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Alan Franciscus
Editor-in-Chief
- Immtech Compounds Show
Promise Against Flavivirus (Hepatitis C and BVDV) And Animal
Market Applications
- Interferon Induction Therapy
Does Not Enhance SVR and Relapsers with Genotypes 1 and
4 Retreated with High Dose Interferon Plus Ribavirin for
48 Weeks Have 50% Response Rate
- HCV Infection of the Central
Nervous System May Cause Neuropsychological Symptoms and
Cognitive Impairment
- Austrian Study Recommends
Twice-Weekly Dosage of PEG-Intron
- Time on Anti-HIV Therapy
Is a Protective Factor for Liver Fibrosis in HIV-HCV Coinfected
Patients
- Antiviral Therapy of Patients
for Patients Awaiting Lliver Transplantation: A Strategy
to Prevent Hepatitis C Recurrence After Transplantation
- Liver Transplant Recipients
Over 60 Years Old Have Lower Survival and Higher Incidence
of Malignancy
- Defective Memory Function
in Early Hepatic Encephalopathy
- Previous HBV Infection
Does Not Affect Liver Histology or the Response to Interferon-based
Therapy in HCV Patients
- Schering-Plough Says It
Is Running Out of Cash
- HBV Detected in Livers
of Patients Said 'Cured'
- In Vivo Immunization
Following Suppression of HBV: A New Approach for Inducing
Immune Control in Chronic Hepatitis B
- Are HBV Vaccine Booster
Doses Unnecessary in Immunocompetent Persons?
- Task Force Formed to
Combat Hepatitis
- Biochemical Markers of
Liver Fibrosis and Activity Can Be Used as Surrogate Markers
for Liver Biopsy in Patients with Chronic Hepatitis C
- Recommendation of Future
Management of Chronic Hepatitis C Without Liver Biopsies
- Hepatitis C on the Rise:
US Based Doctor
- Roche Replenishing Hepatitis
C Medicine
- Regeneration of Hepatocytes
From Intrabiliary Stem Cells in Cirrhosis
- Unique Scholarship Program
Aims to Support African-American and Hispanic Students Challenged
by Hepatitis C
- Preventive Treatment for
HCV Recurrence in Patients with Decompensated Post-hepatitis
C Cirrhosis Before Liver Transplantation: An Editorial
- Treatment of HCV Patients
Awaiting Liver Transplantation Helps to Prevent HCV Recurrence
Following Surgery
- Geneva Pharmaceuticals
Prepares Generic Rebetol(R) - U.S. District Court Rules
Patent Non-Infringement
- Prevalence of Hepatitis
C Virus Infection in Urban Children in the USA
- Histoacryl Injection
or Beta-blockers for the Eradication of Esophogastric varices
- College Students Ignoring
Risks of Unprotected Sex
- Schering-Plough Slashes
Costs. Jobs, Dividend and Perks Among Cutback Targets
- Wane of Hepatitis C Drugs
Wound Schering-Plough
- Vaccination and Anti-HIV
Therapy Lower Hepatitis B Infection Rates
- Hyperlipasemia and/or
Subclinical Pancreatitis May Represent Extrahepatic Manifestations
of HCV Infection
- Twice Daily Dosing with
Interferon Beta Improves Viral Kinetics and Enhances Antiviral
Efficacy
- Management of Hematologic
Disorders Associated with Hepatitis C Virus Infection
- Chinese Scientists Decode
New Hepatitis B Virus Genes
- Antioxidants May be Beneficial
For Transplant Patients
- Risk of Cancer Higher
in Patients with Fatty Liver, Say Japanese Doctors
- Accelerated Schedules
for Vaccinations Against Hepatitis A and B
- High Dose Infergen (consensus
interferon) Produces Sustained Response in Low Percentage
of Nonresponders to Interferon Alfa and Ribavirin
- Prediction at Week 4
of Treatment Effect with Interferon Alfa and Ribavirin in
HCV Patients Identifies One-half of All Nonresponders and
Allows Them Benefit of Early Cessation of Therapy
- Early Response to Individualized
Weight-Based PegIntron(R) and Rebetol(R)
- Early Virologic Response
to Treatment in Patients with Chronic Hepatitis C
- Outcomes and Indicators
of Upper Digestive Bleeding in Cirrhosis
- Factors Influencing the
Outcome of Liver Retransplantation
- Britain Says It Will
Pay Hepatitis C Victims
- Patients with HBV Genotype
B Infection Have More Severe Exacerbations of Disease and
Higher Risk of Hepatic Decompensation and Mortality Compared
with Patients with HBV Genotype C Infection
- Clinical Features and
Outcome in HCV-positive Patients with Aggressive Non-Hodgkin's
Lymphoma
- Retreatment with Interferon
Is Effective in Some Partial Responders and Nonresponders
with Chronic Hepatitis C
- Finding the Right Combination
to Fight Hepatitis C
August 15th, 2003
Immtech Compounds
Show Promise Against Flavivirus (Hepatitis C and BVDV) And
Animal Market Applications
Immtech International, Inc. (Amex: IMM) announced today
publication of scientific data describing the activity of
aromatic cationic molecules against the Bovine Diarrhea Virus
(“BVDV”). BVDV is an RNA Flavivirus genus commonly
found in cows, and is similar to both the human hepatitis
C virus and the virus that causes West Nile infections.
In the paper, published in Antimicrobial Agents and Chemotherapy,
July 2003, Volume 47, entitled “Detection of Inhibition
of Bovine Diarrhea Virus by Aromatic Cationic Molecules,”
the lead authors, Daniel Givens, (Auburn University) and David
Boykin, (Georgia State University) presented data on the activity
of compounds screened in an assay that evaluates the total
life cycle of viral propagation. The scientists identified
five Immtech compounds demonstrating exceptional efficacy,
inhibiting propagation of the BVDV virus at low (nanomolar)
concentrations with low toxicity. Such activity makes these
compounds excellent candidates for advanced testing against
the
hepatitis C virus.
Stephen Thompson, President & CEO of Immtech said, “The
results observed
by our scientists demonstrate the promise of cationic molecules
as anti-viral agents and possibly against hepatitis C. We
believe that there is an advantage in having a reliable assay
system that evaluates the complete viral life cycle for screening
compounds for anti-hepatitis C activity. We are using the
information generated from these studies to further evaluate
specific cationic compounds for anti-hepatitis C activity.”
While the exact mechanism by which these compounds exert anti-viral
activity is unknown, their known capacity to interact with
nucleic acids and inhibit proteases suggests multiple modes
for anti-viral activity. Potential outcomes from this research
include developing a drug to treat Bovine Diarrhea Virus infections
in calves and preventing viral contamination of embryos during
in vitro fertilization, placing Immtech in the multi-billion
dollar animal health market. One of the lead candidates has
advanced into research using bovine embryos to determine if
the compound could prevent BVDV contamination of the embryos
during in vitro fertilization and embryo transfer (BVDV infections
are a common cause of abortion in cows). The study demonstrated
that the compound was safe to use during in vitro fertilization
and that embryos developed after transfer resulted in the
birth of normal calves. The successful elimination of BVDV
from embryos implanted in cows can greatly reduce the abortion
rate of calves during the in vitro fertilization process.
This market can potentially be very profitable because in
vitro fertilization is the most common method used to impregnate
cows. This BVDV research was supported by a grant from the
National Institutes of Health. Immtech International, Inc.
is a pharmaceutical company focused on the commercialization
of oral treatments for infectious diseases such as pneumonia,
fungal infections, malaria, tuberculosis, hepatitis and tropical
diseases such as African sleeping sickness and Leishmania.
The Company has worldwide, exclusive rights to commercialize
a dicationic pharmaceutical platform from which a pipeline
of products may be developed to target global markets.
Back to top
Interferon Induction
Therapy Does Not Enhance SVR and Relapsers with Genotypes
1 and 4 Retreated with High Dose Interferon Plus Ribavirin
for 48 Weeks Have 50% Response Rate
by hivandhepatitis.com
Retreatment of relapser patients with chronic hepatitis C
with the standard dose of interferon (IFN) of 3 million units
(MU) thrice weekly (tiw) plus ribavirin for 24 weeks achieves
a sustained response in 30 and 73% of patients with genotype
1 and 2 or 3, respectively.
The aim of this study was to evaluate the efficacy and safety
of IFN alfa-2b (Intron A) induction therapy, followed by prolonged
treatment with a high dose of IFN alfa-2b plus ribavirin in
relapser patients.
A total of 119 patients were randomized to receive IFN alfa-2b
5 MU daily (Group A: 59 patients) or IFN alfa-2b 5 MU tiw
(Group B: 60 patients) for 4 weeks followed by IFN (5 MU tiw)
and ribavirin (1000-1200 mg/day) for 48 weeks in both groups.
The primary end point was hepatitis C virus (HCV)-RNA clearance
at week 24 after the end of treatment.
A sustained virological response (SVR) was achieved in 68
and 60% of Group A and B patients, respectively (P = 0.37).
Logistic regression analysis identified genotype 2 or 3 as
the only independent factor associated with response, whereas
induction regimen and baseline viremia levels did not affect
the response.
The overall SVR was 53 and 72% in patients with genotype 1
or 4 and 2 or 3, respectively.
In conclusion, induction IFN therapy does not enhance the
SVR to a 48-week combination therapy. Our study suggests that
relapsed patients with genotype 1 or 4 may achieve significant
response rates of approximately 50%, if retreated with 5 MU
tiw IFN plus ribavirin for 48 weeks.
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HCV Infection of
the Central Nervous System May Cause Neuropsychological Symptoms
and Cognitive Impairment
by hivandhepatitis.com
A number of studies have reported an association between chronic
hepatitis C (HCV) infection and significant impairments in
health-related quality of life (QOL). These impairments are
independent of the severity of liver disease.
There are numerous reports documenting the prevalence of symptoms
such as fatigue and depression in chronic HCV infection, which
may in part account for the reductions in quality of life.
