September 29, 2010

Hepatitis C Virus Faces New Weapon From Scientists

Released: 9/29/2010 12:00 PM EDT Source: Florida State University

Newswise — In recent human trials for a promising new class of drug designed to target the hepatitis C virus (HCV) without shutting down the immune system, some of the HCV strains being treated exhibited signs of drug resistance.

In response, an interdisciplinary team of Florida State University biologists, chemists and biomedical researchers devised a novel genetic screening method that can identify the drug-resistant HCV strains and the molecular-level mechanisms that make them that way –– helping drug developers to tailor specific therapies to circumvent them.

The potentially life-saving technology also works when screening other viruses with drug-resistance issues, notably human immunodeficiency virus (HIV) and influenza.

More than 170 million people worldwide are infected with HCV, which leads to both acute and chronic liver diseases.

“In collaboration with pharmaceutical firm Gilead Sciences and researchers from the University of Heidelberg (Germany), what our research team discovered was how the latest drug for HCV works and what changes in the virus that makes it resistant to this unique therapy,” said Hengli Tang, a Florida State University molecular biologist.

“This is knowledge that is essential to drug developers focused on HCV,” said Tang, “but equally important is that our method, which we call ‘CoFIM’ (Cofactor-independent mutant) screening, can also be applied to other drug targets and other viruses.

“And, since we now understand how this latest class of drug works and what causes resistance to it, we can better select other classes of drugs with distinct mechanisms –– in other words, those that target other parts of the virus –– in order to craft a combination therapy, which is the future of HCV therapy and the key to overcoming drug resistance.”

The groundbreaking research is described in a paper published online in the September 2010 issue of the journal PLoS Pathogens.

Florida State biology doctoral student Feng Yang led the research team. The award-winning scholar earned her Ph.D. in August 2010 and is now a postdoctoral associate at Yale University. Yang designed the CoFIM screening methodology with fellow FSU graduate students, postdoctoral associates and distinguished faculty colleagues –– including Associate Professor Tang; chemistry/biochemistry Professor Timothy M. Logan, director of FSU’s Institute of Molecular Biophysics; and Research Assistant Professor Ewa A. Bienkiewicz, of the FSU College of Medicine, where she directs the Biomedical Proteomics Laboratory.

Driving the team’s development of CoFIM screening was the need to identify key “cellular cofactors” and their mechanisms of action –– a fundamental aspect of virus-host interaction research.

“’Cellular cofactors’ are proteins that normally exist in host cells that have been hijacked by viruses to facilitate viral replication.” Tang said. “They became accomplices to the invading viruses.

“Our research team was the first to show that ‘cyclophilin A’ (CyPA) is an essential cellular cofactor for hepatitis C virus infection and the direct target of a new class of clinical anti-HCV compounds, which include cyclosporine A (CsA)-based drugs that are devoid of immunosuppressive function,” Tang said.

“In addition, we went a step further than other research teams by employing our newly developed CoFIM screening method, which we used to demonstrate not only HCV’s dependence on cellular cofactor cyclophilin A and susceptibility to cyclosporine A drugs but also to uncover the molecular-level regulators that determine those two traits in the virus.”

Those molecular-level regulators are known as “small interfering RNA libraries” –– collections of molecules so named for their size and ability to suppress gene expression. They act to individually suppress every gene in the cell, resulting in different consequences depending upon which gene is suppressed by a given member in the library.

The CoFIM screening method involves inducing or “coaxing” the HCV virus to mutate by itself, in vitro, absent the replication assistance it normally receives from a particular cellular cofactor. Then, CoFIM tracks the changes in the virus’s response both to CsA-based drugs and any other drug designed to inhibit the cofactor.

Funding for the research conducted at Florida State University came in largest part from a $1.4 million grant awarded by the National Institutes of Health (NIH). And, because chronic liver disease caused by HCV can lead to liver cancer, a grant from the American Cancer Society provided additional support.

