Merck to Present New Data for VICTRELIS® (boceprevir) and MK-5172 at The American Association for the Study of Liver Diseases 2012 Annual Meeting

WHITEHOUSE STATION, N.J., Oct. 1, 2012 – Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced today that new data from Phase III studies of VICTRELIS® (boceprevir) 200 mg Capsules, the company’s oral hepatitis C virus (HCV) NS3/4A protease inhibitor will be presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). The meeting will take place November 9-13 in Boston.

More than 20 abstracts highlighting Merck medicines and investigational therapies for chronic HCV will be presented at AASLD, including two oral presentations and six posters on VICTRELIS. New data will also be presented on the efficacy and safety of MK-5172, Merck’s investigational, once-daily, second generation oral HCV NS3/4A protease inhibitor, in patients chronically infected with HCV genotype 1.

“We are pleased to present new data on VICTRELIS that provides healthcare professionals with information that may better inform them as they consider VICTRELIS combination therapy for appropriate patients,” said Eliav Barr, M.D., vice president, Infectious Diseases, Project Leadership and Management, Merck Research Laboratories. "We also look forward to continued discussions with the global scientific and patient communities about Merck's investigational medicines for chronic hepatitis C, as we remain committed to reducing the burden of this serious disease worldwide."

The abstracts were published today and can be accessed on the AASLD website. For program information, please visit https://www.aasld.org.

Key presentations for VICTRELIS (boceprevir)
Boceprevir (BOC) Combined with Peginterferon alfa-2b/Ribavirin (P/RBV) in Treatment-Naïve Chronic HCV Genotype 1 Patients with Compensated Cirrhosis: Sustained Virologic Response (SVR) and Safety Subanalyses From the Anemia Management Study. Lawitz, F. et al. Oral Presentation: Sunday, Nov. 11, 3:15 p.m.-3:30 p.m., Hynes Convention Center, Ballroom B/C.
Timing and Magnitude of Ribavirin Dose Reduction (RBV DR) Do Not Impact Sustained Virologic Response Rates with Boceprevir (BOC) + Peginterferon alfa-2b / Ribavirin (P/RBV) in the Anemia Management Study in Chronic HCV Genotype 1 Patients. Poordad, F. et al. Oral Presentation: Monday, Nov. 12, 3:45 p.m.-4:00 p.m., Hynes Convention Center, Ballroom B/C.

Other key Merck presentations
Safety and Sustained Viral Response of MK-5172 for 12 Weeks in Combination with Pegylated Interferon Alfa-2b and Ribavirin for 24 Weeks in HCV Genotype 1 Treatment-Naïve Noncirrhotic Patients. Marcellin, P. et al. Poster 766. Sunday, Nov. 11, 8:00 a.m.-5:30 p.m., Hynes Convention Center Poster Hall.

MK-5172, A Potent Second-Generation HCV NS3/4a Protease Inhibitor, Retains Potent in vitro Activity Against a Panel of Boceprevir Resistant HCV G1a and G1b Patient Isolates. Ogert, R.A. et al. Poster 1724. Tuesday, Nov. 13, 8:00 a.m.-12:00 p.m., Hynes Convention Center Poster Hall. Selected as a Presidential Poster of Distinction.

Indications and usage for VICTRELIS
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (PR), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

• VICTRELIS must not be used as monotherapy and should only be used in combination with PR.
• VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
• VICTRELIS in combination with PR has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with PR. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with PR alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to PR therapy.
• Poorly interferon responsive patients who were treated with VICTRELIS in combination with PR have a lower likelihood of achieving a sustained virologic response (SVR), and higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to PR.

Important safety information about VICTRELIS
All contraindications to PR also apply since VICTRELIS must be administered with PR. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with PR is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers, where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia -- The addition of VICTRELIS to PR is associated with an additional decrease in hemoglobin concentrations compared to PR alone and/or may result in worsening of neutropenia associated with PR therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of PR.

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with PR were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for PR alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with PR alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.
Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the mergerbetween Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

###

Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.

# # #

VICTRELIS^® is a trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Revatio^® and Adcirca^® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

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Vertex Announces Presentation of New Data from Hepatitis C Development Program at AASLD Annual Meeting

October 1, 2012

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that 11 abstracts from its hepatitis C research and development program will be presented at The Liver Meeting^®, the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, November 9 to 13, 2012. Presentations will include data on INCIVEK^® (telaprevir) tablets, Vertex's approved medicine for the treatment of genotype 1 chronic hepatitis C, and two of the company's hepatitis C treatments in development: VX-222, a non-nucleoside polymerase inhibitor, and ALS-2200 (VX-135), a uridine nucleotide analogue pro-drug.

These accepted abstracts are now available on the AASLD website at: https://www.aasld.org/lm2012.

ALS-2200 (VX-135) Presentations

1. "ALS-2200, a Novel Once-Daily Nucleotide HCV Polymerase Inhibitor, Demonstrates Potent Antiviral Activity over 7 Days in Treatment-Naïve Genotype 1 (GT1) Patients." November 11, 2012, 5:00 p.m. EST. Oral Presentation #86

2. "Preclinical Characterization of ALS-2200, a Potent Nucleotide Polymerase Inhibitor for the Treatment of Chronic Hepatitis C." November 13, 2012, 8:00 a.m. - 12:00 p.m. EST. Poster Presentation #1882

3. "Analysis of ALS-2200, a Novel Potent Nucleotide Analog, Combination Drug Interactions in the Hepatitis C Virus (HCV) Subgenomic Replicon System." November 13, 2012, 8:00 a.m. - 12:00 p.m. EST. Poster Presentation #1887

INCIVEK (telaprevir) Presentations

1. "Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR24 Final Study Results." November 11, 2012, 4:15 p.m. EST. Oral Presentation #54

2. "Evaluation of Liver and Plasma HCV RNA Kinetics and Telaprevir Levels in Genotype 1 HCV Patients Treated with Telaprevir using Serial Fine Needle Aspirates." November 13, 2012, 9:00 a.m. EST. Oral Presentation #215

3. "The Safety of Telaprevir in the Absence of Interferon and/or Ribavirin: Analysis of On-Treatment Data from the ZENITH Trial." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #786

4. "Factors Predictive of Anemia Development in Treatment-Experienced Patients Receiving Telaprevir (TVR) Plus Peginterferon/Ribavirin (PR) in the REALIZE Trial." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #771

5. "Rate of Disappearance of Telaprevir Resistant Variants Using Clonal and Population Sequence Data from Phase 3 Studies." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #756

6. "Deep Sequencing of the HCV NS3/4A Region Confirms Low Prevalence of the Telaprevir-Resistant Variants Both at Baseline and End of Study." November 11, 2012, 8:00 a.m. - 5:30 p.m. EST. Poster Presentation #1091

VX-222 Presentations

1. "VX-222, Telaprevir and Ribavirin in Treatment-Naïve Patients with Genotype 1 Chronic Hepatitis C: Results of the ZENITH Study Interferon-Free Regimen." November 13, 2012, 11:15 a.m. EST. Oral Presentation #231

2. "Effect of Hepatic Impairment on the Pharmacokinetics of VX-222: Results From a Multicenter Phase 1 Study." November 13, 2012, 8:00 a.m.- 12:00 p.m. EST. Poster Presentation #1880

About ALS-2200 (VX-135) and VX-222

ALS-2200 (VX-135) is a uridine nucleotide analogue pro-drug that appears to have a high barrier to drug resistance based on in vitro studies. It is designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. In vitro studies of the compound showed antiviral activity across all genotypes, or forms, of the hepatitis C virus, including genotypes more prevalent outside of the United States.