Although there are a large number of potential explanations
for these symptoms, including depression and anxiety associated
with the diagnosis of HCV infection or substance abuse, there
has been recent interest in the possibility of a biological
effect of HCV infection on cerebral function.
There is emerging evidence of mild, but significant neurocognitive
impairment in HCV infection, which cannot be attributed to
substance abuse, coexistent depression or hepatic encephalopathy.
In vivo magnetic resonance spectroscopy and neurophysiological
studies have suggested that a biological mechanism may underlie
these cognitive findings.
The recent detection of HCV genetic sequences in post mortem
brain tissue raises the intriguing possibility that HCV infection
of the central nervous system may be related to the reported
neuropsychological symptoms and cognitive impairment.
Back to top
Austrian Study
Recommends Twice-Weekly Dosage of PEG-Intron
by newsrx.com
University of Vienna internists are recommending at least
twice-weekly dosing of peginterferon-alpha-2b for their patients
with chronic hepatitis C.
They say this schedule is necessary to continually expose
the virus to the drug and to improve initial viral clearance.
“The decline in hepatitis C viral load on treatment
with peginterferon-alpha-2b is not continuous,” said
E. Formann and colleagues. “The aim of this study was
to investigate whether twice weekly dosing of peginterferon-alpha-2b
[PEG-IFN-a-2b] may improve viral kinetics.”
Study subjects were 10 interferon-naive patients with chronic
hepatitis C - genotype 1a or b. They were “randomized
to receive either 10 mcg/kg PEG-IFN-a-2b once (group A) or
twice weekly (group B) for 4 weeks.”
Formann and colleagues reported that “ PEG-IFN-a-2b
reached maximal blood concentrations 24 hours after the first
dose, followed by a linear decline during the subsequent days.
On the day before administration of the next dose, PEG-IFN-a-2b
was undetectable in nine patients in group A (once-weekly
dosing). The same pattern was observed during the next 3 weeks
of therapy.”
They could detect PEG-IFN-a-2b at any time point in patients
under the twice-weekly regimen, the researchers said, adding
that the drug levels always were “higher than in group
A (p between 0.01 and <0.0001).”
“Viral load decreased in all patients within 2 days
after the first dose of peginterferon-alpha-2b, but increased
again on day 3. In group A, it further increased until day
7. A similar pattern was observed in the second week.
“In contrast, in group B, viral load decreased again
on day 4 and remained lower until the end of the study (p<0.001),”
reported Formann’s team.
“To achieve continuous drug exposure and to improve
initial viral clearance, peginterferon-alpha-2b has to be
given at least two times weekly,” they concluded.
Formann and coauthors published their study in the Journal
of Viral Hepatitis (Twice-weekly administration of peginterferon-alpha-2b
improves viral kinetics in patients with chronic hepatitis
C genotype 1. J Viral Hepatitis, 2003;10(4):271-276).
Back to top
Time on Anti-HIV
Therapy Is a Protective Factor for Liver Fibrosis in HIV-HCV
Coinfected Patients
by hivandhepatitis.com
To assess the factors associated with liver fibrosis in HIV
and hepatitis C virus (HIV/HCV) co-infected patients eligible
for anti-HCV therapy, researchers performed an observational,
single-centred, cross-sectional study of 180 HIV/HCV co-infected
patients who underwent liver biopsy between May 1998 and November
2001.
A total of 126 patients with a known date of HCV infection
were evaluated. Liver fibrosis was defined as a Knodell stage
of fibrosis 1-4.
The mean age was 36.7 (3.8) years, 81% were male and had a
mean age of 20.5 (3.8) years at HCV infection. Mean CD4 cell
count and plasma HIV-1 RNA load at the time of biopsy were
552 cell/mm3 (239) and 2.5 log10 (0.9), respectively; 118
patients had been on antiretroviral therapy (ART) for a median
of 45 months (Q1-Q3: 21-75) and 84 on protease inhibitor for
a median of 12.0 months (Q1-Q3: 0-29.5); 55 had an AIDS event
or a CD4 cell count nadir < 200 cells/mm3 prior to biopsy.
Median histological activity index was 6 and 27% had a Knodell
stage of fibrosis 0. On the multivariate analysis time on
ART, CD4 cell count at the time of liver biopsy, age at HCV
infection acquisition and alcohol intake (> 50 g/day) were
associated with liver fibrosis.
The authors conclude, “ART should be a priority in HIV-HCV
co-infected patients eligible for anti-HCV treatment as it
is a protective factor for liver fibrosis.”
Back to top
Antiviral Therapy of Patients for
Patients Awaiting Lliver Transplantation: A Strategy to Prevent
Hepatitis C Recurrence After Transplantation
by gastrohep.com
The utilization of antiviral therapy in hepatitis C virus
infected patients awaiting liver transplantation is a useful
strategy to prevent hepatitis C recurrence after transplantation,
according to a study published in The Journal of Hepatology
(Journal of Hepatology 2003; 39(3): 389-396).
After liver transplantation infection of the graft with the
hepatitis C virus is almost universal. This leads to the development
of chronic hepatitis and cirrhosis in a significant proportion
of patients.
One of the possible strategies to prevent recurrence of hepatitis
C is to eradicate hepatitis C virus prior to liver transplantation.
A team of Spanish doctors evaluated the efficacy and safety
of antiviral therapy to prevent hepatitis C recurrence in
30 patients with hepatitis C and cirrhosis awaiting liver
transplantation.
Antiviral therapy was initiated when the expected time for
liver transplantation was less than 4 months away and continued
until the transplant took place. The median duration of treatment
was 12 weeks.
Antiviral therapy consisted of interferon-2b (3 MU/day) and
ribavirin (800 mg/day).
9 out of the 30 patients achieved a virological response and
21 did not respond to therapy. Viral load decreased in 9 of
the 21 non-responders during treatment.
The 9 patients who responded to antiviral therapy have since
undergone liver transplantation. 6 of the 9 patients remain
free of infection after a median follow-up of 46 weeks, while
hepatitis C viral infection recurred in the remaining 3.
30% of patients had a virological response to antiviral therapy.
Side effects were frequent and dose reduction was necessary
in 19 of the 30 patients.
The authors of the study conclude “Our data support
the utilization of antiviral therapy in hepatitis C-infected
patients awaiting liver transplantation as one of the strategies
to prevent hepatitis C recurrence after liver transplantation.”
However, in an editorial which appears in the same issue of
The Journal of Hepatology, Dr Jean-Pierre Zarski
adds a note of caution.
“Antiviral therapy should be considered experimental
and not be administered outside of prospective trials.”
Back to top
Liver Transplant Recipients
Over 60 Years Old Have Lower Survival and Higher Incidence
of Malignancy
by gastrohep.com
Older liver transplant recipients have a significantly lower
survival than younger patients and malignancy is responsible
for this decreased survival, concludes a study in the American
Journal of Transplantation.
Older age is not considered a contraindication for liver transplantation.
A team of Doctors in Spain reviewed 111 liver transplants
to compare the survival of patients over 60 years old who
undergo liver transplantation with the survival of younger
patients.
They also investigated any factors involved in a potential
difference in mortality.
After transplantation, older patients had a significantly
lower survival.
Of the 111 patients analysed 54 were older than 60 years of
age and 57 were younger.
After transplantation, older patients had a significantly
lower survival. Higher age was associated with increased mortality
independent of other variables.
The incidence of de novo neoplasia and nonskin neoplasia was
significantly higher in older patients.
Malignancy was the cause of death in 12 patients older than
60 years, but only 1 patient younger than 60 years.
Higher age as well as smoking were significantly associated
with the incidence death due to de novo neoplasia.
Increased frequency of malignancy in older transplant patients
appears to lead to increased mortality.
Back to top
Defective Memory Function
in Early Hepatic Encephalopathy
by gastrohep.com
A study in the September issue of The Journal of Hepatology
(Journal of Hepatology 2003; 39(3): 320-5) finds
that although patients with early hepatic encephalopathy score
lower than controls in memory tasks, this is predominantly
due to deficits in attention and visual perception.
Early hepatic encephalopathy is characterized by deficits
in motor performance, visual perception, visuo-constructive
abilities and attention.
Whether defective memory is a feature of early hepatic encephalopathy
remains controversial.
Dr Karin Weissenborn and colleagues in Hannover, Germany,
attempted to resolve this controversy by analysing memory
function in 45 patients with early hepatic encephalopathy.
Memory tests were applied to cirrhotic patients with minimal,
grade 0, or grade 1 hepatic encephalopathy and the results
were compared with those seen in 52 control subjects.
Tasks included short and long term memory tests requiring
free recall or recognition.
Patients’ deficits were in attention and visual perception,
rather than memory.
Patients with early hepatic encephalopathy scored lower than
the controls in all of the memory tasks.
Dr Weissenborn’s team conducted a detailed analysis
of test performance, which revealed that the patients’
deficits were in attention and visual perception, rather than
memory.
Dr Weissenborn concludes “Although patients with early
hepatic encephalopathy score lower than controls in memory
tasks, this is predominantly because of deficits in attention
and visual perception.”
Back to top
Previous HBV Infection Does
Not Affect Liver Histology or the Response to Interferon-based
Therapy in HCV Patients
by hivandhepatitis.com
Patients with chronic hepatitis C frequently have antibodies
to the hepatitis B core antigen (anti-HBc), indicative of
prior hepatitis B virus (HBV) infection. In these patients,
persistence of HBV may exacerbate liver injury and diminish
the response to treatment.
The aim of this study was to evaluate the relationship between
previous HBV infection and liver histology and the sustained
virologic response (SVR) to interferon (IFN)-based therapy
in patients with chronic hepatitis C.
A total of 132 HBsAg-negative, treatment-naive patients were
evaluated. Using multiple logistic regression analysis, the
impact of anti-HBc-positivity on the rate of SVR was determined.
Progression to bridging fibrosis or cirrhosis was assessed
using Cox proportional hazards regression and Kaplan-Meier
survival analysis.
