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by Alan Franciscus
2005 was an incredible year for important news on
advances in knowledge about hepatitis C. Below is a list of what we believe
are the top stories about hepatitis C for 2005. It is difficult to assign a
number to each and every one of the news stories below, but without a doubt
the most important news stories of 2005 were the discovery of a saliva-based
HCV test, replication of HCV in a test tube, followed by news about how HCV
infects a cell and how HCV evades the immune system. There were also many
important news stories about clinical trials on new drugs to treat hepatitis
C.
The other stories are listed alphabetically and not in
any particular order of importance. There may be other news stories that our
readers feel should have been included in our Top Eleven list. If so, please
drop us a line and let us know if we missed any important news.
1. Saliva-Based Test Developed for Hepatitis C.
On December 23, 2005 it was reported that scientists
from Israel have developed a saliva-based test for detecting HCV antibodies.
The scientists found that the results obtained from their salvia test were
as good or even better than the test using serum or blood samples to detect
HCV antibodies. Larger tests are needed to confirm these findings. This
could be a milestone for HCV testing since a salvia test is less expensive,
less labor intensive and easier to perform, thereby making mass screenings a
reality.
2. HCV Replicated in
a Test Tube
The growth of our understanding of hepatitis C was particularly
important this year – more so than in any other year since the discovery or
identification of HCV.
For the first time, scientists at the National
Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) were able
to replicate the hepatitis C virus (genotype 1) in a test tube. This system
only represents the end of the viral life cycle, but a very important
advance. Another HCV model system is needed to show the beginning stages of
the viral life cycle.
Another group – The Rockefeller University – has
produced an infectious form of HCV in a laboratory culture of human cells.
In addition, the Rockefeller group was also able to identify a potential
molecule that plays an important role in the entry of HCV into the host
cell.
Other important breakthroughs are from researchers at
UC Berkeley, New York University School of Medicine, University of Texas and
The Johns Hopkins University School of Medicine who identified various
mechanisms of action with regard to how HCV invades a human cell and how it
evades the immune system.
These discoveries are very important because greater
understanding of how HCV works and the ability to culture HCV in a test tube
will provide important insights that will lead to the development of new
drugs to treat as well as to eradicate HCV.
3. Hepatitis C
Epidemic Control and Prevention Act
S521 and HR1290 was reintroduced in January 2005. This bill will
provide monies to promote hepatitis C testing, counseling and referral to
care in state, local and tribal programs. In order for this bill to pass and
become law, a strong grass roots advocacy is needed. Have you contacted your
local, state and national representatives to make your voice heard on this
important legislation?
On a related note, the Decca high school kids have
embraced the cause of hepatitis C and are actively educating the public and
walking the halls of congress to drum up support for the legislation. In
December 500 students from the DECA club at Robinson Secondary School,
Fairfax, Virginia held a rally and press conference on the steps of the
Capitol building, which I attended. It was heartwarming to see so many kids
take up the cause of hepatitis C – the staff of HCSP are very grateful and
appreciative of their efforts.
4. HIV/HCV
Coinfection Treatment Guidelines
The U.S. Veterans Administration and The European Consensus
Conference issued guidelines for the management and treatment of people
infected with HIV and hepatitis C. This is important since hepatitis C in
the setting of HIV accelerates hepatitis C disease progression and HIV
medications can potentially cause liver damage. Up until now there have been
no influential groups issuing management and treatment guidelines to help
medical providers and their patients manage HIV and hepatitis C coinfection.
The European Consensus Conference panel also included recommendations for
the management of HIV/HBV coinfection.
5. Needle Exchange
Sadly, needle exchange in the U.S. lags behind most other
democratic countries. However, there were some advances and victories in
2005. There also seems to be a change of mentality in some parts of the
country: more people are beginning to see needle exchange in terms of
disease prevention intervention as opposed to viewing it as a practice that
encourages drug use. This is a hotly debated topic that will surely continue
to be in the news for many years to come.
6. Pegasys plus
Copegus FDA Approved for HCV Treatment in HIV/HCV Coinfected Patients
Early this year, the combination of Pegasys plus Copegus (ribavirin)
was approved by the FDA to treat hepatitis C in people with HIV/HCV
coinfection. This is the first (and only) HCV medication approved by the FDA
to treat the estimated 300,000 individuals in the U.S. infected with both
HIV and hepatitis C. This is an important milestone in treatment because
people infected with both viruses are at greater risk for HCV disease
progression. Another first for Pegasys is the FDA approval of Pegasys
monotherapy as the only pegylated interferon for the treatment of chronic
hepatitis B which affects approximately 1.25 million Americans.
