November 7, 2010

J Gastroenterol. 2010 Nov 3. [Epub ahead of print]

Kobayashi Y, Kawaguchi Y, Mizuta T, Kuwashiro T, Oeda S, Oza N, Takahashi H, Iwane S, Eguchi Y, Anzai K, Ozaki I, Fujimoto K.

Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga, Japan.

Abstract

BACKGROUND: Although serum alanine aminotransferase (ALT) activity is an important marker for the management of chronic hepatitis C (CHC), the factors associated with serum ALT levels remain to be fully understood. This study aimed to clarify the association between serum ALT levels and clinical, histological, and virological factors in patients with CHC.

METHODS: We retrospectively analyzed 256 patients with CHC who underwent liver biopsy, and classified them into three groups according to serum ALT levels: normal to minimal (<40 IU/L), mild (40-80 IU/L), and moderate to severe elevation (≥80 IU/L). All demographic and laboratory data were collected at the time of liver biopsy. All biopsies were evaluated for fibrosis, inflammation, and steatosis. Glucose metabolism was assessed by various indices derived from oral glucose tolerance tests, including the homeostasis model assessment for insulin resistance (HOMA-IR). In 180 patients, visceral fat area was measured at the umbilical level by abdominal computed tomography.

RESULTS: Ordered logistic regression analysis showed that higher serum ALT levels were significantly associated with male sex, lower high-density lipoprotein cholesterol (HDL-C), higher HOMA-IR, and higher grades of histological inflammation and steatosis. HOMA-IR, HDL-C, and hepatic steatosis were associated with visceral fat accumulation.

CONCLUSIONS: Metabolic factors, as well as sex and hepatic inflammation, are independent risk factors for serum ALT elevation in hepatititis C virus (HCV)-infected patients. Metabolic factors may offer targets to decrease serum ALT levels.

PMID: 21046172 [PubMed - as supplied by publisher]

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Hepatology. 2010 Nov;52(5):1573-80.

Lam KD, Trinh HN, Do ST, Nguyen TT, Garcia RT, Nguyen T, Phan QQ, Nguyen HA, Nguyen KK, Nguyen LH, Nguyen MH.

Pacific Health Foundation, San Jose, CA, USA.

Abstract

Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open-label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN-α2a 180 μg subcutaneously weekly and weight-based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention-to-treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.3 ± 1.1 IU/mL) were enrolled: 27 patients to 24 weeks and 33 patients to 48 weeks of therapy. In the 24-week and 48-week groups, 96% and 97% achieved early virologic response (P = 0.90); 89% versus 94% achieved end of therapy virologic response (P = 0.48). SVR was achieved in 70% versus 79% of patients assigned to 24 weeks versus 48 weeks (P = 0.45). Rapid virologic response (RVR) was a significant predictor of SVR in the 48-week group and trending towards significance in the 24-week group: 82% and 83% of those with RVR achieved SVR versus 33% and 29% for the 24-week and 48-week groups, respectively (P = 0.07 and P = 0.02). CONCLUSION: There was no significant difference in SVR rates in patients with HCV genotype 6 treated with PEG IFN-α2a and RBV for 24 versus 48 weeks.

PMID: 21038410 [PubMed - in process]

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Gastroenterology. 2010 Oct 26. [Epub ahead of print]

Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Serfaty L, De Backer K, Van Heeswijk R, Luo D, Picchio G, Beumont M.

Service d'Hépatologie and Inserm CRB3, Hôpital Beaujon, APHP University of Paris, Clichy, France.

Abstract

BACKGROUND & AIMS: Recent studies demonstrated that 12 weeks of telaprevir, administered every 8 hours (q8h), combined with peginterferon alfa-2a plus ribavirin (peginterferon alfa-2a/ribavirin), significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype-1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12h), in combination with peginterferon alfa 2a or 2b.

METHODS: Treatment-naïve patients (n=161) infected with HCV genotype-1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8h or 1125 mg q12h), in combination with standard doses of peginterferon alfa-2a (180 μg/week) and ribavirin (1000-1200 mg/day) or peginterferon alfa-2b (1.5 μg/kg/week) and ribavirin (800-1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of peginterferon alfa and ribavirin, based on virologic response.

