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
October 1, 2010
Idera Pharmaceuticals Announces IMO-2125 Presentation at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
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
"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
Medivir Announces Publication Of Five TMC435 Abstracts For Presentation At The 61st AASLD Meeting
~ 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
Comparative efficacy and overall safety of different doses of consensus interferon for treatment of chronic HCV infection: a systematic review and meta-analysis
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
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
Millions of Americans Are Living with Hidden Epidemics of Hepatitis B and C, Top Experts Warn
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
(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
Long-term interferon therapy after radiofrequency ablation is effective in treating patients with HCV-associated hepatocellular carcinoma
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
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
Hepatitis C Virus Seromarkers and Subsequent Risk of Hepatocellular Carcinoma: Long-Term Predictors From a Community-Based Cohort Study
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
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
Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study
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
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
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
Pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis C
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
Source
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
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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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21 Antonucci G, Longo MA, Angeletti C, Vairo F, Oliva A, Comandini UV, Tocci G, Boumis E, Noto P, Solmone MC, Capobianchi MR, Girardi E. The effect of age on response to therapy with peginterferon alpha plus ribavirin in a cohort of patients with chronic HCV hepatitis including subjects older than 65 yr. Am J Gastroenterol 2007; 102: 1383-1391
22 Thabut D, Le Calvez S, Thibault V, Massard J, Munteanu M, Di Martino V, Ratziu V, Poynard T. Hepatitis C in 6,865 patients 65 yr or older: a severe and neglected curable disease? Am J Gastroenterol 2006; 101: 1260-1267
23 Honda T, Katano Y, Shimizu J, Ishizu Y, Doizaki M, Hayashi K, Ishigami M, Itoh A, Hirooka Y, Nakano I, Urano F, Yoshioka K, Toyoda H, Kumada T, Goto H. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int 2010; 30: 527-537
24 Huang CF, Yang JF, Dai CY, Huang JF, Hou NJ, Hsieh MY, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang WL, Yu ML. Efficacy and safety of pegylated interferon combined with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis 2010; 201: 751-759
25 Paroni R, Del Puppo M, Borghi C, Sirtori CR, Galli Kienle M. Pharmacokinetics of ribavirin and urinary excretion of the major metabolite 1,2,4-triazole-3-carboxamide in normal volunteers. Int J Clin Pharmacol Ther Toxicol 1989; 27: 302-307
26 Bruchfeld A, Lindahl K, Schvarcz R, Ståhle L. Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis. Ther Drug Monit 2002; 24: 701-708
27 Kainuma M, Hayashi J, Sakai S, Imai K, Mantani N, Kohta K, Mitsuma T, Shimada Y, Kashiwagi S, Terasawa K. The efficacy of herbal medicine (kampo) in reducing the adverse effects of IFN-beta in chronic hepatitis C. Am J Chin Med 2002; 30: 355-367
28 Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Miyakawa Y, Kumada H. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral loads. Dig Dis Sci 2009; 54: 1317-1324
29 Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS, Wright T, Younossi Z, Goon BL, Tang KL, Bowers PJ. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126: 1302-1311
30 McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007; 357: 2227-2236
31 Berg T, Weich V, Teuber G, Klinker H, Möller B, Rasenack J, Hinrichsen H, Gerlach T, Spengler U, Buggisch P, Balk H, Zankel M, Neumann K, Sarrazin C, Zeuzem S. Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients. Hepatology 2009; 50: 369-377
S- Editor Tian L L- Editor Webster JR E- Editor Lin YP
Source
Impact of early elevation of serum bilirubin during treatment with pegylated interferon and ribavirin in patients with chronic hepatitis C
Hepatology Research
Volume 40, Issue 10, pages 963–970, October 2010
Masatoshi Ishigami, Kazuhiko Hayashi, Yoshiaki Katano, Akihiro Itoh, Yoshiki Hirooka, Hidemi Goto
Department of Gastroenterology, Nagoya University School of Medicine, Nagoya, Japan
*Correspondence: Dr Masatoshi Ishigami, Department of Gastroenterology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. Email: masaishi@med.nagoya-u.ac.jp
Article first published online: 28 SEP 2010
DOI: 10.1111/j.1872-034X.2010.00711.x
Keywords:
bilirubin;hemolytic anemia;hepatitis C virus;pegylated interferon and ribavirin
Aim: Hemolytic anemia is a well-known adverse effect of interferon and ribavirin combination treatment. Herein, we analyzed the impact of early elevation of serum bilirubin level as a marker for predicting severe anemia during treatment.
