The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders).
Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol.
Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia.
Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a (Pegasys) plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception.
If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years.
The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed.
The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.
10/25/04
Reference
W M Lee and others (The HALT-C Trial Group). Evolution of the HALT-C Trial:
pegylated interferon as maintenance therapy for chronic hepatitis C in
previous interferon nonresponders.
Controlled Clinical Trials
25(5): 472-492. October 2004.
Index to
Hepatitis C News Articles by Topic [ A -- Z ]
Roche and Pharmasset Inc Will Jointly Develop Next
Generation Anti-HCV Drug PSI- 6130, an HCV Polymerase Inhibitor, in
Combination with Pegasys/Copegus
Only about half of all patients with HCV genotype 1 who use one of the peginterferons plus ribavirin experience a sustained virologic response and are “cured” of chronic hepatitis C. Although FDA-approval of the pegylated interferons has significantly improved clinical outcomes for people with chronic hepatitis C, there remains a pressing need for more effective and less toxic therapies. Unfortunately, no new anti-HCV therapies are expected to become available for several years, at the earliest.
It is in this somewhat bleak environment that Roche and Pharmasset announced on October 27 a partnership to develop an orally administered nucleoside polymerase inhibitor for use with peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus) in the treatment of chronic hepatitis C virus (HCV) infection. Specifically, the two companies have agreed to jointly develop and market PSI-6130, the lead nucleoside polymerase inhibitor compound of the new partnership.
According to the announcement from Roche, Pharmasset will receive an upfront fee, research and development support, and milestone payments that could total $168 million for PSI-6130. In addition, Pharmasset will receive royalties on product sales and retain certain co-promotion rights in the U.S.
PSI-6130
PSI-6130 is now in “advanced pre-clinical stage testing,” according to Abel De La Rosa, Senior Vice President of Business and Strategy at Pharmasset: “We are excited about this compound, which has direct antiviral activity against HCV,” De La Rosa told HIV and Hepatitis.com in a telephone interview. “Our hope is that PSI-6130 will demonstrate greater effectiveness against HCV, especially when used in combination with Pegasys and Copegus,” he said.
Assuming development of the drug moves forward smoothly and without interruption, using PSI-6130 or its prodrugs in combination with peginterferon and ribavirin could greatly benefit nonresponders to current therapies, according to De La Rosa.
When asked about the available data on 6130, De La Rosa said no data on the drug have yet been presented at any scientific meetings, “but we hope to see a release of data perhaps in time for the 2005 AASLD conference,” he added.
CEOs Viewpoints
“Roche has already established itself in hepatitis C with Pegasys, the most prescribed hepatitis C medication in the U.S. This collaboration with Pharmasset demonstrates our ongoing commitment to advancing therapy for hepatitis C patients with unmet needs,” said George Abercrombie, President and CEO, Hoffmann-La Roche Inc. “We hope that further research and development will show that PSI-6130 is an important new hepatitis C treatment option that complements Pegasys and Copegus.”
“Pharmasset’s expertise in nucleoside drug discovery and early stage clinical development, combined with Roche’s proven track record in bringing new and improved hepatitis C therapies to market is a formula for success,” said Schaefer Price, Pharmasset’s President and CEO. “The economics of this deal are significant. In addition, this partnership will support Pharmasset’s activities toward establishing a commercial infrastructure for our HIV and HCV clinical candidates.”
Pharmasset has two anti-HIV compounds now in Phase II testing, Reverset and Racivir, which are expected to be on the market as prescription drugs for HIV in late 2005. “The company is committed to continuing our strong focus on the development of drugs for the treatment of chronic hepatitis C and for HIV infection,” De La Rosa told HIV and Hepatitis.com.
Under the terms of the agreement, Roche will gain the worldwide rights, excluding Latin America and Korea, to Pharmasset’s PSI-6130 and its prodrugs.
Pharmasset will be responsible for preclinical work, investigational new drug (IND) filings, and phase I proof of concept studies, with Roche managing other preclinical studies and clinical development. Roche will also receive options to related nucleoside polymerase inhibitors, which, if exercised, could result in Pharmasset receiving in excess of $300 million in total milestones under the agreement.
Pharmasset will continue to develop and retain worldwide rights to ongoing and future hepatitis C programs unrelated to the PSI-6130 series of nucleoside polymerase inhibitors. In addition, the Roche Venture Fund has made a $4 million investment in Pharmasset and has received warrants to purchase an additional $6 million in shares within the next two years at a premium price.
About HCV
Hepatitis C is a blood-borne infectious disease of the liver and the leading cause of cirrhosis and liver cancer and the number one reason for liver transplants in the U.S. An estimated 2.7 million Americans are chronically infected with hepatitis C.
About Pegasys
Pegasys, the most prescribed pegylated alfa interferon in the U.S., and Copegus were approved by the FDA in December 2002 for use in combination for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alfa. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis.
HIV and Hepatitis.com Articles on Pegasys and Copegus
About Pharmasset
Pharmasset, Inc., is an emerging pharmaceutical company committed to the discovery, development, and commercialization of novel antiviral drugs. The company leverages its expertise in nucleoside chemistry to develop therapeutics to combat infections caused by drug-resistant human immunodeficiency virus (HIV) and hepatitis viruses. Pharmasset has two drugs in Phase II clinical trials, Reverset and Racivir and several other antiviral compounds in advanced preclinical studies.
In September 2003, Pharmasset entered into a collaborative licensing agreement with Incyte Corporation for the development and commercialization of Reverset in certain territories. Pharmasset retains proprietary development and commercialization rights to the balance of its clinical and preclinical pipeline. Pharmasset’s expanding portfolio of antiviral therapeutics aims to improve the lives of individuals around the world.
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. prescription drug unit of the Roche Group, a leading research-based health care enterprise that ranks among the world's leaders in pharmaceuticals and diagnostics.
For more information on the Roche pharmaceuticals business in the United States, visit the company's web site at: http://www.rocheusa.com
Facts About Pegasys (Peginterferon alfa-2a) in
Combination with Copegus Indication
Pegasys, a pegylated alfa interferon, alone or in combination
with Copegus
(ribavirin) is indicated for the treatment of adults with chronic hepatitis
C who have compensated liver disease and have not previously been treated
with interferon alfa. Patients in whom efficacy was demonstrated included
patients with compensated liver disease and histological evidence of
cirrhosis (Child-Pugh class A).
Dosing and Administration
Pegasys, a premixed solution, is dosed at 180mcg as a subcutaneous injection
once a week. Copegus, available as a 200mg tablet, is administered at 800 to
1200mg taken twice daily as a split dose. The two products are sold
separately.
Combination Therapy Clinical Studies
The two combination therapy pivotal study findings:
Study 5,
published in the March 2, 2004 Annals of Internal Medicine, including
1,284 patients receiving medication, showed that patients with certain
genotypes (strains) of the hepatitis C virus should be treated with
different dosing regimens of Pegasys and Copegus. The treatment regimens and
resulting sustained virological response rates for these groups treated with
Pegasys and Copegus therapy were:
Genotype 1: 48 week duration with 1000 – 1200mg Copegus: 51 percent
Genotype non-1: 24 week duration with 800mg Copegus: 82 percent
Study 4, published in the September 26, 2002 New England Journal of Medicine,
including 1,121 patients receiving medication, showed that Pegasys and Copegus combination therapy is a more effective treatment for chronic hepatitis C than interferon alfa-2b and ribavirin. The sustained virological response rate in the Pegasys and Copegus treated patients was 53 percent compared to 44 percent in the interferon alfa-2b and ribavirin group. Sustained virological response refers to a patient’s continued undetectable serum hepatitis C RNA levels 24 weeks after finishing a course of treatment.