RESULTS: Baseline characteristics were similar for all groups. SVR rates were 81.0%-85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P≥0.787), between the pooled q8h and q12h groups (P = 0.997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = 0.906). The safety profile was similar among all groups.

CONCLUSIONS: A high proportion (>80%) of patients achieved a SVR regardless of the telaprevir dosing frequency (q8h or q12h) or type of peginterferon alfa used (alfa-2a or alfa-2b). All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21034744 [PubMed - as supplied by publisher]

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Article in Press

Naga Suresh Veerapu, Sukanya Raghuraman, T. Jake Liang, Theo Heller, Barbara Rehermann
Received 26 May 2010; received in revised form 24 September 2010; accepted 22 October 2010. published online 01 November 2010.

Accepted Manuscript

Abstract

Background & Aims
Several studies have reported persistence of hepatitis C virus (HCV) RNA in the circulation after treatment-induced or spontaneous recovery. We investigated whether the HCV RNA represents persistence of HCV infection or re-infection.

Methods
We studied 117 patients that recovered from HCV infection (98 following therapy and 19 spontaneously). A reverse transcriptase (RT)-PCR assay was used to detect the 5’UTR of HCV RNA. T-cell responses were studied by ELISpot analysis of interferon-γ.

Results
Plasma samples from 15% of patients who recovered following treatment and none who recovered spontaneously tested positive for HCV RNA. Lymphocytes from 3 patients that responded to therapy and 1 that recovered spontaneously tested positive. The frequency of HCV RNA detection in plasma correlated inversely with the time after the end of treatment. Post-treatment HCV 5’-UTR sequences matched pre-treatment sequences in 85% of cases. T-cell responses were significantly greater at timepoints with detectable trace amounts of HCV RNA than at timepoints without detectable HCV RNA (P=0.035) and were primarily against nonstructural HCV antigens. The immune hierarchy was preserved over 5 years in patients; post-treatment HCV RNA sequences matched pretreatment sequences, indicating HCV RNA persistence. An altered immune hierarchy with dominant immune responses, shifting from nonstructural to structural antigens, was observed in a single patient. The genotype of the detected post-treatment HCV RNA differed from that of the pretreatment genotype in this patient, indicating re-infection with HCV.

Conclusions
Trace amounts of HCV RNA of pretreatment sequence persisted and re-appeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection. Reappearance of HCV RNA induced HCV-specific T-cell responses.

All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

Keywords: IFN, liver disease, virology

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Bob Roehr

November 7, 2010 (Boston, Massachusetts) — The utility of maintenance pegylated interferon (PegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients with advanced chronic hepatitis has been a contentious matter for some time.

The pendulum has swung from support for the idea to early evidence of a lack of efficacy. Now, here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, longer-term data suggest marginal, limited support for its use. Most surprisingly, data opposing its use — and now for its support — have come from the same study, the ongoing Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial.

Anna S. Lok, MD, from the University of Michigan Medical Center in Ann Arbor, presented the latest iteration of data on extended follow-up. "In an earlier report, which included a median follow-up of up to 4.6 years, with a total of 53 HCC cases, we found no difference between the treated and the control groups. The 2 lines basically were identical."

The newer analysis was based on a median of 6.1 years of follow-up. There were "almost double the number of HCC cases, with a total of 88," Dr. Lok reported. The cumulative incidence of HCC at 3, 5, and 7 years for the treated group was 2.3%, 6%, and 8.1%, respectively. Incidence in the control group was 2.5%, 6.2%, and 13.8% at 3, 5, and 7 years, respectively.

"The 2 lines of the Kaplan-Meier Curve completely overlap until the end of year 6, when there is a divergence in the 2 lines, and the P value was not significant," Dr. Lok said.

"However, when we analyzed the data separately, for the fibrosis substratum and the cirrhosis substratum, we saw that the treated group had a significantly lower incidence of HCC compared with the untreated group, with a hazard ratio of 0.45 and a P value of .01."

