by John C. Martin |
Article Date: 10-06-05 |
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Their experiment is reported in the June 9 issue of Science magazine.1
"The inability to reproduce aspects of the hepatitis C virus life cycle in cell culture has slowed research progress on this important human pathogen [disease-causing organism]," said chief investigator Charles Rice, PhD, who heads the Laboratory of Virology and Infectious Disease at Rockefeller University.
Risk Factors and
Symptoms
Hepatitis C infection is a disease of the
liver caused by the hepatitis C virus. Those at risk include the
following people:
• Those who received blood from a donor who later tested
positive for HCV infection.
• Those who have injected illegal drugs, even many years ago.
• Those who received a blood transfusion or solid organ transplant before
1992.
• Those were recipients of clotting factors before 1987.
• Those who have ever been on long-term kidney dialysis.
• Those who have evidence of liver disease, such as persistently high
levels of a liver enzyme called
alanine aminotransferase (ALT).
Signs and symptoms of hepatitis C infection include the following:
• Jaundice
• Fatigue
• Dark urine
• Abdominal pain
• Loss of appetite
• Nausea
The number of new infections per year has plunged from about 240,000 in the 1980s to about 30,000 in 2003. However, nearly 4 million Americans are infected with the viral disease, of whom about 2.7 million are chronically infected.2
Unveiling New Knowledge About HCV
According to experts, hepatitis C cannot replicate (make copies of
itself) by itself. It must first infect cells in the body, and use the
cells' infrastructure to successfully make copies of itself.3
However, up until now, little has been understood about the life cycle of
the hepatitis C virus because medical researchers haven't been able to
reproduce an infectious form of the virus that they can observe in cell
cultures.
"This system lays the foundation for future test tube studies of the virus life cycle, and may help in the development of new drugs for combating HCV," Rice said, in explaining the lab experiment that he and his colleagues described in their study paper.
How HCV Infects Cells
Based on research on the life cycle of hepatitis C, researchers believe
the virus enters a liver cell, and delivers its genetic material, as well
as certain proteins, into the cell's cytoplasm.4 According to
experts, the virus separates its genetic component from the proteins it
releases, copies that genetic component, then joins with new genetic
component with the protein. This new, copied form of the virus is released
from the liver cell to invade other liver cells.
"The hallmark of viruses is their ability to exist in a form outside the host cell capable of infecting new cells," said study researcher Brett Lindenbach, PhD, a postdoctoral fellow in Rice's lab. "Our method replicates and produces virus particles that can infect new cells, initiating replication in them and leading to the production of more virus particles."
In other words, Rice's group managed to create the same process in a lab experiment as what is seen in the human body during the onset of infection.
A Molecule Friendly to HCV
The research team named their infectious cell culture HCVcc, and already,
it's giving them new knowledge about the biology of HCV. In a separate set
of experiments, Rice and his team used HCVcc to confirm that a certain
molecule, which sits on the surface of human cells, mediates the entry of
the hepatitis C virus into the cells.
It's long been known that a protein produced by the hepatitis C virus binds to this molecule,5 and it's believed this interaction is necessary for the virus to bind to targeted liver cells.
In this study, Rice's group found that forms of the molecule that do not sit on the surface of cells compete with those that do, and prevent HCV from entering the cell.
In conclusion, the research team wrote: "HCVcc replication was inhibited by interferon-alpha and by several HCV-specific antiviral compounds, suggesting that this in-vitro system will aid in the search for improved antivirals."
1. Lindenbach BD, Evans MJ, Syder AJ et al. Complete
replication of hepatitis C virus in cell culture. Science 2005
Jul 22;309(5734):623-6. Epub 2005 Jun 9.
2. Centers for Disease Control and Prevention. Viral Hepatitis C.
Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm.
3. Moriishi K, Matsurra Y. Mechanisms of hepatitis C virus infection.
Antivi Chem Chemother 2003 Nov;14(6):285-97.
4. Chang M, Williams O, Mittler J et al. Dynamics of hepatitis C virus
replication in human liver. Am J Pathol 2003 Aug;163(2):433-4.
5. Machida K, Cheng KT, Pavio N, Sung VM, Lai MM. Hepatitis C virus
E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B
cells. J Virol 2005 Jul;79(13):8079-89.
John Martin is a long-time health journalist and an
editor for Priority Healthcare. His credits include overseeing health news
coverage for the website of Fox Television's The Health Network, and
articles for the New York Post and other consumer and trade publications.