The complete package inserts for Pegasys and Copegus are available at
www.pegasys.com, or by calling 1-877-PEGASYS.
10/29/04
Sources
Roche Pharmaceuticals. Roche and Pharmasset Join Forces to Develop New Generation of Hepatitis C Therapies Collaboration Exploring Compounds for Use in Combination with Roche’s Hep C Product Pegasys. Press Release. October 27, 2004.
R Baker. Telephone Interview with Abel De La Rosa, Vice President of Business and Strategy, Pharmasset Inc. October 28, 2004.
Only about half of all patients with HCV genotype 1 who use one of the peginterferons plus ribavirin experience a sustained virologic response and are “cured” of chronic hepatitis C. Although FDA-approval of the pegylated interferons has significantly improved clinical outcomes for people with chronic hepatitis C, there remains a pressing need for more effective and less toxic therapies. Unfortunately, no new anti-HCV therapies are expected to become available for several years, at the earliest.
It is in this somewhat bleak environment that Roche and Pharmasset announced on October 27 a partnership to develop an orally administered nucleoside polymerase inhibitor for use with peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus) in the treatment of chronic hepatitis C virus (HCV) infection. Specifically, the two companies have agreed to jointly develop and market PSI-6130, the lead nucleoside polymerase inhibitor compound of the new partnership.
According to the announcement from Roche, Pharmasset will receive an upfront fee, research and development support, and milestone payments that could total $168 million for PSI-6130. In addition, Pharmasset will receive royalties on product sales and retain certain co-promotion rights in the U.S.
PSI-6130
PSI-6130 is now in “advanced pre-clinical stage testing,” according to Abel De La Rosa, Senior Vice President of Business and Strategy at Pharmasset: “We are excited about this compound, which has direct antiviral activity against HCV,” De La Rosa told HIV and Hepatitis.com in a telephone interview. “Our hope is that PSI-6130 will demonstrate greater effectiveness against HCV, especially when used in combination with Pegasys and Copegus,” he said.
Assuming development of the drug moves forward smoothly and without interruption, using PSI-6130 or its prodrugs in combination with peginterferon and ribavirin could greatly benefit nonresponders to current therapies, according to De La Rosa.
When asked about the available data on 6130, De La Rosa said no data on the drug have yet been presented at any scientific meetings, “but we hope to see a release of data perhaps in time for the 2005 AASLD conference,” he added.
CEOs Viewpoints
“Roche has already established itself in hepatitis C with Pegasys, the most prescribed hepatitis C medication in the U.S. This collaboration with Pharmasset demonstrates our ongoing commitment to advancing therapy for hepatitis C patients with unmet needs,” said George Abercrombie, President and CEO, Hoffmann-La Roche Inc. “We hope that further research and development will show that PSI-6130 is an important new hepatitis C treatment option that complements Pegasys and Copegus.”
“Pharmasset’s expertise in nucleoside drug discovery and early stage clinical development, combined with Roche’s proven track record in bringing new and improved hepatitis C therapies to market is a formula for success,” said Schaefer Price, Pharmasset’s President and CEO. “The economics of this deal are significant. In addition, this partnership will support Pharmasset’s activities toward establishing a commercial infrastructure for our HIV and HCV clinical candidates.”
Pharmasset has two anti-HIV compounds now in Phase II testing, Reverset and Racivir, which are expected to be on the market as prescription drugs for HIV in late 2005. “The company is committed to continuing our strong focus on the development of drugs for the treatment of chronic hepatitis C and for HIV infection,” De La Rosa told HIV and Hepatitis.com.
Under the terms of the agreement, Roche will gain the worldwide rights, excluding Latin America and Korea, to Pharmasset’s PSI-6130 and its prodrugs.
Pharmasset will be responsible for preclinical work, investigational new drug (IND) filings, and phase I proof of concept studies, with Roche managing other preclinical studies and clinical development. Roche will also receive options to related nucleoside polymerase inhibitors, which, if exercised, could result in Pharmasset receiving in excess of $300 million in total milestones under the agreement.
Pharmasset will continue to develop and retain worldwide rights to ongoing and future hepatitis C programs unrelated to the PSI-6130 series of nucleoside polymerase inhibitors. In addition, the Roche Venture Fund has made a $4 million investment in Pharmasset and has received warrants to purchase an additional $6 million in shares within the next two years at a premium price.
About HCV
Hepatitis C is a blood-borne infectious disease of the liver and the leading cause of cirrhosis and liver cancer and the number one reason for liver transplants in the U.S. An estimated 2.7 million Americans are chronically infected with hepatitis C.
About Pegasys
Pegasys, the most
prescribed pegylated alfa interferon in the U.S., and Copegus were approved
by the FDA in December 2002 for use in combination for the treatment of
adults with chronic hepatitis C who have compensated liver disease and have
not previously been treated with interferon alfa. Patients in whom efficacy
was demonstrated included patients with compensated liver disease and
histological evidence of cirrhosis.
HIV and Hepatitis.com Articles on Pegasys and Copegus
About Pharmasset
Pharmasset, Inc., is an emerging pharmaceutical company committed to the discovery, development, and commercialization of novel antiviral drugs. The company leverages its expertise in nucleoside chemistry to develop therapeutics to combat infections caused by drug-resistant human immunodeficiency virus (HIV) and hepatitis viruses. Pharmasset has two drugs in Phase II clinical trials, Reverset and Racivir and several other antiviral compounds in advanced preclinical studies.
In September 2003, Pharmasset entered into a collaborative licensing agreement with Incyte Corporation for the development and commercialization of Reverset in certain territories. Pharmasset retains proprietary development and commercialization rights to the balance of its clinical and preclinical pipeline. Pharmasset’s expanding portfolio of antiviral therapeutics aims to improve the lives of individuals around the world.
About Roche
Hoffmann-La Roche Inc.
(Roche), based in Nutley, N.J., is the U.S. prescription drug unit of the
Roche Group, a leading research-based health care enterprise that ranks
among the world's leaders in pharmaceuticals and diagnostics.
For more information on the Roche pharmaceuticals business in the United States, visit the company's web site at: http://www.rocheusa.com
Facts About Pegasys (Peginterferon alfa-2a) in
Combination with Copegus Indication
Pegasys, a pegylated alfa interferon, alone or in combination
with Copegus
(ribavirin) is indicated for the treatment of adults with chronic hepatitis
C who have compensated liver disease and have not previously been treated
with interferon alfa. Patients in whom efficacy was demonstrated included
patients with compensated liver disease and histological evidence of
cirrhosis (Child-Pugh class A).
Dosing and Administration
Pegasys, a premixed solution, is dosed at 180mcg as a subcutaneous injection
once a week. Copegus, available as a 200mg tablet, is administered at 800 to
1200mg taken twice daily as a split dose. The two products are sold
separately.
Combination Therapy Clinical Studies
The two combination therapy pivotal study findings:
Study 5,
published in the March 2, 2004 Annals of Internal Medicine, including
1,284 patients receiving medication, showed that patients with certain
genotypes (strains) of the hepatitis C virus should be treated with
different dosing regimens of Pegasys and Copegus. The treatment regimens and
resulting sustained virological response rates for these groups treated with
Pegasys and Copegus therapy were:
Genotype 1: 48 week duration with 1000 – 1200mg Copegus: 51 percent
Genotype non-1: 24 week duration with 800mg Copegus: 82 percent
Study 4, published in the September 26, 2002 New England Journal of Medicine,
including 1,121 patients receiving medication, showed that Pegasys and Copegus combination therapy is a more effective treatment for chronic hepatitis C than interferon alfa-2b and ribavirin. The sustained virological response rate in the Pegasys and Copegus treated patients was 53 percent compared to 44 percent in the interferon alfa-2b and ribavirin group. Sustained virological response refers to a patient’s continued undetectable serum hepatitis C RNA levels 24 weeks after finishing a course of treatment.