Subsequent analysis showed that incidence of HCC was significantly lower in patients who had completed at least 2 years of treatment. "They had less advanced liver disease, more normal platelet counts, and normal [aspartate aminotransferase] levels."

Dr. Lok concluded, "Extended follow-up of the HALT-C cohort showed a modest effect of long-term low-dose PegIFN in reducing the incidence of HCC in patients with hepatitis C and cirrhosis, but not in those with advanced fibrosis.

"Given the marginal benefit on HCC, the lack of overall benefit on disease progression, and the side effects of PegIFN, the utility of maintenance PegIFN to prevent HCC in patients with HCV-related cirrhosis who failed to achieve SVR is limited," she acknowledged.

Arun J. Sanyal, MD, American Association for the Study of Liver Diseases president and head of the division of gastroenterology at Virginia Commonwealth University, in Richmond, said, "This, potentially, could be very important."

During the question session, treatment activist Jules Levin said 4 years ago the initial analysis and strong recommendations not to treat "did a lot of damage to patients and to the field. I took issue with the investigators over that" at the time, Mr. Levin said.

Subsequent research and analysis of this trial have shown that they were wrong. "It has done irreparable damage to patients. It is important to take note of this." Mr. Levin said. "Patients and their own clinicians should be able to make their own decision for what benefits them based on a clear understanding of the data."

The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases is funding the HALT-C trial. The speakers have disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting: Abstract 214. Presented November 2, 2010.

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By Cheryl Lathrop

BOSTON -- November 5, 2010 -- Supersonic shear imaging (SSI) appears to be a fast, simple, and reliable method for noninvasive liver fibrosis staging and shows better discrimination than one-dimensional transient elastography for each fibrosis stage, researchers said here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

Eric Bavu, MD, INSERM, and Langevin Institute, Paris, France, and colleagues reported the findings here on November 1.

The study included 113 patients with hepatitis C virus. Patients underwent both SSI one-dimensional transient elastography. Of these, 108 patients had results that were relevant and that were included in the final analysis.

Hepatic fibrosis was determined retrospectively on the basis of liver biopsy, on clinical history, and on 3 noninvasive biomarkers gathered the day of the imaging, aspartate to platelets ratio index, and Forn's Index.

The researchers assessed a comparison between the performances of SSI and one-dimensional transient elastography using receiver operator characteristic (ROC) curves analysis and one-way analysis of variance (ANOVA) analysis between the assessed elasticity value and the fibrosis stage.

There was a better correlation between fibrosis staging and elasticity measurements with SSI (p ~10-16) than with one-dimensional transient elastography (p ~10-15).

The areas under the ROC curves for stiffness values assessed by SSI were 0.948 for fibrosis staging >=2; 0.962 for staging >=3; and 0.968 for staging =4. In comparison, with one-dimensional transient elastography, the values were 0.846 for >=2, 0.857 for >=3, and 0.940 for =4, respectively.

The comparisons between SSI and one-dimensional transient elastography were particularly significant for mild (F0-F1; P =.005) and moderate (F2; P =.001) fibrosis.

"SSI is a fair method to evaluate patients with chronic liver disease, and determine those to treat and those not to treat," said Dr. Bavu.

[Presentation title: A New Potent Morphological Non-Invasive Predictor of Liver Fibrosis Staging by Supersonic Shear Imaging. Abstract 1327]

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SAFE IN COMMON Launches Global Injection Safety Website

Online Community Championing Improved Global Injection Safety Standards Coincides with the 10th Anniversary of the Needlestick Safety and Prevention Act

LEWISBERRY, Pa., Nov. 5, 2010 /PRNewswire/ -- SAFE IN COMMON, an online community of healthcare workers, educators, patients, community leaders and individuals, today announced the launch of its website dedicated to raising awareness of global injection safety challenges.