The median age of the patients was 47 years (IQR, 37-60),
57% were male, and 73% had genotypes 1, 4, 5, or 6. Fifty-one
patients (39%) were anti-HBc-positive. The prevalence of moderate
to severe necroinflammatory activity (P = 0.36) and progression
to bridging fibrosis or cirrhosis (log-rank P = 0.83) was
similar between anti-HBc-positive and -negative patients.
After a median of 48 weeks (IQR, 26-52) of therapy (IFN, n
= 116; IFN and ribavirin, n = 16), 23 patients (17%) achieved
a SVR; the rate of response was similar in anti-HBc-positive
and -negative patients (18%vs 17%, P = 1.00).
After controlling for age, gender, genotype, fibrosis, and
treatment regimen, anti-HBc status did not independently affect
the rate of SVR (P = 0.58).
In conclusion, previous HBV infection does not affect liver
histology or the response to IFN-based therapy in patients
with chronic hepatitis C.
Back to top
Schering-Plough Says It Is
Running Out of Cash
by Lewis Krauskopf
In the latest fallout from its waning Claritin franchise,
Schering-Plough Corp. warned investors Tuesday it may have
to borrow to fund this year’s cash needs.
The Kenilworth-based drug maker said that for the rest of
2003 -- and “possibly beyond”—cash from
its operating activities may not be enough to fund working
capital, capital expenditures, and dividends. The situation
particularly relates to its U.S. operations.
Schering-Plough, which has a solid, investment-grade credit
rating, said it plans short-term borrowing to cover its needs.
But the company has not ruled out job cuts or reducing its
dividend. Schering-Plough employs about 7,000 people in New
Jersey, and nearly 30,000 worldwide.
Sales of the allergy pill Claritin—once a $3 billion-a-year
cash cow making up more than 30 percent of company sales—have
evaporated after the company lost marketing exclusivity and
converted it to an over-the-counter product. In the second
quarter alone, prescription Claritin sales in the United States
dropped to $13 million from $677 million in the 2002 period.
Other products, such as its Intron hepatitis C franchise,
have failed to pick up the slack.
Schering-Plough gave its cash warning as part of an SEC document
filed Tuesday designed to answer frequently asked questions
by investors. The company had described the situation in previous
filings. Shares slipped 15 cents to $16.10, recovering after
falling as much as 11 percent early in the day.
Schering-Plough’s net cash from operating activities
totaled $429 million in the first six months, compared with
$870 million in the first half of last year.
Cash from operations was sufficient in the first quarter.
But in the second quarter, the company paid $250 million as
part of a fine levied by the U.S. Food and Drug Administration
over manufacturing practices. That payment offset cash flow
from operations, the company said, so the company borrowed
to pay for capital expenditures and dividends.
“For the remainder of 2003 and possibly beyond, cash
provided by operating activities will not be sufficient to
fund working capital, capital expenditures, and dividends
if these items remain at levels comparable to that in the
first and second quarters,” the company said.
However, the company also said it has “adequate internal
and external resources” to meet its financial requirements.
Further, the company said it might have further payments related
to other legal and regulatory problems. For example, the SEC
may bring action against the company and its previous CEO,
Richard Jay Kogan, for meetings with investors and analysts
last fall. And the company is a target of a criminal investigation
by the U.S. Attorney’s Office in Massachusetts for its
sales and marketing practices.
During Schering-Plough’s earnings slide, the company’s
dividend has come under scrutiny. At 17 cents per common share,
the quarterly dividend is costing Schering-Plough about $1
billion a year. Schering-Plough has increased its dividend
19 times since 1986.
As the company has stated before, Fred Hassan, the new chief
executive, has been asked to do a “360-degree review”
of the company’s operations, including its dividend.
“The company is generating cash to pay capital expenditures,”
said Todd Lebor, an analyst with Morningstar Inc. “What
it’s not doing is generating enough cash at the end
of the day to pay the dividend as well.” However, Lebor
said, the company’s hole is temporary and it should
be generating enough cash to do both within two years. He
said the company’s new cholesterol treatment Zetia is
expected to be a bigger revenue contributor by then.
Hassan said last month he would seek to wring out $200 million
in annual savings from the company’s current cost structure.
Schering-Plough hired Hassan, the former CEO of Pharmacia
Corp., in April to turn around the company’s fortunes.
Back to top
August 17th, 2003
HBV Detected in Livers of Patients
Said 'Cured'
Yomiuri Shimbun
The hepatitis B virus (HBV) lingers in the liver for a longer
time than previously believed and can reemerge in a carrier’s
blood after a sufferer of the disease is thought cured, according
to findings of research conducted by the Osaka National Hospital
and other medical organizations.
It was widely believed that the disease would not become chronic
in adult carriers more than six months after acute symptoms
had been cured. Such carriers were then allowed to again donate
blood.
The team said that it is unlikely the liver virus would have
an adverse effect on carriers’ health, but it may be
a source of infection in a virus-free blood transfusion recipient.
The finding is likely to have a significant impact on the
blood donation screening system.
Adults with normal immune systems carry antibodies in their
blood to attack HBV and prevent it from becoming a chronic
disease.
Once the antibodies in a carrier’s blood system have
been activated, it was previously believed that the carrier
could not be reinfected with the disease.
However, in a reexamination of 14 former carriers whose livers
have been functioning normally for between 2 and 9 years after
contracting the disease, Nobukazu Yuki, head of the hospital’s
Department of Gastroenterology, and other researchers detected
the virus in the blood of three of the former patients.
Furthermore, an examination of liver tissue from nine of the
14 former carriers, who consented to biopsies, revealed that
all had the virus, and seven were suffering from a slight
inflammation of the liver.
In the Japanese Red Cross Society’s safety checks on
donated blood, it is difficult to detect HBV unless the viral
count is above 1,000 HBVs per milliliter of blood.
However, there have been cases in which carriers with a viral
count thought lower than 50 died from the disease.
The counts in the three former patients found to have the
virus were 770, 1,300 and 24,000, respectively.
Blood donated by the two with the lowest counts could have
slipped through the society’s safety tests and subsequently
infected transfusion recipients.
There have been reports in recent years that the virus would
linger in the liver after carriers were believed to be cured,
but this is the first time the virus was found to have survived
in nine former patients who underwent posttreatment check-ups.
After treatment, it was believed that the viral count could
not rise as antibodies in the immune system had been activated
and were thought to keep the count down. Therefore, it was
not expected that a viral count as high as 24,000 HBVs per
milliliter would have been detected in a previously cured
patient’s blood.
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August 18th, 2003
In Vivo Immunization Following Suppression
of HBV: A New Approach for Inducing Immune Control in Chronic
Hepatitis B
by hivandhepatitis.com
Antiviral treatment of patients with active chronic hepatitis
B may lead to a significant reduction in morbidity and mortality.
However, after stopping nucleoside analogue therapy, relapse
rates are high in those without acquired specific immunity.
Researchers at the University Medical Center Rotterdam, The
Netherlands have treated two chronic hepatitis B patients
with in vivo immunization. In vivo immunization aims to optimize
conditions for an effective immune response: following rapid
and profound virus suppression by interferon-lamivudine combination
therapy, lamivudine is withdrawn intermittently for 4 weeks
during continued interferon therapy.
In both patients with profound virus suppression a rapid rebound
in viral replication was observed after lamivudine withdrawal,
despite continued interferon. These periods of renewed viral
replication were followed by rises in hepatitis activity.
After re-introduction of lamivudine, HBV DNA became undetectable
by PCR followed by normalization of serum ALT. These observations
are a stimulus to further explore the concept of in vivo immunization
as a novel therapeutic approach for chronic hepatitis B.
Clearly, these results in two patients require confirmation
in a larger study.
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Are HBV Vaccine Booster Doses Unnecessary
in Immunocompetent Persons?
by hivandhepatitis.com
This review analyses the cumulated data
from a number of long-term follow-up studies among infants,
children and adults vaccinated against hepatitis B in industrialized
and developing countries.
Despite low or undetectable antibody responses years after
vaccination, the development of HBsAg was a rarity and, if
present, only transient. Some vaccinees developed anti-HBc
responses but none developed an HB carrier state or clinical
manifestations of disease.
Studies demonstrating anamnestic responses among those with
low or undetectable anti-HBs levels following challenge with
HB vaccine, together with the production of anti-HBs in circulating
B-cells by spot ELISA, confirmed the presence of immune memory
among vaccinees.
Anamnestic anti-HBs responses all correlate close in kinetics
and magnitude with proliferative T-cell responses.
The accumulated data from studies assessed in this review
indicate that protection is dependent on immune memory, rather
than declining anti-HBs responses and add additional weight
to the European Consensus recommendations that following a
complete course of vaccination, booster doses are unnecessary
in immunocompetent persons.
If implemented, this recommendation will have considerable
cost benefits world-wide.
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Task Force Formed to Combat Hepatitis
Islamabad: A task force has been established in North West
Frontier Province as part of a province-wide campaign to combat
rapidly spreading hepatitis, an official said on Wednesday.
“It is a one week campaign with different components,
including seminars, workshops, display posters and walks to
create awareness. The NWFP is the first region in Pakistan
to launch such a campaign,” Provincial Health Secretary,
Dr Ihsan-Ul-Haq, said from Peshawar. He added that the federal
government is working on a similar idea for the whole country.
A private pharmaceutical company has pledged to provide discounted
vaccines, he said.
“Cases of hepatitis C have risen dramatically, making
it twice as prevalent as hepatitis B,” said the chairman
of the hepatitis task force in Peshawar, Dr Najibul Haq.
“The main objective of the campaign is to increase awareness
in people about the simple ways to avoid hepatitis. We are
targeting different groups to spread the message,” he
said, noting that the task force is also working on legislation
with the government in respect to preventative measures.
All the districts in NWFP were involved. The three main components
of the campaign were intended to raise awareness among health
workers, to hold public meetings in hospitals and arrange
walks, Najibul Haq said. He added that his task force wanted
to see the activities continue even after the campaign ended.
He said the campaign should involve local religious and community
leaders, members of parliament, heads of local government,
councillors and health workers.