The complete package inserts for Pegasys and Copegus are available at
www.pegasys.com, or by calling 1-877-PEGASYS.
10/29/04
Sources
Roche Pharmaceuticals. Roche and Pharmasset Join Forces to Develop New Generation of Hepatitis C Therapies Collaboration Exploring Compounds for Use in Combination with Roche’s Hep C Product Pegasys. Press Release. October 27, 2004.
R Baker. Telephone Interview with Abel De La Rosa, Vice President of Business and Strategy, Pharmasset Inc. October 28, 2004.
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by John C. Martin |
Article
Date: 10-01-04 |
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Now, doctors in Philadelphia claim a new combination of drugs might result in even fewer rejection episodes in liver transplant patients compared to current therapies.3
A Drug with a Positive History
The therapy they tested is a monoclonal antibody known as basiliximab
(bas-il-IX-ih-mab), an immunosuppressive drug already used in kidney
transplantation. The therapy works by fending off the body's white blood
cells that launch an advance against the newly transplanted organ.4
Basiliximab has traditionally been given by injection.
"… In general, a kidney transplant has a tendency to reject more aggressively than a liver transplant. Therefore, if this drug was proven to be successful in kidneys, I thought maybe we can achieve even better results in livers. And in fact, this was the case," explained Ignazio Marino, MD, head of the Division of Liver Transplantation and Hepato-biliary Surgery at Thomas Jefferson University Hospital in Philadelphia, and the study's chief investigator.
To test the hypothesis that basiliximab might also be beneficial for men and women undergoing liver transplant procedures, Marino and his fellow surgeons studied the results of 50 liver transplant operations they had performed from 2000 to 2002, using basiliximab as part of an anti-rejection treatment protocol that also included the traditional medication, tacrolimus (tuh-CRAW-lih-mus) and low doses of steroids. Their study was the first to use this regimen in liver transplantation. In the end, the study team noted a much lower incidence of liver rejection.
"We were able to prove that with the combination of this drug with the standard immunosuppression regimen using tacrolimus, rejections dropped from the historical rate of 40% to 12%, which is really a striking difference," said Marino, who is also a professor of Surgery at Thomas Jefferson University.
The results also suggest that this immunosuppression protocol may help improve a patient's odds of survival. Eighty-eight percent of the patients on which the study team focused were alive three years after transplantation, Marino and his colleagues noted. That compares to survival odds for the general liver transplant population of 78% after three years.5
The trial, he says, marks the first time that the basiliximab protocol has been tested for its efficacy and safety in liver transplant procedures. Marino notes that in the past 15 months of using this combination of drugs for liver transplants at his hospital, the chances of survival after 1 year has been 100%. Another advantage is that high doses of tacrolimus can be toxic to the nervous system and kidneys, and supplementing that with doses of basilixmab can reduce that risk." We think we have much less toxicity in the short term because we use less tacrolimus," he explains. Fewer steroids are also used in this regimen, which decreases the risk of toxicity even further. As a result, Marino says he and his colleagues expect fewer steroid-related complications, which can include high blood pressure, osteoporosis, and diabetes.
How Immunosuppression Works
Tacrolimus is a drug that suppresses the immune system by inhibiting an
enzyme that's necessary for the production of T-cells, which make up part
of the immune system. In the last decade, Marino says, researchers at the
University of Pittsburgh developed a tacrolimus-based protocol that was
considered an advance in the use of post-liver transplant
immunosuppression.6 Its use greatly decreased the reliance on
steroids, which can produce unwanted side effects. But tacrolimus produces
its own side effects, such as an increased risk of infection in some
cases, and
anemia, among others, as well as its
potential toxicity. Basiliximab inhibits the function of interleukin-2 in
the body—a chemical messenger that calls certain immune system cells into
action against a foreign invader.
"With the standard dose of 20 milligrams of basiliximab given at the time of surgery, and another 20 milligrams four days afterwards, you can decrease the dose of tacrolimus, and actually, you can even postpone the time that you start tacrolimus," Marino explained.
The approach is "revolutionary", he maintained, because rather than treating patients with aggressive immunosuppression immediately following liver transplant, this approach is much less aggressive, but still effective.
Targeting Hepatitis C
Another significant side effect of liver transplantation can be
potentially avoided through the use of basiliximab:
hepatitis C recurrence. "We suspect that
the recurrence of HCV is lower, though we don't have enough data to
confirm this," Marino explains. Typically, patients who undergo liver
transplantation for hepatitis experience high rates of recurrence
postoperatively.7 Perhaps basiliximab possesses some unique
mechanism that blocks HCV replication, or the ability of the virus to make
copies of itself, Marino says. That and other drugs that target
interleukin-2 have hinted that they may be able to reduce the risk of
recurrence.
"If this observation can be confirmed, it's important news because 60 percent of the patients we transplant are diagnosed with HCV," said Marino. "This would mean an immunosuppression that can delay the recurrence of HCV on top of having fewer episodes of rejection and toxicity than before."
While Marino would be interested in examining the mechanisms that underlie basiliximab's ability to keep HCV recurrence at bay, there is another clinical trial he has in mind first; one that would test the use of basiliximab alone, then adding tacrolimus after the transplant, without the use of steroids. "We are going to start this study soon with this aim," he said.
1. United Network for Organ Sharing (UNOS).
2. Scientific Registry of Transplant Recipients. University Renal Research
and Education Association. University of Michigan. Trends in incidence of
rejection at 1 year in liver transplant recipients.
3. Marino I, Doria C, Scott V et al. Efficacy and safety of basiliximab
with a tacrolimus-based regimen in liver transplant recipients.
Transplantation 2004 Sep 27;78(6):886-91.886-91.
4. Pascual J, Marcen R, Ortuno J. Anti-interleukin-2 receptor antibodies:
basiliximab and daclizumab. Neprhol Dial Transplant 2001
Sep;16(9):1756-60.
5. Transplant Liver Registry. United Network for Organ Sharing (UNOS).
6. Abu-Elmagd K, Fung J, Todo S et al. The current status of hepatic
transplantation at the University of Pittsburgh. Clin Transpl
1995;145-70.
7. Davis GL. Chronic hepatitis C and liver transplantation. Rev
Gastroenterol Disord 2004 Winter;4(1):7-17.