SAFE IN COMMON's launch coincides with the 10th anniversary of the passage of the Needlestick Safety and Prevention Act, which mandates the use of safety engineered medical devices, (SEMDs), within U.S. healthcare facilities to protect healthcare workers and patients from the risk of needlestick injuries. Despite this legislation and its enforcement by OSHA, healthcare workers continue to remain at risk of harm. For example, reports in the U.S. indicate that currently available safety syringes are not providing adequate levels of protection. In fact, reported needlestick injuries in Massachusetts have not fallen since 2002, and safety products are responsible for the majority of those injuries.

While steps have been taken in the U.S. and Europe to mandate the use of SEMDs, the harm caused by unsafe injection practices represents a global humanitarian challenge. According to the World Health Organization (WHO), there are more than 1.3 million needlestick related deaths worldwide each year.

"As a former nurse, I have first hand experience with the physical and emotional dangers of a needlestick injury. However, the problems and risks associated with needlestick injuries are real and affect the lives of millions of people around the world, not just those in the healthcare field," commented Dr. Mary Foley, Associate Director, Center for Nursing Research and Innovation. "Much has been accomplished since the signing of the Needlestick Safety and Prevention Act of 2000, but the safety laws and policies currently in place are poorly enforced and need to be addressed. SAFE IN COMMON is in a unique to position to advocate for this change. Not only will SAFE IN COMMON serve as a community for those impacted by unsafe needlestick practices and injuries, but it will also act as a unified voice to educate and fight for better, more effective solutions."

Led by a team of highly experienced and influential board members, SAFE IN COMMON was created to raise awareness and support the global transition to safe, simple injections. As a social community, SAFE IN COMMON will also seek to provide support and coverage to all international markets focused on the enhancement of safe injection practices.

Outside of healthcare facilities, SAFE IN COMMON will also seek to address specific injection safety challenges relating to patients who administer prescription drugs at home, injecting drug users and other stakeholders associated with harm reduction, and the vaccination / immunization programs of developing and emerging nations. With such markets that operate largely outside of healthcare facilities, unsafe injection practices such as the re-use, sharing or unsafe disposal of non-sterile injection devices may accelerate HIV and hepatitis C epidemics.

The new website, http://www.safeincommon.org/, will feature blogs, a resource library, links to industry information, forums for contributors to express thoughts and experiences, surveys, and other ways to interact and promote injection safety.

Current SAFE IN COMMON board members include:

Mary Foley: RN, MS, PhD, Past President American Nursing Association and Associate Director, Center for Nursing Research and Innovation, University of California, San Francisco.

• Ron Stoker: Executive Director of the International Sharps Injury Protection Society (ISIPS).

• Gerald Verollet: Former head of the medical device division at the World Health Organization (WHO).

• Jason Tetro: Infection control advocate, blogger and coordinator at two research centers for microbiology at the University of Ottawa.

• Evelyn McKnight: Patient safety advocate, author of "A Never Event" and founder of HONOReform, a national advocacy organization dedicated to protecting patients through safeguarding the medical injection process.

SAFE IN COMMON is also being sponsored by Unilife Corporation (Nasdaq: UNIS), a medical device company focused on the design, development, manufacture and supply of a proprietary range of retractable syringes.

The Community seeks additional alliances with organizations that share in the goal of reducing the global harms of needlestick injuries and other unsafe injection practices. For more information about SAFE IN COMMON, please visit the website at http://www.safeincommon.org/.

About SAFE IN COMMON:

Launched in November 2010, SAFE IN COMMON is a community of healthcare workers, educators, patients, community leaders and individuals who share one desire…a world where every injection is both simple and safe. SAFE IN COMMON features blogs, a resource library, links to industry information, forums for contributors to express thoughts and experiences, surveys, and other ways to interact and promote injection safety. For more information about SAFE IN COMMON, please visit the community's official website at http://www.safeincommon.org/.

Website development by http://www.trajectory4brands.com/.

Media Contact:
Susan Carr
susan.carr@safeincommon.org

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http://www.safeincommon.org/

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Small protein changes may make big difference in natural HIV control

Submitted by editor on November 7, 2010 - 10:33

Tiny variants in a protein that alerts the immune system to the presence of infection may underlie the rare ability of some individuals to control HIV infection without the need for medications. In a report that will appear in Science and is receiving early online release, an international research team led by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard and from the Broad Institute of MIT and Harvard describe finding that differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only.