Other noteworthy news about Roche was their national
campaign on hepatitis C. Almost every large city in the country ran ads in
newspapers, billboards, buses and kiosks about hepatitis C, and some of the
ads even appeared in national publications.
7. Revised Estimate
on HCV Infection in U.S.
New information revising the prevalence of HCV in U.S. upwards did
not garner that much attention in the media. This is probably due to the
fact that most experts know that the estimate derived from the NHANES III
study was vastly underestimated because many HCV infected high risk groups
or populations were not included in the NHANES III household base study.
Brian Edlin and colleagues mathematically analyzed data on populations
(prisoners, homeless persons, hospitalized persons, active duty personnel
and nursing home residents) who are at a high risk for acquiring HCV. Had
these numbers been included in the NHANES III the estimate would have
increased to approximately 5 million people in the U.S. who have at one time
been infected with HCV –of whom 3.9 million are currently chronically
infected. It will be interesting to see if the CDC and NIH embrace these new
estimates.
8. Schering’s
Protease Inhibitor
Another HCV protease inhibitor came upon the scene in a rapidly
expanding field of potential new HCV therapies. Phase I Data on Schering’s
oral HCV protease inhibitor, SCH503034, was released at this year’s AASLD
and the information looks impressive, showing dramatic viral load reductions
in HCV positive patients who were treated with SCH503034 alone or in
combination with Peg-Intron. Larger phase II studies are underway.
9. Valeant’s
Viramadine
A prodrug of ribavirin, viramidine continues to gain momentum. In
2005 data was released showing that the overall effectiveness of viramidine
in combination with pegylated interferon was similar to the combination of
pegylated interferon and ribavirin, but viramidine had a lower rate of
hemolytic anemia compared to the group that took ribavirin. Larger studies
are underway.
Of interest, it was announced in December that Valeant
had acquired the rights from InterMune to market Consensus interferon
(Infergen). It will be interesting to see what Valeant does with the
marketing strategy that InterMune has employed and if Valeant has a
marketing strategy to leverage Infergen with viramidine.
10. Valopicitabine
Idenix’s Valopicitabine (NM283) is an oral HCV RNA polymerase
inhibitor that in phase I and phase II studies showed a rapid HCV RNA
decline. Preliminary results from a study of Valopicitabine used in
combination with Pegasys showed a synergetic action with dramatic HCV RNA
viral decline. Clinical trials have focused on genotype 1 non-responders to
a previous course of therapy and treatment naïve (never been treated)
patients. Idenix will meet with the FDA in early 2006 for approval of
initiation of phase III studies.
11. VX-950
The data from VX-950, an oral HCV protease inhibitor continues to
be impressive. HCV RNA (viral load) reductions in patients treated with
VX-950 were dramatic. Based on data from phase I and phase II trials, the
FDA has agreed to review the data on an accelerated basis. “Fast track”
status is a designation given to drugs that treat serious or
life-threatening conditions. However, a company spokesperson commented that
Vertex does not expect to apply for FDA marketing approval until 2008.
http://www.hcvadvocate.org/news/newsRev/2005/TopTen_2005.html
Largest Hepatitis C Trial in U.S. Patients Shows
Weight-Based REBETOL in Combination With PEG-INTRON Increases Sustained
Response, Lowers Relapse
Final Results of Community-Based WIN-R Study Also Demonstrate Efficacy
of Shorter, More Tolerable 24-Week Regimen in Patients With Genotype 2 or 3
Virus
SAN FRANCISCO, CA -- (MARKET WIRE) -- 11/14/2005 -- Final
results of the WIN-R trial,(1) the largest hepatitis C study conducted in
U.S. patients, showed that weight-based REBETOL® (ribavirin, USP) in
combination therapy with PEG-INTRON® (peginterferon alfa-2b) achieved
significantly higher rates of sustained virologic response (SVR)(2) and
lower rates of relapse compared to the combination therapy using a flat dose
of ribavirin. The study also showed that, for patients infected with
hepatitis C virus (HCV) genotype 2 or 3, a shorter, 24-week course of
therapy was as effective as the standard 48-week course, with better
tolerability.
These results from WIN-R (Weight-Based Dosing of PEG-INTRON and REBETOL),
a community-based access trial involving more than 4,900 patients at 225
centers across the United States, were reported in an oral presentation
today at the 56th annual meeting of the American Association for the Study
of Liver Diseases (AASLD).
