October 1, 2010

SUMMARY: An ongoing initiative to offer interferon-based therapy for chronic hepatitis C virus (HCV) infection to injection drug users has demonstrated promising outcomes, according to a study presented at the recent 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) in Boston. Retention in the program has been good despite some patients continuing active drug use, and about half of those who underwent treatment have achieved sustained virological response (SVR).

By Liz Highleyman

Some healthcare providers have traditionally been reluctant to offer chronic hepatitis C treatment to current or former injection drug users due to concerns about poor adherence and toxicities. Studies have shown, however, that such patients can do well on treatment, and current practice guidelines state that drug users should be considered on an individual basis and not routinely excluded from therapy.

B. Conway from the University of British Columbia and colleagues performed an evaluation of a program providing hepatitis C treatment to injection drug users in Vancouver's Downtown East Side neighborhood.

Starting in March 2005, participants were recruited at the Pender Community Health Centre and evaluated for possible treatment for HCV infection. Diagnostic testing was offered for HCV and HIV, and patients who were deemed eligible for hepatitis C therapy were offered the opportunity to be included in the program.

Participants attended weekly clinic visits. All treated patients received once-weekly pegylated interferon as directly observed therapy plus daily self-administered ribavirin. Participants also received extensive medical, addiction, and counseling support and a standardized proactive approach to management of treatment-related side effects.

Results
  • At the time the study abstract was submitted, 370 potential participants had been screened and 165 courses of treatment were administered.
  • Most participants (84%) were men, the mean age was 49 years, 52% had hard-to-treat HCV genotype 1, and 10% were coinfected with HIV.
  • 53% reported injection drug use within the previous 30 days.
  • Willingness to undergo hepatitis C treatment was positively associated with male sex (adjusted odds ratio [aOR] 3.73) and current enrollment in an opiate substitution pharmacotherapy program (aOR 1.63).
  • Combined drug use was associated with less willingness to start therapy (aOR 0.36).
  • Among treated participants with an appropriate duration of follow-up, the SVR rate 24 weeks after finishing treatment was 54%:
          --HCV genotype 1: 39%;
          --HCV genotype 2: 75%;
          --HCV genotype 3: 63%.
  • Type of pegylated interferon (Pegasys or PegIntron) and HIV coinfection status were not associated with virological treatment failure. 
"Our expanding program (to deliver over 100 courses of treatment per year in 2010) continues to attract significant numbers of patients into HCV treatment, with good retention and success, despite ongoing illicit drug use in many cases," the researchers concluded. "The flexibility of the program allows us to tailor its delivery to suit individual needs and contributes to its success."

Investigator affiliations: Univ. of British Columbia, Vancouver, Canada; Vancouver Coastal Health, Vancouver, Canada.

9/28/10

Reference
B Conway, L Gallagher, E Knight, and others. Treatment of HCV Infection in Injection Drug Users (IDUs): An Update on a Multidisciplinary Program in Vancouver. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. Abstract V-1790.

Source
SUMMARY: Nearly 75% of people with chronic hepatitis C virus (HCV) infection in 3 U.S. states have HCV genotype 1, the hardest type to treat, according to public health surveillance data presented at the recent 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) in Boston. Among African-Americans -- a group known to respond poorly to interferon-based therapy -- more than 90% had genotype 1.

By Liz Highleyman

Hepatitis C virus genotype is a key factor in predicting how well interferon-based therapy will work. Patients with HCV genotype 1 are treated with pegylated interferon plus ribavirin for a standard duration of 48 weeks, with a sustained virological response (SVR) rate just under 50%, while those with genotypes 2 or 3 are typically treated for 24 weeks and have an SVR rate of 70%-80%. Genotypes 4 (which is also considered hard to treat), 5, and 6 are seldom seen in the U.S.

Monina Klevens from the Centers for Disease Control and Prevention (CDC) and colleagues collected data on hepatitis C cases reported during 2009 to health departments in Connecticut, Minnesota, 34 counties in New York State, and New York City, as part of an enhanced population-based surveillance project.

Results
  • A total of 16,620 confirmed cases of HCV infection were reported by the participating sites.
  • 3081 of these individuals (18.5%) had an available HCV genotype test result
          --62.2% were reported in New York City;
          --20.2% were from elsewhere in New York State;
          --15.5% were from Minnesota;
          --2.1% were from Connecticut.
  • Overall, the genotype distribution in these cases was as follows:
          --HCV genotype 1: 73.3% (range 64.6%-77.5% across sites);
          --HCV genotype 2: 11.9% (range 10.2%-16.6%);
          --HCV genotype 3: 11.6% (range 8.0%-18.5%);
          --HCV genotypes 4, 5, or 6: 3.3%.
  • Younger adults (age 18-39 years) were more likely to have HCV genotype 3 than people age 40-59 years or those age 60 and older (16.6%, 11.9%, and 5.5%, respectively).
  • Genotype 1 frequency varied across racial/ethnic groups:
          --Blacks (non-Hispanic): 90.7%;
          --Hispanics/Latinos: 78.7%;
          --Whites (non-Hispanic): 68.1%.
  • Most people with HCV genotypes 1, 2, and 3 were born in the U.S. (87.4%, 81.2%, and 70.8%, respectively)
  • In contrast, most people (71.4%) with genotype 4 and all those with genotype 6 were foreign-born.
Based on these findings, the investigators concluded, "In 2009, there was limited variability in genotype by geographic area, but surveillance is needed as more persons are screened and those with HCV infection are referred for medical care including treatment."

Investigator affiliations: Centers for Disease Control and Prevention, Atlanta, GA; Colorado Dept. of Public Health, CO; Connecticut Dept. of Public Health, CT; Minnesota Dept. of Health, MN; New York State Dept. of Health, NY; New York City Dept. of Health and Mental Hygiene, New York, NY.

10/1/10

Reference
M Klevens, R Jiles, D Daniels, and others. Distribution of Reported Hepatitis C Genotypes in Sites Conducting Enhanced Hepatitis Surveillance, 2009. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. Abstract V-1789.

Source

September 2010 Briefing - HIV & AIDS

Friday, October 01, 2010

Here are what the editors at HealthDay consider to be the most important developments in HIV & AIDS for September 2010. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the most likely to affect clinical practice.

FDA: Certain Lots of Epogen and Procrit Recalled

MONDAY, Sept. 27 (HealthDay News) -- The U.S. Food and Drug Administration and Amgen have notified health care professionals that certain lots of epoetin alfa (Epogen and Procrit) are being recalled, as product vials may contain extremely thin glass flakes (lamellae) that could result in serious adverse events.

More Information

HIV Prevalence 19% Among Men Who Have Sex With Men

FRIDAY, Sept. 24 (HealthDay News) -- The prevalence of HIV among men who have sex with men (MSM) remains high in the United States, and 44 percent of infected MSM do not know they are infected, according to research published in the Sept. 24 issue of the U.S. Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report.

Full Text

Gel Not Shown to Reduce HIV-1 Incidence in Women

MONDAY, Sept. 20 (HealthDay News) -- PRO2000 microbicide gel is not efficacious against vaginal HIV-1 transmission, according to research published online Sept. 20 in The Lancet.

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Sacrifice Makes Industry Gifts Seem More Acceptable

TUESDAY, Sept. 14 (HealthDay News) -- Residents who are reminded of the sacrifices they made to attain their medical education tend to rate the acceptability of industry-sponsored gifts higher than those who are not reminded, according to research published in the Sept. 15 issue of the Journal of the American Medical Association.

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Re-Consent Important Before Secondary Use of Genetic Data

MONDAY, Sept. 13 (HealthDay News) -- Most research participants want to be asked for secondary consent -- referred to as re-consent -- before their existing personal genetic data are added to the federal database of Genotypes and Phenotypes (dbGaP), according to research published in the September issue of the Journal of Empirical Research on Human Research Ethics.

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High HIV Rate for Men Having Sex With Men in France

FRIDAY, Sept. 10 (HealthDay News) -- Although overall HIV incidence rates in France declined between 2003 and 2008, the rate was drastically higher among men who have sex with men (MSM) than among other groups, according to research published online Sept. 9 in The Lancet Infectious Diseases.

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Annual Medical Liability Costs Surpass $50 Billion

THURSDAY, Sept. 9 (HealthDay News) -- The annual costs of the medical liability system in the United States total more than $50 billion, which accounts for a relatively small but non-trivial portion of total health care spending, according to an article in the September issue of Health Affairs.

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Nevirapine Reuse in Children With HIV May Be Safe

WEDNESDAY, Sept. 8 (HealthDay News) -- After achieving viral suppression with protease inhibitor-based therapy, most children infected with HIV at birth despite being given nevirapine may safely be switched back to nevirapine-based therapy without fear of drug resistance, according to a study published in the Sept. 8 issue of the Journal of the American Medical Association.

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Urban Clinic Increases HIV Testing Uptake in Adolescents

TUESDAY, Sept. 7 (HealthDay News) -- After the publication of national recommendations for routine HIV testing and the implementation of rapid testing, the rate of HIV testing among adolescents at an urban adolescent primary care clinic substantially increased, according to research published in the September issue of the Archives of Pediatrics & Adolescent Medicine.

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Breaking News – Governor Vetoes Hepatitis Bills

Posted on October 1, 2010

From our friends at Cal Hep:

Late in the evening on September 30th, two hours before deadline to sign or veto bills, Governor Schwarzenegger vetoed two bills that would have reduced the number of new HIV, hepatitis B and hepatitis C cases. Having worked to develop, draft and support these bills, the staff and member organizations of the California Hepatitis Alliance (calHEP) are extremely disappointed by this news. The Governor’s Office chose to ignore the recommendations of numerous medical and scientific bodies, including the Institute of Medicine of the National Academies of Medicine and Science, and his own administration’s Department of Public Health to make syringes more widely available through pharmacies and needle exchanges in order to reduce the number of viral hepatitis infections among injection drug users.