We found that, of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS, says Bruce Walker, MD, director of the Ragon Institute and co-senior author of the Science article. Understanding where this difference occurs allows us to sharpen the focus of our efforts to ultimately harness the immune system to defend against HIV.

Earlier studies had showed that certain genes involved with the HLA system were important for HIV control, adds Paul de Bakker, PhD, of the Broad Institute and Brigham and Womens Hospital, co-senior author. But they couldnt tell us exactly which genes were involved and how they produced this difference. Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function.

It has been known for almost two decades that a small minority – about one in 300 – of individuals infected with HIV are naturally able to suppress viral replication with their immune system, keeping viral load at extremely low levels. To identify genetic differences that may underlie this rare ability, Florencia Pereyra, MD, at the Ragon Institute established the International HIV Controllers Study(http://www.hivcontrollers.org/) in 2006, with a goal of enrolling 1,000 HIV controllers from medical clinics and research institutes around the world. That goal was expanded to 2,000 controllers in 2008, and thus far over 1,500 controllers have been enrolled.

The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection, through a collaboration with the AIDS Clinical Trials Group. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins. Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia – a medical student in the Harvard-MIT Health Sciences and Technology program, working with de Bakker at the Broad – pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control.

HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 killer T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.

Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not, de Bakker says. Our work demonstrates that these variants could make a crucial difference in the individuals ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system.

Walker adds, HIV is slowly revealing its secrets, and this is yet another. Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer.

The investigators note that these findings would not have been possible without the participation of the hundreds of HIV controllers, many of whom traveled to Boston for testing, who have enrolled in the study. The enthusiasm among the patients we have enrolled and the HIV providers who referred them has been amazing, says Pereyra. They tell us that being part of this collaborative study means a lot to them.

###

Original support for the International HIV Controllers study came through a 2006 grant from the Mark and Lisa Schwartz Foundation, and the study was expanded in 2008 through the support of the Bill and Melinda Gates Foundation. Additional supporting agencies include the Harvard Center for AIDS Research and the National Institutes of Health.

Walker is a professor and de Bakker an assistant professor of Medicine at Harvard Medical School. Under the leadership of Pereyra, more than 300 investigators at over 200 institutions around the world contributed to the Science study. Study co-authors include, among others, Steven Deeks, MD, University of California, San Francisco; Amalio Telenti, MD, PhD, University of Lausanne, Switzerland; Mary Carrington, PhD, National Institutes of Health; Vincent Marconi, MD, Emory University; David Haas, MD, Vanderbilt University; John Fangman, MD, AIDS Resource Center of Wisconsin: Martin Markowitz, MD, Aaron Diamond AIDS Research Center; Richard Harrigan, PhD, British Columbia Centre for Excellence in HIV/AIDS; James Braun, DO, Physicians Research Network, New York; Ronald Nahass, MD, I.D. Care Associates, Hillsborough, New Jersey: and Otto O. Yang, MD, University of California. Los Angeles.

The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community. Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to http://www.broadinstitute.org/.

The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Philip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. The primary initial focus of the institute is to contribute to the development of an effective AIDS vaccine. The Ragon Institute draws scientists and engineers from diverse backgrounds and areas of expertise across the Harvard and MIT communities and throughout the world, in order to apply the full arsenal of scientific knowledge to understanding mechanisms of immune control and immune failure and to apply these advances to directly benefit patients. For further information visit http://www.ragoninstitute.org/

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Pharmasset Makes Remarkable Recovery on Hepatitis C Franchise

November 07, 2010

With so much attention paid to the relative merits of novel protease inhibitors, telaprevir and boceprevir, at the recent American Association for the Study of Liver Diseases (AASLD) meeting, arguably the biggest beneficiary from the conference was Pharmasset (VRUS).