Vertex gained worldwide rights to ALS-2200 through an exclusive worldwide licensing agreement signed with Alios BioPharma, Inc. in June 2011. The agreement also includes a research program that will focus on the discovery of additional nucleotide analogues that act on hepatitis C polymerase. Vertex has the option to select additional compounds for development emerging from the research program.

VX-222 is an oral medicine in development that is a non-nucleoside inhibitor of the HCV NS5B polymerase. Vertex has worldwide commercial rights for VX-222.

About INCIVEK

INCIVEK^® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication.

INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).

Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO^® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic^®.

IMPORTANT SAFETY INFORMATION

Indication

INCIVEK^® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.

Important Safety Information

INCIVEK should always be taken in combination with peginterferon alfa and ribavirin. Ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Patients must use two forms of effective birth control during treatment and for the 6 months after treatment with these medicines. Hormonal forms of birth control, including birth control pills, vaginal rings, implants or injections, may not work during treatment with INCIVEK.

INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.

INCIVEK can cause serious side effects including skin reactions, rash and anemia that can be severe. The most common side effects of INCIVEK include itching, nausea, diarrhea, vomiting, anal or rectal problems, taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare providers about any side effect that bothers them or doesn't go away.

Please see full Prescribing Information for INCIVEK including the Medication Guide, available at www.INCIVEK.com.

About Hepatitis C

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹

Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.² However, approximately 60 percent of people do not achieve SVR,^3,4,5 or viral cure,⁶ after treatment with 48 weeks of pegylated-interferon and ribavirin alone. If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^7,8

More than 170 million people worldwide are chronically infected with hepatitis C.⁶ In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.^9,10 Hepatitis C is four times more prevalent in the United States compared to HIV.¹⁰ The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting 82 percent of people with the disease.¹¹ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.^12,13 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.¹⁰

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences

Vertex's press releases are available at www.vrtx.com.

(VRTX-GEN)

References:

¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010. Accessed September 21, 2012.

² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.

³ Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.

⁴ Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

⁵ McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.

⁶ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.

⁷ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).

⁸ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.

⁹ Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.

¹⁰ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed September 21, 2012.

¹¹ Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.

¹² Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.

¹³ S.D. Holmberg, K.N. Ly., et.al. The Growing Burden of Mortality Associated with Viral Hepatitis in the United States, 1999-2007. AASLD 2011 Annual Meeting.

Vertex Pharmaceuticals Incorporated
Media:
Erin Emlock or Zach Barber, 617-444-6992
mediainfo@vrtx.com
or
Investors:
Kelly Lewis, 617-444-7530
or
Michael Partridge, 617-444-6108

Source: Vertex Pharmaceuticals Incorporated

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3-V Biosciences To Present Data on HCV Product Candidates at the American Association for the Study of Liver Disease Annual Meeting 2012

PRESS RELEASE

Oct. 1, 2012, 9:15 a.m. EDT

Small Molecule FASN Inhibitors Demonstrate Antiviral Activity

MENLO PARK, Calif., Oct. 1, 2012 /PRNewswire via COMTEX/ -- 3-V Biosciences, Inc., announced today that two abstracts have been accepted for presentation at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (The Liver Meeting®) being held November 9-13 in Boston, Massachusetts.

3-V Biosciences is discovering and developing oral antiviral therapeutics designed to have broad-spectrum activity and a high barrier to resistance. Data characterizing the preclinical antiviral activity of the company's novel small molecules targeting the fatty acid synthase (FASN) pathway for the potential treatment of chronic hepatitis C virus (HCV) infection will be featured in oral and poster presentations.

Oral PresentationSunday, November 11, 2012 at 5:30pm ET:HCV Therapy: Preclinical and Early Clinical Development"Potent Hepatitis C Antiviral Activity By Inhibiting Fatty Acid Synthase"(Parallel 13, Hynes: Room 21)

Poster Presentation (Presidential Poster of Distinction award)Tuesday, November 13, 2012 from 8:00am - 12:00pm ET:HCV Therapy: Preclinical and Early Clinical Development"TVB-2640, a Novel Anti-HCV Agent, Safely Causes Sustained Host-Target Inhibition in Vivo"(Poster Hall, #1876)

About FASNFASN is a cellular enzyme implicated in HCV replication and several cancers. First-generation FASN inhibitors have shown preclinical benefits in a variety of viral infections, including HCV, as well as in models of pancreatic, prostatic, breast and colorectal tumors, but their development has been hindered by poor bioavailability and systemic tolerability. 3-V has discovered and is advancing proprietary FASN inhibitors with pharmaceutical properties that overcome the shortcomings of earlier generations of inhibitors, and have the potential to become potent therapeutics for chronic HCV and other indications.

About 3-V Biosciences3-V Biosciences, Inc. is a privately held biopharmaceutical company that discovers and develops antiviral therapeutics designed to have broad-spectrum activity, including efficacy against viruses resistant to other classes of antiviral drugs, and a high barrier to resistance. The 3-V team applies an integrated approach with internal expertise in virology, biology, drug discovery and development to drive programs forward. The company is located in Menlo Park, California.

For additional information on 3-V Biosciences, please visit www.3vbio.com .

Contact information

Stephen R. BradyChief Business Officer650-561-8600

Media Inquiries

BCC Partners on behalf of 3-V Biosciences, Inc. Karen L. Bergman650-575-1509kbergman@bccpartners.com  Michelle Corral 415-794-8662 mcorral@bccpartners.com 

SOURCE 3-V Biosciences, Inc.

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Common HIV drug may cause memory loss

Washington, Sept 29, 2012 PTI:

A commonly prescribed drug for HIV patients may lead to memory decline by increasing the risk of damage to nerve cells, a new study by Johns Hopkins has claimed.

Nearly 50 per cent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities, the researchers said.

It has long been assumed that the disease was causing the damage, but Johns Hopkins researchers say the drug ‘efavirenz’ may play a key role.People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades.

Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain.

Researchers say more caution is needed because there may be long-term effects of these drugs on the brain.

“People with HIV infections can’t stop taking anti-retroviral drugs. We know what happens then and it’s not good,” said Norman J Haughey, associate professor of neurology at Johns Hopkins University School of Medicine.

“But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV,” he said.

Investigators examined the effects of 8-hydroxyefavirenz and other metabolites and found major structural changes when using low levels of the drug, including loss of the important spines of the cells. Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons.

In the case of efavirenz, a minor modification in the drug’s structure may be able block its toxic effects but not alter its ability to suppress the virus.

Source

Map of key target brings hope of blocking HIV attack

Saturday, Sep. 29, 2012

Kyodo

NAGOYA — A team of Japanese researchers has identified the structure of an immune-cell protein targeted by HIV, increasing hope for the development of new medicines that could block attacks by the virus.

The discovery by researchers at the National Hospital Organization Nagoya Medical Center and at Nagoya University was published Sept. 23 in the online edition of the U.S. journal Nature Structural & Molecular Biology.

A central part of the human immune system is lymphocyte cells that have virus-fighting proteins on their surface. But an HIV protein called Vif (viral infectivity factor) is able to bind to and destroy these proteins, allowing the AIDS-causing virus to enter the cells and multiply.

The researchers analyzed the molecular structure of an antivirus protein called APOBEC3C, and found that it contains a cavity that Vif can bind to. They confirmed the process through which this phenomenon occurs, and found that the APOBEC3C protein disintegrates once the two combine, their report in Nature said.