Governor Schwarzenegger did sign a bill to sustain the status quo: cities and counties may authorize pharmacists to furnish 10 or fewer syringes to an adult, and cities and counties may authorize syringe exchange services. Currently almost half of Californians live in jurisdictions where there is no safe legal access to sterile syringes without a prescription, and where law enforcement may arrest a person for attempting to comply with the U.S. Public Health service recommendation to injection drug users that they use a new sterile syringe for each injection. Contact CalHEP for information on how to support your local efforts to improve syringe access.

VETOED: SB 1029 by State Senator Leland Yee would have allowed pharmacists and physicians to furnish 30 or fewer syringes without prescription and would have allowed adults to possess up to 30 for personal use.

VETOED: AB 1858 would have allowed California Department of Public Health to authorized syringe exchange services in locations where the conditions exist for the rapid spread of viral hepatitis, HIV and other deadly or disabling diseases spread by the sharing of syringes.

Both bills were supported by California Medical Association, California Nurses Association, Health Officers Association of California, as well as numerous health and patient advocacy groups. We are grateful to the work of Drug Policy Alliance and San Francisco AIDS Foundation in providing support for the lobbying effort throughout the year. We are especially grateful to Senator Leland Yee (D-San Francisco) and Assemblymember Bob Blumenfield (D-Van Nuys) and their offices for leading these life saving efforts.We encourage you to contact the lawmakers to thank them for their commitment to improving California’s health.

CalHEP will continue to fight for evidence-based policies and programs to reduce the burden of the hepatitis B and C epidemics in California. We thank those of you who contacted your legislators and the Governor to encourage support for these bills.

Source

Advanced HIV test may benefit high-risk groups

Updated: 2010-09-30 08:14:17 CST

In areas of the country that struggle with higher than average HIV rates, more early-stage testing may be needed to help newly infected individuals start therapy at the point when the virus is most treatable.

A new report from the Centers for Disease Control and Prevention states that this may be one of the most cost effective ways for reducing HIV rates in areas that have the largest problems.

Pooled nucleic acid amplification HIV testing - which tests for genetic material from the virus, rather than antibodies produced by the body to fight it - typically detects infections earlier than traditional testing methods. However, the report states that the procedure may only be cost-effective to implement in areas hit the hardest by the epidemic.

Clinics that treat high-risk populations reported that administering the test was more cost-effective than dealing of the consequences of allowing infections to progress to later stages.

While the screening strategy may not be feasible to implement at all HIV testing locations, researchers said that it may significantly improve the quality of life of individuals in areas where the disease is more common.

Source

Achillion begins anti-hepatitis drug trials

New Haven drug developer Achillion Pharmaceuticals Inc. says it has begun two human clinical trials in the U.S. and Europe to determine the dosing effectiveness of a prototype treatment against the hepatitis C virus.

Some 120 patients with chronic hepatitis C participating in the two double-blind trials -- one to run 28 days, the other 12 weeks -- will be randomly dosed with small-molecule ACH-1625 drug or with a placebo.

The trial will determine the dosing at which ACH-1625 blocks a particular enzyme the hepatitis C virus needs to replicate, Achillion officials say.

Results of the 28-day trial will be disclosed in the first quarter of 2011; the 12-week study findings will come near the end of next year.

"This Phase II clinical trial will allow us to establish the most appropriate once-daily dose to use in longer-term trials, and will augment our existing safety database for ACH-1625 in humans," said Elizabeth A. Olek, Achillion's chief medical officer. "The results will also provide important combination data for use of ACH-1625 with standard of care.''

Achillion officials are eager to prove their treatment, with a more convenient dosing, is a safer and more tolerable viral suppressant over a longer period.

Source
 
Also See: Achillion Announces Dosing of First Patient in Phase II Trial of ACH-1625 for the Treatment of Hepatitis C
PRINCETON, N.J., Oct 01, 2010 (BUSINESS WIRE) -- New data on multiple Bristol-Myers Squibb Company /quotes/comstock/13*!bmy/quotes/nls/bmy (BMY 27.28, +0.03, +0.10%) compounds will be presented at the 61st annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston from October 29 to November 2.

Data will be presented on BARACLUDE(R) (entecavir) in patients with chronic hepatitis B, and on compounds in clinical development for the treatment of hepatitis C, using multiple scientific approaches to target the hepatitis C virus (HCV). Key hepatitis C presentations include data on novel combinations of investigational agents, including BMS-790052, a NS5A inhibitor, and BMS-650032, an NS3 inhibitor. Additionally, 12-week Phase 2a data on PEG-Interferon lambda, a novel type 3 interferon with enhanced specificity for hepatocyte binding, will be presented.

The Company will also present outcomes research data in both hepatitis C and hepatocellular carcinoma.

"Bristol-Myers Squibb is focused on developing innovative medicines to treat liver disease," said Elliott Sigal, M.D., Ph.D., executive vice president, chief scientific officer and president, Research and Development, Bristol-Myers Squibb. "Building on our established expertise in viral hepatitis and oncology, the data at this year's Liver Meeting demonstrates the breadth and strength of our hepatitis C portfolio. We are pursuing multiple targets with the potential to be used in combination regimens to advance the treatment of this serious disease."

BARACLUDE, BMS-790052, and BMS-650032 were discovered by Bristol-Myers Squibb Research and Development. PEG-Interferon lambda was discovered by ZymoGenetics, Inc. Bristol-Myers Squibb and ZymoGenetics announced a global collaboration for PEG-Interferon lambda and its related development program in 2009. In September 2010, Bristol-Myers Squibb announced its intent to acquire ZymoGenetics.

The Bristol-Myers Squibb data presentations at AASLD are as follows:

Hepatitis B

October 30 2:00 - 7:30 p.m. Efficacy and Safety of Entecavir in Nucleos(t)ide Naive Asians with HBeAg Positive and Negative Chronic Hepatitis B: Results from Studies ETV-022/027 (Abstract #485)

R. Gish
California Pacific Medical Center
San Francisco,California

October 30 2:00 - 7:30 p.m.  Long-term Entecavir Treatment for up to 5 Years in Asians with  HBeAg- Positive Nucleos(t)ide Naive Chronic Hepatitis B: Results from ETV-022 and -901 (Abstract #478)

C. Pan
Mount Sinai School of Medicine
New York, New York

Hepatitis C

October 31, 8:00 - 5:30 p.m. Pegylated Interferon Lambda (PEG-IFN-) Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naive HCV Patients (Genotypes 1, 2, 3 or 4): Safety Viral Response, and Impact of IL-28B Host Genotype through Week 12 (Abstract #821)

A.J. Muir
Duke University School of Medicine
Durham, North Carolina

October 31, 8:00 - 5:30 p.m. Co-administration of BMS-790052 and BMS-650032 Does Not Result in a Clinically Meaningful Pharmacokinetic Interaction in Healthy Subjects (Abstract #827)

M. Bifano
Bristol-Myers Squibb

October 31, 8:00 - 5:30 p.m. Pharmacokinetics of PEG-Interferon Lambda (PEG-IFN-) Following Fixed Dosing in Treatment-Naive Hepatitis C Subjects (Single Dose Interim Data from a Dose-Ranging Phase 2a Study) (Abstract #830)

K.A. Byrnes-Blake
ZymoGenetics

October 31, 8:00 - 5:30 p.m. The Effect of Treatment Group, HCV Genotype, and IL-28B Genotype on Early HCV Viral Kinetics in a Phase 2a Study of PEG-Interferon Lambda (PEG-IFN-) in Hepatitis C Patients (Abstract #831)

J.A. Freeman
ZymoGenetics

November 1, 8:00 a.m. - 5:30 p.m. Combination therapy with BMS-790052 and BMS-650032 alone or with pegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders (Abstract # LB-8)

A. S. Lok
University of Michigan
Ann Arbor, Michigan

November 2, 7:00 a.m. - 12:00 p.m. Genotypic and Phenotypic Analysis of HCV NS5A Inhibitor Resistance Variants: Correlations Between In Vitro and In Vivo Observations (Abstract #1853)

M. Gao
Bristol-Myers Squibb

November 2, 7:00 a.m. - 12:00 p.m. In Vitro Activity of the Combination of Pegylated Interferon-Lambda with Direct-Acting Antivirals in the HCV Replicon Model (Abstract #1854)

F. McPhee
Bristol-Myers Squibb

November 2, 7:00 a.m. - 12:00 p.m. BMS-824393 is a Potent Hepatitis C Virus NS5A Inhibitor with Substantial Antiviral Activity When Given as Monotherapy in Subjects with Chronic Genotype 1 HCV Infection (Abstract #1858)

R. Nettles
Bristol-Myers Squibb

November 2, 7:00 a.m. - 12:00 p.m. BMS-790052, a First-in-Class Potent Hepatitis C Virus NS5A Inhibitor, Demonstrates Multiple-Dose Proof-of-Concept in Subjects with Chronic Genotype 1 HCV Infection (Abstract #1881)

R. Nettles
Bristol-Myers Squibb

November 2, 7:00 a.m. - 12:00 p.m. Chronic Hepatitis C Infections and the Risk of Depression and Other Adverse Events (Abstract #1895)

J. McCombs
University of Southern California
Los Angeles, California

November 2, 7:00 a.m. - 12:00 p.m. The impact of hepatitis C on health-related quality of life, work productivity, and healthcare utilization (Abstract #1942)

M. daCosta DiBonaventura
Kantar Health
New York, New York

Hepatocellular Carcinoma

November 2, 7:00 a.m. - 12:00 p.m. Treatment of Hepatocellular Carcinoma (HCC) in Two Major Care Centers in the United States (US) (Abstract #1846)

Tertiary M. Schwartz
Mt. Sinai
New York, New York

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.comor follow us on Twitter at http://twitter.com/bmsnews .

Full prescribing information for BARACLUDE is available at http://www.bms.com/.