Methods: We studied 245 chronic hepatitis C patients who received pegylated interferon and ribavirin combination treatment, and divided them using two different threshold levels: (i) elevation of total bilirubin of 0.5 mg/dL or more within 1 week of starting treatment; and (ii) drop of hemoglobin (Hb) by 3 g/dL or more within 4 weeks of starting treatment. We compared the dynamics in each group and then investigated independent factors for predicting a severe Hb drop (≥3 g/dL) at 4 weeks after beginning treatment and dose reduction of ribavirin.
Results: Total bilirubin levels at 1 week were significantly higher in patients with a Hb drop of 3 g/dL or more as compared to those with a drop of less than 3 g/dL (P < 0.0001). Hb levels at 4 weeks were significantly lower in the group of 0.5 mg/dL or more increase of total bilirubin levels than in the group with a less than 0.5 mg/dL increase (P < 0.0001). Therefore, elevation of total bilirubin after 1 week of treatment was shown to be an independent factor for predicting severe Hb drop (≥3 g/dL) at 4 weeks (P < 0.0001), and dose reduction of ribavirin during treatment (P = 0.0321).
Conclusion: Early elevation of serum bilirubin level was found to be a possible predictive marker of both a severe drop of Hb in the early phase of treatment and dose reduction of ribavirin.
Source
Volume 40, Issue 10, pages 963–970, October 2010
Masatoshi Ishigami, Kazuhiko Hayashi, Yoshiaki Katano, Akihiro Itoh, Yoshiki Hirooka, Hidemi Goto
Department of Gastroenterology, Nagoya University School of Medicine, Nagoya, Japan
*Correspondence: Dr Masatoshi Ishigami, Department of Gastroenterology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. Email: masaishi@med.nagoya-u.ac.jp
Article first published online: 28 SEP 2010
DOI: 10.1111/j.1872-034X.2010.00711.x
Keywords:
bilirubin;hemolytic anemia;hepatitis C virus;pegylated interferon and ribavirin
Aim: Hemolytic anemia is a well-known adverse effect of interferon and ribavirin combination treatment. Herein, we analyzed the impact of early elevation of serum bilirubin level as a marker for predicting severe anemia during treatment.
Methods: We studied 245 chronic hepatitis C patients who received pegylated interferon and ribavirin combination treatment, and divided them using two different threshold levels: (i) elevation of total bilirubin of 0.5 mg/dL or more within 1 week of starting treatment; and (ii) drop of hemoglobin (Hb) by 3 g/dL or more within 4 weeks of starting treatment. We compared the dynamics in each group and then investigated independent factors for predicting a severe Hb drop (≥3 g/dL) at 4 weeks after beginning treatment and dose reduction of ribavirin.
Results: Total bilirubin levels at 1 week were significantly higher in patients with a Hb drop of 3 g/dL or more as compared to those with a drop of less than 3 g/dL (P < 0.0001). Hb levels at 4 weeks were significantly lower in the group of 0.5 mg/dL or more increase of total bilirubin levels than in the group with a less than 0.5 mg/dL increase (P < 0.0001). Therefore, elevation of total bilirubin after 1 week of treatment was shown to be an independent factor for predicting severe Hb drop (≥3 g/dL) at 4 weeks (P < 0.0001), and dose reduction of ribavirin during treatment (P = 0.0321).
Conclusion: Early elevation of serum bilirubin level was found to be a possible predictive marker of both a severe drop of Hb in the early phase of treatment and dose reduction of ribavirin.
Source
Chronic cough associated with interferon/ribavirin therapy for hepatitis C
Journal of Clinical Pharmacy and Therapeutics
Early View (Articles online in advance of print)
P. V. Dicpinigaitis MD, F. R. Weiner MD
Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
*Correspondence: Peter Dicpinigaitis, MD, Weiler Division/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel.: (718) 904 2676; fax (718) 904 2880; e-mail: pdicpinigaitis@pol.net
Article first published online: 30 SEP 2010
DOI: 10.1111/j.1365-2710.2010.01182.x
© 2010 Blackwell Publishing Ltd
Summary
What is known and Objective: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy.