While existing medicines to combat HIV often cause side effects or become less potent if used over a long period, the team's finding raises "the possibility for the development of a new AIDS treatment that taps into the human body's own defense mechanism," said Yasumasa Iwatani, who heads the medical center's laboratory of infectious diseases.

The team said it now plans to look for compounds that can fit into the protein cavity and block attacks by HIV to study the effectiveness of different candidate compounds.

Source

Ethicists question doctor’s pitch for a hepatitis C drug trial

An audience listened during a forum by doctors and attorneys about hepatitis C in Exeter, N.H., in August.

By Sarah Schweitzer

Globe Staff / September 25, 2012

Hepatitis C patients told of potential cure

EXETER, N.H. — They filed into the hotel conference room, faces pinched with worry, drawn by the prospect of an escape from hepatitis C.

It was a disease they never saw coming. They had gone to Exeter Hospital seeking treatment for other ailments, and wound up exposed to the hepatitis virus, allegedly by a technician now under federal indictment.

On this August evening, the patients had the opportunity, promotional materials from an advocacy group promised, to learn about “new wonder drugs” with a “75 percent cure rate in clinical trials” from a Harvard Medical School instructor and liver disease researcher at Massachusetts General Hospital.

As he took the microphone, Dr. Raymond T. Chung offered an authoritative message of deliverance: “We want to get about the business of helping these folks undo what’s been done unto them.”

But the drug combination that Chung hoped would undo hepatitis C’s damage had not been approved by the Food and Drug Administration, remained in clinical trials, and would not be approved for study by the committee that oversees Mass. General research until a month after Chung’s presentation.

Ethicists said in interviews that Chung’s comments appear to have breached ethics principles by potentially leaving his audience with outsize hope for drugs undergoing testing. Doing so, they said, was particularly striking at a moment when patients felt violated and vulnerable.

“I believe Dr. Chung is very well meaning, and it is possible that his study drug may be better than what is currently available,” said Dr. Brian O’Sullivan, director of the University of Massachusetts Medical School’s Bioethics Core. “But to sell it as such to a scared, desperate audience is not appropriate. He is misconstruing a promising but as yet unproven drug as a therapeutic alternative.”

Chung and hospital officials disputed the ethicists’ conclusions. In an interview, Chung said his comments reflected the promise of the drugs and his desire to make them available to patients who could benefit most — a presentation that, he said, conformed to ethical standards for clinical trials.

“We were very clear that this was a study,” Chung said in the telephone interview, “that this is a protocol and that patients would have to go through the next steps of private discussion and informed consent with a discussion of risks and benefits.

“That’s an absolute foundation of what we do with our clinical trials.”

For Jean Burke’s husband, who is among the infected and attended an earlier presentation by Chung in the summer, the doctor proved persuasive — so much so that her husband met privately with him and plans to enroll in the study, should it go forward.

“His reputation is nationally known. He’s a really excellent doctor and has been doing research on this for years,” said Burke, who said she and her husband understood Chung was talking about a drug trial. “He’s assured us that it’s probably going to be really successful.”

* * *

Human drug trials remain among the thorniest areas in medical ethics, poised between the need for scientific advancement and the mandate to protect patients. The revelation in the 1970s of the Tuskegee syphilis experiments, in which researchers deliberately withheld treatment from African-American men, spurred Congress to pass laws governing scientific trials.

A key area of oversight is recruitment, which can pose a hurdle for researchers. While patients stricken with life-ending illnesses, desperate for anything, sometimes seek out researchers and their trials, patients suffering diseases that do not pose an imminent threat may be less willing to submit to experimental interventions.

“Most people don’t want to be in research,” said George Annas, an ethics specialist at Boston University School of Public Health. “They want to be in treatment.”

Institutional review boards, composed of at least five members designated by the research institution, are charged with ensuring that researchers do not intentionally mislead patients about side effects and risks of an experimental drug. The review boards must also be on the lookout for well-meaning scientists who possess an exaggerated belief in their research and convey that to subjects — a phenomenon known as the therapeutic misconception.

“Researchers hope their drugs do well,” said Dr. Michael Grodin, a bioethicist at BU’s public health school. “There’s a bias on the investigator’s part. And that’s exactly why we want patients to know it’s research and not therapy.”

* * *

For months, the news out of Exeter sounded a steady drumbeat of despair. In May, word came that four cases of hepatitis C — a disease that over time can attack the liver and can ultimately lead to death — had been linked to the hospital’s cardiac department. That was only the start.

The numbers climbed, federal investigators arrived, and on July 19, with at least 30 people having tested positive, prosecutors announced they had identified the source of the infections: a former technician at the hospital.

Prosecutors allege that 33-year-old David Kwiatkowski stole syringes of a powerful anesthetic called fentanyl from the cardiac catheterization lab, injected himself, and then returned the tainted needles, which were reused on patients. Kwiatkowski worked in seven other states before New Hampshire, raising the specter that he infected others — possibly hundreds across the country, according to prosecutors.

For the patients in Exeter, the revelations heaped a new health problem onto old ones. Many had underlying conditions that had brought them to Exeter Hospital. Some had primary care doctors affiliated with the hospital — a place from which they no longer wished to receive care.

That led some two dozen of them to the “Hepatitis C Patient Information Night” in the conference room at the Georgian-styled Exeter Inn.

The evening was billed by its attorney-organizer, Domenic Paolini, as a chance to learn about advances in hepatitis C treatment and to hear attorneys explain the legal landscape for medical malpractice in New Hampshire and possible settlement options.

Paolini organized the evening under the umbrella of the Patients Speak, a not-for-profit advocacy group that he formed with Elenore Casey Crane, a public relations consultant, after the outbreak. The group held an initial meeting in June, at which Chung also spoke, assuring patients that hepatitis C was not a death sentence and could be treated.

On this August evening, sandwiched between Paolini and another medical malpractice lawyer, Chung waited his turn to make a pitch — his latest foray in the fierce race to conquer hepatitis C, which affects an estimated 3.2 million people in the United States.

* * *

The standard treatment for hepatitis C for years has been weekly injections with interferon, a regimen that, on average, cures fewer than half of patients with the most common form of the virus and sometimes spawns flu-like side effects.

The terrain shifted dramatically last year when the FDA approved two new drugs, Vertex Pharmaceuticals’s telaprevir and Merck & Co.’s boceprevir, which, when taken in combination with interferon, increased cure rates to roughly 80 percent and 65 percent, respectively. Chung was an investigator for trials of both drugs.

Now, Chung is seeking to be at the forefront of the next frontier: identifying a combination of oral medications that would not require interferon.

“We are on the threshold of a treatment revolution,” Chung wrote in the New England Journal of Medicine in January.

But in late August, Bristol-Myers Squibb announced it was discontinuing development of an oral hepatitis C drug after nine patients in a clinical trial were hospitalized and one died. The FDA that month put a hold on trials of a drug in the same class being tested by Idenix Pharmaceuticals.

The oral combination that Chung hopes to test in Exeter is made by Gilead Sciences, according to Dr. Elizabeth Hohmann, director of Partners Human Research Committee, charged with overseeing Mass. General’s clinical trials. Chung, who said he does not have a financial stake in the research, said the combination had already been tested in phase one trials to establish safety, phase two trials to assess efficacy, and has entered phase three trials, often the last step before submission for FDA approval.

The Exeter patients, who would be in a phase 2 trial, represent a singular research opportunity because they contracted the disease in the same recent time span, potentially providing a window into how the infection plays out in its early stages — a vital piece of knowledge in tackling the disease.