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Short Course PegIntron plus Rebetol Approved in Europe for
HCV Patients with Genotype 1 and Low HCV Viral Load
The European Commission has approved revised dosing instructions that allow for a shorter, 24-week course of PegIntron (1.5 mcg/kg once weekly) and Rebetol (800 – 1,200 mg daily) combination therapy among a subgroup of patients with chronic hepatitis C virus (HCV), according to an announcement form Schering-Plough.
The revised treatment regimen is specifically for chronic HCV patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who have achieved rapid virologic response, defined as undetectable virus (HCV-RNA negative) at week 4 of treatment that is maintained through week 24.
Approval of this shorter PegIntron and Rebetol combination treatment regimen cuts by half the duration of therapy for a subset of hepatitis C patients with genotype 1 and low viral load. This is the only treatment regimen approved in the European Union (EU) for a 24-week course of therapy in certain genotype 1 patients.
In clinical studies supporting the approval, 92 percent of patients who met the criteria for early response achieved a sustained virologic response (SVR) with 24 weeks of treatment. In the , PegIntron (1.5 mcg/kg once weekly) is approved in combination with Rebetol (800 mg daily) for a duration of treatment of 48 weeks.
“Physicians now have the opportunity to consider a shorter course of therapy for their patients with hepatitis C genotype 1 who meet specific criteria,” said Professor Stefan Zeuzem, M.D., Saarland University, Homburg, Germany, and lead investigator of the study supporting the approval. “Tailoring treatment so that those with an early response are treated for only 24 weeks rather than 48 weeks may make therapy more appealing to patients, providing comparable efficacy with better tolerability,” he said.
“Approval of this shorter course of PegIntron and Rebetol combination therapy reflects the ongoing commitment of Schering-Plough to define optimal dose and treatment schedules to better meet the needs of hepatitis C patients,” said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute.
The Commission approval results in Marketing Authorization with unified labeling that is valid in the current EU 25 member states as well as in and . PegIntron and Rebetol combination therapy was previously approved in the EU for a 48-week course of therapy for all patients with genotype 1 who exhibit virological response at week 12.
Study Results
The approved labeling change for PegIntron and Rebetol is based on results of a clinical study involving 235 patients with HCV genotype 1 and low viral load who received 24 weeks of combination therapy with PegIntron (1.5 mcg/kg once weekly) and Rebetol (800 – 1,400 mg daily); only two patients weighing >105 kg received the 1,400 mg dose. In the study, 41 percent of patients (97/235) had undetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. Patients in this subgroup achieved a 92 percent (89/97) rate of sustained virological response. The high SVR in this group of patients was identified in an interim analysis and prospectively confirmed.
Genotype 1 virus is the most common worldwide, the most difficult to treat successfully and accounts for about 70 percent of HCV infections among European patients overall, varying by geography. For patients with HCV genotypes 2 or 3, the EU labeling for PegIntron recommends that all patients be treated for 24 weeks. Patients infected with HCV genotype 4 are considered harder to treat and generally 48 weeks of therapy is recommended. In the , PegIntron is indicated in combination with Rebetol (800 mg daily) for 48 weeks.
About PegIntron and Rebetol Combination Therapy
PegIntron and Rebetol combination therapy for chronic hepatitis C was approved in the European Union in March 2001. The recommended dose in the EU for combination therapy is PegIntron 1.5 mcg/kg once weekly plus Rebetol 800-1,200 mg daily, adjusted to body weight. PegIntron had previously received centralized marketing authorization in the EU and is marketed as a monotherapy in cases of intolerance or contraindication to ribavirin for the treatment of adult patients with chronic hepatitis C.
PegIntron, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy dosed according to patient body weight that is designed to achieve an effective balance between antiviral activity and elimination half-life. Rebetol is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity.
Chronic hepatitis C is estimated to affect more than 10 million people in major world markets, including 5 million in Europe. It is a leading cause of chronic liver disease and one of the most common reasons for liver transplant in Europe.