Case summary: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2–6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C5, the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016).
What is new and Conclusion: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.
Source
Early View (Articles online in advance of print)
P. V. Dicpinigaitis MD, F. R. Weiner MD
Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
*Correspondence: Peter Dicpinigaitis, MD, Weiler Division/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel.: (718) 904 2676; fax (718) 904 2880; e-mail: pdicpinigaitis@pol.net
Article first published online: 30 SEP 2010
DOI: 10.1111/j.1365-2710.2010.01182.x
© 2010 Blackwell Publishing Ltd
Summary
What is known and Objective: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy.
Case summary: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2–6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C5, the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016).
What is new and Conclusion: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.
Source
September 30, 2010
NVHR: In Fighting for 'Six Winnable Battles,' CDC May Lose the Nation's Overall Public-Health War
WASHINGTON, Sept. 30 /PRNewswire-USNewswire/ -- In response to the Centers for Disease Control (CDC) Director Dr. Thomas Frieden's release of "six winnable battles" in health care, Ms. Lorren Sandt, Chair of the National Viral Hepatitis Roundtable (NVHR) and Executive Director of Caring Ambassadors Program, based in Portland, Oregon, released the following statement:
"The CDC's newly released 'six winnable battles' strategy makes a mockery of the broad-based, comprehensive, and integrated public-health strategy that our nation so desperately needs. In seeking to win six narrowly defined health care battles, the CDC may well lose the overall public-health war.
"Chronic viral hepatitis B and C are among dozens of conditions that are shortchanged by this PR-driven public-health approach from CDC. We can and must do better. How can a vaccine preventable virus, hepatitis B, and the only virus we can cure, hepatitis C, fail to make this list?
"Chronic viral hepatitis afflicts more than 5 million Americans directly and, by extension, tens of millions more of their loved ones. Most Americans are not aware they are infected until they present with serious related illnesses. Without adequate screening and treatment, chronic viral hepatitis often progresses to cirrhosis, liver cancer, and liver failure.
"Over the past year, experts from the Institute of Medicine, the American Association for the Study of Liver Diseases, and the Trust for America's Health have all identified how best to address the viral hepatitis epidemic with common-sense action plans. Regrettably, the Administration is lacking the political will to implement them.
"The CDC's omission of viral hepatitis from its list of 'winnable battles' is not simply an oversight – it's an abdication of duty to many Americans who may well lose their battle with chronic viral hepatitis in the decades to come."
NVHR is a coalition of more than 170 public, private, and voluntary organizations dedicated to reducing the incidence of infection, morbidity, and mortality from chronic viral hepatitis that afflicts more than 5 million Americans. http://www.nvhr.org/
SOURCE National Viral Hepatitis Roundtable
RELATED LINKS
http://www.nvhr.org/
Source
Also See: CDC chief picks 6 'winnable battles' in health
"The CDC's newly released 'six winnable battles' strategy makes a mockery of the broad-based, comprehensive, and integrated public-health strategy that our nation so desperately needs. In seeking to win six narrowly defined health care battles, the CDC may well lose the overall public-health war.
"Chronic viral hepatitis B and C are among dozens of conditions that are shortchanged by this PR-driven public-health approach from CDC. We can and must do better. How can a vaccine preventable virus, hepatitis B, and the only virus we can cure, hepatitis C, fail to make this list?
"Chronic viral hepatitis afflicts more than 5 million Americans directly and, by extension, tens of millions more of their loved ones. Most Americans are not aware they are infected until they present with serious related illnesses. Without adequate screening and treatment, chronic viral hepatitis often progresses to cirrhosis, liver cancer, and liver failure.
"Over the past year, experts from the Institute of Medicine, the American Association for the Study of Liver Diseases, and the Trust for America's Health have all identified how best to address the viral hepatitis epidemic with common-sense action plans. Regrettably, the Administration is lacking the political will to implement them.
"The CDC's omission of viral hepatitis from its list of 'winnable battles' is not simply an oversight – it's an abdication of duty to many Americans who may well lose their battle with chronic viral hepatitis in the decades to come."