At present, 18 percent of all patients admitted to general
wards in hospitals in the NWFP suffer from some type of hepatitis,
the chief of NWFP government’s Health Sector, Research
and Reform Unit, Dr Mohammed Rafiq, said. “There are
nine million hepatitis B carriers in Pakistan.” IRIN
Back to top
Biochemical Markers of Liver Fibrosis
and Activity Can Be Used as Surrogate Markers for Liver Biopsy
in Patients with Chronic Hepatitis C
by hivandhepatitis.com
In patients infected with hepatitis C virus (HCV), recent
studies have demonstrated the predictive value of combinations
of simple serum biochemical markers.
Abbreviations:
HCV - hepatitis C virus
FT - Fibrotest
AT - Actitest
ALT - alanine aminotransferase
SVR - sustained virologic response
GGT - glutamyl transpeptidase
ROC - receiver operating characteristic AUROC - area under
the ROC curves
These markers include Fibrotest (FT) for the diagnosis of
significant fibrosis (ranging from few septa to cirrhosis)
and Actitest (AT) for the assessment of necroinflammatory
activity fibrosis and activity. Such results were not obtained
by other diagnostic tests.
The usual indication for liver biopsy in patients with chronic
hepatitis C is to aid in the discussion of treatment options
with the patient and for the long-term follow-up of patients
to determine whether their disease is stable or whether it
has progressed.
Prior data suggest that FT-AT, if accurate, could act as a
surrogate and lead to a significant reduction in the number
of liver biopsies performed.The aim of this study was to validate
the usefulness of FT-AT as surrogate markers of histologic
features using the data generated from a recent randomized
trial of peginterferon alfa-2b and ribavirin.
Three hundred fifty-two patients who had had 2 interpretable
liver biopsies and stored serum sample before and after treatment
were selected. Two hundred eight patients received peginterferon
alfa-2b 1.5 mcg per kg and ribavirin and 144 patients interferon
alfa-2b 3 MU three times a week and ribavirin for 48 weeks.
A fibrosis and an activity index combining 5 and 6 biochemical
markers were assessed at baseline and at end of follow-up
(24 weeks after treatment).
The biochemical markers have significant predictive values
both for the diagnosis of fibrosis and for activity. For the
diagnosis of bridging fibrosis and/or moderate necroinflammatory
activity, the area under the receiver operating characteristics
curve of the activity index was 0.76 1 0.03 at baseline and
0.82 1 0.02 at end of follow-up. A cutoff of activity index
at 0.30 (range, 0.00-1.00) had 90% sensitivity and 88% positive
predictive value for the diagnosis of bridging fibrosis or
moderate necroinflammatory activity.
Sensitivity analyses with biopsy specimens of size greater
than 15 mm suggest that a part of discordances between biochemical
markers and histology were due to biopsy specimen sampling
error.
In conclusion, these biochemical markers of fibrosis and activity
could be used as surrogate markers for liver biopsy in patients
with chronic hepatitis C, both for the initial evaluation
and for follow-up.
This study is the seventh demonstrating that a combination
of 5 (FT) or 6 biochemical markers (AT) can have high positive
or negative predictive values for diagnosing significant fibrosis
and significant activity in patients with chronic hepatitis
C. Although retrospective, the analyses of this study were
made with an independent assessment of FT-AT, of fibrosis
stages, and of activity grades.
These scores are derived from tests that are not yet routine
in many countries. However, all the 6 components are available
in most countries. When compared with routine laboratory tests
found to be predictive of activity or fibrosis, the researchers
found better diagnostic values for their scores. In addition
to superior diagnostic power, FT is not genotype dependent,
whereas the Forns et al. index includes serum cholesterol,
which varies with HCV genotype.
The results show that FT-AT can also be used as surrogate
markers of the histologic impact of treatment. Both indexes
were associated with the virologic responses and with the
histologic variations.
In chronic hepatitis C, the impact of treatment on fibrosis
progression and activity is related to the virologic response
and, for virologic nonresponders, to the baseline stage of
fibrosis and to the duration of treatment. Therefore, FT-AT
could be used as surrogate markers in trials evaluating the
risk-benefit of maintenance therapy, without increasing the
risk and the cost because of repeated liver biopsies.
Back to top
Recommendation of Future Management
of Chronic Hepatitis C Without Liver Biopsies
From the previous results and those presented here, a simplification
of the management of chronic hepatitis C is possible, particularly
using a cutoff of 0.30 for AT. Because this analysis is retrospective,
a randomized trial of 2 strategies comparing a strategy without
and with biopsy is certainly the best scientific comparison
of the respective utilities. However, this type of trial would
require a very large number of patients to estimate the severe
adverse events.
The authors conclude, “Because of the improvement of
biochemical markers and the limits and the risk of biopsy,
liver biopsy should not be mandatory anymore. It is perhaps
time to leave the decision regarding liver biopsy to the physician
and to the patient. There is, worldwide, a lack of screening
and an under prescription of treatment despite its efficacy.
A simplification of liver damage assessment should accelerate
the management of chronic hepatitis C.”
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Hepatitis C on the Rise: US Based
Doctor
Staff Report
LAHORE: A US based Pakistani physician Dr Farrukh Ali Khan
has cautioned that hepatitis C is on the rise in Pakistan
and could lead to liver failure or cancer for most of the
affected if they were not diagnosed early.
Dr Khan, who is on a short visit to Pakistan, was speaking
at a Free Hepatitis Camp arranged by the Mumtaz Bakhtawar
Memorial Trust Hospital on Raiwind road. He said the hepatitis
virus leads to cirrhosis of the liver, causing it to scar
and shrink, and eventually, liver cancer.
He said the Hepatitis C virus was transmitted through improperly
screened blood transfusions, inadequately sterilized surgical
instruments and syringes, ear piercing and hair salon instruments.
To prevent the spread of the disease it is vital to ensure
the blood is screened properly, that disposable syringes,
razors, needles be made standard practice and sterilized equipment
used. He said Hepatitis C has infected three percent of the
total world’s population with 180 million carriers worldwide.
Early and effective treatment is vital to arrest the infection,
he said.
Dr Khan said there are six genotypes of the Hepatitis-C virus
of which genotype 3 is present in 80 per cent of those infected
with the disease in Pakistan. Genotype 1 is more common in
the West. Genotype 3 is the most curable form of the virus
with around 80 percent cure rate, he said.
Unchecked the Hepatitis B and C will triple in 10 years. Pakistan
needs to take drastic measures to block its growth. Health
experts maintained that hepatitis carriers in Pakistan are
rapidly increasing due to ignorance about the virus.
In Pakistan, a sense of complacency in the general public
and the medical community prevents a holistic approach towards
diagnosis and treatment of liver diseases, including hepatitis
and different progressive liver ailments.
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Roche Replenishing Hepatitis C Medicine
The pharmaceutical company Roche is offering samples of Pegasys
(peginterferon alfa-2a) to physicians in the Memphis area
through a program designed to replenish vials of the hepatitis
C medication that may have been lost as a result of power
outages following the July 22 storm.
Patients undergoing treatment for hepatitis C who lost one
or more vials of Pegasys should contact their physicians,
who can request samples.
Roche will be making samples of Pegasys available until Aug.
15 to physicians in Shelby, Fayette, and Tipton counties.
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August 19th, 2003
Regeneration of Hepatocytes From
Intrabiliary Stem Cells in Cirrhosis
by gastrohep.com
The biliary tree, from at least its smaller branches up to
the canals of Hering, is composed of or at least harbors facultative
hepatic stem cells, finds a study in the Journal of Hepatology
(Journal of Hepatology 2003 ; 39 (3) : 357-64).
After massive liver cell necrosis, reactive ductules at the
periphery of the necrotic area are thought to contain hepatic
stem cells which differentiate into intermediate hepatocytes,
regenerating the damged area. In cirrhosis, it is still debated
whether the reactive ductules are activated stem cells (so
called ‘buds’) or ductular metaplasia of cholestatic,
injured hepatocytes.
Dr.Olga Falkowski and colleagues investigated the differentiation
of intermediate hepatocytes from reactive ductules in cirrhosis.
The research team examined tissue explants from patients with
cirrhosis associated with alcohol, hepatitis or with primary
sclerosing cholangitis and from patients with primary biliary
cirrhosis.
“Intraseptal heaptocytes largely represent ‘buds’
of newly formed hepatocytes,” said Dr.Olga Falkowski
777 out of 830 (94%) intraseptal heaptocytes (intermediate
hepatocytes) were associated with reactive ductules.
In 3-D reconstructions, intermediate hepatocytes were seen
to bud directly from the biliary tree.
Intermediate hepatocytes were rarely found to be cholestatic.
Reactive ductules throughout the biliary tree are though to
contain stem cells which give rise to new intermediate hepatocytes
in cirrhosis.
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Unique Scholarship Program Aims to Support African-American
and Hispanic Students Challenged by Hepatitis C: Thurgood
Marshall Scholarship Fund and Hispanic Scholarship Fund Partner
On New Horizons Scholars Program
The Thurgood Marshall Scholarship Fund (TMSF) and the Hispanic
Scholarship Fund (HSF) announced today the launch of the second
year of the New Horizons Scholars Program which will provide
college scholarships to Hispanic and African-American students
entering college in 2004 who have hepatitis C or are dependents
of a person with the disease. The New Horizons Scholars Program
is funded by The Roche Foundation.
These scholarships will help support the
educational imperatives of African-American and Hispanic students
in this country. According to a recent report by American
Council on Education’s Office of Minorities in Higher
Education, college participation rates for African-American
high-school graduates, ages 18-24 was at 39.4 percent in 2000
while the college participation rate for Latinos reached 36.5
percent in 2000. “The New Horizons Scholars Program
is a unique partnership that was established last year, and
aims to create additional financial resources to cover the
costs of higher education for Hispanic and African-American
students impacted by hepatitis C,” said Nicole Lee-Haley,
major gift officer for TMSF. “We’re very excited
to continue this program with our partners and hope to positively
impact the lives of these students through this important
scholarship program.”