Forward-Looking Statements

This press release contains "forward-looking statements" relating to the acquisition of ZymoGenetics by Bristol-Myers Squibb. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the acquisition will be completed, or if it is completed, that it will close within the anticipated time period. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2009, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.

Except for the historical information presented herein, matters discussed herein may constitute forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from any future results, performance or achievements expressed or implied by such statements. Statements that are not historical facts, including statements preceded by, followed by, or that include the words "future"; "anticipate"; "potential"; "believe"; or similar statements are forward-looking statements. Risks and uncertainties include uncertainties as to the timing of the tender offer and merger; uncertainties as to how many of the ZymoGenetics shareholders will tender their shares in the offer; the risk that competing offers will be made; the possibility that various closing conditions for the transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transaction; the effects of disruption from the transaction making it more difficult to maintain relationships with employees, licensees, other business partners or governmental entities; as well as risks detailed from time to time in ZymoGenetics' public disclosure filings with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009, subsequent quarterly filings on Form 10-Q and the Solicitation/Recommendation Statement filed in connection with the tender offer. The information contained in this release is as of September 28, 2010.

This press release is neither an offer to purchase nor a solicitation of an offer to sell shares of ZymoGenetics. Bristol-Myers Squibb Company and Zeus Acquisition Corporation have filed a tender offer statement with the SEC, and have mailed an offer to purchase, forms of letter or transmittal and related documents to ZymoGenetics shareholders. ZymoGenetics has filed with the SEC, and has mailed to ZymoGenetics shareholders a solicitation/recommendation statement on Schedule 14D-9. These documents contain important information about the tender offer and stockholders of ZymoGenetics are urged to read them carefully when they become available.

 These documents will be available at no charge at the SEC's website at http://www.sec.gov/. The tender offer statement and the related materials may be obtained for free by directing a request by mail to Georgeson Inc., 199 Water Street, 26th Floor, New York, New York 10038 or by calling toll-free (800) 491-3096. In addition, a copy of the offer to purchase, letter or transmittal and certain other related tender offer documents (once they become available) may also be obtained free of charge from Bristol-Myers Squibb by directing a request to: Public Affairs, Telephone No.: (609) 252-6579; E-Mail: jennifer.mauer@bms.com.

SOURCE: Bristol-Myers Squibb Company

Bristol-Myers Squibb Company
Media:
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

Source

Vertex Edges Merck In First Round of Hepatitis C Fight

Oct. 1 2010 - 3:13 pm
By ROBERT LANGRETH

New details of studies of rival hepatitis C drugs from Merck and Vertex Pharmaceuticals were released today in advance of a crucial upcoming meeting of liver specialists at the end of the month in Boston. The drugs, so-called hepatitis C protease inhibitors, represent the first class of agents that directly target the hepatitis C virus. Both have substantially boosted the cure rate in big trials, raising excitement among hepatitis c specialists.

While the drugs haven’t been compared directly, it appears that Vertex’s telaprevir drug is is a nudge better. Unless differences in tolerability and side effects emerge, if both drugs are approved, doctors may look at the data and go with the Vertex drug first because its cure rates appear to be a few percentage points higher.

Here’s what Howard Liang of Leerink Swann wrote in a note today:

“Apples-to-apples” comparison of boceprevir vs. telaprevir in treatment-experienced patients is possible for the first time and appears to favor telaprevir. In prior relapsers, SVR was 69%-75% for boceprevir vs. 83-88% for telaprevir. In what we would call partial responders MRK has a different definition, SVR was 40-52% for boceprevir vs. 54-59% for telaprevir. Cross-trial comparisons are always difficult but we believe the totality and consistency of both treatment-experienced and treatment-naïve data give an impression that telaprevir may be more potent.

If there are significant side effects to the Vertex compound that haven’t emerged yet, it could totally negate Vertex’s apparent advantage. But if Vertex’s drug is perceived by doctors as slightly more effective, who does Merck sell its drug to?

Merck R&D head Peter Kim may have some answers to this question. He is going to the liver meeting where he will face lots of questions from Wall Street types about where Merck’s drug will fit in. He needs to rebut the doubts about his company’s drug.

Source
Oct 01, 2010 09:05 ET

Immunology Data Also to Be Presented in Poster Session

LOUISVILLE, CO--(Marketwire - October 1, 2010) - GlobeImmune Inc. today announced that an abstract related to GI-5005, its Phase 2 investigational hepatitis C virus (HCV) product candidate, has been accepted for a late breaking oral presentation at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which will take place October 29 through November 2, 2010, in Boston.

At the AASLD annual meeting, GlobeImmune will present end-of-study data, including sustained virologic response (SVR) rate from prior non-responders, from a Phase 2 clinical study investigating the safety and efficacy of GI-5005. The study compared GI-5005 plus peg-interferon (peg-IFN) and ribavirin, the current standard of care (SOC), versus SOC alone in patients with chronic type 1 hepatitis C infection. Prior non-responders were defined as those patients who did not achieve viral negativity by PCR after a minimum of 12 weeks of SOC. Patients that had achieved viral negativity by PCR during prior SOC but had relapsed during or after completion of SOC therapy were excluded from the study.

The abstract, titled "GI-5005 Therapeutic Vaccine Plus PEG-IFN/Ribavirin Improves Sustained Virologic Response Versus PEG-INF/Ribavirin in Prior Non-Responders With Genotype 1 Chronic HCV Infection," is published online at the AASLD Web site.

Dr. Paul J. Pockros of Scripps Clinic is the lead author of the abstract that will be presented as part of a late breaker oral session beginning at 6 p.m. EDT on Monday, November 1, 2010 in the Hynes Auditorium. The presentation will include complete response and sustained virologic response rates for patients who received the GI-5005 plus SOC as well as SOC patients in the control arm of the study.

Additionally, Dr. John M. Vierling of Baylor College of Medicine will present a poster titled "GI-5005 Therapeutic Vaccine Improves Deficit in Cellular Immunity in IL28B Genotype T/T, Treatment-Naïve Patients with Chronic Hepatitis C Genotype 1 When Added to Standard of Care PEG-IFN-Alfa-2A/Ribavirin," on Tuesday, November 2, 2010 in the Hynes Exhibit Hall C.

GI-5005 is a therapeutic vaccine candidate that the company believes generates HCV specific T-cell responses and improves virologic responses in patients with chronic hepatitis C infection.

About GlobeImmune

GlobeImmune Inc. is a private company developing active immunotherapies called Tarmogens for the treatment of cancer and infectious diseases. Tarmogens generate activated killer T cells that are designed to locate and eliminate cancer cells and/or virally-infected cells. The Company's lead product candidate, GI-5005, is a Tarmogen being developed for the treatment of chronic hepatitis C infection (HCV). GI-5005 is designed to complement both the current standard of care and emerging novel therapies for HCV. The Company's lead oncology program, GI-4000, targets cancers caused by mutated versions of the Ras oncoprotein. GI-4000 is being investigated in clinical trials for the treatment of pancreas cancer as well as other cancers that contain mutated Ras, including non-small cell lung cancer and colorectal cancer. In May 2009, the Company announced a global partnership with Celgene focused on the discovery, development and commercialization of multiple product candidates for the treatment of cancer.

For additional information, please visit the company's Web site at http://www.globeimmune.com/.

This news release and the anticipated presentation contain forward-looking statements that involve risks and uncertainties, including statements relating to initiation and progress of the Company's clinical trial programs and the results from the clinical trials. Actual results could differ materially from those projected and the Company cautions readers not to place undue reliance on the forward-looking statements contained in the release and anticipated presentation.

Source
CAMBRIDGE, Mass., Oct. 1 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that three abstracts have been accepted for presentation at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, October 29-November 2, 2010 in Boston, Massachusetts). The abstracts being presented are on three of the company's hepatitis C clinical programs: IDX184, IDX320 and IDX375. Full abstracts can now be viewed at the AASLD website at http://www.aasld.org/.

The accepted abstracts are as follows:

• Lalezari, et al, "A Phase IIa Study of IDX184 in Combination with Pegylated Interferon (PegIFN) and Ribavirin (RBV) in Treatment-Naïve HCV Genotype 1-Infected Subjects" will be featured as an oral presentation on Sunday, October 31st at 3:45 p.m.

• Reesink, et al, "Antiviral Activity, Safety and Pharmacokinetics of IDX320, a Novel Macrocyclic HCV Protease Inhibitor, in a 3-Day Proof-of-Concept Study in Patients with Chronic Hepatitis C" will be presented in a late-breaking poster session on Monday, November 1st between 8:00 a.m. – 5:30 p.m.

• Bruijne, et al, "Phase I Study in Healthy Volunteers and Patients with IDX375, a Novel Non-Nucleoside HCV Polymerase Inhibitor" will be presented in a poster session on Tuesday, November 2nd between 7:00 a.m. – 12:00 p.m.

About Idenix

Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of infections caused by hepatitis C virus. For further information about Idenix, please refer to http://www.idenix.com/.

Forward-looking Statements

This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding the company's future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "will," "expects," "goal," "estimates," "projects," "would," "could," "targets," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the company's clinical development programs or commercialization activities in hepatitis C, or any potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of our drug candidates, the likelihood and success of any future clinical trials involving our drug candidates or successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected regulatory actions or delays, including the current clinical hold on IDX184 and IDX320; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, development and commercialization activities; the company's dependence on its collaborations with Novartis Pharma AG and GlaxoSmithKline; changes in the company's business plan or objectives; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in each of the company's annual report on Form 10-K for the year ended December 31, 2009 and quarterly report on form 10-Q for the quarter ended June 30, 2010, as filed with the Securities and Exchange Commission (SEC) and in any subsequent periodic or current report that the company files with the SEC.

All forward-looking statements reflect the company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. While Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the company's estimates change.

Idenix Pharmaceuticals Contact:
Jonae Barnes (617) 224-4485 (investors)
Kelly Barry (617) 995-9033 (media)

SOURCE Idenix Pharmaceuticals, Inc.