At the Exeter Inn, Chung introduced that drug combination as a “strand of hope.”

“We were able to approach a company that was developing these newfangled drugs,” he told the audience. “And this isn’t just any set of compounds. This is a set of compounds that have already been in trials . . . that have demonstrated not just safety, but as well, effectiveness against hepatitis C. And effectiveness here means not only the clearance of virus during the administration of the medications but a permanent clearance.

“You can essentially equate that with a cure, a cure of the infection.” These drugs, he said, were accomplishing in as little as three months what an interferon-based regimen took six months or longer to achieve. The new drugs were doing so “in a manner that does not disrupt or interrupt quality of life to anywhere near the extent that interferon might,” Chung said.

“That’s way over the top,” said Arthur Caplan, head of the division of medical ethics at NYU Langone Medical Center. “When you are doing research, you have to make sure that people understand it’s promising, that you’re making no guarantee of benefit. That’s getting very close to guaranteeing a benefit. That language is irresponsible.”

* * *

Five ethicists and researchers who reviewed Chung’s comments at the Globe’s request said they appeared to violate ethical standards requiring that researchers convey a balanced message about clinical trials to possible research subjects.

“It’s inappropriate, and I would argue unethical, to approach people about a research study that hasn’t been approved and to say the potential benefits outweigh the risks,” Grodin said.

“That was definitely overselling,” O’Sullivan said. “There needed to be, ‘We hope there will be fewer side effects. We hope it will be more effective, but we don’t know that.’ ”

Chung made little mention of side effects. After prompting by an audience member’s question, he said, “The important point to make about this combination therapy is that it has been very well tolerated . . . and we believe that the side effect profile described in those [earlier] trials will be something we will be able to manage effectively in this group of patients.”

Hohmann said Chung’s comments were not “hyperbolic.”

“I think it’s enthusiastic but justified based on these drugs, which are really looking very good,” she said.

Chung, too, defended his comments. “This is not a hard sell. This is simply a restatement of facts in an informational setting.”

Indeed, he said, he felt it was his responsibility to alert the patients to the drug combination’s promise so they could, if they wished, access it before approval, which he said could come as early as next year.

He also noted that the evening’s promotional materials — which called the combination he hopes to test “wonder drugs” — were the work of the Patients Speak; neither he nor Mass. General officials reviewed the materials.

The FDA, which enforces laws governing clinical research trials, declined to comment on Chung’s presentation. But agency spokeswoman Michelle Bolek pointed to laws that bar investigators from representing “in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.”

Some ethicists questioned Chung’s timing, saying he should have held off on taking names and contact information of interested patients until he had secured approval from the Partners Human Research Committee. That panel did not approve Chung’s study until a month after the Exeter presentation.

FDA guidelines note that institutional review boards — widely known by the acronym IRB — should review the “methods and material that investigators propose to use to recruit subjects.”

“In his capacity as an educator and a doctor, he may want to educate people broadly about what’s going on in hepatitis C and how there is a sea change afoot in hepatitis C drug treatment options,” said Dr. Timothy Lahey, cochairman of the Dartmouth-Hitchcock Medical Center Ethics Committee.

“But he would have to be very careful not to actively recruit anyone to a specific study without IRB approval or to overstate the expected potency of an experimental regimen.”

And taking names, some ethicists said, clearly constituted recruitment.

“If you are taking names so you can contact them, that’s recruiting,” said Lisa Bero, a University of California, San Francisco specialist in clinical trial ethics.

Chung and Hohmann disagreed. “This is simply collecting names and contact information for when [the study] is ready to rock,” Hohmann said.

She compared Chung’s presentation to notices about upcoming trials placed by researchers and institutions on the Internet. Those are permitted, under FDA guidelines, so long as they are restricted to basic information, such as the study’s title, purpose, protocol, eligibility criteria, and study site.

Chung said he notified Hohmann before the meeting in Exeter and advised her that he planned to discuss the upcoming trial.

Some ethicists said Chung’s recruitment methods reflected real-world pressures and demands on researchers.

“I have a little sympathy,” Annas said. “It’s hard to recruit people for a study. The key thing is, did he tell people clearly that this is research?”

At root, Chung said, “I was responding to what I perceived and I felt was a very strong, intense need for information on behalf of an aggrieved group of patients who were confused and had nowhere to turn.”

For Jean Burke and her 61-year-old husband, whose work days have been marked by fatigue and other symptoms they attribute to hepatitis C, Chung offered an infusion of good news.

“It was very exciting for us to hear because we are in such a bad situation,” Jean Burke said.

Sarah Schweitzer can be reached at schweitzer@globe.com.

Source

Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Subject Category: Liver

Am J Gastroenterol 2012; 107:1388–1398; doi:10.1038/ajg.2012.137; published online 12 June 2012

Chihiro Morishima MD¹, Mitchell L Shiffman MD², Jules L Dienstag MD^3,4, Karen L Lindsay MD, MMM⁵, Gyongyi Szabo MD, PhD⁶, Gregory T Everson MD⁷, Anna S Lok MD⁸, Adrian M Di Bisceglie MD⁹, Marc G Ghany MD, MHSc¹⁰, Deepa Naishadham MA, MS¹¹, Timothy R Morgan MD^12,13 and Elizabeth C Wright PhD^10,14 for the HALT-C Trial Group¹⁵

1. ¹Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
2. ²Liver Institute of Virginia, Bon Secours Health System, Newport News, Virginia, USA
3. ³Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
4. ⁴Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
5. ⁵Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
6. ⁶Department of Medicine, Division of Gastroenterology, Hepatology and Liver Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA
7. ⁷Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
8. ⁸Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
9. ⁹Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
10. ¹⁰Department of Health and Human Services, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
11. ¹¹New England Research Institutes, Watertown, Massachusetts, USA
12. ¹²Division of Gastroenterology, University of California—Irvine, Irvine, California, USA
13. ¹³Gastroenterology Service, VA Long Beach Healthcare System, Long Beach, California, USA
14. ¹⁴Department of Health and Human Services, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA

Correspondence: Chihiro Morishima, MD, Research Associate Professor, Department of Laboratory Medicine, University of Washington, Box 358050, 850 Republican Street, Seattle, Washington 98109, USA. E-mail: chihiro@u.washington.edu

¹⁵The HALT-C Trial was registered with clinicaltrials.gov (#NCT00006164).

Received 14 December 2011; Accepted 17 April 2012
Advance online publication 12 June 2012

Abstract

OBJECTIVES:

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.

METHODS:

Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.

RESULTS:

Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.

CONCLUSIONS:

Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

Source

High-dose ribavirin induction shows no benefit in HIV/HCV coinfection

Labarga P. J Infect Dis. 2012;206:961-968.

September 24, 2012

Researchers from Spain have found that high ribavirin induction did not improve sustained virological response rates among patients with HIV and hepatitis C virus coinfection.

The Peginterferon Ribavirin in Coinfection (PERICO) trial was a randomized prospective trial of the safety and efficacy of peginterferon alpha-2a with two different doses of ribavirin in coinfected patients. Patients received the standard dose or ribavirin according to weight, or a high fixed dose of 2,000 mg/day during the first 4 weeks of therapy. Those who received the high dose also received erythropoietin beta.

“Whereas the use of higher dosing of peginterferon alpha has not shown any benefit in terms of treatment success, the use of higher ribavirin exposure has led to improvements in the rate of HCV clearance, although the development of anemia is a major limitation of this approach,” the researchers wrote.

