Friday Round Up - Hepatitis News Ticker:

 This Weeks Updates:

Muscle and Mortality in Cirrhosis
The 2012 AASLD Hepatitis Single Topic Conference (STC)
Entry point of hepatitis C virus identified
Big Pharma:The Hepatitis C Race For Tolerable Therapies
Germany’s IQWiG sees added benefits for Incivo
Pharmasset's Hepatitis C Drug: How it Could Change Australia
Watch-Beware of Hepatitis B at the nail salon
Magic mushrooms point to new depression drugs
Pot-based prescription drug looks for FDA OK 
Drop in effectiveness of HCV treatment in national VA practice
New Hepatitis C Regimen Stimulates Changes in Therapy Management
Hepatitis C Virus Infection In Non-Hodgkin’s Lymphoma: A Case Control Study 
Dietary Fiber for the Treatment of Type 2 Diabetes Mellitus
Editorial-How to Optimize Treatment of Hepatitis C

Today In The News

Big Pharma

Biotech Stock Mailbag: Vical, Hep C Drugs

Two basic defining characteristics of nucs make them ideal drugs for hepatitis C. First, nucs are prodrugs, which means they're inactive until the body (in this case, the liver) metabolizes the drug into an active form. Having a drug that concentrates and activates in the liver is ideal for viral liver disease like hepatitis C.

Second, nucs, unlike PIs, have a high barrier to viral resistance, meaning the virus has a difficult time mutating or changing into forms that can fight off the drug. Nucs probably can't effectively cure hepatitis C on their own (at least not the current nucs) but Gilead's PSI-7977 (obtained from Pharmasset) may only need to be combined with ribavirin for a short time to be highly effective in treating genotype 2/3 patients -- and perhaps genotype 1 patients as well.

Drawbacks to nucs are that these drugs are generally less potent than PIs (although again, PSI-7977 surprised a lot of people by having PI-like potency) and the risk of serious side effects. Recently, Pharmasset had to shelve another of its nucs due to unacceptable liver toxicity.
Researchers -- and investors -- are so excited about nucs (more so than PIs) these days because the nucs' high barrier to viral resistance means combinations of all-oral drugs can be designed that exclude the need for weekly injections of interferon.

An all-oral therapy against hepatitis C is the golden ticket that every drug company involved in the field is shooting for. At this point, nucs more so than PIs, appear to have the edge as the backbone of future all-oral regimens, and that explains the billions of dollars spent recently to acquire nucs.

Two updates on old friends of the Mailbag who may be nearing their respective ends:
Generex Biotechnology(GNBT_) disclosed in a regulatory filing Tuesday night that it took out second mortgages on company-owned property to raise money to remain in business. I've seen a lot of crazy financing schemes in my days covering biotech, but I've never seen a company resort to real-estate loans (with a 10% annual interest rate, mind you) to keep the lights on. 

Read Complete Article Here 


Ex-doc to have fitness hearing in Vegas hep C case

By: The Associated Press | 01/27/12 7:02 AM
The Associated Press

A Nevada judge is due to consider the fitness of a once prominent Las Vegas physician to stand trial on criminal charges in a 2008 hepatitis outbreak.
Clark County District Court Judge Kathleen Delaney is scheduled to hear arguments Friday whether 62-year-old Dipak Desai (DEE'-pak des-EYE') is mentally competent for trial with two former employees on felony racketeering, fraud and patient neglect charges.
The three men have pleaded not guilty. They could face decades in prison.
Each is accused of infecting patients at Desai clinics with incurable hepatitis C by reusing endoscopy scopes and vials of an injected anesthetic during outpatient procedures.
Defense lawyer Richard Wright says Desai is incapacitated by strokes and can't help his defense.
Prosecutor Michael Staudaher contends Desai is exaggerating his ailments to avoid trial.

HCV Management for Individuals on Methadone Maintenance
This article takes an in-depth look at hepatitis C treatment options in a specialized community of people on methadone maintenance.
Journal of Viral Hepatitis, January 2012

Effect of IL28B Genotype on Early Viral Kinetics during Interferon-Free Treatment of Patients with Chronic Hepatitis C
Kulkarni R, Gane EJ, Roberts SK, Stedman C, Angus PW, Ritchie B, Lu XY, Ipe D, Lopatin U, Germer S, Iglesias VA, Elston R, Smith PF, Shulman NS; Gastroenterology (Jan 2012)

Abstract
Background & Aims
Although IL28B genotype affects the response of patients with chronic hepatitis C (CHC) to peginterferon and ribavirin, little is known its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and hepatitis C virus (HCV) protease inhibitor danoprevir.
Methods
We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment-naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts, then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hrs or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a bi-phasic model to describe first- and second-phase slopes of viral decay during therapy.
Results
At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log₁₀ IU/mL) than those without (4.59 log₁₀ IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up.
Conclusions
IL28B genotype appears to affect early VKs in patients with CHC receiving interferon-free treatment.