NVHR is a coalition of more than 170 public, private, and voluntary organizations dedicated to reducing the incidence of infection, morbidity, and mortality from chronic viral hepatitis that afflicts more than 5 million Americans. http://www.nvhr.org/
SOURCE National Viral Hepatitis Roundtable
RELATED LINKS
http://www.nvhr.org/
Source
Also See: CDC chief picks 6 'winnable battles' in health
Achillion Announces Dosing of First Patient in Phase II Trial of ACH-1625 for the Treatment of Hepatitis C
Sept. 30, 2010, 4:00 p.m. EDT
NEW HAVEN, Conn., Sep 30, 2010 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 3.02, -0.03, -0.98%) , a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today announced that the Company has initiated patient dosing in a Phase II clinical trial of ACH-1625 for the treatment of hepatitis C virus (HCV) infection. ACH-1625 is a potent small molecule inhibitor of HCV protease, an enzyme necessary for viral replication. The drug candidate was discovered and is being advanced by Achillion.
The clinical trial is a Phase IIa, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and antiviral activity of oral ACH-1625 in combination with pegylated interferon alfa-2a and ribavirin after 28 days of dosing and after 12 weeks of dosing in subjects with chronic hepatitis C virus genotype 1. The trial will take place in the United States and Europe and is designed to enroll approximately 120 HCV-infected patients. The 28-day and 12-week trial data are anticipated to be announced in the first and fourth quarters of 2011, respectively.
"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," stated Elizabeth A. Olek, D.O., Vice President and Chief Medical Officer of Achillion. "The results will also provide important combination data for use of ACH-1625 with standard of care. We anticipate that the 28-day segment of the trial will provide us with rapid viral response (RVR) data early next year, and that the 12-week segment will provide extended viral response (cEVR) data by the end of next year."
"The initiation of Phase II dosing for ACH-1625 is a very important step in further solidifying this compound's profile as a potentially best-in-class protease inhibitor for HCV treatment," said Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "We believe ACH-1625 has the potential to provide an improved safety and tolerability profile, a more convenient dosing schedule and an extended period of viral suppression compared to currently available treatments for HCV-infected patients."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, and no clinically significant changes in vital signs, electrocardiograms (ECGs) or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, injectable route of administration and high cost.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease --hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
ACHN-G
This news release was distributed by GlobeNewswire, http://www.globenewswire.com/
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Source
NEW HAVEN, Conn., Sep 30, 2010 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 3.02, -0.03, -0.98%) , a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today announced that the Company has initiated patient dosing in a Phase II clinical trial of ACH-1625 for the treatment of hepatitis C virus (HCV) infection. ACH-1625 is a potent small molecule inhibitor of HCV protease, an enzyme necessary for viral replication. The drug candidate was discovered and is being advanced by Achillion.
The clinical trial is a Phase IIa, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and antiviral activity of oral ACH-1625 in combination with pegylated interferon alfa-2a and ribavirin after 28 days of dosing and after 12 weeks of dosing in subjects with chronic hepatitis C virus genotype 1. The trial will take place in the United States and Europe and is designed to enroll approximately 120 HCV-infected patients. The 28-day and 12-week trial data are anticipated to be announced in the first and fourth quarters of 2011, respectively.
"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," stated Elizabeth A. Olek, D.O., Vice President and Chief Medical Officer of Achillion. "The results will also provide important combination data for use of ACH-1625 with standard of care. We anticipate that the 28-day segment of the trial will provide us with rapid viral response (RVR) data early next year, and that the 12-week segment will provide extended viral response (cEVR) data by the end of next year."
"The initiation of Phase II dosing for ACH-1625 is a very important step in further solidifying this compound's profile as a potentially best-in-class protease inhibitor for HCV treatment," said Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "We believe ACH-1625 has the potential to provide an improved safety and tolerability profile, a more convenient dosing schedule and an extended period of viral suppression compared to currently available treatments for HCV-infected patients."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, and no clinically significant changes in vital signs, electrocardiograms (ECGs) or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, injectable route of administration and high cost.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease --hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
ACHN-G
This news release was distributed by GlobeNewswire, http://www.globenewswire.com/
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Source
CDC chief picks 6 'winnable battles' in health
By MIKE STOBBE (AP) – 37 minutes ago
ATLANTA — Where would you start if you were charged with keeping the nation healthy? Dr. Thomas Frieden, director of the Centers for Disease Control and Prevention, has chosen six priorities — winnable battles, he calls them.