Shares in the New Jersey biotech have gained 20% since the meeting started and now trade at a record high of $41, valuing the viral specialist with just two phase II hepatitis C candidates at a highly impressive $1.4bn. Key value driver is nucleoside polymerase inhibitor, RG7128, partnered with Roche (RHHBY.PK) and widely regarded as posing a genuine competitive threat to telaprevir and boceprevir. For Pharmasset the recovery over the last 18 months has been quite remarkable since the stock slumped to $7.80 with the failure of its lead pipeline candidate (Pharmasset hepatitis B failure focuses attention on hepatitis C, April 20, 2009).

Looking to the next generations

For the moment all eyes are on Vertex Pharmaceuticals (VRTX) and Johnson & Johnson’s (JNJ) telaprevir and Merck & Co’s (MRK) boceprevir, oral drugs with the potential to transform the way patients are treated for hepatitis C.

The current standard of care is a combination of pegylated alpha interferon and ribavirin, taken for up to 48 weeks. However, the long-treatment duration with weekly injections and modest efficacy - sustained virologic response (SVR) is around 55% - mean only a fraction of hepatitis C patients receive treatment.

The protease inhibitors, with much shorter treatment times of 12-24 weeks, twice-daily oral dosing and greater SVR rates up to 80%, offer obvious advantages and are expected to significantly increase the numbers of patients treated; currently patients are being ‘warehoused’ until these new drugs reach the market in the second half of 2011.

Pivotal data presented at AASLD suggest there is little to choose between the two candidates, with telaprevir appearing to hold an edge, although perhaps not quite to the extent that current consensus forecasts suggest. Telaprevir sales in 2016 of $3.55bn are more than five times higher than boceprevir at $686m (Where now for Vertex and Lilly's regrets after hat trick of telaprevir wins, September 9, 2010).

While protease inhibitors will undoubtedly be a major advance in treating hepatitis C, there are concerns about a higher rate of adverse events, particularly anemia and rashes, with these drugs over standard of care, as well as the potential for viral resistance.

Which is where Pharmasset, with its slightly different approach of nucleoside polymerase inhibitors, comes in.

Propelling data

Pharmasset’s pipeline of hepatitis C candidates are all nucleoside polymerase inhibitors. As well as RG7128, the company has unpartnered assets in PSI-7977, undergoing a phase IIb study, and PSI-938, which reported positive preliminary phase I data last week.

For now though the successful development of RG7128 is key to Pharmasset’s future.

Phase IIb data from the Propel study showed that more than 80% of patients receiving twice-daily oral dosing with the drug for 12 weeks had undetectable levels of the virus, a so-called early virologic response (EVR) rate; standard of care alone gave a 49% EVR. Importantly as well there was no evidence of viral resistance after 12 weeks.

Another phase IIb, called Jump-C, started earlier this year and is testing a 24-week dose with the drug. Meanwhile, a phase III trial is expected to start next year in comparison to standard of care; this is significant in that these are likely to be the last pivotal trials which use current therapy as the comparator and therefore a clearer regulatory pathway to approval.

Valuable franchise

Roche and Pharmasset signed a broad collaboration in 2004 to develop nucleoside polymerase inhibitors, in a deal worth up to $300m in upfront fees and milestones. Pharmasset will receive royalties and with some analysts forecasting sales of RG7128 to reach $2bn by 2016, just three years after launch, these should be significant.

Analysts covering Pharmasset have penciled in royalties of $268m by 2016, which potentially values the drug at $1.49bn, according to EvaluatePharma’s NPV Analyzer, assuming it reaches the market by 2013.

With the market already valuing Pharmasset at a similar level to this best-case scenario, it seems investors are currently placing a major bet that nucleoside polymerase inhibitors could be just as much of a breakthrough in treating hepatitis C as the current crop of protease inhibitors.

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How to Recognize the Symptoms of Liver Disease


Symptoms that indicate liver disease include changes in skin coloration, hyper-pigmentation, jaundice and a yellowing of the eyes. Learn about symptoms of liver disease, such as difficulty clotting blood, from a family practice physician in this free video series on health care and medical conditions.

Expert: Ken Savage
Contact: http://www.wearehdtv.com/
Bio: Ken Savage is a graduate of Kansas City University of Medicine and Biosciences.
Filmmaker: Christopher Rokosz

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