The study included 357 patients, of whom 160 attained a sustained virological response. There were no differences found in the rate of sustained virological response between the two groups. The level of undetectable HCV RNA and the mean ribavirin trough concentration were similar in both groups at week 4.

Ninety-one patients discontinued treatment due to nonresponse and 29 discontinued due to adverse effects. HCV genotypes 2 and 3, IL28B CC variants, nonadvanced liver fibrosis and rapid virological response were predictors of sustained virological response.

“The use of preemptive erythropoietin may have blunted the increased disposition of free ribavirin by promoting erythrocyte sequestration,” the researchers wrote. “While awaiting the arrival of new direct acting antivirals against HCV, it seems worthwhile to ensure maximal ribavirin exposure when treating HIV/HCV-coinfected patients, limiting the indication of erythropoietin only to patients who develop severe anemia on therapy.”

Disclosure: The researchers report no relevant financial disclosures.

Source

Hepatitis B vs. Hepatitis C Infection on Viral Hepatitis-Associated Hepatocellular Carcinoma

From BMC Gastroenterology

Spiros P Hiotis; Nuh N Rahbari; Gerald A Villanueva; Eunjie Klegar; Wei Luan; Qin Wang; Herman T Yee

Posted: 09/18/2012; BMC Gastroenterol. 2012;12(64) © 2012 BioMed Central, Ltd.

Abstract and Introduction

Abstract

Background To determine clinical-pathologic variables in patients with a new diagnosis of hepatocellular carcinoma (HCC) and underlying hepatitis B vs. C infection.
Methods Patients presenting to a single urban hospital with a new diagnosis of HCC were entered into a clinical database. Variables including number and size of tumors, presence of metastases, serum alpha-Fetoprotein, hepatitis serologies, severity of hepatic dysfunction, and presence of cirrhosis were evaluated in 127 patients.
Results Patients with hepatitis B (HBV) were more likely to develop HCC at a younger age than patients with hepatitis C (HCV) (HBV-26% under age 40, HCV-0% under age 40; p < 0.001), with greater serum alpha-Fetoprotein production (median level: HBV-1000 ng/ml vs. HCV-37 ng/ml; p = 0.002), with larger tumors (HBV-78% >5 cm, HCV-28% >5 cm; p < 0.001), in the absence of cirrhosis (HBV-40%, HCV-0%; p < 0.001), and a decreased eligibility for curative treatment (HBV-14%, HCV-34%; p < 0.05). Conversely, patients with HCV were more likely to develop HCC in association with multiple co-morbidities, cirrhosis, and older age.
Conclusions Significant clinical-pathologic differences exist among HCC patients with underlying HBV vs. HCV. These differences impact eligibility for potentially-curative therapy and prognosis.

Background

Hepatocellular Carcinoma (HCC) is the third leading cause of cancer related mortality worldwide.^[1] The global prevalence and mortality resulting from HCC is directly related to underlying risk factors for primary liver cancer in at-risk populations. Although several chronic liver diseases are associated with HCC, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) statistically are the most commonly implicated risk factors. Combined they are responsible for 85% of total new HCC cases worldwide; 54% occurring as a result of HBV, and 31% as a result of HCV.^[2,3] HBV, which is endemic in developing geographic regions such as Eastern Asia and Sub-Saharan Africa, is responsible for up to 90% of new HCC cases in such areas.^[4]

Epidemiologic analyses and clinical series which lead to our understanding of the behavior and natural history of HCC do not usually subset results according the underlying viral risk factors for the disease.^[5] Most survival analyses from institutions with broad experience in surgical resection, transplantation, ablation, transarterial chemoembolization, or other treatments usually combine patients, irrespective of their underlying viral hepatitis status or association to other risk factors.^[6,7] Therefore variations in patterns of presentation, tumor biology, or treatment outcomes for HCC according to underlying association to viral hepatitis B or C remain unclear.

Despite histologic similarities in end-organ damage and eventual carcinomas, adequate scientific rationale supports a proposed hypothesis that distinct pathophysiologic mechanisms may be responsible for hepatocarcinogenesis due to either HBV or HCV. This is based in part on marked virologic differences seen among the 2 pathogens. Hepatitis B is a DNA virus belonging to the Hepadna virus family, which persists in the hepatocyte nucleus predominantly in the form of covalently closed circular DNA (cccDNA), the functional template for viral transcription and replication.^[8] Conversely, Hepatitis C is an RNA virus belonging to the flavivirus family which replicates in the hepatocyte cytoplasm, with a completely distinct life cycle and pattern of viral replication.^[9,10] Differences in natural history of resulting benign liver disease is well-described among the 2 viruses.^[11]

In this study, an attempt has been made to evaluate potentially significant clinical-pathologic differences in HCC's that develop in association with chronic HBV vs. HCV. Comparisons have been made among two otherwise comparable groups according to data collected upon initial cancer diagnosis at a single, urban hospital. Demographic data and widely accepted relevant clinical-pathologic features of newly diagnosed HCC's have been collected with the intended purpose of delineating potentially significant differences in cancers which arise in HBV vs. HCV infected patients.

Methods

Database Enrollment

Patients were enrolled into a clinical database based upon a diagnosis of HCC at a single New York City public hospital (Bellevue Hospital Center). The database was approved by the IRB of New York University Medical Center and was in compliance with the Helsinki Declaration. The overall period of enrolment spanned the years of 1993 to 2005. Data for patients diagnosed between 1993 and 2001 was collected in a retrospective manner, while data collected between the years of 2001 and 2005 was entered prospectively. This study was exempt from IRB approval according to the institutional criteria at New York University Medical Center. Hence, informed consent was not required for this study.

Demographic data including age, sex, race, and ethnicity were collected. Several clinical-pathologic features were also recorded upon initial HCC diagnosis including the following: tumor size, tumor number, presence of synchronous distant metastases, macro-vascular invasion (tumor thrombus), viral hepatitis serologies, serum biochemistries including liver function tests, serum alpha-fetoprotein, presence and severity (according to Childs-Pugh classification) of coexisting cirrhosis, and underlying co morbidities.

In subsequent retrospective analysis of database variables, patients were stratified according to underlying risk factors for HCC. In order to facilitate a cohort comparison of HBV vs. HCV as risk factors for cancer, patients with either HBV or HCV only were included for analysis. Those co-infected both with HBV and HCV, or neither hepatitis virus were excluded from this analysis.

Diagnosis of HCC

The diagnosis of HCC was based upon histology or cytology, when tissue was available following surgical resection or biopsy. For cases in which no tissue was available, patients were diagnosed with HCC if dynamic imaging findings (CT with intravenous contrast or MRI only) of a hypervascular solid liver mass with features characteristic for HCC were present in a setting of underlying risk factors, along with a clearly elevated serum alpha-fetoprotein (>100 ng/ml). A diagnosis of HCC for all patients that presented with non-AFP-producing tumors was confirmed by biopsy. Of all 127 patients, 76 (60%) were diagnosed based upon histology or cytology, while 51 (40%) were diagnosed with imaging along with other features.

Diagnosis of Cirrhosis

A diagnosis of cirrhosis was made based on a combination of clinical parameters. For patients in whom tissue (from biopsy of resection specimens) was available from the non-neoplastic liver, a diagnosis of cirrhosis was made if histologic findings of hepatic fibrosis were observed in conjunction with clinical evidence of severe hepatic dysfunction (such as hypoalbuminemia). Patients with available histologic specimens demonstrating no evidence of hepatic fibrosis were deemed non-cirrhotic. For patients in whom non-neoplastic liver tissue was unavailable, a diagnosis of cirrhosis was based upon a combination of axial imaging features (including hepatic macronodularity and ascites), serum biochemistries indicative of severe hepatic dysfunction (such as hypoalbuminemia), and physical exam findings such as documented ascites.