In addition to now-doctoral alumna Feng Yang and faculty members Hengli Tang, Timothy M. Logan and Ewa A. Bienkiewicz, the Florida State University co-authors of the PLoS Pathogen paper (“A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach”) are current biology doctoral students Henry Grise and Stephen Frausto and postdoctoral associates Anita Nag and Jason M. Robotham. Co-authors from the University of Heidelberg Department of Infectious Diseases are Vanesa Madan, Margarita Zayas and Ralf Bartenschlager, and from Gilead Sciences (Foster City, Calif.), Andrew E. Greenstein and Margaret Robinson.

Source

Hep C may benefit from genetic fingerprinting, research says

September 28, 2010 Genetic fingerprinting may predict who will benefit from early hepatitis C treatment and who will clear the virus spontaneously, new research shows.

The way doctors think about hepatitis C treatment is changing, with researchers saying it is now possible to use genotyping to predict which patients are likely to clear the infection spontaneously and which will benefit from early therapy.

A team of UNSW researchers, led by Professor Gregory Dore and Dr. Jason Grebely, has determined that genetic changes near the human IL28B gene - identified recently as linked to the ability to control hepatitis C infection - may also be used to identify those patients with recent infection whose own immune system is likely to clear the virus without therapy.

“The use of human genotyping may change the landscape of how we treat patients with recent HCV infection,” said Dr. Grebely, a lecturer in the Viral Hepatitis and Clinical Research Program at UNSW’s National Centre in HIV Epidemiology and Clinical Research (NCHECR).

It’s the first time that patients with early hepatitis C infection, who are likely to clear the virus on their own, might be identified and spared treatment, which is expensive and has side effects, Dr. Grebely said.

“IL28B genetic testing, prior to treatment for HCV infection, is likely to be incorporated into clinical care to identify those most likely to respond,” Dr. Grebely said. “For those patients without the favourable genotype, the doctor can proceed with treatment, knowing it is better to treat early than waiting until the condition has become chronic.”

The findings will be published this week in the journal Hepatology.

Source
Novel Agents Will Also Yield Faster Treatment Initiation of Newly Diagnosed HCV Patients, According to a New Report from Decision Resources

BURLINGTON, Mass., Sept. 27 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that the launch of novel therapies for the treatment of Hepatitis C Virus (HCV), including Vertex/Johnson & Johnson/Mitsubishi Tanabe's telaprevir and Merck's boceprevir, will precipitate several changes in HCV treatment. According to Patient Flow in Hepatitis C Virus, surveyed physicians plan to initiate treatment in at least half of their "warehoused" HCV1 patients one year after novel therapies become available. Patient "warehousing" is a term that has been coined to characterize the phenomenon of HCV patients opting out of treatment with current standard of care in anticipation of new therapies; psychiatric events, adverse events and liver health are top reasons keeping patients away from current therapies.

The report also finds that time from initial diagnosis to treatment initiation will decrease once novel HCV therapies are available. On average, surveyed physicians stated they wait 17 months to initiate treatment in HCV1 treatment-naive patients; this time will decrease to 7 months once novel treatment options are available.

"The arrival of telaprevir and boceprevir will alter more than the drug-treatment rate and treatment initiation timing in HCV," said Alexandra Makarova, M.D., Ph.D. "Physicians indicate they would increase the capacity of their HCV practice to accommodate the additional patients expected once novel therapies are available."

About Patient Flow in Hepatitis C Virus

Patient Flow in Hepatitis C Virus is a 15-year, annualized patient forecast for each of the G7 countries that estimates the total size of the declining prevalent HCV population and segments it by viremic status, HCV genotype and line of therapy. It includes two components: an Excel workbook containing quantitative analysis, including patient forecast and modifiable assumptions and a PowerPoint slide deck of primary research survey results of 100 U.S. gastroenterologists and hepatologists.

About Decision Resources

Decision Resources (http://www.decisionresources.com/) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

About Decision Resources, Inc.

Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at http://www.decisionresourcesinc.com/.

All company, brand or product names contained in this document may be trademarks or registered trademarks of their respective holders.

For more information, contact:

Decision Resources
Lisa Osgood
781-993-2606
losgood@dresources.com

Decision Resources, Inc.
Chris Comfort
781-993-2597
ccomfort@dresources.com

SOURCE Decision Resources

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