RELATED LINKS
http://www.idenix.com/

Source
CAMBRIDGE, Mass., Oct 01, 2010 (BUSINESS WIRE) -- Idera Pharmaceuticals, Inc. /quotes/comstock/15*!idra/quotes/nls/idra (IDRA 3.25, -0.04, -1.22%) today announced that data related to IMO-2125, its novel immune modulator for the treatment of chronic hepatitis C virus (HCV) infection, will be presented at the 61st Annual Meeting of the American Association of the Study of Liver Diseases in Boston, Massachusetts October 29 -- November 2, 2010. The full abstract can now be accessed through the AASLD website, http://www.aasld.org/.

"IMO-2125, a TLR9 Agonist, Induces Immune Responses which Correlate with Reductions in Viral Load in Null Responder HCV Patients", M. Rodriguez-Torres, et al., will be presented in a session entitled HCV Therapy: From Discovery to Clinical Development on Sunday, October 31, 2010 at 3:30 p.m. ET.

About IMO-2125

IMO-2125, a Toll-like Receptor (TLR) 9 agonist, is a novel immune modulator being developed as a potential component of treatment for chronic hepatitis C virus (HCV) infection. IMO-2125 is designed to stimulate an immune response in HCV patients, causing the body to generate natural interferons and other cytokines to suppress the virus. IMO-2125 is currently in a Phase 1 clinical trial in null-responder patients, defined as those who did not achieve a 2 log10 reduction with prior standard of care treatment, as monotherapy for 4 weeks. IMO-2125 is also being evaluated in a Phase 1 clinical trial in treatment-naive patients in combination with ribavirin for 4 weeks.

About Idera Pharmaceuticals, Inc.

Idera Pharmaceuticals develops drug candidates to treat infectious diseases, autoimmune and inflammatory diseases, cancer, and respiratory diseases, and for use as vaccine adjuvants. Our proprietary drug candidates are designed to modulate specific Toll-like Receptors, which are a family of immune system receptors that direct immune system responses. Our pioneering DNA and RNA chemistry expertise enables us to create drug candidates for internal development and generates opportunities for multiple collaborative alliances. For more information, visit http://www.iderapharma.com/.

Idera Forward Looking Statements

This press release contains forward-looking statements concerning Idera Pharmaceuticals, Inc. that involve a number of risks and uncertainties. For this purpose, any statements contained herein that are not statements of historical fact may be deemed to be forward-looking statements. Without limiting the foregoing, the words "believes," "anticipates," "plans," "expects," "estimates," "intends," "should," "could," "will," "may," and similar expressions are intended to identify forward-looking statements. There are a number of important factors that could cause Idera's actual results to differ materially from those indicated by such forward-looking statements, including whether results obtained in preclinical studies and early clinical trials will be indicative of results obtained in future clinical trials; whether products based on Idera's technology will advance into or through the clinical trial process on a timely basis or at all and receive approval from the United States Food and Drug Administration or equivalent foreign regulatory agencies; whether, if the Company's products receive approval, they will be successfully distributed and marketed; whether the Company's collaborations with Merck KGaA and an affiliate of Merck & Co., Inc. will be successful; whether the patents and patent applications owned or licensed by the Company will protect the Company's technology and prevent others from infringing it; whether Idera's cash resources will be sufficient to fund the Company's operations; and such other important factors as are set forth under the caption "Risk Factors" in Idera's Quarterly Report on Form 10-Q for the three months ended June 30, 2010, which important factors are incorporated herein by reference. Idera disclaims any intention or obligation to update any forward-looking statements.

SOURCE: Idera Pharmaceuticals, Inc.

Idera Pharmaceuticals, Inc.
Teri Dahlman, 617-679-5519
tdahlman@iderapharma.com
or
MacDougall Biomedical Communications
Chris Erdman, 781-235-3060
cerdman@macbiocom.com

Source

~ Including a Late-breaking Oral Presentation of 24-Week interim data of the TMC435 phase 2b PILLAR study ~

STOCKHOLM, Oct 01, 2010 (BUSINESS WIRE) -- Regulatory News:

Medivir AB (omx:MVIR), a research-based speciality pharmaceutical company focused on infectious diseases, today announces that five abstracts related to its hepatitis C drug in development, TMC435, have been accepted for presentation at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place from 29 October -- 2 November 2010 in Boston, USA. The abstracts have been published today and can be accessed on the AASLD website http://www.aasld.org/ (http://www.aasld.org/). In accordance with the AASLD embargo policy, information about the studies and the accepted titles only are provided below. TMC435, a hepatitis C protease inhibitor, is being jointly developed by Medivir and Tibotec Pharmaceuticals.

At the meeting, in a late-breaking oral presentation, the results from a pre-planned Week 24 interim analysis of the ongoing Phase 2b PILLAR study of TMC435 will be presented. In this study, patients were dosed once-daily with TMC435 in combination with peg interferon a-2a (PegIFN) and ribavirin (RBV) in treatment naive patients infected with HCV genotype 1 (G1). 24-Week interim analysis data will be reported including rapid virologic response (RVR), complete early viral response (cEVR), sustained viral response rates after four weeks (SVR4), and twelve weeks (SVR12) respectively. Secondary endpoints, including the assessment of antiviral activity, viral breakthrough, safety and tolerability, and response rates in IL-28B genotypes, will also be presented.

Additionally, there will be four poster presentations shown at the meeting. Two poster presentations will describe the antiviral activity, safety, tolerability, and pharmacokinetics from a phase 2a open-label, proof-of-concept study of TMC435 in patients infected with HCV genotype 2 to 6.

The other two poster presentations will describe the virologic analysis of G1 infected patients following treatment with once-daily TMC435 in the phase 2a (OPERA-1) study and in vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters.

Accepted titles for Abstracts to be presented at the 2010 AASLD meeting are as follows:

Late Breaker Oral Presentation for presentation at Monday 1 Nov. 17:45 (EST):

LB-5. "Efficacy and safety of TMC435 in combination with peginterferon a-2a and ribavirin in treatment-naive genotype-1 HCV patients: 24-week interim results from the PILLAR study."

Poster Presentations:

278. "In vitro studies investigating the mechanism of interaction between TMC435 and hepatic transporters." To be presented: Saturday 30 Oct, 14:00 (EST).

812. "Virologic analysis of genotype-1-infected patients treated with once-daily TMC435 during the Optimal Protease inhibitor Enhancement of Response to Therapy (OPERA)-1 study." To be presented: Sunday 31 Oct, 08:00 (EST).

895. "A Phase 2a, open-label study to assess the antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2--6." To be presented: Sunday 31 Oct, 08:00 (EST).

1873. "Pharmacokinetic-pharmacodynamic analyses of TMC435 in patients infected with Hepatitis C Virus (HCV) genotypes 2 to 6." To be presented: Tuesday 2 Nov, 07:00 (EST).

About Medivir

Medivir is a research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product Xerese(TM)/Xerclear(TM). Medivir's key pipeline asset, TMC435, a protease inhibitor, is in phase 2b clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals.

Xerese(TM)/Xerclear(TM) is an innovative treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GSK to be sold OTC in Europe and Russia and with Meda in North America. Medivir has retained the Rx rights for Xerclear(TM) in Sweden and Finland.

For more information about Medivir, please visit the Company's website: http://www.medivir.se/ (http://www.medivir.se/)

About TMC435 clinical trial programs

TMC435 is a once daily protease inhibitor jointly developed by Medivir and Tibotec Pharmaceuticals to treat hepatitis C virus infections. TMC435 is currently being studied in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naive and in G1 patients that failed previous IFN-based treatment. TMC435 is planned to enter phase 3 studies early 2011.

PILLAR Study (TMC435-C205)

TMC435-C205 is an ongoing randomized double-blind global phase 2b study in 386 genotype-1 treatment-naive patients. It evaluates once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.

ASPIRE Study (TMC435-C206)

TMC435-C206 is an ongoing randomized double-blind global phase 2b study in 463 genotype-1 treatment-experienced patients. It evaluates once daily treatment of TMC435 in with different doses of given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A.

TMC435-C215

TMC435-C215 is an ongoing Japanese phase 2b study in 92 genotype-1 treatment-naive patients. It evaluates once daily treatment of TMC435 with different doses and durations given in addition to standard of care treatment, consisting of ribavirin and pegIFNalpha-2A. Opera-2 (TMC435-C202) TMC435-C202 is a completed phase 2a study in treatment-naive genotype 2 to 6 HCV patients. It is a once daily treatment of TMC435 during seven days, at 200 mg. Subsequently, patients could continue with SoC treatment consisting of pegylated interferon and ribavirin upon agreement with the study doctor.

About Hepatitis C

Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.

This information was brought to you by Cision http://www.cisionwire.com/

SOURCE: Medivir

http://www.medivir.se/
Rein Piir
CFO & VP Investor Relations
Office: +46 8 546 831 23
Mobile: +46 708 537 292
or
M:Communications
Europe:
Mary-Jane Elliott/Emma Thompson
+44(0)20 7920 2330
or
M:Communications
USA: Jason Marshall
+1 212 897 5497
Medivir@mcomgroup.com (Medivir@mcomgroup.com)

Source
European Journal of Clinical Pharmacology
DOI: 10.1007/s00228-010-0881-7

Seyed-Moayed Alavian, Bita Behnava and Seyed Vahid Tabatabaei

Abstract

Background

About one-half of patients with hepatitis C genotype 1 and one-third with genotype 2/3 have treatment failure with peginterferon alpha and ribavirin. Consensus interferon (CIFN) is an option for retreatment of these patients.

Objective

To summarize comparative safety and efficacy of different regimens of CIFN for the treatment of patients with chronic hepatitis C infection.

Data source

Medline, Scopus, ISI, and Cochran Central Register of Clinical Trials were used.

Study eligibility criteria

Randomized clinical trials (RCTs) were eligible for inclusion in the study.