Statistical Analyses

Comparisons of patient cohorts were performed using Fisher's exact test. A p value of <0.05 was used to designate a statistically significant difference among observed vs. expected outcomes.

Results

Demographics, Age Distribution, and Underlying Comorbidities

A total of 149 HCC patients were enrolled during the study period: 89 (59.7%) with HBV-associated cancers, 38 (25.5%) with HCV-associated cancers, 4 (2.7%) with cancers associated with both HBV and HCV, and 18 patients (12.1%) with cancers not associated with either hepatitis virus (Figure 1). HCC patients with HBV and HCV co-infection, as well as those without underlying viral hepatitis were excluded from the present analysis. HCC developed more commonly among males in both groups, however the association to male gender was stronger in the HBV group. Only 5% of HBV-associated HCC's developed in female patients compared with 21% of HCV-associated HCC's (p = 0.007, Table 1). The majority of HBV-associated HCC patients were of Asian race (90%), compared with only 5% in HCV-associated HCC patients (p < 0.001, Table 1).

Figure 1. HCC incidence according to underlying etiology (current series). Underlying risk factors for HCC in current series closely resembles global demographic: worldwide epidemiologic data estimate HCC due to HBV in 53-54% of total cases, and due to HCV in 25%-31% of cases

The median age upon initial diagnosis for patients with either HBV or HCV-associated HCC's was similar (HBV, 50 years; HCV, 58 years); however, the age distribution in the two groups differed considerably. Approximately one fourth (26%) of all HBV-associated HCC's occurred in patients aged 40 years or younger, while no cancers developed in patients under the age of 40 in the HCV group (p < 0.001, Table 1). In fact, only 2 HCC's (5%) occurred in the HCV group at 50 years of age or less. This contrasted with the HBV group, in whom nearly half (49%) of cancers had already occurred by the age of 50 (Table 1).

As a group, patients who developed HCC associated with underlying HBV had fewer systemic comorbidities than those with underlying HCV. A mean of 1.0 underlying systemic comorbidity was present in HBV patients at the time of initial cancer diagnosis, compared with a mean of 2.9 associated systemic comorbidities in HCV patients (Table 1, p < 0.001). A coincident history of alcohol abuse was also less frequent in the HBV group (7% in HBV vs. 32% in HCV, p < 0.001), as was the frequency of HIV co-infection (1% in HBV vs. 13% HCV, p < 0.001).

Co-existence of Cirrhosis in the Non-neoplastic Liver

Patients with underlying HBV were less likely to have developed cirrhosis at the time of progression to cancer compared with patients with underlying HCV (p < 0.001, Table 1). Without exception, all patients who developed HCC in a setting of chronic HCV had established cirrhosis at the time of initial cancer diagnosis. However, 40% of patients with underlying HBV developed HCC in the absence of cirrhosis. When HCC patients with established cirrhosis due to either HBV or HCV were compared, the severity of cirrhosis as determined by the Childs-Pugh classification, was similarly distributed in both viral hepatitis groups.

Alpha-fetoprotein Production

A significant difference in serum alpha-fetoprotein (AFP)-production was observed in HCC's associated with underlying HBV as opposed to those associated with HCV (Table 1). The median level of serum AFP in HBV-associated HCC was greater than HCV-associated HCC (1000 ng/ml vs. 37 ng/ml, p = 0.002). While the proportion of patients with normal level of serum AFP (<20 ng/ml) was similar between HBV- and HCV-associated HCC, the proportion of HCC producing higher amount of AFP (>100 ng/ml) was greater in HBV-associated HCC. Sixty five percent of HBV-associated HCC, in contrast to only 27% of HCV-associated HCC, produced AFP greater than 100 ng/ml (p < 0.001). Similarly, the proportion of HBV-associated HCC producing AFP greater than 1,000 ng/ml or 10,000 ng/ml was higher compared with HCV-associated HCC (52% vs. 16%, and 25% vs. 5%, respectively, Table 1).

Oncologic Prognostic Variables

The presence upon initial cancer diagnosis of several well established oncologic variables associated with a poor cancer specific prognosis was assessed according to underlying viral hepatitis status. These include tumor size, tumor number, macrovascular invasion, and the presence of synchronous distant metastases.

Patients with HBV-associated HCC were significantly more likely to be diagnosed with larger tumors, than those with HCV-associated HCC. Seventy eight percent of HBV-associated tumors exceeded 5 cm in greatest cross-sectional diameter, as compared with only 28% of those associated with HCV (p < 0.001, Table 2). Analysis of all other selected variables failed to demonstrate a significant difference according to viral hepatitis status. Multifocal tumors and macrovascular invasion occurred with similar frequency in both the HBV and HCV groups (HBV-49% vs. HCV-54% and HBV-31% vs. HCV-24%, respectively). The incidence of synchronous distant metastases was observed with double the frequency in HBV patients, when compared to those with HCV (HBV-15% vs. HCV-6%). However, this trend did not achieve statistical significance, likely due to statistical underpowering of the study at the current sample size.

Eligibility for Treatment With Curative Intent

Eligibility for liver transplantation and surgical resection with expected favorable long-term survival, according to underlying viral hepatitis status, was determined by application of the Milan criteria.^[12,13] Patients with HBV-associated cancers were far less likely to meet these criteria upon initial HCC diagnosis than were those with HCV-associated cancers (14% vs. 34%, respectively, p < 0.05). This more commonly precluded treatment with expectation for cure in patients with HBV-associated HCC, when compared to patients with HCV.

Discussion

Viral Hepatitis B and Hepatitis C are the most commonly implicated risk factors for HCC, with HBV responsible for the majority of cases worldwide. The epidemiologic predominance of HBV-associated HCC worldwide is largely due to the endemic nature of HBV infection in East Asian and subsaharan African populations.^[14] Given the broad ethnic and racial diversity of patients seen at the single New York institution from which data was collected (Bellevue Hospital Center), patients included in the current analysis closely resemble the global demographic for HCC.^[2,3] Sixty percent of all HCC cases were due to underlying HBV, and 25% were due to HCV. The majority of patients in the HBV group were of East Asian race (90%), compared to only 5% in the HCV group. This statistic potentially explains the significant disparity in age at initial cancer diagnosis among HBV vs. HCV-infected patients. HBV transmission in East Asian populations predominantly follows vertical (maternal-fetal) patterns of transmission.^[15] In contrast, HBV in non-Asian populations, and HCV are more frequently transmitted in horizontal patterns as a result of exposure to infected body fluids.^[16–18] Thus HCV exposure usually occurs later in life compared to HBV in the largest worldwide at risk populations. This finding from our study is consistent with previous studies in Japan showing younger detection age in HBV HCC patients compared with HCV HCC patients.^[19,20] Although the mechanistic sequence of events required for progression from chronic viral hepatitis infection to HCC are poorly understood, a reasonable conclusion based on the current data could imply that the young age associated with HBV-HCC occurs as a direct result of vertical HBV transmission. Thus screening for HCC in patient populations known to be at risk for vertically-transmitted HCC should begin at an early age, no later than early adulthood.