John Martin is a long-time health journalist and an
editor for Priority Healthcare. His credits include coverage of health
news for the website of Fox Television's The Health Network, and articles
for the New York Post and other consumer and trade publications.
http://www.hepatitisneighborhood.com/content/in_the_news/archive_2083.aspx
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Long-Term Outcomes in HCV with SVR:
cure, regression of fibrosis |
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Long term clinical outcome of chronic hepatitis C
patients with sustained virological response to interferon monotherapy:
study finds - 29% of SVRs show regression of fibrosis; HCV is curable &
long-term outcome of sustained viral responders is good; Five year
survival of European sustained virological responders was similar to the
general population, matched for age & sex and no HCCs were detected
during long term follow up. Gut October 2004;53:1504-1508 B J Veldt1, G Saracco2, N Boyer3, C Cammà4, A Bellobuono5, U Hopf6, I Castillo7, O Weiland8, F Nevens9, B E Hansen10 and S W Schalm1 1 Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, the Netherlands 2 Department of Gastroenterology, Ospedale Molinette, Torino, Italy 3 Hôpital Beaujon, Clichy, France 4 Cattedra e Unità Operativa di Gastroenterologia, University of Palermo, and IBIM, Consiglio Nazionale delle Richerche, Palermo, Italy 5 Ospedale Generale di zona "San Giuseppe", Milan, Italy 6 Charité, Campus Virchow-Klinikum Universitätsmedizin, Berlin, Germany 7 Fundacion Estudio Hepatitis Virales, Madrid, Spain 8 Karolinska Institute, Huddinge Hospital, Huddinge, Sweden 9 University Hospital Leuven, Belgium 10 Department of Gastroenterology and Hepatology, and Department of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, the Netherlands SVR Shows Regression of Fibrosis: "...One hundred and twenty five patients (110 sustained virological responders and 15 biochemical responders) underwent liver biopsy both before and after treatment. Mean time between these two biopsies was 1.6 years. Thirty two sustained virological responders (29%) and none of the biochemical responders showed regression of fibrosis. Progression of fibrosis was seen in six sustained virological responders (5%) and in three biochemical responders (20%)..." "Cure" "...In this study, sustained virological response was associated with a decrease in fibrosis score. Similar findings have been reported for sustained responders to pegylated interferon. Previous studies have shown that regression of fibrosis can also occur in biochemical responders and non-responders to interferon. In common with our study, sustained virological responders show the highest rate of regression. Because of the large proportion of sustained virological responders that showed regression of fibrosis and the low incidence of clinical events in these patients, in our view, non-cirrhotic patients with a sustained virological response can be regarded as cured..." "...A limitation of our study is that all patients had been treated with interferon monotherapy whereas the current standard therapy for chronic hepatitis C is pegylated interferon with ribavirin. This current standard however dates from 2002 and long term follow up data of peginterferon and ribavirin were not available at the time of this study. In general, combination therapy leads to higher sustained virological response rates and also the late relapse rate seems to decrease...As the late relapse rate seems to decrease with newer treatment regimens (Peginterferon), long term clinical outcomes may be similar or even better than results obtained with interferon monotherapy. Therefore, in our opinion, the favourable clinical outcome of sustained virological responders is likely to hold true in the era of pegylated interferon and ribavirin..." ABSTRACT/SUMMARY The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world. The aim of this study is to assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy. The study methodology was a meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C. Results: A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0--7.4) among sustained virological responders; all late relapses occurred within four years after treatment. Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0--2.3) and none developed hepatocellular carcinoma (HCC). Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3--2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5--17.7) and 7.1% (95% CI 0--15.0), respectively. The authors concluded that five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up. INTRODUCTION Chronic infection with the hepatitis C virus (HCV) can lead to decompensated liver cirrhosis and hepatocellular carcinoma (HCC). However, treatment of hepatitis C is based on surrogate end points, and evaluation of treatment for clinical end points has only slowly been forthcoming due to the slow course of the disease and the small number of clinical events in patients treated for hepatitis C. Protocolled studies use sustained virological response as the key outcome measure for hepatitis C treatment. This sustained virological response is defined as no detectable HCV-RNA in serum at six months after treatment. The aim of this study was to determine the long term clinical outcome of sustained virological responders who had been treated in protocolled studies. RESULTS Study population Data were obtained for 343 patients treated for chronic hepatitis C. A total of 286 patients had a sustained virological response and 50 had a biochemical response. Seven patients did not fit the entry criterion of HCV-RNA data availability at the end of treatment and after six months of follow up and were excluded from further analysis. Characteristics of sustained virological responders and biochemical responders are shown in table 1. Patients had been treated with recombinant interferon a2a, a2b, or natural interferon monotherapy. Patients were treated for an average duration of 39 weeks (range 11--96). Patients with genotype 1 were treated longer (mean duration 41 weeks v. 38 weeks in other genotypes; p<0.01) and received a higher total dose of interferon (581 mega units (MU) v 525 MU in other genotypes; p<0.01, Mann-Whitney U test). Table 1.
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Biochemical responders Fifty patients had normal transaminase levels at the end of follow up and six months after treatment while HCV-RNA was still detectable. Of these biochemical responders, three patients died during long term follow up, all of liver related causes. The occurrence of decompensation and HCC among biochemical responders was 9.1% (95% CI 0.5--17.7) and 7.1% (95% CI 0--15.0), respectively. Biochemical responders were older and had a higher prevalence of cirrhosis. Although there was a trend to a higher standard mortality ratio (corrected for age and sex) in biochemical responders after five years of follow up, the difference did not reach statistical significance. Liver histology One hundred and twenty five patients (110 sustained virological responders and 15 biochemical responders) underwent liver biopsy both before and after treatment. Mean time between these two biopsies was 1.6 years (SD 0.8). Thirty two sustained virological responders (29%) and none of the biochemical responders showed regression of fibrosis. Progression of fibrosis was seen in six sustained virological responders (5%) and in three biochemical responders (20%). Baseline characteristics of sustained virological responders and biochemical responders who underwent two biopsies were different, with sustained virological responders being younger (mean 39 (SD 13) v 47 (14) years), having a lower mean pretreatment fibrosis stage (1.75 (1.1) v 2.5 (1.4)), and having a shorter time between the two biopsies (1.5 (0.6) v 2.3 (1.5) years). Therefore, we performed a multiple regression analysis to determine independent risk factors for progression of fibrosis. Fibrosis progression was associated with older age, lower pretreatment fibrosis score, and biochemical response rather than sustained virological response. Late relapsers Twelve sustained responders had a late virological relapse. In six patients (50%), late virological relapse was accompanied by an elevation in transaminase levels. Multivariate Cox regression analysis did not show any pretreatment factors to be associated with an increased risk for late virological relapse. None of the late relapsers developed decompensation or HCC during follow up. No late virological relapses were seen after four years of follow up, the maximal delay between the last negative polymerase chain reaction (PCR) and the first positive PCR result being 12 months. |