Participants

HIV and HBV seronegative patients with positive HCV-RNA during the 6 months before the start of the study were eligible for inclusion.

Interventions

Different regimens of CIFN were studied.

Study appraisal and synthesis methods

Studies were appraised based on methods of random sequence generation, allocation concealment, and blinding. The random effects model of DerSimonian and Laird was employed to run the meta-analysis. The end-point was sustained virological response (SVR).

Results

Data of 10 RCTs including 1,600 subjects were extracted. High daily induction dose regimen of CIFN did not yield a higher rate of SVR than low daily induction dose treatment regimen, RR = 0.83 (95% CI 0.58–1.17). A dose of 9 μg thrice weekly (tiw) was associated with a significantly higher rate of SVR compared with 3 μg [RR = 3.14 (95% CI 1.68–5.58)]‹. Withdrawal rate was similar [RR = 1.28 (95% CI 0.65–2.50)] but dose modification was higher in 9 μg [RR = 3.22 (95% CI 1.08–9.60)]. A dose of 18/15 μg tiw was not more effective than 9 μg over a similar treatment duration [RR = 1.02 (95% CI 0. 87–1.19)].

Limitations

Limitations include inadequate reporting of methodological information and side effects, lack of publication bias assessment due to the small number of studies in each analysis.

Conclusions

High dose daily induction therapy with CIFN is not superior to low dose therapy in terms of SVR. It seems that 9 μg tiw is the optimal treatment dose of CIFN for treatment of HCV infection. Optimal duration and safety profile of CIFN therapy have yet been elucidated.

Keywords Consensus interferon - Induction therapy - High dose - Low dose - Meta-analysis - Systematic review

Source
WASHINGTON, Sept. 27 /PRNewswire-USNewswire/ -- The American Association for the Study of Liver Diseases (AASLD) and the Trust for America's Health (TFAH) issued a new report today calling for action to be taken to transform how the country deals with viral hepatitis – to help identify millions of Americans who know they are living with chronic forms of hepatitis B and C and to assure access to treatment for all who need it, to prevent even more Americans from becoming infected.

(Logo: http://www.newscom.com/cgi-bin/prnh/20100204/TFAHLOGO)
(Logo: http://photos.prnewswire.com/prnh/20100204/TFAHLOGO)

"This report is a critical next step that builds on a recent groundbreaking Institute of Medicine report on viral hepatitis and translates it into a series of action items which will be critically important to control the silent epidemic of viral hepatitis in the U.S.," said Arun J Sanyal MD, President of AASLD.

The report, HBV & HCV: America's Hidden Epidemics, examines how new measures included in the Patient Protection and Affordable Care Act (ACA) combined with new scientific advancements could be used to spare millions of Americans from developing cirrhosis, liver cancer, or other life threatening complications as they age – which could also lead to billions of dollars in health care savings.

"HBV and HCV are ticking time bombs. If we don't act now to diagnose the millions of Baby Boomers and others, we'll be too late to spare them from developing serious liver diseases. We'll all end up paying the price, since Medicare and Medicaid will end up picking up the tab for much of the care," said Jeff Levi, Ph.D., Executive Director of TFAH. "Health reform and new science give us a once-in-a-generation opportunity to rethink how we deal with these silent killers."

Some key findings in the report include that:

• An estimated 65 to 75 percent of the five million Americans currently infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) do not even know they have the virus;

• The Institute of Medicine (IOM) estimates that 150,000 Americans could die from liver cancer or end-stage liver disease associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) in the next decade;

• The death rate from HCV is expected to triple in the next 10 to 20 years;

• An independent analysis found total medical costs for HCV patients could more than double over the next 20 years – from $30 to $80 billion per year;

• Liver cancer treatment can be more than $62,000 for the first year cost and the first-year cost of a liver transplant can be more than $267,000;

• Two-thirds of HCV cases are Baby Boomers – and if they are left untreated, it could lead to a major increase in upcoming Medicare spending;

• One in 10 Asian and Pacific Islander Americans are estimated to have a chronic HBV infection;

• An estimated 540,000 to 858,000 African Americans are estimated to have a chronic HCV infection;

• Approximately 800 to 1,000 infants in the United States are infected with HBV at birth each year; and

• At least 100,000 patients have been notified about potential exposure to HBV, HCV, and/or HIV while receiving health care since 1998.

Some highlight recommendations from AASLD and TFAH in the report include:

• HBV and HCV screening and HBV vaccination should be the standard of care in the reformed health system. All Americans should be screened for HBV and HCV and all Americans should be vaccinated for HBV;

• All pregnant women should be screened for HBV and appropriate health measures should be taken to prevent perinatal transmission from infected mothers to their newborns. All newborns should receive their initial (birthdose) of hepatitis vaccine within twelve hours of birth;

• Every person diagnosed with HBV or HCV should have access to and receive a minimum standardized level of care and receive support services;

• Strong public education campaigns and improved surveillance must be put in place to help prevent new infections;

• Policies must be established to ensure that health care associated hepatitis infections are treated as a "never event;" and

• The investment in hepatitis-related biomedical and behavior must be significantly increased – and should be more proportionate to the public health threat associated with hepatitis.

The full report is available on AASLD's website http://www.aasld.org/ and TFAH's website http://www.healthyamericans.org/.

The American Association for the Study of Liver Diseases (AASLD) is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease and whose vision is to prevent and cure liver disease through its mission to advance the science and practice of Hepatology, Liver Transplantation and Hepatobiliary Surgery, thereby promoting liver health and optimal care of patients with liver and biliary tract diseases. http://www.aasld.org/

Trust for America's Health is a non-profit, non-partisan organization dedicated to saving lives by protecting the health of every community and working to make disease prevention a national priority. www.healthyamericans.org

SOURCE Trust for America's Health

RELATED LINKS
http://www.healthyamericans.org/
http://www.aasld.org/

Source
Hepatology International
DOI: 10.1007/s12072-010-9214-2

Soji Shimomura, Naoto Ikeda, Masaki Saito, Akio Ishii, Tomoyuki Takashima, Yoshiyuki Sakai, Shohei Yoshikawa, Nobuhiro Aizawa, Hironori Tanaka and Yoshinori Iwata, et al.

Abstract

Purpose

This study investigates the usefulness of long-term interferon (IFN) therapy following radiofrequency ablation (RFA) for HCV-associated hepatocellular carcinoma (HCC).

Methods

This is a retrospective observational study. Patients underwent pegylated IFN-α/ribavirin combination therapy for 48 weeks and then were maintained on IFN-α administration on average for 68 weeks (mean total duration 116 weeks). Patients who underwent IFN monotherapy were maintained on IFN administration on average for 78 weeks.

Results

There were biases in the background factors between the IFN and non-IFN groups. Therefore, a covariate adjustment was performed using the propensity score. An analysis of 20-matched patients from each group showed the 5-year cumulative survival rate was higher in the IFN group than in the non-IFN group (100 and 76%, respectively), and the 3-year cumulative recurrence rate was significantly lower in the IFN group than in the non-IFN group (38.0 and 64.2%, respectively). In 14 patients (i.e., IFN responders), the serum alanine aminotransferase (ALT) level remained normalized at 30 IU/mL or lower, regardless of disappearance of serum HCV RNA. In these patients, the cumulative recurrence rate was low, the hazard ratio was 0.158 (95% confidence interval = 0.045–0.561, P = 0.004), and the serum albumin level was retained.

Conclusion

These results show the importance of maintaining the liver function and suggest that long-term IFN administration after RFA inhibits recurrence and contributes to an improved outcome in patients (in particular, IFN responders) who initially develop HCC.

Keywords Hepatitis C virus - Interferon - Hepatocellular carcinoma - Prevention - Radiofrequency ablation

S. Shimomura and N. Ikeda equally contributed to this study.

Source
Journal of Clinical Oncology
Published online before print September 20, 2010,
doi: 10.1200/JCO.2010.29.1500
JCO.2010.29.1500
©American Society of Clinical Oncology 

Mei-Hsuan Lee, Hwai-I Yang, Sheng-Nan Lu, Chin-Lan Jen, Shiou-Hwei Yeh, Chun-Jen Liu, Pei-Jer Chen, San-Lin You, Li-Yu Wang, Wei J. Chen and Chien-Jen Chen

+ Author Affiliations

Corresponding author: Chien-Jen Chen, ScD, Genomics Research Center, Academia Sinica, 128 Academia Rd, Section 2, Nankang, Taipei, 115, Taiwan; e-mail: cjchen@ntu.edu.tw.

Abstract

Purpose Hepatitis C virus (HCV) contributes to one third of hepatocellular carcinoma cases worldwide. Long-term predictors for HCV-related hepatocellular carcinoma are essential for early intervention. Serum HCV RNA and ALT levels and HCV genotype were assessed for their predictability of hepatocellular carcinoma risk.

Methods A prospective cohort of 925 participants positive for antibodies against HCV and age 30 to 65 years was recruited and followed from 1991 to 2006. Serum HCV RNA and ALT levels and HCV genotypes at enrollment and during follow-up were examined. Newly developed hepatocellular carcinoma was identified by health examination and computerized linkage with national cancer registration and death certification profiles. Multivariate adjusted hazard ratios with 95% CIs were estimated using Cox regression models.

Results Fifty-five participants newly developed hepatocellular carcinoma during 8,476 person-years of follow-up, giving an incidence rate of 648.9 per 100,000 person-years. The cumulative hepatocellular carcinoma risk increased from 1.1% for HCV RNA seronegative status to 6.4% for low HCV RNA levels and to 14.7% for high HCV RNA levels (P < .001). The cumulative risk also increased with elevated serum ALT levels from 1.7% for persistently ≤ 15 U/L to 4.2% for ever more than 15 U/L but never more than 45 U/L and to 13.8% for ALT ever ≥ 45 U/L (P < .001). Having HCV genotype 1 was associated with a higher cumulative hepatocellular carcinoma risk (12.6%) than not having HCV genotype 1 (4.5%; P < .001).