"These findings help further define optimal therapy for U.S. hepatitis C
patients treated in real-world community settings," said principal
investigator Ira M. Jacobson, M.D., Vincent Astor Professor of Clinical
Medicine at Weill Medical College of Cornell University and chief of the
division of gastroenterology and hepatology at NewYork-Presbyterian
Hospital/Weill Cornell Medical Center in New York City.
Treating U.S. hepatitis C patients can be especially challenging as they
tend to have disease characteristics that are associated with poor response
to treatment, including high prevalence of HCV genotype 1, the most
difficult type of the virus to treat; high viral load; and advanced liver
fibrosis. Other factors such as age, high body weight and African-American
ethnicity also have been shown to be associated with poor response.
"Our findings showed that the weight-based dosed combination therapy
significantly increased efficacy compared to the flat-dosed ribavirin
regimen, especially in more difficult-to-treat patient groups, such as
patients with genotype 1 and African-American patients. This confirms what
many treating physicians have come to know in their everyday practice and
experience," Jacobson said. "Importantly, sustained virologic response rates
in this community-based U.S. study were consistent with those seen in the
U.S. cohorts of the earlier pivotal studies for the two approved
peginterferon combination therapies."(3,4)
Study Design
In the WIN-R study, 4,913 patients were randomized to receive
weight-based PEG-INTRON (1.5 mcg/kg weekly) in combination with REBETOL
given either as a flat dose (800 mg daily) or a weight-based dose (800 mg,
1,000 mg, 1,200 mg or 1,400 mg daily for body weights of less than 65 kg, 65
to 85 kg, 86 to 105 kg, or 106 to 125 kg, respectively). Patients were
treated for 48 weeks (genotype 1) or 24 weeks (genotype 2 or 3). Patients in
the treatment arms were evenly matched for gender, age, body weight,
genotype, viral load and stage of liver fibrosis.
Key Results
A challenge with conducting large community-based HCV studies such as
WIN-R, as opposed to registration trials with their more intensive
monitoring capabilities, is the tendency for a high rate of patients to miss
their follow-up viral testing (PCR) visit 24 weeks after treatment ends due
to the limited ability of many sites to conduct rigorous monitoring of
patients once they have received their final treatment dose. In the WIN-R
study, 13.1 percent (164/1,256) of patients in the weight-based dose group
and 13.7 percent (163/1,193) of patients in the fixed-dose group who were
responders at the end of treatment were lost to follow up and subsequently
counted as treatment failures under a strict intent-to-treat (ITT) analysis.
Nonetheless, the WIN-R study showed significantly better outcomes for the
weight-based combination regimen as compared to the flat-dosed ribavirin
regimen, including:
-- Significantly higher SVR overall (44.3 percent vs. 40.6 percent,
p=0.01, ITT) and for patients with genotype 1 (34 percent vs. 29 percent,
p=0.004, ITT). These SVR rates are consistent with those seen in the U.S.
cohorts of the earlier pivotal studies for the two approved peginterferon
combination therapies.(3,4)
-- Using an estimated SVR analysis, based on results for patients who had
undetectable virus at the end of treatment and were subsequently lost to
follow up, SVR was 53 percent vs. 48 percent (p=0.008), respectively, for
the weight-based vs. flat-dosed ribavirin groups.
-- Consistent SVR rates were seen across all weight groups for patients
in the weight-based dosed regimen compared to the flat-dosed ribavirin
regimen where SVR rates declined in the higher weight groups, ranging from
52 percent to 34 percent. Consistent with other U.S. studies, patient
weight tended to be high in the WIN-R study, with 45 percent of patients
weighing 86 kg (189 lbs) or more.
-- For patients with HCV genotype 2 or 3 virus, a 24-week course of the
combination therapy was as effective as 48 weeks, with better tolerability.
In the weight-based dose arms, SVR was 68 percent for the 24-week course
compared to 60 percent for the 48-week course, with the lower percentage
attributable to more missing follow-up data.
-- Lower rates of relapse were seen for patients receiving the weight-
based combination therapy compared to the flat-dosed ribavirin regimen, 15
percent vs. 19 percent overall, and 23 percent vs. 29 percent for patients
with HCV genotype 1. Relapse is defined as patients with undetectable virus
levels at the end of treatment who subsequently had detectable virus at 24
weeks post-treatment.