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AUTHOR DISCUSSION This large European study allows, for the first time, an approximation of the incidence of clinical events during long term follow up of sustained virological responders in Europe. The most important finding is that clinical events are rare in this population, indicating that sustained virological responders have an excellent prognosis. The largest European study to date describing clinical outcome in sustained responders to interferon treatment did not report any events among 74 patients followed up for 2.7 years. Two other European studies, involving seven and 56 sustained responders, also showed no clinical events during 4.6 and 5.2 years of follow up, respectively. Bruno et al described 32 sustained responders of whom one cirrhotic patient developed HCC.17 Although another HCC has been reported recently in a Western sustained responder, these cases seem to be rare and limited to patients with cirrhosis. In the present study, no HCCs occurred during long term follow up. According to several large studies, the yearly incidence of HCC among Japanese sustained virological responders still varies between 0.02% and 0.5% per year; the difference in the incidence of HCC between East and West apparently persists in conditions without detectable viral replication. The lowest rates in Japan were reported by Yoshida et al, with one HCC among 817 sustained responders during 5.4 years of follow up.26 The highest incidence of HCC reported among sustained responders in Japan was by Kasahara et al who reported five HCCs among 313 sustained virological responders followed up for three years. Fifteen cirrhotic patients were included in this study. Only two patients with decompensated cirrhosis were reported. Among untreated cirrhotics, occurrence of clinical events of 38% (28% decompensation and 10% HCC) would be expected, according to Fattovich and colleagues. These results suggest, but do not prove, a change in the natural course of chronic hepatitis C. Further studies, including more cirrhotics, will be necessary to investigate the effect of treatment on the natural course of chronic hepatitis C. In this study, sustained virological response was associated with a decrease in fibrosis score. Similar findings have been reported for sustained responders to pegylated interferon. Previous studies have shown that regression of fibrosis can also occur in biochemical responders and non-responders to interferon. In common with our study, sustained virological responders show the highest rate of regression. Because of the large proportion of sustained virological responders that showed regression of fibrosis and the low incidence of clinical events in these patients, in our view, non-cirrhotic patients with a sustained virological response can be regarded as cured. A limitation of our study is that all patients had been treated with interferon monotherapy whereas the current standard therapy for chronic hepatitis C is pegylated interferon with ribavirin. This current standard however dates from 2002 and long term follow up data of peginterferon and ribavirin were not available at the time of this study. In general, combination therapy leads to higher sustained virological response rates32,33 and also the late relapse rate seems to decrease. In this study with data on interferon monotherapy, the late relapse rate was 4.7% (95% CI 2.0--7.4); Camma et al reported 8.7% in a meta-analysis of 14 trials with interferon monotherapy. After four years of follow up of treatment with interferon and ribavirin, late virological relapse rates of 3% (95% CI 1.4--4.6) and 1% (95% CI 0--2.0) have been reported for patients treated for 24 weeks and 48 weeks, respectively. After treatment with pegylated interferon with or without ribavirin, a late relapse rate of 0.8% was reported after four years of follow up. The possibility of reinfection could not be ruled out in our cohort as data on risk behaviour and concordance of genotypes were not available. However, introduction of more sensitive PCR methods may also have contributed to a decrease in late virological relapse over time. It is possible that with an insensitive assay, patients with low viraemia are regarded as sustained virological responders. As the late relapse rate seems to decrease with newer treatment regimens, long term clinical outcomes may be similar or even better than results obtained with interferon monotherapy. Therefore, in our opinion, the favourable clinical outcome of sustained virological responders is likely to hold true in the era of pegylated interferon and ribavirin. In conclusion, the long term clinical outcome of patients with a sustained response to interferon is favourable. Five year survival of European sustained virological responders was similar to the general population, matched for age and sex, and no HCCs were detected during long term follow up. STUDY METHODS Study design All European centres that had published long term data on patients treated for chronic hepatitis C before 1997 were invited to participate in the protocol and to include patients with response to treatment. Additional entry criteria were study follow up longer than one year and availability of HCV-RNA data. Nine centres met these criteria. Patients from eight European hepatology units were included in the study. Patient selection Data from 343 consecutive chronic hepatitis C patients with response to interferon monotherapy were obtained. All patients had participated in protocolled studies (clear cohort or randomised controlled trial). Data were collected on separate case record forms, one per patient, by the local investigator. The case record forms were sent to the coordination centre in Rotterdam where data were entered into a central database. Before the data were entered, they were checked and, in case of doubt, contact was made with the local investigator. Data recorded Information was obtained on demographics (date of birth, sex) and on details of treatment (initial dose, duration of treatment, and total dose of interferon). Virological data (genotype, viraemia) and biochemical data (platelet count, bilirubin, albumin, and transaminase levels) were measured in certified laboratories of participating hospitals and added to the case record form by the local investigator. Centrally, results were corrected for local normal values. Results of pre- and post-treatment liver biopsies were recorded using the HAI score for activity and the Knodell score for fibrosis. All centres used polymerase chain reaction (PCR) methods with a detection limit of 100 copies/ml, except for one centre where PCR with a detection limit of 1000 copies/ml was used before 1998. No late virological relapses were reported from this centre after introduction of a test with a sensitivity of 100 copies/ml. Follow up data were recorded every six months and included alanine aminotransferase (ALT) levels, HCV-RNA, and the occurrence of clinical events (decompensation, HCC, death). Patients were considered to have decompensation if they showed any of the following symptoms: ascites, bleeding varices, jaundice, or hepatic encephalopathy. Patients were classified as having developed cirrhosis on the basis of ultrasound (nodular contour, diminished hepatopetal flow, collaterals), serology (platelets <80000, albumin <35 g/l, clotting factors<50%), or liver biopsy. Patients were considered to have HCC if the {alpha} fetoprotein level was >400 and ultrasound confirmed a focal lesion, or if biopsy proved so. Death was classified as liver related or liver unrelated. Sustained virological response was defined as no detectable HCV-RNA at the end of treatment and after six months of follow up. Patients with normal ALT levels at these time points, but with detectable HCV-RNA at the end of treatment or six months thereafter, were referred to as biochemical responders. Sustained virological responders were considered to have a late virological relapse if HCV-RNA was detectable on any occasion after six months of follow up, confirmed by either a second PCR or elevation of ALT levels above the upper limit of normal. Statistical analysis To evaluate factors of influence on late virological relapse, univariate and multivariate Cox regression analyses were performed. The Kaplan-Meier method was used to evaluate the five year late relapse rate and to determine the rate of occurrence of clinical events during five years of follow up. The number of expected deaths and the expected survival probability were calculated based on sex and age ranked mortality among the Dutch general population, which is similar to most European countries. The standard mortality ratio was calculated by dividing the observed number of deaths by the expected number of deaths. We used multiple regression analysis to identify risk factors for fibrosis progression. Statistical analyses were performed using SPSS for Windows (SPSS Inc, Chicago, Illinois, USA). All analyses were performed by the Meta-Analysis of Individual Data group in Rotterdam (BEH, SWS, BJV), which is experienced in the conduct of such studies. |
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Article
Date: 09-29-04 |
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Now, a new study suggests that the combination of hepatitis, alcohol consumption and diabetes plays a significant role in liver cancer risk.2 Doctors at the University of Southern California in Los Angeles write that while it's well known that heavy alcohol consumption, viral hepatitis and diabetes pose individual risk factors for hepatocellular carcinoma, information about the risk of liver cancer related to the combination of any of these factors "is sparse".
Rising Numbers
"The incidence of
hepatocellular carcinoma in the U.S. has
reportedly doubled during the past two decades, but to our knowledge, the
reasons for such an increase are unknown," wrote Jian-Min Yuan, MD, PhD,
an assistant professor in the department of Internal Medicine at USC, and
colleagues.
In hopes of finding some answers, Yuan and associates conducted a population-based, case-control study of liver cancer risk in relation to lifestyle factors in a group of people diagnosed with liver cancer between 1984 and 2002. The researchers recruited nearly 300 people with liver cancer, and matched them—based on race, age and gender—to 435 people without cancer, all of whom lived in the Los Angeles area.
Information on each person's lifestyle was then gathered through face-to-face interviews, and each patient was also tested for hepatitis B and C infection. The researchers found that 86 of those men and women with liver cancer also tested positive for hepatitis B, but no one in the control, or comparison, group had HBV infection. Nearly 100 patients tested positive for HCV.
Measuring the Risk
Infection with either hepatitis B or C increased the risk of liver cancer
for the people with either of those viruses in this study, which was not a
surprising finding, though infection with HCV tended to boost the risk
more often, Yuan and the study investigators reported.
When analyzing the risk of hepatocellular carcinoma in relation to other factors, such as alcohol consumption and cigarette smoking, the researchers learned there was a two-to-threefold increased risk, even in people without hepatitis B or C. Compared to non-smokers and those who no longer smoked, current smokers faced a 60% increased risk of developing liver cancer, the research team found.