Conclusion Elevated serum levels of HCV RNA and ALT and HCV genotype 1 infection are independent risk predictors of hepatocellular carcinoma. These findings have strong implications for the management of chronic HCV.

Received March 5, 2010.
Accepted July 6, 2010.
 
Source
Gastroenterology. 2010 Sep 18. [Epub ahead of print]

Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA.

Gastroenterology and Hepatology Service, Department of Medicine; Brooke Army Medical Center.

Abstract

INTRODUCTION: The prevalence of nonalcoholic fatty liver disease (NAFLD) has not been well established. The purpose of this study was to prospectively define the prevalence of both NAFLD and nonalcoholic steatohepatitis (NASH).

METHODS: Outpatients 18 to 70 years old were recruited from Brooke Army Medical Center. All patients completed a baseline questionnaire and ultrasound. If fatty liver was identified, then laboratory data and a liver biopsy (LB) were obtained.

RESULTS: 400 patients were enrolled. 328 patients completed the questionnaire and ultrasound. Mean age (range 28-70) was 54.6 years (7.35); 62.5% Caucasian, 22% Hispanic, and 11.3% African American; 50.9% female; mean body mass index (BMI) was 29.8 kg/m(2) (5.64); diabetes and hypertension prevalence were 16.5% and 49.7% respectively. The prevalence of NAFLD was 46%. NASH was confirmed in 40 patients (12.2% of total cohort, 29.9% of ultrasound positive patients). Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African-Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older (p=0.004), hypertensive (p<0.00005), and diabetic (p<0.00005). They had a higher BMI (p<0.0005), ate fast food more often (p=0.049) and exercised less (p=0.02), than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs 9.8%, p=0.03). ALT, AST, BMI, insulin, QUICKI, and CK 18 correlated with NASH. Among the 54 diabetic patients, NAFLD was found in 74% and NASH in 22.2%.

CONCLUSION: The prevalence of NAFLD and NASH are higher than previously estimated. Hispanics and diabetic patients are at greatest risk for both NAFLD and NASH.

PMID: 20858492 [PubMed - as supplied by publisher]

Source

Hepatitis D virus: an update

Liver International
Early View (Articles online in advance of print)

Stéphanie Pascarella 1, Francesco Negro 2,3

Article first published online: 28 SEP 2010
DOI: 10.1111/j.1478-3231.2010.02320.x
© 2010 John Wiley & Sons A/S

1 Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
2 Division of Clinical Pathology, University Hospital, Geneva, Switzerland
3 Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland

*Correspondence: Correspondence Prof Francesco Negro, Divisions of Clinical Pathology and of Gastroenterology and Hepatology, University Hospital, 4 rue Gabrielle-Perret-Gentil, 1211 Geneva 14, Switzerland Tel: +41 22 3795 800 Fax: +41 22 3729 366 e-mail: francesco.negro@hcuge.ch

Keywords:
cirrhosis;delta hepatitis;fulminant hepatitis;hepatitis D virus
 
Abstract

Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.

Source
ISSN 1007-9327 CN 14-1219/R World J Gastroenterol 2010 September 21; 16(35): 4400-4409

ORIGINAL ARTICLE

Mosaburo Kainuma, Norihiro Furusyo, Eiji Kajiwara, Kazuhiro Takahashi, Hideyuki Nomura, Yuichi Tanabe, Takeaki Satoh, Toshihiro Maruyama, Makoto Nakamuta, Kazuhiro Kotoh, Koichi Azuma, Junya Shimono, Shinji Shimoda, Jun Hayashi,

The Kyushu University Liver Disease Study Group

--------------------------------------------------------------------------------

Mosaburo Kainuma, Norihiro Furusyo, Jun Hayashi, Department of General Internal Medicine, Kyushu University Hospital, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan

Eiji Kajiwara, Department of Internal Medicine, Nippon Steel Yawata Memorial Hospital, Harunomachi, Yahatahigashi-ku, Kitakyushu 805-0050, Japan

Kazuhiro Takahashi, Department of Medicine, Hamanomachi Hospital, Maiduru Chuo-ku, Fukuoka 810-8539, Japan

Hideyuki Nomura, The Center for Liver Disease, Shin-Kokura Hospital, Kanada, Kokurakita-ku, Kitakyushu, Fukuoka 803-8505, Japan

Yuichi Tanabe, Department of Medicine, Fukuoka City Hospital, Yoshiduka-honmachi, Hakata-ku, Fukuoka 812-0046, Japan

Takeaki Satoh, Center for Liver Disease, National Hospital Organization Kokura Medical Center, Harugaoka, Kokuraminami-ku, Kitakyushu 802-0803, Japan

Toshihiro Maruyama, Department of Medicine, Kitakyushu Municipal Medical Center, Bashaku, Kokurakita-ku Kitakyushu 802-0077, Japan

Makoto Nakamuta, Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Jigyohama, Chuou-ku, Fukuoka 810-8563, Japan

Kazuhiro Kotoh, Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan

Koichi Azuma, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan

Junya Shimono, Saiseikai Yahata General Hospital, Haruno-machi, Yahatahigashi-ku, Kitakyushu, Fukuoka 805-0050, Japan

Shinji Shimoda, Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, Higashi-Ku, Fukuoka 812-8582, Japan

The Kyushu University Liver Disease Study Group, Kyushu University, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan

Author contributions: Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S and The Kyushu University Liver Disease Study Group carried out the field research for the study; Kainuma M analyzed the data and wrote the paper; Furusyo N and Hayashi J were instrumental in developing and coordinating the research project and reviewed the manuscript.

Correspondence to: Jun Hayashi, MD, PhD, Professor, Department of General Internal Medicine, Kyushu University Hospital, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. hayashij@gim.med.kyushu-u.ac.jp

Telephone: +81-92-6425909   Fax: +81-92-6425916

Received: February 18, 2010 Revised: April 19, 2010
Accepted: April 26, 2010
Published online: September 21, 2010

Abstract

AIM: To analyze the efficacy and safety of a combination therapy of pegylated interferon (PEG-IFN) a-2b plus ribavirin (RBV) in older Japanese patients (65 years or older) infected with hepatitis C virus (HCV).

METHODS: This multicenter study included 938 patients with HCV genotype 1 who received 1.5 mg/kg per week PEG-IFN a-2b plus RBV 600-1000 mg/d for 48 wk and 313 HCV genotype 2 patients who received this treatment for 24 wk.
RESULTS: At 24 wk after the end of combination therapy, the overall sustained virological response (SVR) for genotypes 1 and 2 were 40.7% and 79.6%, respectively. The SVR rate decreased significantly with age in each genotype, and was markedly reduced in genotype 1 (P < 0.001). Moreover, the SVR was significantly higher in patients with genotype 1 who were less than 65 years (47.3% of 685) than in those 65 years or older (22.9% of 253) (P < 0.001) and was higher in patients with genotype 2 who were less than 65 years (82.9% of 252) than in those 65 years or older (65.6% of 61) (P = 0.004). When patients received a dosage at least 80% or more of the target dosage of PEG-IFN a-2b and 60% or more of the target dosage of RBV, the SVR rate significantly increased to 66.5% in patients less than 65 years and to 45.2% in those 65 years or older (P < 0.001). Adverse effects resulted in treatment discontinuation more often in patients with genotype 1 (14.4%) than in patients with genotype 2 (7.3%), especially by patients 65 years or older (24.1%).

CONCLUSION: PEG-IFN a-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum acceptable treatment dosage.

© 2010 Baishideng. All rights reserved.

Key words: Hepatitis C virus; Gerontology; Pegylated interferon; Ribavirin

Peer reviewer: Emanuel K Manesis, MD, Professor of Medicine, Athens University School of Medicine, Liver Unit, Euroclinic, 19 Mavromateon Street, Athens 10 34, Greece

Kainuma M, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S, Hayashi J, The Kyushu University Liver Disease Study Group. Pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis C. World J Gastroenterol 2010; 16(35): 4400-4409 Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i35/4400.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i35.4400

INTRODUCTION

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, affecting 170 million individuals worldwide[1]. It is well known that patients with chronic hepatitis C eventually develop hepatocellular carcinoma (HCC)[2]. Previous studies have made clear that interferon (IFN) treatment is effective for eliminating HCV[3,4] and that it significantly reduces the progression of liver fibrosis and the risk of HCC[5,6]. Antiviral treatment for chronic hepatitis C has greatly improved, and the combination treatment of pegylated (PEG)-IFN a-2b plus ribavirin (RBV) has been approved and recommended in Japan since 2004, as the first choice for chronic hepatitis C. This combination treatment attained a sustained virological response (SVR) rate of 50%-60% for genotype 1 in the United States and Europe[7]. However, SVR was relatively low (42.4%) in Japan[8], where chronic hepatitis C patients are older, indicating that older patients did not respond well to IFN treatment[9]. Moreover, the combination treatment was associated with more adverse effects than IFN monotherapy[7,10]. Older patients who have decreased cardiovascular, pulmonary and renal function have a higher incidence of adverse effects than younger patients. The rate of discontinuation due to adverse effects was reported to be significantly higher in patients aged 65 years or more than in those less than 65 years[11]. Older patients with HCV infection are at risk for progressive liver disease. It was reported that clearance of HCV after IFN therapy significantly reduces the incidence of HCC and death in older chronic hepatitis C patients[6,12]. Ikeda et al[13] demonstrated that IFN treatment is needed for 65-70-year-old patients with chronic hepatitis C to prevent the occurrence of HCC. We also consider older patients to be acceptable candidates for antiviral treatment to prevent the development of HCC, and previously reported that monotherapy with natural IFN a was not effective in older patients[9]. Therefore, in an attempt to ameliorate these problems, we decided to treat older patients with a combination of PEG-IFN plus RBV therapy.