The New Horizons Scholars Program will
provide up to 50 scholarships to students planning to enroll
for the first time in a four-year college during the fall
of 2004. Scholarships will be awarded to students of Hispanic
or African-American heritage who are infected or are dependents
of someone infected with hepatitis C. Students will be eligible
for $2,500 per year for four years, and must maintain the
program’s academic standard of 2.5 G.P.A.
Scholarship winners will be notified in
the late spring of 2004. Applications
are available at http://www.hsf.net or http://www.thurgoodmarshallfund.org
or by calling Toll-Free 1-866-346-7496. Applications must
be postmarked no later than February 20, 2004.
“Supporting the higher education
of Hispanics and African Americans is a critical investment
in America’s future,” said Mario De Anda, HSF
director of scholarship programs. “The New Horizons
Scholars Program is a strong partnership with the Thurgood
Marshall Scholarship Fund to help provide educational opportunities
to our communities and make a difference in the lives of our
students.”
“The Roche Foundation is committed
to helping create specialized educational opportunities for
students impacted by hepatitis C,” said Vivian Beetle,
Executive Director of The Roche Foundation, “This program
is part of The Roche Foundation’s ongoing efforts to
help lessen the long term impact of hepatitis C on patients
and their families.”
About Hepatitis C
Hepatitis C virus, a blood-borne disease of the liver, is
the leading cause of cirrhosis and liver cancer and the number
one reason for liver transplants in the U.S. Hepatitis C is
transmitted through body fluids, primarily blood or blood
products, and by sharing needles. Unfortunately, most people
infected with hepatitis C are unaware of it because it may
take years for symptoms to develop. Approximately 2.7 million
Americans are chronically infected with hepatitis C with an
estimated 30,000 new infections yearly.
Hepatitis C disproportionately affects the African-American
and Hispanic community. In the United States, 3.2 percent
of African Americans are infected with hepatitis C, as compared
with 2.1 percent of Hispanics and 1.5 percent of Caucasians.
About the Thurgood Marshall Scholarship Fund
The Thurgood Marshall Scholarship Fund, the first and only
national organization of its kind, supports 45 public historically
black colleges and universities through merit scholarships,
programmatic and capacity-building support. Scholarships are
awarded based on merit and need. Since 1987, the organization
has distributed over $20 million in scholarships and programmatic
support. TMSF serves as an economic gateway to thousands of
students who may not otherwise have the opportunity to go
to college.
About the Hispanic Scholarship Fund
The Hispanic Scholarship Fund (HSF) is the nation’s
leading organization supporting Hispanic higher education.
Founded in 1975, HSF’s vision is to strengthen the country
by advancing college education among Hispanic Americans, the
fastest-growing segment of the U.S. population. In support
of its mission to double the rate of Hispanics earning college
degrees, HSF, a 501©3 not-for profit organization, provides
the Latino community more college scholarships and educational
outreach support than any other organization in the country.
Headquartered in San Francisco, HSF has opened regional offices
in Southern and Central California, the Northeast, the Southeast,
Midwest and Texas. In addition, HSF launched the Washington,
D.C.-based Hispanic Scholarship Fund Institute to generate
public partnerships in support of its work. During its 28-year
history, HSF has awarded more than 61,000 scholarships in
excess of $115 million to Latinos from all 50 states, Puerto
Rico and the U.S. Virgin Islands who have attended more than
1,700 colleges and universities.
About The Roche Foundation
The Roche Foundation (formerly known as the Hoffmann-La Roche
Foundation) was created in 1947 as an independent charitable
entity, solely funded by the company. Today, it continues
to complement the corporate contributions program and helps
support selected community organizations and initiatives.
The Roche Foundation focuses its support on health promotion
and science and math education. The establishment of The Roche
Foundation over 50 years ago demonstrated the company’s
commitment to the importance of good corporate citizenship—a
belief that remains today.
For More Information on the New Horizons Scholars Program
Go To:
http://www.hsf.net
http://www.thurgoodmarshallfund.org
Back to top
August 20th, 2003
Preventive Treatment for HCV Recurrence
in Patients with Decompensated Post-hepatitis C Cirrhosis
Before Liver Transplantation: An Editorial
by hivandhepatitis.com
There is no consensus or compelling evidence for a single,
standard approach to treatment for the prevention of HCV recurrence
following liver transplantation, which unfortunately occurs
almost universally.
In the following editorial, published in the Journal of
Hepatology (September 2003), researchers in the Gastroenterology
Department at the Michallon Hospital in Grenoble, France review
the most recent therapeutic approaches to this serious post
transplantation complication:
After liver transplantation (LT), hepatitis C virus (HCV)
recurrence is almost universal, particularly if HCV RNA is
detectable at the time of transplant and can lead in a great
number of patients to recurrent cirrhosis and graft failure.
This recurrence is often rapid. Several studies have shown
that combination therapy using interferon alfa and ribavirin
is possible after liver transplantation but the virological
response rate is low and the treatment is usually associated
with major side effects, requiring dose reduction or stopping
treatment.
Another strategy is the eradication of HCV RNA before LT in
order to prevent HCV recurrence after LT and reduction in
the level of HCV RNA to reduce the severity of post-transplantation
liver disease.
Forns et al evaluated the efficacy and safety of antiviral
therapy in 30 patients with post-hepatitis C cirrhosis awaiting
liver transplantation. Only patients having an expected time
on the waiting list shorter than four months were included.
Patients with hepatic encephalopathy, renal failure or co-infection
by hepatitis B virus or human immunodeficiency virus were
excluded. Patients were treated with interferon alfa-2b (Intron
A) 3MUI/day and ribavirin 800 mg/day. Dose reductions were
utilized according to the laboratory recommendations.
Fifty patients were screened during a 15-month period, but
19 (38%) were excluded due to contra-indication or refusal.
The median duration of treatment was 12 weeks (2-33). Virological
response was observed in nine patients (30%). Variables associated
with a good response to treatment were age, ALT level, genotype
non 1 and low viral load. A decrease of viral load > or
= 2 log had a positive predictive value of 100% at week 4.
After liver transplantation, among the nine patients with
virological response, HCV infection recurred in only three
patients at week 2, 4, 5, respectively after liver transplantation.
All these patients were infected with genotype 1b.
Six patients became HCV RNA negative after a mean follow-up
of 46 weeks (24-80). Indeed, 4/5 patients also tested in the
liver were HCV RNA negative. Side effects were frequent. Two
patients developed sepsis; in both cases, neutrophil counts
were above 1.2W109/l at the time of hospital admission.
Interferon dose reduction was necessary in 60% of cases and
ribavirin dose reduction in 24% of cases. Eleven patients
required filgrastim due to neutropenia and eight erythropoetin
due to anemia. No patients died during therapy.
Assessment of interferon in patients with decompensated chronic
hepatitis C was until now based on limited small case series.
A gradually increasing dose regimen of combination therapy
with interferon and ribavirin has been used in patients with
both compensated and decompensated cirrhosis due to hepatitis
C by Everson et al.
Patients were started on low dose of interferon (1.5 MUI,
tiw) and ribavirin (600 mg/day) with slowly increasing dose
of both drugs every 2 weeks as tolerated. Preliminary results
of treating 91 patients, the majority infected with genotype
1, were recently reported.
On-treatment virological responses occurred in 38% and a sustained
virological response in 22% of patients. Sustained responses
were more common in patients treated for more than 6 months.
Eight patients who were treated and were HCV RNA negative
at the time of transplantation remained virus free post-transplantation.
On the other hand, recurrent and persistent HCV infection
of the allograft was observed in all patients with detectable
HCV RNA at the time of transplantation. No significant change
was observed regarding the hepatic synthetic function and/or
Child Pugh score. Indeed, 27 of non-responders were reported
to develop adverse events.
Less favorable outcome has been reported by Crippin et al.
(6) in a collaborative study of five US liver transplant centers.
Patients were treated with a common protocol using low dose
of interferon with or without low dose of ribavirin. Only
half the patients screened for the study were enrolled, many
being excluded because of severe cytopenias. All patients
had advanced liver disease with a mean Child-Pugh score of
12, as well as elevated serum bilirubin, prolonged prothrombin
time and moderated impaired renal function.
On treatment, 33% of patients became HCV RNA negative. Two
patients underwent liver transplantation and both developed
recurrent infection. Adverse events were common and sometimes
severe, including profound thrombocytopenia, marked neutropenia,
new-onset hepatic encephalopathy and life-threatening infections
that ultimately led to the early termination of the study.
Of course, because both studies did not include an untreated
control group for comparison, it is unclear whether interferon
and ribavirin combination therapy per se precipitated these
life-threatening infections or whether they merely represented
complications of end stage liver disease.
All together these three studies suggest that antiviral therapy
with post-hepatitis C cirrhosis awaiting liver transplantation
is possible and can prevent HCV disease recurrence in several
patients, especially in patients with favorable predictive
factors of response.
However, recurrence of HCV infection after LT is possible
even if HCV RNA is negative in the serum or the liver at the
time of transplantation. Two explanations can be proposed
to explain this discrepancy: first the method of detection
of HCV RNA was not sensitive enough; in this case it would
be interesting to compare this result with a more sensitive
method of detection such as real-time PCR.
The second explanation could be the persistence of the virus
in a second compartment such as peripheral blood mononuclear
cells; to confirm this hypothesis, it is necessary to study
quasispecies distribution in each compartment.
The best results observed by Everson et al. and Forns et al.
suggest that the treatment is better tolerated in patients
with Child A and B than in patients with Child C and leads
to less severe complications such as neutropenia and thrombocytopenia.
All these studies clearly show also that it is necessary in
some cases to use growth factors including GM-CSF and erythropooetin
to boost peripheral blood cell counts in patients with severe
neutropenia and erythropenia to prevent profound cytopenias
and infections.
From these studies, it seems very difficult to define the
best regimen. In Forns et al. study, authors used daily dose
of recombinant interferon. By contrast, Everson et al. as
well as Crippin et al. used low doses of interferon three
times a week.