While moderate drinking actually lowered the risk by about 40%, drinking heavy amounts of alcohol significantly boosted the chances of developing liver cancer; as much as 17-fold. The risk increased, as well, for those with longer histories of alcohol consumption. While the increased risk was not as strong when taking wine consumption into account compared with consuming beer and spirits, the study researchers still suggest avoiding it. "Wine contains a relatively high concentration of polyphenols, antioxidants that fight against reactive oxygen species that are related to aging and aging-related diseases, including cancer and cardiovascular disease," explained Yuan, in an interview with Priority Healthcare. "However, for a person who already possesses one or more risk factors for hepatocellular carcinoma, consumption of alcohol, even wine, may [have a] more harmful than beneficial effect on the liver."
Antioxidants can still be derived from fresh fruits and vegetables, he said.
Diabetes' Impact on Liver Cancer
Meanwhile, those with a history of
diabetes faced more than 2-and-a-half
times the risk of developing liver cancer, as well, compared to those
patients without diabetes. The investigators found that 21 percent of the
patients with diabetes had liver cancer, compared to only 9 percent of
those without diabetes.
But the risk greatly increased when the researchers combined two of these factors together. For instance, there is a approximately a 48-fold increased risk of liver cancer in those who have hepatitis and diabetes or in those with hepatitis and who consume significant amounts of alcohol (greater than 4 drinks per day), Yuan and his team reported. Even in those who drank less than 4 drinks per day and had hepatitis face nearly 9 times the risk, the researchers found.
"Heavy alcohol consumption, diabetes, and viral hepatitis were found to exert independent and synergistic effects on risk of hepatocellular carcinoma in U.S. blacks and whites," the study team concluded.
"It is conceivable that heavy alcohol consumption, HCV infection and the current epidemic of obesity/diabetes have contributed to the increasing incidence of hepatocellular carcinoma in the U.S.," they wrote.
How these factors in combination increase the risk of liver cancer isn't known, Yuan said, in an interview with Priority Healthcare. "Based on our study results, these three risk factors affect the risk of hepatocellular carcinoma in an additive manner," he explained, "which suggests that they may exert their roles in hepatocarcinogenesis [liver cancer development] via different pathways." No matter what the cause, these are behaviors that, without a doubt, place a tremendous burden on the liver, he said.
Making the Connection
The researchers point to other studies that have found that 40 to 100% of
people diagnosed with
non-alcoholic steatohepatitis (NASH) are
obese, and that up to three-quarters of them have a history of type II
diabetes. It's also been shown that a large percentage of patients with
idiopathic
cirrhosis are obese and may or may not
have diabetes. The severity of fibrosis has also been shown in patients
with NASH, and is linked to
obesity and diabetes. Based on that
information, it's possible that obesity/diabetes are risk factors for
fibrosis and cirrhosis progression, which is recognized as a primary risk
factor for liver cancer, Yuan and the other researchers pointed out, in
making the connection between diabetes and hepatocellular carcinoma. The
reasons why people with diabetes are more prone to liver cancer are still
unknown, they add.
Take-Home Message: Be Cognizant
Yuan says based on the apparent evidence in this study, physicians should
pay close attention to patients with these risk factors, and screen them
more closely for the development of liver cancer.
There is one positive aspect to this study. "If a patient infected with hepatitis C (or B) virus avoids alcohol and reduces body weight through exercise, he or she will gain positive impacts against the risk of hepatocellular carcinoma," Yuan said.
1. National Cancer Institute. National Institutes of
Health (NIH).
2. Yuan JM, Govindarajan S, Arakawa K, Yu MC. Synergism of alcohol,
diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in
blacks and whites in the U.S. Cancer 2004 Sep 1;101(5):1009-17.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications
http://www.hepatitisneighborhood.com/content/in_the_news/archive_2081.aspx
Mumbai, Sep 30 (UNI) With the objective of drawing people's attention towards a virus that has infected approximately three per cent of the world population, October 1 will be observed as the World Hepatitis C Awareness Day.
Hepatitis C is a blood-borne viral infection of the liver that was first identified only in 1989. It is the most infectious virus having 50 per cent chronicity and is responsible for cirrhosis in large number of patients.
In India alone, it is estimated that 10.9 million people have chronic Hepatitis C. National trends indicate a sizeable concentration of Hepatitis C cases in north-eastern India.
Among the metros, four lakh Delhiites are suffering from Hepatitis C and Mumbai accounts for three lakh cases. Gujarat also carries a patient load of 3.37 lakh.
According to officials, the day aims at educating people on a virus that has emerged as a major global healthcare problem.
Every year the number of people infected with Hepatitis C virus (HCV) increases by three to four million worldwide, adding to the 170 million people already infected. The spurt in number is primarily attributed to low awareness about the disease.
''Hepatitis C treatment is one of the challenges that we need to take on seriously. Number of cases in India requiring treatment is increasing at a very rapid pace. Creating awareness about HCV is the first important step towards controlling the spread of this disease.
Treatment for the virus has come a long way in just 15 years,'' Roche Scientific Company India Pvt Ltd Managing Director Dr G L Telang said.
He said when the virus was first identified and doctors started treating it, they could only help control or get rid of the virus in about 10 to 20 per cent of cases. Today, new therapies have been shown to successfully treat between 50 to 80 per cent of people.
''Currently Roche offers strong hope to Hepatitis C patients through Pegylated Interferon Alpha 2A (40KD). Roche is involved in significant research on HCV. However we believe that first and foremost it is essential to raise awareness and detection to combat the spread of the disease,'' he said.
Going by sheer numbers, Hepatitis C has outpaced HIV/AIDS menace in India. Compared to people suffering from Hepatitis C, there are 3.8 million Indians suffering from HIV/AIDS. But a lesser known fact is that approximately 30 per cent of HIV patients simultaneously suffer from Hepatitis C, officials said.