Little data concerning the response and safety of this combination treatment in a large number of older patients with chronic HCV infection has been published. A multicenter study of the efficacy and safety of antiviral treatments for Japanese patients with chronic liver disease, the Kyushu University Liver Disease Study (KULDS), was launched in 2003[8,14]. The present prospective study was carried out to analyze the efficacy and safety of the combination treatment of PEG-IFN a-2b plus RBV in older patients.

MATERIALS AND METHODS

Patients

Treatment of chronic hepatitis C with a combination of PEG-IFN a-2b plus RBV was accepted by the Japanese Ministry of Health in October, 2004. We used this combination treatment from December 2004 to July 2008, and enrolled chronic hepatitis C patients with exclusion criteria which included: (1) clinical or biochemical evidence of hepatic decompensation, advanced cirrhosis identified by bleeding, high-risk esophageal varices, history of gastrointestinal bleeding, ascites, encephalopathy, or HCC; (2) hemoglobin level < 11.5 g/L, white blood cell count < 3 × 109/L, and platelet count < 50 × 109/L; (3) concomitant liver disease other than hepatitis C (hepatitis B surface antigen positive or HIV positive); (4) excessive active alcohol consumption > 60 g/d or drug abuse; (5) severe psychiatric disease; or (6) antiviral or corticosteroid treatment within 12 mo prior to enrollment. Patients who fulfilled the above criteria were recruited at Kyushu University Hospital and 32 affiliated hospitals in the northern Kyushu area of Japan. We have treated 2270 Japanese patients aged 18 years or older with PEG-IFN a-2b plus RBV. All patients who were positive for both antibody to HCV and HCV RNA for over 6 mo were enrolled in KULDS. Three months before the start of treatment and every 3 mo during the treatment period, each patient was tested for a-fetoprotein (AFP) and had an abdominal ultrasonographic examination. If an abnormal AFP level of 40 ng/mL and/or focal lesions on ultrasonographic examination were found at any testing, further testing for HCC was carried out, which included dynamic computed tomography, and angiography. Patients confirmed to have HCC within 3 mo after starting treatment were excluded from this study (n = 14). Of 2270 patients, 1021 were currently under combination treatment or we were not yet able to judge the effect of the combination treatment. This left the data of 1251 patients (938 with genotype 1 and 313 with genotype 2) available for analysis.

Informed consent was obtained from all patients before enrollment in this study. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization of guidelines for good clinical practice.

Table 1 (genotype 1) and Table 2 (genotype 2) show the baseline characteristics of the enrolled patients, who were further classified into four groups according to age and genotype status: group A, genotype 1 aged less than 65 years (n = 685); group B, genotype 1 aged 65 years or older (n = 253); group C, genotype 2 aged less than 65 years (n = 252); and group D, genotype 2 aged 65 or older (n = 61). In group B, body mass index, prior combined IFN plus RBV treatment, alanine aminotransferase, albumin, white blood cell count, hemoglobin, platelet count, and creatinine clearance calculated using the Modification of Diet in Renal Disease equation[15] were significantly lower than in group A (P < 0.010). In group D, albumin, hemoglobin, platelet count, creatinine clearance and serum HCV RNA level were significantly lower than in group C (P < 0.010). The percentage of patients with platelet counts below 10 × 1010/L was significantly higher in group B (36 of 253, 14.2%) than in group A (56 of 685, 8.2%) (P = 0.006), however, there was no significant difference between group C (16 of 252, 6.3%) and group D (7 of 61, 11.5%).

Liver histology

Liver biopsy was performed in 555 patients (59.2%) with genotype 1 and 209 patients (66.8%) with genotype 2. The other patients refused liver biopsy. Fibrosis was staged on a 0-4 scale as follows: F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = portal fibrosis with few septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis. Liver fibrosis was more advanced in group B than in group A and was more advanced in group D than in group C (P = 0.008, P < 0.001, respectively).

Treatment regimen

All patients were treated with a weight-based, 1.5 mg/kg weekly dose of subcutaneous PEG-IFN a-2b (PegIntron, Schering-Plough, Osaka, Japan), in combination with RBV (Rebetol, Schering-Plough), which was given orally at a daily dose of 600-1000 mg based on body weight (600 mg for patients weighing less than 60 kg, 800 mg for those weighing 60-80 kg, and 1000 mg for those weighing 80 kg or over). The length of treatment was 48 wk for patients with HCV genotype 1 and 24 wk for patients with genotype 2. The above duration and dosage are those approved by the Japanese Ministry of Health, Labor and Welfare. Patients were considered to have RBV-induced anemia if the hemoglobin level decreased to less than 100 g/L. In such cases, a reduction in the dose of RBV was required. Patients aged 65 years or older had a significantly higher frequency of RBV dose reduction during the treatment period than those aged less than 65 years old (HCV genotype 1: group A vs group B, 41.2% vs 49.0%, P = 0.032, genotype 2: group C vs group D, 28.6% vs 54.1%, P < 0.001). Some patients also had PEG-IFN a-2b-induced psychological adverse effects or a decrease in white blood cell and platelet counts. In such cases, a reduction in the dosage of PEG-IFN a-2b was required. Both PEG-IFN a-2b and RBV were discontinued if the hemoglobin level, white blood cell count, or platelet count fell below 85 g/L, 1 × 109/L, and 25 × 109/L, respectively. The treatment was discontinued if severe general fatigue, hyperthyroidism, interstitial pneumonia, or severe hemolytic disorders developed, continuation of treatment was judged not to be possible by the attending physician, or if the patient desired discontinuation of treatment.

Determination of baseline HCV RNA level and HCV genotype

The pretreatment, baseline, serum HCV RNA level was measured by a quantitative HCV RNA polymerase chain reaction (PCR) assay (COBAS Amplicor HCV Monitor Test v 2.0 using the 10-fold dilution method; Roche Diagnostics, Tokyo, Japan), which has a lower limit of quantitation of 5000 IU (13 500 copies)/mL (5 kIU/mL) and an outer limit of quantitation of 5 100 000 IU/mL (5100 kIU/mL). The HCV genotype was determined by type-specific primers of the core region of the HCV genome. The protocol for genotyping was carried out as previously described[3].

Efficacy of treatment

End of treatment (EOT) response and SVR were defined as serum HCV RNA undetectable at the end of treatment and at 24-wk follow-up after the end of treatment, respectively. EOT response and SVR were defined as non-detectable HCV-RNA as measured by qualitative COBAS Amplicor HCV Monitor Test v 2.0, with the results labeled as positive or negative. The lower limit of detection was 50 IU/mL (0.5 kIU/mL). The analysis of EOT and SVR was performed on an intention-to-treat basis.

Statistical analysis

Continuous data are expressed as mean ± SD. The statistics were carried out using a commercially available software package (BMDP Statistical Software Inc., Los Angeles, CA, USA) for the IBM 3090 system computer. The c2 test, Fisher’s exact test and Kruskal-Wallis test were used to determine the differences in baseline clinical characteristics, safety, efficacy of the combination therapy, adherence to the total dose, and the association between the adherence and SVR. Logistic regression analysis was used to identify the association between age and SVR. A P < 0.05 was considered significant.

RESULTS

EOT response rate by intention-to-treat analysis

Among patients with genotype 1, the EOT response rate was significantly higher in group A (497 of 685, 72.5%) than in group B (129 of 253, 45.0%) (P < 0.001). Among patients with genotype 2, there was no significant difference between groups C (239 of 252, 94.8%) and D (55 of 61, 90.1%).

SVR rate by intention-to-treat analysis

Of 1251 patients, 631 (50.4%) achieved SVR in the intention-to-treat analysis. The SVR rate was significantly higher for genotype 2 (249 of 313, 79.6%) than for genotype 1 patients (382 of 938, 40.7%) (P < 0.001). Among patients with genotype 1, the SVR rate was significantly higher in group A (324 of 685, 47.3%) than in group B (58 of 253, 22.9%) (P < 0.001). Among patients with genotype 2, SVR was also significantly higher in group C (209 of 252, 82.9%) than in group D (40 of 61, 65.6%) (P = 0.004). The rate of SVR was significantly higher for females (113 of 128, 88.3%) than for males (96 of 124, 77.4%) in group C only (Figure 1). Furthermore, we analyzed whether or not the SVR rate differed according to the age at which the combination treatment of PEG-IFN a-2b plus RBV was started. The results showed that the SVR rate decreased significantly with age for both genotype 1 and 2. SVR was achieved by 5.6%-26.3% of genotype 1 patients aged 70 years or older, and by 57.1%-100% of genotype 2 patients aged 70 years or older (Figure 2).

We previously reported a minimum acceptable dose of at least 80% or more of the target dosage of PEG-IFN a-2b and 60% or more of the target dosage of RBV for the successful treatment of Japanese patients with genotype 1[8]. Therefore, we analyzed the SVR rates in patients with genotype 1 by the dosage they actually received during treatment (a total dose of at least 80% or more of PEG-IFN a-2b and 60% or more of RBV) (Table 3). The number who received at least this minimum acceptable dosage during treatment were 278 (40.6%) of 685 patients in group A and 62 (24.5%) of 253 in group B, significantly lower in group B than in group A (P < 0.001). Compared with patients who received less than the minimum acceptable dosage, in patients who received at least this minimum dosage, the SVR rates increased from 34.2% to 66.5% in group A patients and from 15.7% to 45.2% (P < 0.001) in group B patients. No significant difference between groups C and D was observed. On comparing patients whose platelet count was under 10 × 1010/L, the SVR rate for genotype 1 was significantly lower in group B (2 of 36, 5.6%) than in group A (16 of 56, 28.6%) (P < 0.001). Among the patients with genotype 2, SVR was not significantly different between group C (9 of 16, 56.3%) and group D (2 of 7, 28.6%).