Important Information Regarding US Labeling
for PEG-INTRON and REBETOL
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WARNING Alpha interferons, including PEG-INTRON, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping PEG-INTRON therapy. Ribavirin causes hemolytic anemia. Anemia associated with REBETOL therapy may exacerbate cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated. REBETOL and combination REBETOL/PEG-INTRON therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. REBETOL and combination REBETOL/PEG-INTRON therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of REBETOL. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064. |
PegIntron plus Rebetol Articles Posted on HIV and
hepatitis.com
10/07/05
Source
Schering-Plough. SHORTER COURSE OF PEG-INTRON®
AND REBETOL® COMBINATION THERAPY
APPROVED IN EUROPEAN UNION FOR CERTAIN HEPATITIS C PATIENTS WITH GENOTYPE 1
AND LOW VIRAL LOAD. Press Release. October 5, 2005.
http://www.hivandhepatitis.com/hep_c/news/2005/ad/100705_a.html
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| Viral load level at week 8 may be as accurate as "12-week rule" for predicting failure to achieve SVR in HCV patients |
September 23, 2005 ˇŞ The currently accepted 12-week threshold for cessation of therapy in chronic hepatitis C patients who fail to have an early virologic response was firmly upheld by a recent retrospective, international study. Investigators further determined that even earlier time points of 4 and 8 weeks can reliably be used to predict therapeutic response using specific viral load levels. These findings by Terrault and colleagues represent the combined effort of a multicenter cohort study based at the University of California San Francisco, San Francisco, California.
Although interferon formulations in combination with ribavirin have been very successful in treating chronic hepatitis C, they are associated with significant and sometimes severe side effects. Predicting early during therapy that a patient is unlikely to respond to treatment can substantially reduce morbidity and cost. The "12-week rule"--stopping therapy upon failure to exhibit at least a 2-log drop or undetectable HCV RNA by 12 weeks of treatment--has been shown to accurately predict the failure to achieve a sustained virologic response (SVR) 24 weeks after the end of therapy. This "rule" has a negative predictive value (NPV) of 98%, and accordingly has been adopted as a recommendation in the National Institutes of Health Consensus Development Conference Statement.
The current study was undertaken to investigate the use of precise viral loads levels for predicting whether chronic HCV patients given interferon plus ribavirin will achieve SVR. Alternate decision rules were tested with the idea of accurately predicting nonresponse as early as feasible for the widest scope of patients. Performance of various stopping rules combining viral load and decline in viral load from baseline was also evaluated.
Researchers collected archive data on 351 patients at 5 North American centers as well as 1 center in France. Previously recorded baseline demographic and medical data including age, ethnicity, gender, stage of hepatic disease, nature and duration of prior HCV therapy, and genotype specifics were used for analysis.
All patients were at least 18 years of age, had documented serologic evidence of HCV infection, and had undergone recent liver biopsy confirming either cirrhosis or a defined constellation of inflammatory changes. Study subjects were gathered from clinical trials (n = 231) as well as from private practice (n = 138) and were divided into a 24-week group (minimum of 20 weeks of therapy) and a 48-week group (minimum of 44 weeks of therapy).
Most of the patients were white males, treatment-naive, and without cirrhosis, and roughly half were in the 24-week treatment group. A total of 165 patients achieved SVR, while the remaining 186 were defined as nonresponders. Not surprisingly, they found SVR patients more likely to be treatment naive with non-1 viral genotypes and recipients of a 48-week regimen.
Univariate logistic regression analysis of baseline data showed viral genotype, viral load, treatment duration, and age were all significantly predictive of SVR.
Viral load determinations not only validated the existing "12-week" guideline but also established that 8-week decision thresholds were comparable in performance to 12-week measures, an outcome yet to be verified with other drug combinations. Moreover, predicted nonresponse rates (%) for an expanded range of specific viral loads could enable more confident clinical decisions when discontinuation of treatment is being considered.
Specifically, the study revealed that the failure to achieve SVR for patients with non-1 viral genotypes could be predicted with high accuracy. A 4-week viral load ˇÝ 100,000 IU/mL or an 8- or 12-week viral load ˇÝ 10,000 IU/mL were equally indicative of a 0% chance for SVR. Similarly, these cut-off values provided valuable early time points for considering stopping therapy for genotype 1 patients. At 4 weeks, an HCV RNA level ˇÝ 100,000 IU/mL had an NPV of 96.5% for failure to achieve SVR, and at 8 and 12 weeks, an HCV RNA level ˇÝ 100,00 IU/mL had an NPV of 98.5% and 96.9%, respectively. These NPV values were comparable to a 2-log decline or undetectable HCV RNA at 12 weeks, which in this study was 97.1% for genotype 1 patients.
Researchers noted that the thresholds for stopping therapy were accurate for all patients studied, despite a variety of treatments and settings. No exceptions were encountered in either treatment-naive or treatment-experienced patients or in clinical trial participants vs those from clinical practice. The investigators noted that these results need to be verified in patients receiving peginterferon plus ribavirin, the current standard of treatment, as this study was limited to patients taking interferon plus ribavirin. Nevertheless, they wrote that "this study confirms the central role of viral quantitation in the clinical management of HCV-infected patients undergoing antiviral therapy."