Another important difference in the progression to HCC among HBV vs. HCV infected patients is the association to pre-existing cirrhosis at the time of initial cancer diagnosis. The occurrence of HCC in the absence of cirrhosis in a substantial percentage of HBV-HCC patients (40%), compared to the invariable association to established cirrhosis in those with HCV-HCC, suggests a potential cirrhosis-independent pathway to cancer unique (among viral hepatitis-associated cancers) to HBV-HCC. Much of the literature suggests a generally accepted common pathway to hepatocarcinogenesis, proposed in both HBV and HCV patients, based on: active viral replication, chronic hepatocellular necroinflammatory activity, hepatic parenchymal fibrosis, cirrhosis, and eventually cancer.^[21–23] Although this model appears valid for patients with HCV, some with HBV do not experience such a predictable sequence of events prior to developing liver cancer.^[24–26]

Considerations relevant to the care of patients who are subject to a cirrhosis-independent pathway to HCC should lead to proposed changes in current widely-adopted practices of screening for HCC in patients with chronic HBV.^[27–29] Proposed changes in surveillance practices, particularly in those suspected of perinatal infection, should include a high level of vigilance for cancer even in the absence of cirrhosis. Several levels of evidence, in addition to the current data, reinforce that HBV patients are at risk for HCC even prior to the development of cirrhosis. Thus HCC screening should not be withheld until evidence of active hepatocellular necroinflammation or cirrhosis are observed.

Several additional significant clinical-pathologic differences in HCC were also observed according to underlying viral hepatitis status, including AFP production. This observation is particularly interesting, given that the utility of serum AFP as a cancer screening tool has been the subject of considerable recent debate, leading some experts in the field to not advocate its use as a tumor marker.^[30] In the current study, median AFP level in HCV-associated HCC was 37 ng/ml, compared with 1000 ng/ml in HBV-associated HCC, and only 27% among HCV-associated cancers produced serum AFP greater than 100 ng/ml, compared with 65% in of HBV-associated HCC. This result suggests a higher sensitivity of serum AFP as a tumor marker when used in patients with HBV, but maybe less so in screening patients with HCV for cancer.

Oncologic variables with established prognostic significance were evaluated according to viral hepatitis status. Both macrovascular invasion and synchronous metastases occurred with greater frequency in the HBV-HCC group, although these observations did not achieve statistical significance. Only tumor size on initial HCC diagnosis, an important prognostic indicator, was statistically different among HBV vs. HCV patients.^[31–33] This tumor size discrepancy may be explainable by less rigorous cancer screening recommendations for patients with chronic HBV, compared to more uniform and frequent screening programs for patients with HCV.^[34,35] Many of the accrued HBV-HCC patients would not have met current American Association for the Study of Liver Diseases (AASLD) guidelines for HCC screening due to their young age, absence of cirrhosis or other variables.^[30] Thus a relatively delayed cancer diagnosis may be attributable in part to under screening of HBV patients for HCC, when compared to those with chronic HCV.

Often due to initial presentation with large tumors, patients in the HBV-HCC group were less likely to meet Milan eligibility criteria for liver transplantation (single tumor <5 cm in greatest diameter or multiple tumor each <3 cm in greatest diameter).^[12] Due to the similar prognostic importance of applying Milan criteria to surgical resection series, this association to larger tumors also predicted a lower likelihood of surgical resection with expected favorable long term survival.^[13,36,37] Overall a staggeringly small fraction of all patients with HCC associated with either hepatitis virus met Milan criteria, underscoring the fact that most patients (80%) cannot be treated with the two most effective treatments or an expectation for favorable long term outcome. However, despite this observation in both viral hepatitis patients, inoperable or poor prognosis cancers were significantly more common in patients with HBV. Whether HBV or HCV viral etiology is an independent prognostic factor in patients with HCC following surgical resection or liver transplantation remains controversial and requires further investigation.^[38–42]

Conclusions

In summary, patients with HBV-associated HCC were more likely to present with poor-prognosis cancers, often at a young age, and in the absence of cirrhosis. In contrast, patients with HCV-associated HCC often were diagnosed in a setting of pre-existing cirrhosis, with multiple comorbidities, but with more favorable oncologic features. These data suggest a role for more aggressive screening and management of chronic HBV patients, particularly those subjected to maternal-fetal viral transmission. The importance of earlier screening and more aggressive treatment is especially emphasized by the advanced oncologic nature of HCC associated with HBV on typical initial diagnosis.