Minimal Hepatic Encephalopathy Does Not Impair Health-related Quality of Life in Patientswith Cirrhosis
A Prospective Study

Ewa Wunsch; Barbara Szymanik; Michał Post; Wojciech Marlicz; Marta Mydłowska; Piotr Milkiewicz

Posted: 01/23/2012; Liver International. 2011;31(7):980-984. © 2011 Blackwell Publishing

Discussion Only
Click Here To View-Abstract,Patients,Methods and Results

In order to clarify the real impact of minimal HE on daily functioning, we have studied HRQoL in cirrhotic patients without clinical evidence of overt HE, but with abnormal neurophysiological profile. We noted that patients with minimal HE experienced HRQoL similar to other cirrhotics without minimal HE, an observation in contrast with other studies.^[4,6] Only one study indicated unimpaired daily functioning in subjects with minimal HE when assessed with specific CLDQ.^[17] Two main reasons may explain these observations. Firstly, there is no standard diagnostic procedure for minimal HE.^[18] Electrophysiological tools such as the electroencephalogram, evoked potentials and single psychometric tests have been used to identify patients with minimal HE.^{[5, 6, 17, 19–21]} The electroencephalogram has fallen behind psychomotor tests, mainly because of the lower diagnostic sensitivity.^[22] Psychometric tests are now recommended for the diagnosis of minimal HE; nevertheless, a standardized battery of such tools should be used to counteract the poor sensitivity of a single test.^[1,23,24] To date, PHES has been used in none of the studies of HRQoL.
Secondly, the majority of studies have assessed HRQoL with general questionnaires, such as Sickness Impact Profile or SF-36.^[4–6] These widely used instruments measure an overall impact of a disease on the patient's well-being but do not evaluate symptoms specific for liver disease and are less responsive to small but clinically significant changes. Therefore, disease-specific questionnaires perhaps should be more appropriate in establishing the effect of liver disease on daily functioning. CLDQ was developed for the assessment of HRQoL in chronic liver damage and contains questions that are specific for advanced liver disease such as ascites, fatigue or pruritus.^[15] It is possible, however, that this tool is not sensitive enough to measure the real effect of mild hepatic dysfunction and subclinical condition such as minimal HE. So far, however, no specific instrument was developed for the evaluation of HRQoL in minimal HE. In summary, this study showed no significant effect of minimal HE on patients' HRQoL measured both with SF-36 and CLDQ. This finding requires validation in larger cohorts of patients with minimal HE.
This project was supported by grant N402-100-31/3038 from the Ministry of Science and Higher Education.

FDA

FDA Supplement Guidance Not Strict Enough, MD Says
An FDA proposal to require dietary supplement manufacturers to submit data proving their product is safe doesn't go far enough, according to a physician writing in the New England Journal of Medicine.
More than 100 million Americans spend more than $28 billion on vitamins, minerals, herbal ingredients, amino acids and other natural products in the form of dietary supplements each year, "assuming they are both safe and effective," wrote Pieter A. Cohen, MD, of Harvard Medical School and the Cambridge Health Alliance. 

But they have no assurance that the products are safe because FDA regulation of supplements is too weak, Cohen wrote in a Perspective piece.

By law, ingredients that were used and sold in supplements prior to 1994 can be marketed without any proof that they are safe or effective. But under a law called the Dietary Supplement Health and Education Act (DSHEA), manufacturers of any ingredient introduced after 1994 must provide the FDA with evidence supporting "a reasonable expectation of safety."
Cohen said that part of the law "has thus far not been enforced."

Since DSHEA became law more than 15 years ago, the number of supplements on the market has gone from 4,000 to more than 55,000. Since 1994, the FDA has received proper notification for 170 new supplement ingredients, "undoubtedly a small fraction of the ingredients for which safety data should have been submitted," Cohen said.