References
Terrault N, Pawlotsky J-M, McHutchison J, et al. Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy. J Viral Hepatitis. 2005;12:465-472.
National Institutes of Health Consensus on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19:1-46.
http://clinicaloptions.com/hep/news/news_imed_398.asp
October Is Liver Awareness Month - American Liver Foundation Urges Americans to Take Care of Their Liver
NEW YORK, NY -- October is
National Liver Awareness
Month, a great opportunity for Americans to learn how to care for this
underappreciated and vital organ and to make real progress in the fight
against what is rapidly becoming one of the nation's most serious public
health problems -- liver disease.
More than 30 million Americans -- one in 10 -- are affected by liver
disease, including hepatitis. The incidence of liver cancer, unlike most
cancers, is actually increasing. Many forms of liver disease, however, are
vaccine-preventable and treatable by simply getting the facts and knowing
how
to protect yourself from infection.
During October, the American Liver Foundation (ALF) urges Americans to
take control of their health by learning about the functions of the liver,
common signs of liver disease and steps people can take to protect their
liver.
"Surprisingly, many people don't realize that they cannot survive without
a healthy liver," said Frederick G. Thompson, president and CEO of the
American Liver Foundation. "ALF strongly urges people to protect their
health
by taking care of their liver and speaking to a physician about their risk
of
liver disease."
The liver, the largest organ in the body, is essential for survival and
acts as the body's filter, processing everything we eat, drink, breathe and
even put on our skin.
When not functioning properly, the liver can lead to acute and chronic
illnesses, sometimes resulting in death. Liver disease ranks as a top 10
cause of death for Americans -- over 26,000 people in the U.S. die each year
from chronic liver disease and cirrhosis.
However, by leading a healthy lifestyle with a good diet and exercise, one
can maintain a vital, healthy liver. Here are a few ways people can maintain
good liver health:
- Drink alcohol only in moderation
- Consult a physician before mixing medications; taking too many
medicines can be toxic to your liver
- Avoid mixing alcohol with other drugs or medication unless consulted
by a physician
- Take precautions when using aerosol cleaning sprays to ensure proper
ventilation
- Be careful working with chemicals -- pesticides and other chemicals
that come into contact with the skin must be processed by the liver
Unfortunately, many people do not recognize the symptoms of liver disease
and are unaware they have an illness until it's too late. Common signs of
liver disease include:
People exhibiting one or more of these symptoms should contact their
physician. However, people with liver disease often experience no symptoms,
so it is important that patients know their risk factors and talk to their
health care provider about whether they may be at risk for hepatitis or
liver
disease.
Many forms of liver disease and hepatitis are preventable through healthy
lifestyle choices, particularly hepatitis A and B which are vaccine-
preventable. If undiagnosed and left untreated, Hepatitis B can lead to
cirrhosis and liver cancer, therefore getting screened for hepatitis B and
getting the vaccine can often be pre-emptive to preventing cancer.
The American Liver Foundation urges people to talk to their physicians about
their risks for hepatitis and to discuss options of vaccination, when
needed.
For more information about liver health, liver disease and ways to maintain
healthy liver functionality, visit < a href=http://www.liverfoundation.org>
http://www.liverfoundation.org.
The ALF has 25 chapter offices nationwide and provides educational
workshops and seminars, support groups, and community outreach to increase
the
awareness of hepatitis and other liver diseases. The ALF also provides
guidance to local, state and federal policy makers on issues relating to
hepatitis and liver disease and to help affect positive change in the
outcomes
of the disease. ALF is also a leader in generating local and national
support
for research by advocating federal policy makers to secure increases in
government funding for liver disease, and by funding young scientists and
researchers to help improve the study of liver disease and patient care and
to
encourage the discovery of more scientific breakthroughs in the disease. ALF
sponsors numerous fundraising events and campaigns around the country to
support all of these efforts.
About the American Liver Foundation
The American Liver Foundation (ALF) is a national voluntary health agency
dedicated to promoting liver wellness and to preventing, treating, and
curing
hepatitis and other liver diseases through research, education and advocacy.
For additional information about hepatitis and other liver diseases, contact
the ALF at 1-800 GO LIVER or visit < a href=http://www.liverfoundation.org>
http://www.liverfoundation.org.
CONTACTS:
Andrea Iraheta
American Liver Foundation
1-212-668-1000
airaheta@liverfoundation.org
Jaymie Gustafson
1-202-965-7811
jaymie.gustafson@zenogroup.com