In a comparison of the SVR rate in patients with or without one or more previous courses of IFN plus RBV, there was no significant difference between the genotypes (genotype 1: 118 of 310, 38.1% vs 264 of 628, 42.0%, genotype 2: 44 of 72, 61.1% vs 141 of 241, 58.5%). Furthermore, we compared the EOT response rate and SVR rate of cirrhosis patients whose liver fibrosis was F4, and found no significant difference between groups A (EOT: 16 of 30, 53.3%, SVR: 7 of 30, 23.3%) and B (EOT: 6 of 17, 35.3%, SVR: 2 of 17, 11.8%). In addition, no significant difference was found between groups C (EOT: 8 of 10, 80.0%, SVR: 6 of 10, 60.0%) and D (EOT: 9 of 12, 75.0%, SVR: 5 of 12, 41.7%).

Discontinuation of PEG-IFN a-2b plus RBV treatment and adverse effects

Of 1251 patients, 314 (25.1%) did not complete PEG-IFN a-2b plus RBV treatment due to adverse effects or other reasons. The discontinuation rate was significantly higher in patients with genotype 1 (273 of 938, 29.1%) than in those with genotype 2 (41 of 313, 13.1%) (P < 0.001) (Tables 4 and 5). Furthermore, the rate of discontinuation due to adverse effects was significantly higher in patients with genotype 1 (135 of 938, 14.4%) than in those with genotype 2 (23 of 313, 7.3%) (P < 0.010). The rates of discontinuation due to lack of treatment efficacy and for economic reasons (loss of job, inability to pay the medical costs) were also significantly higher in patients with genotype 1 (55 of 938, 5.9%, 15 of 938, 1.6%) than in those with genotype 2 (1 of 313, 0.3%, 0 of 938, 0%) (P < 0.001 and P = 0.025, respectively).

For genotype 1 patients, the discontinuation rate was significantly higher in group B (106 of 253, 42.9%) than in group A (167 of 685, 24.4%) (P < 0.001), and the rate of discontinuation due to adverse effects was also significantly higher in group B (61 of 253, 24.1%) than in group A (74 of 685, 10.8%) (P < 0.001). General fatigue was the most frequent adverse effect, and was significantly more frequent in group B than in group A (P < 0.001). However, in these group 1 patients, RBV was reduced due to anemia in 12.5% (3 of 24) of group A and in 30.4% (7 of 23) of group B. Furthermore, rash and thrombocytopenia were significantly more frequent in group B than in group A (P = 0.014 and P = 0.007, respectively). In group A, depression was significantly more frequent in females than in males (P = 0.012). In genotype 2 patients, treatment discontinuation did not differ between group C (33 of 252, 13.1%) and group D (8 of 61, 13.1%), and the rate of discontinuation due to adverse effects did not differ between these groups (17 of 252, 6.7%, 6 of 61, 9.8%, respectively).

The mean time to discontinuation in group A (21.6 ± 11.9 wk) was not significantly different from group B (21.5 ± 12.6 wk), and the mean time in group C (11.0 ± 6.8 wk) was also not significantly different from group D (11.6 ± 6.0 wk). There was no significant difference between male and female patients in each group (male: 21.0 ± 12.4 vs female: 22.1 ± 11.8 in group 1, male: 11.3 ± 7.1 vs female: 10.9 ± 6.1 in group 2).

HCC was not seen in genotype 2 patients; only in patients with genotype 1 (29.5 ± 9.9 wk) and was more frequent in group B (5 of 253, 2.0%) than in group A (2 of 685, 0.3%) (P = 0.008).

DISCUSSION

In a large, national, multicenter Greek study involving 993 treated and 734 untreated patients with chronic hepatitis C, patients with cirrhosis, showed a protective effect of treatment even among those without SVR. For patients without cirrhosis, the beneficial effect of IFN a treatment was particularly evident in older patients; patients with the worst prognosis if left untreated. Therefore, IFN a-based treatment should be offered to older persons, as these are the patients with the greatest potential benefit and may achieve SVR[16]. In Japan, the prevalence of chronic HCV infection increases with age, however, the optimal management of older patients has not yet been accurately defined. Whether or not to treat patients older than 65 years with antiviral treatment is highly debated, especially in terms of cost/benefit ratio. In addition, the natural history of chronic hepatitis C in elderly patients is not accurately known, as the presence of comorbidity can affect illness progression and life expectancy. HCV became more prevalent in Japan decades before the United States[17]. Japanese patients with chronic hepatitis C treated with IFN are currently 10 to 15 years older than corresponding patients in the United States and European countries, where patients treated with antiviral treatment tend to average 45 years of age[18-20]. Therefore, our results can serve as a world-wide model for the treatment of older chronic hepatitis C patients.

It has been well documented that the combination therapy of PEG-IFN a-2b plus RBV is more effective than previous IFN monotherapy in chronic hepatitis C patients[7,8]. There have been four studies on the efficacy of PEG-IFN plus RBV therapy in patients 65 years or older with genotype 1, which revealed low rates of SVR (31.1%-51.9%)[21-24]. However, these studies were too small (11-93 patients) for conclusive recommendations to be made. Because the present study was a large multicenter design, it is useful for clarifying the efficacy and safety of PEG-IFN plus RBV combination therapy in older patients. The present study confirmed the results of our previous study which showed that the SVR rate was significantly higher for genotype 2 than for genotype 1 patients[8]. Another important result was that the ability to take at least a minimum acceptable dosage during treatment increased the SVR rate by about three times in older patients with genotype 1. This result also confirmed previous studies which indicated the importance of giving at least the minimum acceptable treatment dosage in patients infected with HCV genotype 1, especially older patients[23,24].

Secondly, we compared discontinuation of treatment by genotype and sex. In genotype 1 patients, adverse effects were seen more often in older than in younger patients. This was the most important reason why the rate of treatment discontinuation was higher in older than in younger patients, and affected the outcome of PEG-IFN a-2b plus RBV combination therapy. General fatigue was the most common adverse effect in older patients. Because older patients often have impaired renal function, they have increased blood levels of RBV[25,26]. They are also inclined to be anemic and to have general fatigue. However, only a small number of older patients in the present study had reduced RBV due to anemia. Therefore, general fatigue is probably a direct adverse effect of PEG-IFN a-2b. We previously reported that herbal medicine relieved the adverse effects of IFN, including general fatigue[27]. Herbal medicine may be useful for mitigating general fatigue during PEG-IFN a-2b plus RBV combination treatment, especially in older patients.

The rate of discontinuation was lower in patients with genotype 2 than in patients with genotype 1, and there was no difference between the older and the younger patients with genotype 2. These results are possibly a consequence of the shorter term of treatment in genotype 2 and the many genotype 1 patients who discontinued due to lack of efficacy.

Two of the characteristics of older patients in the present study were that both hemoglobin and platelet count were significantly lower than in younger patients. The SVR rate was significantly lower when the platelet count was less than 10 × 1010/L. Furthermore, the older genotype 1 patients were often forced to discontinue treatment due to thrombocytopenia and the occurrence of HCC. These findings appear to result from advanced liver fibrosis in older chronic hepatitis C patients. Therefore, the possibility of HCC during long-term IFN treatment in older patients must be considered.

We previously reported that older female patients had a low response to IFN-a monotherapy[9], and other investigators have reported that older female patients have a poor response to PEG-IFN a-2b plus RBV[22,28]. Although our data showed that sex was not related to SVR, the reason for this finding was not fully elucidated. In any case, studies have conclusively shown that it is important to begin treatment with PEG-IFN a-2b plus RBV combination therapy as soon as possible. Our data suggest that age may be a more important factor than sex for increasing the rate of SVR. Resistance to treatment in older patients may be due to IFN-immunomodulation, advanced liver fibrosis, or reduced dosage.

To maximize adherence to the optimal treatment regimen, the treatment schedule can be modified or other therapeutic modalities added, such as hematopoietic growth factors[29] or the new thrombopoietin-receptor agonist, eltrombopag, for the antiviral treatment of older patients with chronic hepatitis C[30]. A further individualized treatment protocol based on viral kinetics might be more practical[31].

In conclusion, PEG-IFN a-2b plus RBV treatment was effective in the treatment of older chronic hepatitis C patients when they received at least the minimum acceptable treatment dosage. However, there were frequent adverse effects and treatment discontinuation. It is necessary to control for adverse effects that might interrupt treatment and to begin this combination therapy as soon as possible, especially in older patients.

ACKNOWLEDGMENTS

We greatly thank Drs. Yasunori Sawayama, Masayuki Murata, Shigeru Otaguro, Hiroaki Taniai, Eiichi Ogawa, Kazuhiro Toyoda, Haru Mukae, Tsunehisa Koga, Kunimitsu Eiraku, Takeshi Ihara, Hiroaki Ikezaki and Takeo Hayashi of our department for their clinical and research assistance with the present study.

COMMENTS

Background
Whether or not to treat patients older than 65 years with antiviral treatment is highly debated, especially in terms of cost/benefit ratio. However, there is little data concerning the response and safety of combination treatment for a large number of older patients with chronic hepatitis C virus infection. Therefore, in an attempt to ameliorate these problems, the authors decided to treat older patients with pegylated interferon (PEG-IFN) a-2b plus ribavirin (RBV) combination therapy.

Research frontiers
The combination treatment of PEG-IFN a-2b plus RBV improved the sustained virological response rate in chronic hepatitis C patients. However, the current issue is whether or not to treat older patients because of low response and high dropout rate.

Innovations and breakthroughs
There have been four studies on the efficacy of PEG-IFN plus RBV therapy in patients 65 years or older with genotype 1. However, these studies were too small (11-93 patients) for conclusive recommendations to be made. This study is very useful for clarifying the efficacy and safety of PEG-IFN plus RBV combination therapy in older patients, because of its large scale, multicenter design.

Applications
The study demonstrated that PEG-IFN a-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum required treatment dosage. Furthermore, this study suggested that the combination treatment and beginning this therapy as soon as possible are important, especially in older patients.

Peer review
The study has been well conducted and includes a large number of patients. Results have been described in a lucid and informative manner and are of clinical relevance.

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S- Editor Tian L L- Editor Webster JR E- Editor Lin YP

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