The FDA has mounted a new effort to discourage the sale and use of nutritional supplements that contain ingredients that are regulated as drugs. Last year, the agency issued draft guidance meant to inform supplement manufacturers about what information they must submit to the FDA, including spelling out when an ingredient is considered old and when it's considered new. (A synthetically produced replica of a botanical product, for instance, would be considered new).
In addition, the FDA is proposing that the guidance call for in vitro, animal, and long-term tolerability testing for supplements that would be marketed at higher doses than those historically ingested.
"The FDA's guidance provides a thoughtful framework for evaluating the safety of new ingredients and if implemented it would lead to substantial improvement in safety," Cohen wrote, but he said he didn't think the FDA goes far enough.

He said under the guidance, companies can use historical data (instead of clinical trials) to prove that a supplement is safe, and Cohen said that the FDA can't assess the safety of new products scientifically without experimental data.

Cohen also said that under the guidance, manufacturers would not be required to submit both favorable and unfavorable data to the FDA, so they could cherry-pick only positive data to submit.
The dietary supplement industry largely opposes the draft regulation.

One opponent is the Natural Products Association, whose 1,900 members include small health food stores and large supplement manufacturers. The group submitted its official response to the FDA's proposal in November and said the agency is "overstepping" and that the rules would have a "chilling effect" on the dietary supplement industry.

"The draft guidance as currently written sets up inappropriate barriers to market entry, imposes food additive criteria, and requires multiple ... notifications beyond those required by law," the group wrote.

Cohen said it's true that the proposed requirements would impose similar standards on supplements and food additives.

"Industry advocates are correct insofar as DSHEA does not hold established (pre-1994) supplement ingredients to the same safety standards as food additives: a chemical preservative sprayed inside a can of tomato soup or the purple dye in Jell-O requires much more evidence of safety than ingredients used in supplements," Cohen wrote.

Cohen urged the FDA to not change its proposal because of protests from industry.
"If the FDA succumbs to industry pressure, the public health consequences will be significant, as hundreds of thousands of Americans continue to turn to new supplements to sustain their health and treat their ailments," he said.

The FDA is accepting comments on the draft guidance until Feb. 1

Women And Chronic Pain

Stanford study of electronic medical records that found women reported more-intense pain than men may in virtually every disease category..

read more here at Scope.

Off The Cuff

 Researchers Show How New Viruses Evolve, and in Some Cases, Become Deadly

Michigan State researchers show how new viruses evolve, and in some cases, become deadly.

January 26, 2012


View a video with Michigan State University researchers who showed how a new virus evolved potentially dangerous traits.

Researchers at Michigan State University (MSU) have demonstrated how a new virus evolves, shedding light on how easy it can be for diseases to gain dangerous mutations. The findings appear in the current issue of the journal Science.

The scientists showed for the first time how the virus called "Lambda" evolved to find a new way to attack host cells, an innovation that took four mutations to accomplish. This virus infects bacteria, in particular the common E. coli bacterium. Lambda isn't dangerous to humans, but this research demonstrated how viruses evolve complex and potentially deadly new traits, noted Justin Meyer, MSU graduate student, who co-authored the paper with Richard Lenski, MSU Hannah Distinguished Professor of Microbiology and Molecular Genetics.

"We were surprised at first to see Lambda evolve this new function, this ability to attack and enter the cell through a new receptor--and it happened so fast," Meyer said. "But when we re-ran the evolution experiment, we saw the same thing happen over and over."

This paper follows recent news that scientists in the United States and the Netherlands produced a deadly version of bird flu. Even though bird flu is a mere five mutations away from becoming transmissible between humans, it's highly unlikely the virus could naturally obtain all of the beneficial mutations at once. However, it might evolve sequentially, gaining benefits one-by-one, if conditions are favorable at each step, Meyer added.

Through research conducted at BEACON, MSU's National Science Foundation Center for the Study of Evolution in Action, Meyer and his colleagues' ability to duplicate the results implied that adaptation by natural selection, or survival of the fittest, had an important role in the virus' evolution.
Read the full MSU news release here.

Funding for the research was provided in part by NSF and MSU AgBioResearch.

-NSF-

For Your Reading Pleasure

Explore the History of Medical Discoveries
Posted by Karen Buckley • January 26th, 2012

Over 200 years, the New England Journal of Medicine has published early descriptions of disease, groundbreaking new treatments for particular conditions, and the first steps toward significant changes in how physicians care for patients.  The 200^th anniversary website has an interactive timeline that allows you to search and rediscover the progress of centuries past.   Each image links to historical information or the full text of the article, as originally written in NEJM.