They are smoking, AIDS, obesity/nutrition, teen pregnancy, auto injuries and health care infections. These are long-standing, major challenges that get a lot of attention already.
But elevating a handful of problems above dozens of others is a bold move for a public health official. So far, it's been received like a bucket of cold water — invigorating some, infuriating others.
Many advocates, legislators and others in public health have devoted their lives to problems that did not make Frieden's short list. So there are complaints.
A CDC employee blog is peppered with postings like, "I guess climate change is not a battle worth winning," and "Don't we still owe the patients of tomorrow an investment in things that may not pay off immediately?"
Some advocates wonder aloud just how targeted federal public health dollars are going to be. A particular point of concern is hepatitis C, a long under-recognized liver-destroying virus which has infected more than 3 million Americans. Some experts consider the issue a ticking time bomb and have called for the government to step up efforts to prevent it and better diagnose and treat people who already are infected.
Hepatitis B and C already are "badly neglected" by the CDC, and their omission from Frieden's winnable battles list is more bad news, said Bruce Burkett, past president of the National Hepatitis C Advocacy Council.
"I was very disappointed that it wasn't on there. This is going to affect millions by not being on there," he said.
Frieden, who took over CDC in June last year, already had a reputation as something of a public health maverick. When he started his previous job as New York City's health commissioner in 2002, he began by identifying the city's most pressing health issues. He led campaigns to ban smoking in the workplace, tax soda, cut salt in processed foods, and ban artificial trans fats in restaurants.
It's no surprise that he is boldly painting targets at the CDC, said Dr. Jo Ivey Boufford, president of the New York Academy of Medicine. She's a fan of Frieden's who worked with him as a member of an advisory council to the city health department.
Frieden's CDC job, ironically, does not provide the same kind of power he had in New York City to engineer bans or tax increases. But Frieden calls his new short list "winnable battles" because, he says, proven programs can save lives and reduce harm from each of these health problems. He believes government can make dramatic improvements if available money and manpower are focused.
"In each of these areas we know what to do to make a difference and we need to do it to a much greater extent," he said in an interview.
Frieden, with a low-key demeanor, has said relatively little about this to the public, though he seems to be building support within the public health community.
There is some nervousness about how far Frieden's going to take this.
"I think everyone is going to be cautious in how the focus on winnable battles is balanced against other areas" that are also deemed important but may not be as easy to dent, said Jeff Levi, who heads Trust for America's Health, a research group.
Top CDC officials have been quick to say they have no intention of walking away from other public health missions. They couldn't even if they wanted to, because much of the agency's funding is directed to certain causes by Congress. According to one estimate, less than one-tenth of 1 percent of CDC's $6.6 billion budget is discretionary money that can be channeled into the winnable battles campaign. Indeed, the agency has been asking for more flexibility.
But there's power in perception, especially concerning CDC's grant money to states. Nearly a quarter of that is targeted at the six battle areas, which already were major areas of interest. State health officers say they're acutely aware of Frieden's priorities and want him to know it when they apply for CDC money.
"We're in the position of focusing pretty much on what we can get federal funds for," said Will Humble, director of the Arizona Department of Health Services.
Humble and several other public health leaders applaud Frieden's priorities as an overdue attempt to narrow the public health message and better market health improvement to Americans.
"You can't market if your message is too diffuse," Humble said. "If we're all on the same page and working in the same direction, we can get a lot more momentum."
This isn't how many public health officials traditionally operate, partly because they tend to worry about alienating employees, legislators and advocates, observed Stanton Glantz, a University of California-San Francisco expert on the health effects of smoking.
Other top federal health officials have not been as specific. U.S. Surgeon General Dr. Regina Benjamin, the government's chief health educator, has made the broader themes of prevention and wellness her focus.
But Frieden clearly has the blessing of his Obama administration bosses to set clear targets.
"Getting focused, and getting some quick wins under your belt, is terribly important," said Victor Strecher, a University of Michigan health behavior expert.
Progress in these areas has long been measured by health statistics. What exactly will constitute a win? Frieden hasn't said yet.
___
Online:
CDC Web page describing winnable battles: http://bit.ly/bCd8Lr
Source
ATLANTA — Where would you start if you were charged with keeping the nation healthy? Dr. Thomas Frieden, director of the Centers for Disease Control and Prevention, has chosen six priorities — winnable battles, he calls them.