There are no data on the safety and/or efficacy of peginterferon
with or without ribavirin in patients with decompensated post
hepatitis C cirrhosis. Indeed, the combination of peginterferon
plus ribavirin was only tested in patients with severe fibrosis
(F3 and F4) and was well tolerated.
However, because peginterferon regimens are associated
with higher rate of neutropenia and thrombocytopenia, treatment
is likely to be associated with even greater infection complications
than regimens using standard infection interferon and slower
recovery from these complications when the interferon is stopped
[emphasis added--Ed.]
It will be very interesting in the future to compare these
different regimens. Indeed, the best duration of treatment
remains to be defined.
The rationale for Forns et al. (4) to treat for a short time
was that most virological responders had a viral load decrease
of > or = 2 log 10 at week 4 and were HCV RNA negative
by week 12. However these results are very surprising, especially
in patients with genotype 1b and were not found by others,
and we do not know which treatment schedule is more convenient.
In conclusion, in patients with decompensated HCV cirrhosis,
antiviral therapy as suggested by Wright et al. in the last
American consensus conference should be considered experimental
and not be administered outside of prospective trials.
If the results of these prospective trials are confirmed,
this strategy could be then used in patients with post-hepatitis
C cirrhosis without severe hepatocellular insufficiency awaiting
LT.
Back to top
Treatment of HCV Patients Awaiting
Liver Transplantation Helps to Prevent HCV Recurrence Following
Surgery
by hivandhepatitis.com
After liver transplantation (LT) infection of the graft with
the hepatitis C virus (HCV) is almost universal and chronic
hepatitis and cirrhosis develop in a significant proportion
of patients. One possible strategy to prevent HCV infection
recurrence is to eradicate HCV before LT.
Researchers at four liver transplant units in Spain evaluated
the efficacy and safety of antiviral therapy to prevent HCV
recurrence in 30 HCV-cirrhotic patients awaiting LT. At the
time of inclusion 15 patients were Child-Pugh A and 15 Child-Pugh
B/C. The infecting genotype was 1b in 25 patients. Treatment
with interferon alfa-2b (Intron A) 3 MU/day and ribavirin
800 mg/day was initiated when the expected time for LT was
less than 4 months and continued until LT. The median duration
of treatment was 12 weeks.
Study Results
Nine patients (30%) achieved a virological response and 21
did not respond to therapy. In nine (43%) of the 21 non-responders
viral load decreased \ge 2 log10 during treatment. A viral
load decrease \ge 2 log10 at week 4 of treatment was the strongest
predictor of virological response.
All nine virological responders have already undergone LT;
six patients remain free of infection after a median follow-up
of 46 weeks and HCV infection recurred in three patients after
LT. In one of these patients HCV-RNA was still detectable
in the explanted liver.
Side effects were frequent and dose reduction was necessary
in 19 (63%) of the 30 patients; no patient died while on therapy.
The authors conclude, “Our data support the utilization
of antiviral therapy in HCV-infected patients awaiting LT
as one of the strategies to prevent hepatitis C recurrence
after transplantation.”
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Geneva Pharmaceuticals Prepares
Generic Rebetol(R) - U.S. District Court Rules Patent Non-Infringement
Geneva Pharmaceuticals, Inc. (“Geneva”), an affiliate
of Novartis AG, announced today that on July 14, 2003, the
U.S. District Court Judge for the Central District of California
granted Geneva’s motion for summary judgment of non-infringement
on U.S. Patent No. 5,767,097; 6,063,772; and 6,150,337 concerning
Rebetol® (Ribavirin.) Rebetol® (Ribavirin) is used
for the treatment of hepatitis C. According to IMS data, sales
for Rebetol® for the 12-month period ended March 2003
reached $721 million. Geneva has settled related patent litigation
with Schering-Plough Corporation (Schering-Plough) and has
entered into a non- exclusive license agreement with Schering-Plough
that will enable Geneva to launch its Ribavirin product as
soon as it receives final approval from the Food and Drug
Administration (FDA) of its Abbreviated New Drug Application
(ANDA).
FDA approval of Geneva’s ANDA is pending. Additionally,
the FDA has yet to determine which company or companies will
receive 180 days of marketing exclusivity for the product.
Said John Sedor, Geneva President and Chief Executive Officer,
“We believe Geneva will have an exclusive or shared
exclusive position with respect to the launch of generic Ribavirin.
This could make Geneva the first generic company to launch
a generic version of Ribavirin. This product is being manufactured
in our Broomfield, Colo., facility using isolation suite technology.
We are fully prepared to launch this product and provide a
lower-cost drug alternative for patients. We are working closely
with the FDA in order to make Ribavirin available in the marketplace
as quickly as possible.”
Rebetol® is a registered trademark of Schering-Plough.
This release contains certain “forward-looking statements”
relating to Geneva Pharmaceuticals, an affiliate of Novartis
AG and its business or products, which can be identified by
the use of forward-looking terminology such as “will
be,” “continue to,” or similar expressions,
or by express or implied discussions regarding strategies,
plans and expectations. Such statements reflect the current
plans or views of Geneva with respect to future events and
are subject to certain risks, uncertainties and assumptions.
Management’s expectations and sales of Ribavirin could
be affected by, among other things, ability to obtain or maintain
patent or other proprietary intellectual property, competition
in general, and other risks referred to in Novartis AG’s
Form 20-F on file with the U.S. Securities and Exchange Commission.
Should one or more of these risks or uncertainties materialize,
or should underlying assumptions prove incorrect, actual results
may vary materially from those described herein as anticipated,
believed, estimated or expected.
Geneva Pharmaceuticals, Inc. is one of
the largest prescription generic pharmaceutical companies
in the U.S. Geneva produces more than 200 products each year,
with an annual manufacturing capability exceeding 10 billion
tablets and capsules. Geneva products range across many therapeutic
drug categories including anti-infectives, anti-arthritics,
cardiovasculars, gastrointestinal agents and psychotherapeutics.
Geneva is an affiliate of the Novartis AG (NYSE: NVS) group
of companies (the Group), a world leader in healthcare with
core businesses in pharmaceuticals, consumer health, generics,
eye-care and animal health. Novartis AG (NYSE: NVS) is a world
leader in pharmaceuticals and consumer health. In 2002, the
Group’s businesses achieved sales of CHF 32.4 billion
(USD 20.9 billion) and a net income of CHF 7.3 billion (USD
4.7 billion). The Group invested approximately CHF 4.3 billion
(USD 2.8 billion) in R&D. Headquartered in Basel, Switzerland,
Novartis Group companies employ about 72,900 people and operate
in more than 140 countries around the world. For more information
on Novartis, http://www.novartis.com. For more information
about Geneva Pharmaceuticals, please see our website at genevarx.com
Back to top
August 22nd, 2003
Prevalence of
Hepatitis C Virus Infection in Urban Children in the USA
by gastrohep.com
A study in The Journal of Pediatrics (Journal
of Pediatrics 2003; 143(1): 54-60) reports that only
1 out of 1034 children screened for hepatitis C virus in an
urban hospital in Baltimore, USA, was positive for hepatitis
C virus antibodies.
Dr Samer El-Kamary and colleagues investigated the prevalence
of hepatitis C virus infection in children attending an urban
hospital pediatric primary care clinic in Baltimore, USA.
1034 children were tested for HCV antibodies after excluding
children known to be HIV-positive.
Dr El-Kamary’s team also assessed maternal hepatitis
C virus risk factors through structured interviews with a
sample of mothers and a review of available medical records.
Intravenous drug use was significantly underreported.
Only 1 child (0.1%) tested positive for hepatitis C virus
antibodies.
History of blood transfusion was reported by 7% of mothers
and intravenous drug use by 1.8%.
However, analysis of medical records revealed that intravenous
drug use was significantly underreported.
Dr El-Kamary concludes. “Universal screening of children
for HCV in high-risk urban communities is not warranted.”
“Self-report may not be reliable for identifying mothers
with a history of intravenous drug use.”
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Histoacryl Injection or Beta-Blockers
for the Eradication of Esophogastric Varices
by gastrohep.com
A study in the September issue of Endoscopy (Endoscopy
2003; 729-735) finds that repeated injections of histoacryl
are no more effective than beta-blocker administration in
the eradication of esophagogastric varices, and are associated
with more complications compared with beta-blocker administration.
Histoacryl is highly effective in controlling active bleeding
of esophageal and gastric varices. However, it is not known
whether repeated histaoacryl injections are effective for
long-term eradication of esophagogastric varices.
A team of Belgian doctors compared the efficacy and safety
of endoscopic histoacryl injection with beta-blocker (propranolol)
administration in the secondary prevention of esophagogastric
variceal bleeding.
41 patients with primary bleeding from esophageal or gastric
varices were included in the study.
Primary hemostasis was achieved with histoacryl obliteration
of the varices.
Subsequently, the research team randomised patients to undergo
complete histoacryl obliteration of the remaining varices
with histoacryl or to receive long-term propranolol administration
for the prevention of rebleeding.
There was no significant difference in the incidence of early
rebleeding between the 2 treatment groups. 5 of the 21 patients
who underwent histoacryl injection and 3 of the 20 patients
taking propanolol re-bled within the first 6 weeks.
There was also no significant difference in long-term rebleeding
or mortality between the 2 treatment groups.
Complications, however, were significantly more likely in
patients who underwent histoacryl variceal eradication.
Repeated injections of histoacryl are associated with more
complications compared with beta-blocker administration, with
similar results in terms of rebleeding rate and survival in
the long term.
10 out of 21 patients receiving histoacryl injections suffered
adverse effects, compared with only 2 of the 20 patients receiving
beta-blockers.
Back to top
College Students Ignoring Risks
of Unprotected Sex
by Gary Gately, HealthDay Reporter
An alarming number of American college students engage in
unprotected sex, but most fail to realize the risk of contracting
sexually transmitted diseases, says a new national survey.
Among college students who live away from home, 56 percent
had been sexually active while attending college, and 73 percent
of that group reported having unprotected sex while in college,
says the survey by the Society for Adolescent Medicine.
Underscoring widespread ignorance about sexually transmitted
diseases, the online survey of 516 students found that 68
percent of those who had unprotected sex did not believe they
were at risk of contracting an STD.