References

1. Parkin DM, Bray FI, Devesa SS: Cancer burden in the year 2000. The global picture. Eur J Cancer 2001, 37(Suppl 8):S4–S66.
2. Parkin DM: The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006, 118:3030–3044.
3. Perz JF, Armstrong GL, Farrington LA, Hutin YJF, Bell BP: The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006, 45:529–538.
4. Raza SA, Clifford GM, Franceschi S: Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. Br J Cancer 2007, 96:1127–1134.
5. Varela M, Sala M, Llovet JM, Bruix J: Review article: natural history and prognostic prediction of patients with hepatocellular carcinoma. Aliment Pharmacol Ther 2003, 17(Suppl 2):98–102.
6. Lopez PM, Villanueva A, Llovet JM: Systematic review: evidence-based management of hepatocellular carcinoma–an updated analysis of randomized controlled trials. Aliment Pharmacol Ther 2006, 23:1535–1547.
7. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodés J, EASL Panel of Experts on HCC, EASL Panel of Experts on HCC: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. J Hepatol 2001, 35:421–430.
8. Beck J, Nassal M: Hepatitis B virus replication. World J Gastroenterol 2007, 13:48–64.
9. Pawlotsky JM, Chevaliez S, McHutchison JG: The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 2007, 132:1979–1998.
10. Moradpour D, Penin F, Rice CM: Replication of hepatitis C virus. Nat Rev Microbiol 2007, 5:453–463.
11. Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005, 5:215–229.
12. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996, 334:693–699.
13. Cha CH, Ruo L, Fong Y, Jarnagin WR, Shia J, Blumgart LH, DeMatteo RP: Resection of hepatocellular carcinoma in patients otherwise eligible for transplantation. Ann Surg 2003, 238:315–321.
14. Shepard CW, Simard EP, Finelli L, Flore AE, Bell BP: Hepatitis B virus infection: Epidemiology and vaccination. Epidemiologic Reviews 2006, 28:112–125.
15. Custer B, Sullivan SD, Hazlet TK, Iloeje U, Veenstra DL, Kowdley KV: Global epidemiology of hepatitis B virus. J Clin Gastroenterol 2004, 38:S158–S168.
16. Deuffic-Burban S, Abiteboul D, Lot F, Branger M, Bouvet E, Yazdanpanah Y: Costs and cost-effectiveness of different follow-up schedules for detection of occupational hepatitis C virus infection. Gut 2009, 58(1):105–110.
17. Thomson EC, Main J: Epidemiology of Hepatitis C virus infection in HIV-infected individuals. Journal of Viral Hepatitis 2008, 15(1):773–781.
18. Santantonio T, Wiegand J, Gerlach JT: Acute Hepatitis C: Current status and remaining challenges. J Hepatol 2008, 49(4):625–633.
19. Tanizaki H, Ryu M, Kinoshita T, Kawano N, Konishi M, Cho A, Nakatsura T, Natsume T, Takahashi S, Sugita M, Izuishi K, Yoshino M, Furuse J, Iwasaki M, Tsubono Y: Comparison of clinical features and survival in patients with hepatitis B and C virus-related hepatocellular carcinoma. Jpn J Clin Oncol 1997, 27(2):67–70.
20. Shiratori Y, Shiina S, Imamura M, Kato N, Kanai F, Okudaira T, Teratani T, Tohgo G, Toda N, Ohashi M, Ogura K, Niwa Y, Kawabe T, Omata M: Characteristic difference of hepatocellular carcinoma between hepatitis B- and C- viral infection in Japan. Hepatology 1995, 22(4 Pt 1):1027–1033.
21. Blanc P, Desprez D, Fabre JM, Pageaux G, Daures JP, Larrey D, SaintAubert B, Michel H, Maurel P: Contribution of primary cultures of adult human hepatocytes to the pathophysiology of hepatocellular carcinoma. J Hepatol 1996, 25(5):663–669.
22. Schuppan D, Afdhal NH: Liver cirrhosis. Lancet 2008, 371(9615):838–851.
23. Rosenthal P: Hepatocarcinoma in viral and metabolic liver disease. J Pediatr Gastroenterol Nutr 2008, 46(4):370–375.
24. Kumar M, Kumar R, Hissar SS, Saraswat MK, Sharma BC, Sakhuja P, Sarin SK: Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: A case-controlled study of 213 hepatocellular carcinoma patients from India. J Gastroenterol Hepatol 2007, 22(7):1104–1111.
25. Chen CH, Eng HL, Lee CM, Kuo FY, Lu SN, Huang CM, Tung HD, Chen CL, Changchien CS: Correlations between hepatitis B virus genotype and cirrhotic or non-cirrhotic hepatoma. Hepato-Gatroenterology 2004, 51(56):525–555.
26. Grando-Lemaire V, Guettier C, Chevret S, Beaugrand M, Trinchet JC: Hepatocellular carcinoma without cirrhosis in the West: epidemiological factors and histopathology of the non-tumorous liver. J Hepatol 1999, 31(3):508–513.
27. Lin SY, Chang ET, So SK: Why we should routinely screen Asian American adults for hepatitis B: A cross-sectional study of Asians in California. Hepatology 2007, 46(4):1034–1040.
28. Davila JA, Weston A, Smalley W, El-Serag HB: Utilization of screening for hepatocellular carcinoma in the United States. J Clin Gastroenterol 2007, 41(8):777–782.
29. Yamazaki Y, Kakizaki S, Sohara N, Sato K, Takagi H, Arai H, Abe T, Katakai K, Kojima A, Matsuzaki Y, Mori M: Hepatocellular carcinoma in young adults: The clinical characteristics, prognosis, and findings of a patient survival analysis. Dig Dis Sci 2007, 52(4):1103–1107.
30. Bruix J, Sherman M: Management of hepatoceullular carcinoma. Hepatology. 2005, 42:1208–1236.
31. Martins A, Cortez-Pinto H, Marques-Vidal P, Mendes N, Silva S, Fatela N, Gloria H, Marinho R, Tavora I, Ramalho F, de Moura MC: Treatment and prognostic factors in patients with hepatocellular carcinoma. Liver Int 2006, 26(6):680–687.
32. Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: The BCLC staging classification. Seminars in Liver Disease 1999, 19(3):329–338.
33. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J: Clinical angement of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001, 35(3):421–430.
34. Chalasani N, Horlander JC, Said A, Hoen H, Kopecky KK, Stockberger SM, Manam R, Now PY, Lumeng L: Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol 1999, 94(10):2988–2993.
35. Patel D, Terrault NA, Yao FY, Bass NM, Ladabaum U: Cost-effectiveness of hepatocellular carcinoma surveillance in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 2006, 3(1):75–84.
36. Morioka D, Tanaka K, Matsuo K, Takeda K, Ueda M, Sugita M, Nagano Y, Endo I, Sekido H, Togo S, Shimada H: Applicability of the Milan criteria for determining liver transplantation as a first-line treatment for hepatocellular carcinoma. Ann Surg Oncol 2006, 13:1500–1510.
37. Margarit C, Escartin A, Castells L, Vargas V, Allende E, Bilbao I: Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class A patients with cirrhosis who are eligible for liver transplantation. Liver Transpl 2005, 11:1242–1251.
38. Roayaie S, Haim MB, Emre S, Fishbein TM, Sheiner PA, Miller CM, Schwartz ME: Comparison of surgical outcomes for hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a western experience. Ann Surg Oncol 2000, 7(10):764–770.
39. Huang YH, Wu JC, Chen CH, Chang TT, Lee PC, Chau GY, Lui WY, Chang FY, Lee SD: Comparison of recurrence after hepatic resection in patients with hepatitis B vs. hepatitis C-related small hepatocellular carcinoma in hepatitis B virus endemic area. Liver Int 2005, 25(2):236–241.
40. Li Q, Li H, Qin Y, Wang PP, Hao X: Comparison of surgical outcomes for small hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a Chinese experience. J Gastroenterol Hepatol 2007, 22(11):1936–1941.
41. Ahmad SA, Bilimoria MM, Wang X, Izzo F, Delrio P, Marra P, Baker TP, Porter GA, Ellis LM, Vauthey JN, Dhamotharan S, Curley SA: Hepatitis B or C virus serology as a prognostic factor in patients with hepatocellular carcinoma. J Gastrointest Surg 2001, 5(5):468–476.
42. Kao WY, Su CW, Chau GY, Lui WY, Wu CW, Wu JC: A Comparison of Prognosis between Patients with Hepatitis B and C Virus-related Hepatocellular Carcinoma Undergoing Resection Surgery. World J Surg. 2011, 35(4):858–867.

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Silymarin Is Ineffective for Chronic Hepatitis C Virus Infection

From Journal Watch > Journal Watch Gastroenterology

Atif Zaman, MD, MPH

Posted: 09/21/2012; Journal Watch © 2012 Massachusetts Medical Society

Abstract and Introduction

Abstract

In the most rigorous trial to date, oral silymarin was not superior to placebo in decreasing disease activity.

Introduction

Silymarin is a botanical extract of milk thistle commonly used by patients with liver disease. In vitro studies have demonstrated antiviral, anti-inflammatory properties of silymarin in hepatitis C virus (HCV) replicon systems. However, the few efficacy studies conducted in patients with chronic HCV infection have produced mixed results.

In a new multicenter, double-blind, placebo-controlled efficacy trial, investigators randomized 154 patients (median age, 54; 71% men) with chronic HCV infection who previously failed interferon-based therapy to receive 420 mg of silymarin, 700 mg of silymarin, or placebo three times daily for 24 weeks. The two oral doses of pure silymarin were determined by earlier dose finding studies and were three to five times higher than concentrations used in previous studies. The primary endpoint was a serum alanine aminotransferase (ALT) level of ≤45 U/L or a 50% reduction from baseline ALT to a level <65 U/L. Secondary endpoints included HCV RNA levels and quality-of-life indicators.

After 24 weeks of treatment, only two patients in each group achieved the primary endpoint. The mean decline in ALT levels at the end of treatment, the mean change in HCV RNA levels, and the quality-of-life indicators did not differ among the three groups.

Comment

This trial definitively demonstrates that silymarin, even at three to five times the typical dose, is ineffective in treating patients with chronic HCV infection. Unlike previous trials, this study used a pure, quantifiable formulation of silymarin and well-defined outcomes, its cohort was large and representative of the patient population, the treatment period was sufficiently long, and both medication and visit adherence rates were high. Clinicians should quote this study when addressing patients' questions regarding the use of milk thistle for treating HCV infection.

References

1. Fried MW et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: A randomized controlled trial. JAMA 2012 Jul 18; 308:274.

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