http://www.deepikaglobal.com/latestnews.asp?ncode=20683
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Fatty Liver Accelerates
Fibrosis: diabetes, mitochondrial dyfunction, obesity associated
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"Natural history of nonalcoholic steatohepatitis: A
longitudinal study of repeat liver biopsies" Hepatology Volume 40, Issue 4, October 2004 Eduardo Fassio 1 *, Estela Álvarez 2, Nora Domínguez 1, Graciela Landeira 1, Cristina Longo 1 1Hepatology Unit, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina 2Pathology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina "...Our study shows that 31.8% of 22 patients with NASH had a progression of liver fibrosis over a median follow-up of 4.3 years. These findings confirmed the progressive potential of NASH. However, most of the patients (68.2%) had no fibrosis progression... ... A two-hit hypothesis has been proposed to explain the mechanisms of liver damage in NASH... The first hit has been associated with insulin resistance... in only a proportion of patients with insulin resistance and NASH will an advanced liver disease develop, and other factors, or hits (like oxidative stress, mitochondrial dysfunction, and abnormal cytokine production), should be present to produce severe cellular injury or fibrosis... ... Among 12 variables studied at baseline, we found that the prevalence of obesity and BMI were the only variables [associated with fibrosis]... Presence of diabetes has been shown to be an independent predictor of severe fibrosis in a retrospective study that analyzed a large number of patients. Among our patients, four of seven (57%) from group P and 4 of 15 (27%) from group NP had diabetes... ... Some very recent, noncontrolled studies have shown that insulin-sensitizing agents (rosiglitazone and pioglitazone) can lead to improvement in histological features in NASH patients after 48 weeks of treatment. If these results were confirmed in larger, controlled studies, this kind of therapy would be accepted as being able to modify the natural evolution of NASH and would be recommended promptly for clinical practice..." ABSTRACT/SUMMARY Nonalcoholic steatohepatitis may cause severe fibrosis, cirrhosis, and hepatocellular carcinoma, but supporting evidence is based on indirect data. Few publications have examined the results of repeat liver biopsies to evaluate progression of fibrosis. The aims of this study were to assess rate of fibrosis progression in untreated patients with nonalcoholic steatohepatitis and to identify associated variables. Among 106 patients, a second liver biopsy was proposed to those who had undergone their first liver biopsy at least 3 years before. None of them had been given pharmacological therapy. Liver biopsy samples were evaluated blindly. Variables were compared between patients with (group P) and without (group NP) fibrosis progression, using a Wilcoxon rank-sum test for numerical variables and a difference of two binomial proportions for categorical ones. Twenty-two patients (median age, 45 years; age range, 20-69 years; 13 women; diabetes in 8 patients, obesity in 10 patients) underwent a second liver biopsy 4.3 years (range, 3.0-14.3 years) after the first. Fibrosis progression was found in 7 patients in group P (31.8%), no progression was found in 15 patients in group NP. There were no differences between both groups regarding age, gender, diabetes, hyperlipidemia, ALT levels, AST-to-ALT ratio levels, albumin levels, prothrombin activity, steatosis, or inflammation. Obesity was significantly more prevalent in group P (86%) than in group NP (27%; P = .01). Basal body mass index was higher in group P (median, 33.2; range, 29.1-38.2) than in group NP (median, 29.0; range, 24.0-38.1; P = .024). Time between biopsies was not different between groups. In conclusion, progression of liver fibrosis was found in a third of nonalcoholic steatohepatitis patients 4.3 years after the first liver biopsy, and obesity and body mass index were the only associated factors with such progression. Article Text Nonalcoholic fatty liver disease is probably the main cause of chronic liver disease in the West. The histological spectrum of nonalcoholic fatty liver disease includes simple steatosis (type 1), steatosis plus lobular inflammation (type 2), steatosis plus ballooning degeneration (type 3), and steatosis plus ballooning degeneration plus Mallory bodies or fibrosis (type 4). This classification is clinically important. Whereas simple steatosis seems to be a benign and nonprogressive condition, nonalcoholic steatohepatitis (NASH) that includes the types 3 and 4 of nonalcoholic fatty liver disease is recognized as a potentially progressive disease that may cause cirrhosis and liver-related death. However, our knowledge of the natural history of NASH is still very limited and is largely based on indirect evidence. Cross-sectional series have shown that 30% to 40% of patients have advanced liver fibrosis at the time of presentation, whereas 10% to 15% of them may have established cirrhosis. Three studies have found that patients with cryptogenic cirrhosis have a greater rate of diabetes, obesity, or both than those with cirrhosis resulting from other causes, suggesting that cryptogenic cirrhosis may represent burned out NASH. In patients who underwent liver transplantation for cryptogenic cirrhosis, steatosis, and NASH have been shown in the graft during follow-up. Finally, the appearance of hepatocellular carcinoma has been reported in NASH patients, and in two large series of patients with hepatocellular carcinoma evaluated retrospectively, it has been found that cryptogenic cirrhosis (with the clinical phenotype of NASH) was the underlying liver disease in 7% to 13% of the cohort. Therefore, indirect data suggest that NASH may cause the entire spectrum of complications of chronic liver disease: progressive fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, longitudinal studies showing what percentage of patients with NASH will have a progressive course are lacking. To our knowledge, the published results of repeat liver biopsies come from only 56 patients without cirrhosis but with NASH (included in six different studies). The second biopsies were performed 1.2 to 15.7 years after the first and showed fibrosis progression in 39.3% of patients. The first four studies were clinical series examining NASH in which only a minority of patients underwent a repeat biopsy, whereas the last two studies were specially designed to evaluate histological changes. Furthermore, none of the previous studies addressed whether basal variables could differentiate patients with and without progression. These previous results are very interesting, but the number of patients studied is still very limited, and further prospective studies should be conducted to expand the knowledge of the natural history of NASH. Thus, the aims of this prospective, longitudinal study were to assess the progression rate of liver fibrosis in nontreated NASH patients and to identify clinical, biochemical, and histological variables associated with fibrosis progression. AUTHOR DISCUSSION Our study shows that 31.8% of 22 patients with NASH had a progression of liver fibrosis over a median follow-up of 4.3 years. These findings confirmed the progressive potential of NASH. However, most of the patients (68.2%) had no fibrosis progression. The different evolution can not be explained by a smaller time span between biopsies in the NP group. These patients underwent their second liver biopsy at a median time of 4.3 years after the first (range, 3.2-7.9 years), not significantly different from those in the P group. It is important to emphasize that both the pathogenesis and the natural history of nonalcoholic fatty liver disease and NASH are still incompletely understood, but they may be closely related. It has been postulated that most of the patients with nonalcoholic fatty liver disease have a fatty liver alone, a smaller proportion has steatohepatitis, and a percentage has advanced fibrosis. A two-hit hypothesis has been proposed to explain the mechanisms of liver damage in NASH. The first hit has been associated with insulin resistance, which has been demonstrated in almost all NASH patients studied and would cause the accumulation of excess fat in the hepatocytes. However, in only a proportion of patients with insulin resistance and NASH will an advanced liver disease develop, and other factors, or hits (like oxidative stress, mitochondrial dysfunction, and abnormal cytokine production), should be present to produce severe cellular injury or fibrosis. Considering that only approximately one third of NASH patients will have increasing liver fibrosis in the midterm, it would be useful to know the factors associated with that evolution, and our study sought to identify clinical, biochemical, and histological variables able to predict progression. Among 12 variables studied at baseline, we found that the prevalence of obesity and BMI were the only variables that were significantly different between the groups (with 86% and 27% of patients being obese in the groups P and NP, respectively). Interestingly, the changes in BMI during the follow-up were not different between the groups. In fact, the gradients (final vs. basal values) of BMI were very close to 0 in both groups. Thus, among NASH patients, those with obesity would be very prone to fibrosis progression. Furthermore, in this subgroup of patients, the dietary recommendations seem to be insufficient to prevent progression, and they should be included in trials of experimental pharmacological therapy (or immediately treated when a drug is accepted as being efficacious). Presence of diabetes has been shown to be an independent predictor of severe fibrosis in a retrospective study that analyzed a large number of patients. Among our patients, four of seven (57%) from group P and 4 of 15 (27%) from group NP had diabetes. The P value (.2267) was far from being significant, but we can not exclude a type II error because of the small sample size of patients having both NASH and diabetes. All the patients were referred to the Nutrition Department and encouraged to follow a low-calorie and low-fat diet. However, it is known that it is difficult for these patients to adhere to dietary therapy in the long term. During the follow-up, 27% of patients (6 of 22) achieved a 5% or more reduction in their body weight, and that percentage was not different between groups P and NP. Thus, we believe that it is unlikely that the