And almost half of the sexually active students had never
been tested for an STD, even though one in five college students
knew someone who has contracted a sexually transmitted disease
while in college, according to the survey, which was conducted
last spring by Harris Interactive.
“I’m actually troubled by the findings, particularly
the one about unprotected sex,” says Helen E. Johnson,
co-author of the book Don’t Tell Me What to Do,
Just Send Money: The Essential Parenting Guide to the College
Years.
“I think part of it is people at this age really do
feel immortal; they don’t understand that their behavior
has real consequences,” says Johnson, who contributed
to a free booklet the Society for Adolescent Medicine prepared
for parents on ways to help protect children while they’re
away at school.
Johnson says parents often share much of the blame for their
college-age kids’ risky behavior.
“I think too many parents today want to be their kids’
friends and—sort of by default, not intentionally—they
abrogate that important parental responsibility, which is
making it really clear to your kids what your values are,”
Johnson says.
“Even though they will act like they’re tuning
you out, they hear you, and what I found working with college
students is that they really care what their parents think
about these things, and they generally don’t know,”
she adds.
Charlotte A. Gaydos, an associate professor of medicine at
Johns Hopkins University School of Medicine, says the survey’s
findings came as no surprise.
“Kids are having high-risk sexual behaviors, and they
are not getting screened,” Gaydos says. “One of
the reasons is most of the sexually transmitted diseases are
asymptomatic.” She encourages college students to not
be shy about asking to be screened.
But Gaydos says physicians also could do more to prevent STDs
among young patients.
“Many pediatricians are hesitant to ask whether [their
patients] are sexually active,” she says.
She also believes better high school education about STDs
would help.
The survey also found little awareness among students about
hepatitis B, which can be spread not only through sex but
also through body piercing, tattooing, contact sports and
sharing a razor or toothbrush.
Forty percent of college students either have a tattoo or
body piercing or are likely to get one or the other before
graduating, the survey found, and a third of students admitted
to sharing either a razor or toothbrush with a roommate, partner
or friend. But while almost all students surveyed had heard
of hepatitis B, more than half were not protected by a vaccine
or didn’t know if they were, the survey says.
Hepatitis B—a potentially life-threatening viral liver
disease—is one of the few STDs that can be prevented
by a vaccine, the Society for Adolescent Medicine says.
In its booklet, the society also recommends that parents:
• Review your child’s health history and make
sure all medical information is updated.
• Make sure your child has appropriate medical insurance
and carries a health insurance card. Up to 30 percent of college
students have no health insurance, the society says.
• Check with your doctor about your child’s immunizations
for hepatitis A, hepatitis B, influenza, meningococcal meningitis,
polio (news - web sites), tetanus-diptheria, chickenpox and
measles, mumps and rubella.
• Get a tuberculosis skin test for your child if it’s
required by the college or recommended by a health care provider.
• Have your primary health care provider send the campus
information about care, medications and restrictions on activity
if your child has chronic medical problems. If a disability
requires special accommodations, let the campus disabilities
office know.
• Check into health resources on and near campus so
your child will know about after-hours care, emergency services,
pharmacy services and the location of the nearest hospital.
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Schering-Plough Slashes Costs. Jobs,
Dividend and Perks Among Cutback Targets
by Ed Silverman, Star-Ledger
Fred Hassan has a dramatic prescription for an ailing Schering-
Plough: Eliminate jobs and bonuses, cut the dividend, close
the executive dining room and sell the company jet.
The eye-popping moves come at a time of turmoil for the Kenilworth-based
drug maker, which is reeling from government probes over its
business practices and a stunning drop in sales of Claritin,
a medicine that was once a franchise product.
The cutbacks, which were announced yesterday after the stock
market closed, are designed to save at least $200 million
and come just one week after the
company disclosed that cash from operations may not be sufficient
to cover expenses this year.
“My review of the situation we inherited
confirmed the need for aggressive measures, including aggressive
cost containment and cost cutting in order to stabilize the
company and to create a realistic base on which to build a
turnaround,” Hassan said in a statement.
The belt-tightening pronouncement, which
includes reducing head count by about 1,000 positions, capped
a “100-day, 360-degree review” of operations by
the new CEO. Hassan, who previously headed Pharmacia, was
billed as a gifted turnaround artist when he was hired by
Schering-Plough in April.
For now, the job cuts will take place through an early retirement
program, but still more jobs will be lost, and a company spokeswoman
said layoffs are possible. Globally, the drug maker employees
about 30,000 people, including 6,900 in New Jersey.
To set the tone, Hassan is foregoing his own bonus this year,
which could have been as much as $2 million, and is eliminating
various perks, such as flying first class and exclusive health
plans for executives.
“We will all be making sacrifices as a result of these
actions,” Hassan’s statement said.
Still, he was criticized last night by Wall Street analysts
for not participating in a conference call with company spokespeople.
“He’s leaving us dangling at 7 o’clock at
night at the end of August,” complained Barbara Ryan,
an analyst at Deutsche Bank Securities, in remarks during
the conference call. “It damages his credibility.”
The most unusual cost-cutting move involves slashing the dividend,
to 5.5 cents per share from 17 cents. It’s a step rarely
taken in the profit-rich pharmaceutical industry, and a further
sign of the company’s breathtaking reversal of fortunes.
The dividend costs the company $250 million every quarter.
But with shares down 70 percent over the past two years, it
has become a luxury.
Schering’s 4.13 percent dividend yield was among the
top 10 percent of companies in the Standard & Poor’s
500 index. With the cut, the yield will be 1.33 percent.
To underscore the financial difficulties, Hassan also noted
that earnings for the second half of this year are expected
to fall short of the 24 cents per share posted in the first
half of 2003. Moreover, 2004 earnings are likely to be lower
than this year’s earnings, he said.
Schering-Plough has struggled since its blockbuster Claritin
allergy drug lost patent protection last year, resulting in
cheaper generic rivals. At one time, Claritin generated $3
billion in annual revenue. In this year’s second quarter,
Claritin sales were just $83 million.
Since then, competition emerged for yet another huge-selling
product, a treatment for hepatitis C. The one-two punch sent
this year’s second-quarter sales diving 17 percent,
to $2.3 billion.
At the same time, the company signed a consent decree and
agreed to pay a $500 million fine as a result of a protracted
investigation over its manufacturing procedures by the Food
and Drug Administration.
Meanwhile, the U.S. Attorney’s Office in Newark is investigating
manufacturing problems. And federal prosecutors in Massachusetts
and Pennsylvania are investigating a host of marketing and
sales practices
.
Among the other cost-cutting measures being ordered by Hassan
are freezing routine employee merit increases through 2004;
zero payout of profit sharing; and severely restricting hiring.
In trading prior to last night’s announcement, Schering-Plough
stock closed at $16.48, up 24 cents, or 1.5 percent.
Back to top
August 24, 2003
Wane of Hepatitis
C Drugs Wound Schering-Plough
by Ransdell Pierson
Schering-Plough Corp., which rocked Wall Street with a warning
its earnings will fall again next year, owes much of its troubles
to falling sales of a hepatitis C therapy.
The company, already hit by plunging sales of allergy drug
Claritin, next year will likely see its hepatitis drugs eclipsed
by a cheaper and more convenient treatment recently launched
by Roche Holding AG, doctors and analysts said.
Schering-Plough’s combination therapy against the hepatitis
C virus was introduced two years ago and is now the company’s
biggest product line. It includes a long-acting interferon
medicine called Peg-Intron and the antiviral pill ribavirin.
Sales of the therapy fell 14 percent to $569 million in the
second quarter, hurt by Roche’s injectable Pegasys interferon
and its version of ribavirin, called Copegus.
“We are seeing a downward slope in sales of our biggest
products, including Peg-Intron,” Chief Executive Fred
Hassan told Reuters in an interview.
Decline of the Schering-Plough hepatitis business comes at
the worst possible time, just months after the U.S. patent
on Claritin expired. Sales of the allergy pill, once $3 billion
a year, have tumbled almost 90 percent now that it is being
sold over the counter at a fraction of its previous price.
The Kenilworth, New Jersey-based drugmaker expects 2003 earnings
to fall by two-thirds, and it has slashed its dividend to
preserve cash. Its shares sank to a six-year low on Friday
after it warned profits will decline again next year.
Hassan, who was hired earlier this year to turn around the
company, said Roche spurred sales of Pegasys largely by giving
away the first three months of treatment to 15,000 American
patients. The same patients then had to pay for remaining
months of therapy.
About 4 million Americans are believed infected with the hepatitis
C virus, which is the biggest cause of liver transplants.
The virus quietly attacks the liver for decades before symptoms
develop, but can be eliminated with the Roche and Schering-Plough
drugs.
“Roche’s marketing skills are alarming Schering-Plough,
which had taken its own hepatitis products for granted and
assumed they would prevail in the leadership role,”
said Sena Lund, a drug analyst for Cathay Financial LLC.
The Schering-Plough combination had a U.S. monopoly until
Swiss drugmaker Roche launched its rival drugs in January,
pricing its ribavirin at an approximate 43 percent discount.
Pegasys now boasts a 42.1 percent share of the U.S. market
for long-acting interferons, leaving Peg-Intron with less
than 58 percent, according to SG Cowen analyst Steve Scala.
Sund said the combined wholesale cost of Roche’s two
medicines is $23,000 for a year’s course of treatment,
versus $26,000 for Schering-Plough’s.
That cost advantage could allow Roche’s products to
catch up with or overtake Schering-Plough’s by year’s
end, he added, even if other companies launch cheaper generic
forms of ribavirin.
“Schering-Plough now has to lower its prices or do something
else to protect its market share,” Sund said.
Pegasys has also become popular with many doctors and patients
because it comes pre-mixed in a single vial, which is drawn
by a syringe and injected once a week. All patients take the
same fixed dose.
By contrast, Peg-Intron requires patients to use two syringes
and two vials in a process that combines a liquid and a powder.
In addition, the dose must be adjusted by body weight.