-- Although there was a higher rate of anemia (hemoglobin < 10 gm/dl) in
the weight-based dosing group and more dose reductions (29 percent vs. 23
percent), no difference was seen in the rate of occurrence of serious
adverse events between the two groups (12 percent vs. 11 percent) and there
were similar rates of discontinuations for adverse events (15 percent vs.
14 percent).
WIN-R Study
Serving with Dr. Jacobson as co-principal investigator of the WIN-R study
is Dr. Robert S. Brown Jr., associate professor of clinical medicine at
Columbia University College of Physicians and Surgeons; and chief of
clinical hepatology and medical director of the Center of Liver Disease and
Transplantation at NewYork-Presbyterian Hospital/Columbia University Medical
Center. Drs. Jacobson and Brown are also co-directors of NewYork-Presbyterian
Healthcare System's Liver Clinical Trials Network (LCTN).
Dr. Jacobson also is medical director of the Center for the Study of
Hepatitis C, a unique interdisciplinary center established jointly by The
Rockefeller University, NewYork-Presbyterian Hospital and Weill Cornell
Medical College in New York City.
WIN-R is an investigator-initiated clinical study supported by
Schering-Plough Corporation and monitored by Schering-Plough Research
Institute as part of a post-marketing commitment to the U.S. Food and Drug
Administration (FDA). PEG-INTRON and REBETOL are registered trademarks of
Schering-Plough.
About Hepatitis C
Hepatitis C is the most common blood-borne infection in America,
affecting approximately 4 million people or about one in every 50 adults.
Chronic hepatitis C can cause cirrhosis, liver failure and liver cancer. It
has been estimated that at least 20 percent of patients with chronic
hepatitis C develop cirrhosis, and a smaller percentage of patients with
chronic disease develop liver cancer. Patients with chronic hepatitis C and
related cirrhosis are 100 times more likely to develop liver cancer than
uninfected persons.(5) About half of all cases of primary liver cancer in
the developed world are caused by hepatitis C, and hepatitis C related liver
disease is now the leading cause for liver transplants.(6)
About NewYork-Presbyterian Hospital/Weill Cornell Medical Center
The NewYork-Presbyterian Hospital/Weill Cornell Medical Center, located
in New York City, is one of the leading academic medical centers in the
world, comprising the teaching hospital NewYork-Presbyterian Hospital and
its academic partner Weill Cornell Medical College. NewYork-Presbyterian/Weill
Cornell provides state-of-the-art in-patient, ambulatory, and preventive
care in all areas of medicine, and is committed to excellence in patient
care, research, education, and community service.
References
1. Jacobson I, Brown Jr. R, Freilich B, Afdahl N, Kwo P, Santoro J,
Becker S, Wakil A, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S,
Bala N, Araya V, Davis M, Monsour H, Vierling J, Regenstein F, Balan V,
Dragutsky M, Epstein M,. Herring RW, Rubin R, Galler G, Pauly MP, Griffel LH,
Brass CA, the WIN-R Study Group. Weight based ribavirin dosing (WBD)
increases sustained viral response (SVR) in patients with chronic hepatitis
C (CHC): final results of the WIN-R study, a U.S. community-based trial.
Oral presentation at: 56th Annual Meeting of the American Association for
the Study of Liver Diseases, San Francisco, CA, Nov 11-15, 2005.
2. Sustained virologic response (SVR) is defined as undetectable virus (HCV-RNA)
levels in the blood at 6 months after the end of therapy.
3. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar
R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus
ribavirin compared with interferon alfa-2b plus ribavirin for initial
treatment of chronic hepatitis C: a randomised trial. Lancet. 2001 Sep
22;358(9286):958-65.
4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr,
Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu
J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus
infection. N Engl J Med. 2002 Sep 26;347(13):975-82.
5. Ince N, Wands JR. The increasing incidence of hepatocellular
carcinoma. N Engl J Med 1999 March 11;340:10.
6. Centers for Disease Control and Prevention. Recommendations for
prevention and treatment of hepatitis C virus (HCV) and HCV-related chronic
disease. MMWR Weekly Report 1998 Oct. 16;1.
Contact:
Andrea Ziltzer
Chandler Chicco Agency
(914) 522-4804
(212) 229-8433
Email Contact
Jonathan Weil
NewYork-Presbyterian/Weill Cornell
(212) 821-0560
Email Contact
SOURCE: NewYork-Presbyterian/Weill Cornell
http://www.marketwire.com/mw/release_html_b1?release_id=101076&tsource=3
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