dietary treatment could have played an important role in modifying the evolution of our patients' courses, but we can not exclude a mild beneficial effect. Among the four patients showing a decrease in the final fibrosis score, only one had had that kind of weight reduction. Comparing our results with those of 59 patients without cirrhosis but with NASH and repeat liver biopsies previously published in the literature, we found in our study a lower rate of fibrosis progression (32%) during a longer follow-up (median, 4.3 years; mean, 5.3 years) than those observed in the first four studies that were clinical series and included 30 patients. It is difficult to determine the reasons for that difference, because the demographical or analytical data are not fully available in the papers. However, among 24 patients whose clinical data are known, 22 (91.7%) were obese (the only predictor of progression, according to our results), and this could be the main explanation for a faster progression. The last two studies, like ours, were designed to analyze changes in histological findings, and Harrison et al. reported results impressively similar: 7 of their 22 patients showed fibrosis progression in a mean time of 5.7 years between biopsies. The clinical data of their patients also were similar to ours, but the obesity prevalence was slightly higher (77%). Other findings of our study worth noting are as follows. First, the inflammatory activity in the basal liver biopsy was not different between patients with or without fibrosis progression, in contrast to what was expected. However, it should be noted that the grade of inflammation was mild in most of the patients (19 of 22). Second, changes in grade of steatosis run an independent course from those in fibrosis, being found in the final liver biopsy a decrease in steatosis and an increase in fibrosis, either in the entire population or in group P patients. This observation is consistent with the suggestion that NASH patients may lose the fatty infiltration when they reach the stage of cirrhosis, which becomes a cryptogenic cirrhosis. Third, the evolution of ALT values was not different between both groups and, especially in group P, a normalization of ALT values was observed in six of seven patients. It is important to emphasize that a normalization of ALT levels does not guarantee fibrosis stabilization or improvement, because many pilot studies evaluating pharmacological treatments in NASH have claimed different drugs to be efficacious based only on the decreasing ALT values. The rate of progression of liver fibrosis has not been studied previously in NASH. Considering the entire population, the rate of liver fibrosis progression was estimated in 0.059 units of fibrosis per year. In a recent study, in patients with chronic hepatitis C, Ghany et al. found progression of liver fibrosis in 39% over a mean interval of 44 months (range, 2-211 mo) between both biopsies. The rate of liver fibrosis progression was estimated in 0.12 fibrosis units per year. Thus, our figure of fibrosis progression in NASH patients is approximately half of that found in hepatitis C patients. However, in patients from group P, the rate of progression was estimated to be 0.280 units of fibrosis per year. Some very recent, noncontrolled studies have shown that insulin-sensitizing agents (rosiglitazone and pioglitazone) can lead to improvement in histological features in NASH patients after 48 weeks of treatment. If these results were confirmed in larger, controlled studies, this kind of therapy would be accepted as being able to modify the natural evolution of NASH and would be recommended promptly for clinical practice. In that eventuality, studies like ours, aimed at understanding natural history, no longer would be carried out because they would be considered unethical, and the knowledge of the natural history of NASH would remain rather limited. In summary, the results of this longitudinal study have shown progression of liver fibrosis in approximately one third of patients with NASH in a median follow-up of 4.3 years, the presence of obesity being the only factor associated with the progression. Patients with NASH who are obese should be included in controlled trials of experimental pharmacological therapy or should be treated promptly when some agreement exists regarding the efficacy of any drug in retarding the progression of fibrosis. Patients and Methods From October 1986 through December 2002, 106 patients were diagnosed with NASH in the Liver Unit at the Professor Alejandro Posadas Hospital. The diagnosis of NASH was based on the following four criteria. Persistently abnormal alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, or both was the first criterion. A daily alcohol intake of less than 40 g in men and less than 20 g in women, as confirmed by patient anamnesis and interview of close family members, was the second criterion. These cutoff levels of ethanol intake were chosen because they were the usual ones when we designed the study. Surrogate biochemical markers of alcohol consumption were not used. Appropriate exclusion of other causes of chronic liver disease, such as hepatitis B and C, autoimmune hepatitis, drug-induced hepatitis, primary biliary cirrhosis, hemochromatosis, Wilson disease, was the third criterion. The fourth criterion was characteristic features in the liver biopsy, including macrovesicular steatosis (>10% of hepatocytes) and lobular inflammation plus ballooning degeneration, Mallory hyaline fibrosis, sinusoidal fibrosis, or a combination thereof. Patients demonstrating only steatosis and lobular inflammation in their biopsy results were not considered to have NASH. Either ballooning degeneration or sinusoidal fibrosis had to be present to confirm the diagnosis of NASH. This population included 55 males and 51 females with a median age of 45 years (range, 17-78 years). Patients were considered to have diabetes mellitus either if they were receiving insulin or oral hypoglycemic treatment or if a fasting plasma glucose test result was 126 mg/dL or more, according to the American Diabetes Association definition. Hyperlipidemia was diagnosed when fasting levels of cholesterol were more than 200 mg/dL, fasting levels of triglycerides were more than 200 mg/dL in two occasions, or both. Obesity was defined as a body mass index (BMI) of more than 30, both in men and women. BMI was calculated using the following formula: kg(weight)/m2(height). Waist circumference or waist-to-hip ratio measurements were not obtained in these patients. All the patients were referred to the Nutrition Department for the treatment of their metabolic disorders (hyperlipidemia, obesity, glucose intolerance, or diabetes), but no experimental pharmacological treatment for NASH (e.g. ursodeoxycholic acid, vitamin E, glitazones) was given to any patient. No patient was taking drugs associated with secondary NASH, such as corticosteroids, perhexiline, tamoxifen, and amiodarone. All the patients were scheduled to undergo a repeat liver biopsy at least 3 years after the previous biopsy. Patients lost to follow-up were contacted by phone calls or conventional mailing. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics and research committees of our hospital. Informed consent was obtained from each enrolled patient. Liver biopsy samples were obtained by the percutaneous route using the Menghini method. One or two passes were performed to assure samples at least 25 mm in length. Formalin-fixed, paraffin-embedded liver sections were stained routinely with hematoxylin and eosin, silver reticulin, Masson trichrome, Perls' Prussian blue, and diastase-resistant periodic acid-Schiff. After determining patient inclusion, all the liver biopsy specimens (basal and final samples) were reexamined in a blind and nonpaired manner by an experienced pathologist (E.A.) who was unaware of the clinical and biochemical data of the patients or the order of the biopsies. Studies on the liver specimens included a semiquantitative assessment of the grades of steatosis (mild or grade 1, >10% but <33% of hepatocytes affected; moderate or grade 2, 33%-66% of hepatocytes affected; severe or grade 3, >66% of hepatocytes affected); of inflammatory activity (according to Brunt classification); and of fibrosis (according to Brunt classification and to Ishak classification). Brunt classification of fibrosis assessment includes five stages: stage 0, no fibrosis; stage 1, zone 3 perisinusoidal or pericellular fibrosis, focally or extensively present; stage 2, zone 3 perisinusoidal or pericellular fibrosis with focal or extensive periportal fibrosis; stage 3, zone 3 perisinusoidal or pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis; stage 4, cirrhosis. Ishak classification ranges from zero to six stages: stage 0, no fibrosis; stage 1, fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, fibrous expansion of most portal areas with occasional portal to portal bridging; stage 4, fibrous expansion of portal areas with marked bridging (portal to portal) as well as portal to central; stage 5, marked bridging with occasional nodules (incomplete cirrhosis); stage 6, cirrhosis, probable or definite. Progression of liver fibrosis was defined as an increase 1 grade or more in the final stage with respect to the basal biopsy, in any of the two classifications. Although Brunt classification was designed especially for NASH patients, we decided to analyze changes in fibrosis according to Ishak classification as well, because of its greater flexibility in evaluating septal fibrosis (score 3 for occasional bridging, score 4 for marked bridging), incomplete cirrhosis (score 5), and definite cirrhosis (score 6). http://www.natap.org/ |
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September 29, 2004
Interferon and cirrhosis tied to liver failure in HIV/HCV coinfection
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NEW YORK (Reuters Health) - In patients coinfected with HIV and hepatitis C virus (HCV), and who are also affected by cirrhosis, treatment with interferon (IFN) raises the risk of hepatic decompensation, according to German researchers.
However, this does not necessarily mean that interferon-based therapy should be avoided, Dr. Stefan Mauss and colleagues write in the September 3rd issue of AIDS. Instead, "coinfected patients with histological progression of their chronic hepatitis C should be considered for interferon-based treatment before they develop late stage liver disease."
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