. As Don Abrams, an oncologist with an extensive academic and medical background who now heads the Osher Center for Integrative Medicine at the University of San Francisco, said it during our recent interview, “The demand for placebo-controlled, randomized clinical trials is something we need when talking about cytotoxic drugs, but how dangerous could it be to eat more cruciferous vegetables and heavily pigmented fruit?” And the necessary corollary to that, “How much do we need to spend to prove it?”

Clinical trials enable researchers to compare two treatment approaches, yes, but they also enable researchers to keep patients safe from a potentially harmful new agent. When it comes to something like eating broccoli, that hardly qualifies as dangerous, but it’s also very hard to compare patients who eat more to patients who eat less as part of their overall treatment regimen.

Now that’s not to say that one should go blindly into integrating dietary changes or TCM into their medical care, but it does call up that punch-line. Can you get there from here? Can we start to think about the how’s and why’s of complementary medicine from a modern medicine standpoint? Is that the right approach? Is that valid? Is it the only approach?

One of the issues raised about TCM is that it’s based on anecdotal evidence. That’s a reasonable concern. Anecdotal evidence is subjective. The National Comprehensive Cancer Guidelines would consider it Category 3 evidence. But do you know what? Trial and error is exactly how many of the first effective combination chemotherapy regimens came about. The efficacy of methotrexate, the first curative cancer drug, was realized through the treatment of one person. A young woman was ill with choriocarcinoma was given methotrexate starting in October 1955, and by February 1956, all evidence of her disease was gone. In the days when treatment options were incredibly slim, people tried anything – giving a certain drug for five days in a row, or every other day, or whatever seemed like a good idea to try. Of course there were always clinical trials and organized research, but that wasn’t the only approach. Behind thin hospital curtains, patients with no hope were given experimental combinations of nitrogen mustard and vincristine or whatever other agents had shown promise or concrete benefit, to see what that concoction might do. And when that combination worked, making the tumor recede without killing the patient in the process, word of the success was broadcast far and wide.

All of which brings us to the issue of evidence-based medicine, and the fact that there should be ample evidence supporting the choices and recommendations made by doctors. And yet, anecdotal evidence is an inherent part of Western medicine. See this article, in the Archives of Internal Medicine, showing the extent to which decisions are made based on evidence that is not derived from a rigorous clinical trial. And this letter, from the New England Journal of Medicine, about adverse anecdote, highlights another interesting aspect. That’s not to say that the reliance on anecdotal evidence is right or wrong, but just to state the fact that it happens in conventional medical care, too.

In the earliest days of chemotherapy, many people thought that radiation and surgery were sufficient to treat cancer, and that where these interventions didn’t work, the cancer wasn’t treatable. Obviously the naysayers of that era were wrong, but it took giving the drugs to patients to show them the error of their ways. That is not to say that eventually acupuncture will be used to treat cancer. All of the doctors that I spoke with – many with one foot solidly grounded in the West and the other in the East – were very definite that tumors need to be treated with drugs, radiation, and surgery – that only these medical interventions can get at the cancer cells.

It’s also important to remember that many anticancer drugs have their origin in natural sources – not just the familiar Taxol, a synthetic compound derived from the Pacific Yew tree, but also vincristine, which comes from periwinkle (Vinca rosea), among others. The National Cancer Institute maintains an incredible collection of natural products from around the world, everything from deep sea sponges from off the coast of New Zealand to bacteria found at the top of the Andes mountains to samples of soil found in an average backyard (for their microbial value). Now of course any of those products would be studied in vitro, and then in animals, and then in people, in accordance with the clinical trials process.

But TCM and other approaches, like changes in diet and stress-reducing practices, can go a long way toward helping people heal, and we don’t know what role they might have in prevention. Yes, one shouldn’t walk naively into these practices thinking they will miraculously reverse the problem (and plenty of people are guilty of walking into a phase I clinical trial thinking that they might be the patient on whom a revolutionary compound works its unexpected miracle). But is it helpful to deliver a judgment against TCM practices because they haven’t been scrutinized in clinical trials? Can they be studied in clinical trials? Many people argue that the number of variables at play just can’t be controlled for, and that it’s impossible to isolate the exact mechanism by which dietary changes, etc. work their wonders.

Can you get there (building the evidence for complementary medicine) from here (modern medicine)? Is it possible that understanding traditional Eastern medicine requires an entirely different school of thought? Is it possible that there is some rigorous way to examine things like acupuncture and herbal teas that satisfies our need for evidence without dismissing the notion that these approaches may work according to pathways that somehow do not come under the radar of a clinical trial process?

History is littered with stories of people who were first mocked by their colleagues before being celebrated (Bose, of sound system fame, comes to mind). Simply dismissing complementary medicine as a sham is the sign of a closed mind, not a scientific one.

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