They are smoking, AIDS, obesity/nutrition, teen pregnancy, auto injuries and health care infections. These are long-standing, major challenges that get a lot of attention already.
But elevating a handful of problems above dozens of others is a bold move for a public health official. So far, it's been received like a bucket of cold water — invigorating some, infuriating others.
Many advocates, legislators and others in public health have devoted their lives to problems that did not make Frieden's short list. So there are complaints.
A CDC employee blog is peppered with postings like, "I guess climate change is not a battle worth winning," and "Don't we still owe the patients of tomorrow an investment in things that may not pay off immediately?"
Some advocates wonder aloud just how targeted federal public health dollars are going to be. A particular point of concern is hepatitis C, a long under-recognized liver-destroying virus which has infected more than 3 million Americans. Some experts consider the issue a ticking time bomb and have called for the government to step up efforts to prevent it and better diagnose and treat people who already are infected.
Hepatitis B and C already are "badly neglected" by the CDC, and their omission from Frieden's winnable battles list is more bad news, said Bruce Burkett, past president of the National Hepatitis C Advocacy Council.
"I was very disappointed that it wasn't on there. This is going to affect millions by not being on there," he said.
Frieden, who took over CDC in June last year, already had a reputation as something of a public health maverick. When he started his previous job as New York City's health commissioner in 2002, he began by identifying the city's most pressing health issues. He led campaigns to ban smoking in the workplace, tax soda, cut salt in processed foods, and ban artificial trans fats in restaurants.
It's no surprise that he is boldly painting targets at the CDC, said Dr. Jo Ivey Boufford, president of the New York Academy of Medicine. She's a fan of Frieden's who worked with him as a member of an advisory council to the city health department.
Frieden's CDC job, ironically, does not provide the same kind of power he had in New York City to engineer bans or tax increases. But Frieden calls his new short list "winnable battles" because, he says, proven programs can save lives and reduce harm from each of these health problems. He believes government can make dramatic improvements if available money and manpower are focused.
"In each of these areas we know what to do to make a difference and we need to do it to a much greater extent," he said in an interview.
Frieden, with a low-key demeanor, has said relatively little about this to the public, though he seems to be building support within the public health community.
There is some nervousness about how far Frieden's going to take this.
"I think everyone is going to be cautious in how the focus on winnable battles is balanced against other areas" that are also deemed important but may not be as easy to dent, said Jeff Levi, who heads Trust for America's Health, a research group.
Top CDC officials have been quick to say they have no intention of walking away from other public health missions. They couldn't even if they wanted to, because much of the agency's funding is directed to certain causes by Congress. According to one estimate, less than one-tenth of 1 percent of CDC's $6.6 billion budget is discretionary money that can be channeled into the winnable battles campaign. Indeed, the agency has been asking for more flexibility.
But there's power in perception, especially concerning CDC's grant money to states. Nearly a quarter of that is targeted at the six battle areas, which already were major areas of interest. State health officers say they're acutely aware of Frieden's priorities and want him to know it when they apply for CDC money.
"We're in the position of focusing pretty much on what we can get federal funds for," said Will Humble, director of the Arizona Department of Health Services.
Humble and several other public health leaders applaud Frieden's priorities as an overdue attempt to narrow the public health message and better market health improvement to Americans.
"You can't market if your message is too diffuse," Humble said. "If we're all on the same page and working in the same direction, we can get a lot more momentum."
This isn't how many public health officials traditionally operate, partly because they tend to worry about alienating employees, legislators and advocates, observed Stanton Glantz, a University of California-San Francisco expert on the health effects of smoking.
Other top federal health officials have not been as specific. U.S. Surgeon General Dr. Regina Benjamin, the government's chief health educator, has made the broader themes of prevention and wellness her focus.
But Frieden clearly has the blessing of his Obama administration bosses to set clear targets.
"Getting focused, and getting some quick wins under your belt, is terribly important," said Victor Strecher, a University of Michigan health behavior expert.
Progress in these areas has long been measured by health statistics. What exactly will constitute a win? Frieden hasn't said yet.
___
Online:
CDC Web page describing winnable battles: http://bit.ly/bCd8Lr
Source
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