“I personally now only prescribe Pegasys because so
many patients say it is so much easier to use than Peg-Intron,”
said Dr. Samuel Daniel, chief executive at North General Hospital
in New York, who noted Roche has financial ties to the hospital.
Schering-Plough hopes to win U.S. approval for a pen-like
device that would allow patients to inject Peg-Intron directly,
without need to mix vials. But the company has not predicted
when it will be launched or how many patients will embrace
it.
Although the battling therapies have never been compared head-to-head
in clinical trials, many doctors consider them similarly effective
and well tolerated.
Dr. Mitchell Shiffman, a professor at Virginia Commonwealth
University Health System, said the greater convenience of
Roche’s combination therapy could make it the preferred
choice within a year.
Schering-Plough is attempting to stem Roche’s assault
by suggesting that Peg-Intron—with its personalized
dosing—may be more appropriate for overweight patients
than Pegasys. But it acknowledges a trial directly comparing
the two drugs would be needed to draw firm conclusions.
Back to top
August 25th, 2003
Vaccination and
Anti-HIV Therapy Lower Hepatitis B Infection Rates
by Will Boggs, MD, hivandhepatitis.com
Vaccination and antiretroviral therapy lower the very high
rates of hepatitis B virus (HBV) infection among HIV-infected
patients, according to a report in the August 15th issue of
The Journal of Infectious Diseases (J Infect
Dis 2003;188:571-577).
The incidence of acute HBV infection is approximately 0.033
cases per 1000 person-years in the general population, with
about 0.4% of the general population having chronic HBV infection,
the authors explain. Data are limited about rates of HIV and
HBV coinfection since highly active antiretroviral therapy
(HAART) for HIV infection became available.
Dr. Scott E. Kellerman and colleagues from Centers for Disease
Control and Prevention in Atlanta investigated the incidence
of acute HBV and prevalence of chronic HBV, vaccination rates,
and potential risk factors in the 16,248 HIV-infected subjects
enrolled in the Adult/Adolescent Spectrum of HIV Disease Project.
Among these HIV-infected patients, rates were much higher
than in the general population for acute HBV incidence (12.2
cases per 1000 patient-years) and for chronic HBV prevalence
(7.6%), the authors report.
The incidence of acute HBV infection was higher among black
subjects, subjects with a history of alcohol abuse in the
6 months before an observation, and among those who injected
drugs, the report indicates. On the other hand, incidence
rates were lower among patients treated with HAART (with or
without lamivudine) and among those who had received at least
one dose of hepatitis B vaccination.
Chronic HBV infection was more prevalent among men than among
women, the researchers note, and was most prevalent among
men who had sex with men and were intravenous drug users and
was least prevalent among Hispanics.
Antiretroviral drug regimens that contained lamivudine were
associated with a much lower prevalence of chronic HBV (2.3%)
than were regimens that did not contain lamivudine (7.8%),
the results indicate. Prevalence was 22.1% among subjects
not treated with antiretroviral drugs.
“Considering the amount of time that many HIV-positive
persons spend in the medical care system, it is unfortunate
that many are not being adequately assessed regarding their
HBV (and hepatitis A virus, for that matter) immunization
status,” Dr. Kellerman told Reuters Health.
“We found that only 14% of HIV positive persons had
been previously vaccinated against HBV, despite recommendations
for HBV vaccination in HIV-positive persons that have been
available for years,” he added.
Dr. Kellerman advises physicians to “ask your HIV-positive
patients if they’ve been immunized against HBV, and
if they haven’t or can’t remember, consider immunizing.
HIV-positive persons can still be at risk for blood-borne
or sexually transmitted infections.”
Back to top
Hyperlipasemia
and/or Subclinical Pancreatitis May Represent Extrahepatic
Manifestations of HCV Infection
by hivandhepatitis.com
Extrahepatic manifestations of chronic hepatitis C virus (HCV)
infection have been well described. However, hyperlipasemia
and/or pancreatitis have not been reported.
Following the observation that several HCV patients had elevated
lipase levels, this retrospective study, conducted at the
Veterans Affairs Medical Center, Baylor College of Medicine,
Houston, Texas, assessed the association between hyperlipasemia
and/or pancreatitis with hepatitis C infection.
Of 204 subjects who underwent evaluation for hepatitis C,
103 had lipase levels determined at baseline. The control
group consisted of 41 non-HCV subjects with a variety of gastrointestinal
diseases including 18 with nonalcoholic liver disease. Twenty-five
percent of HCV patients had elevated lipase at baseline as
compared to 10% of controls (P = 0.04). Mean lipase levels
were 253 +/- 72 units/liter (normal range 114-286 units/liter
and 210 +/- 42 units/liter for the HCV and control groups,
respectively (P = 0.002).
No significant difference in amylase was found between the
groups. There was a significant association between ALT (>
1.5 times the upper limit of normal) and lipase (P = 0.02).
Among 30 patients who received interferon-based therapy +/-
ribavirin, 11 had elevated lipase at baseline. Six of these
patients responded to therapy and demonstrated normalization
of lipase levels.
In contrast, all nonresponders with baseline hyperlipasemia
continued to have high lipase levels (P = 0.17). Furthermore,
only 3 of 8 (37.5%) patients with normal lipase responded
to treatment as compared to 6 of 10 (60%) of hyperlipasemic
patients (P = 0.36).
The authors conclude, “Hyperlipasemia and/or subclinical
pancreatitis may represent extrahepatic manifestations of
HCV infection and should not preclude treatment.”
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Twice Daily Dosing
with Interferon Beta Improves Viral Kinetics and Enhances
Antiviral Efficacy
by hivandhepatitis.com
The aim of the current study was to address the molecular
mechanism for enhanced antiviral efficacy associated with
a frequent dosing of interferon (IFN)-beta.
Prior studies have indicated that twice daily dosing of interferon
beta produces an enhanced antiviral response and that twice
daily dosing is the more efficient form for induction therapy
for chronic hepatitis C.
Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated
protein kinase (PKR) mRNA and MxA mRNA levels in peripheral
blood mononuclear cells (PBMC) were analyzed serially in 140
patients who were randomly assigned to a twice daily (3MU
bid) or once daily (6MU qd) administration group.
In the twice daily group, the rate of HCV decline during the
second phase was 2-fold greater than in the once daily group
(P=0.04). Peak PKR and MxA gene expression levels in the first
phase (observed 4 h after a single administration) were 2-fold
higher in the once daily group. However, the expression in
the second phase was maintained at a significantly higher
level in the twice daily group. Initial and peak expression
levels were related to initial viral load. Basal expressions
in PBMC were significantly correlated with those in the liver
tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001).
These data suggest that elimination of HCV-infected cells
is enhanced by twice daily dosing of intravenous (IV) natural
interferon beta (Feron), and that this enhanced effect is
associated with a higher intracellular expression of PKR and
MxA during the second phase.
Back to top
Management of Hematologic
Disorders Associated with Hepatitis C Virus Infection
by hivandhepatitis.com
More than 4 million people in the United States are acutely
or chronically infected with hepatitis C virus (HCV). Of those
individuals with acute HCV infection, 54% - 86% will develop
chronic infection, and at least 20% of individuals who are
chronically infected will develop cirrhosis. HCV is the most
common cause of cirrhosis and is responsible for >50% of
liver transplants performed.
To date, the most effective treatment for chronic HCV infection
is the combination of either interferon (IFN) alfa or pegylated
IFN-alfa and ribavirin. For a sustained virologic response,
treatment adherence and dose maintenance are essential.
However, both IFN-alfa and ribavirin induce hematologic toxicity,
which can compromise treatment adherence and dose maintenance.
Preliminary data suggest that the infection itself can also
induce autoimmune hemolytic anemia, leukopenia, and thrombocytopenia.
Although no approved treatments for HCV-related hematologic
complications exist, this review by Dr. Dieterich (Mount Sinai
Medical Center) and Dr. Spivak (Johns Hopkins Medical Institutions)
summarize the pharmacology, risks, and benefits of the investigational
use of hematopoietic growth factors for treating such complications.
The most important factors in successful eradication of HCV
are adherence to therapy and dose maintenance. Optimal results
have been obtained in patients infected with HCV genotype
1 when treatment with at least 80% of the IFN-alfa dose and
at least 80% of the RBV dose was maintained for at least 80%
of the time.
However, combination therapy significantly increases the risk
of dose modifications and discontinuations due to treatment-related
adverse effects and dose modifications appear to be less than
optimal for HCV eradication.
Thus, treatment success may be compromised by the adverse
effects of HCV therapy. As detailed in the 2002 National Institutes
of Health Consensus Statement on the Management of Hepatitis
C, “There is a need to assess the effectiveness of supportive
therapy to ameliorate the side effects of antiviral therapy.”
Side effects of IFN-alfa and PEG-IFN-alfa (hereafter, where
both IFN-alfa and PEG-IFN-alfa are meant, “[PEG]IFN-alfa”
is used) include depression, transient flu-like symptoms (headache,
fatigue, myalgia, chills, and fever), more severe or persistent
fatigue, alopecia, and bone marrow suppression leading to
anemia and neutropenia.
Leukopenia and thrombocytopenia are also common; however,
they tend to be mild and generally are not associated with
complications. Neutropenia and thrombocytopenia appear to
occur at higher rates with use of PEG-IFN-alfa than with use
of nonpegylated IFN-alfa, whereas anemia tends to occur less
frequently with PEG-IFN-alfa than with nonpegylated IFN-alfa.
The major side effect of treatment with RBV is dose-dependent
hemolytic anemia. At RBV doses of > or = 800 mg/day, RBV-induced
hemolytic anemia causes a dramatic decrease in hemoglobin
levels (of 2 - 3 g/dL), usually > or = 4 weeks of initiation
of treatment. When combination therapy with IFN-alfa/RBV is
used, hemoglobin levels <11 g/dL occur in 25% - 30% of
patients. Anemia has been found to be more pronounced with
combination therapy than with IFN-alfa monotherapy.
The incidence of dose modifications due to anemia increased
from 0% with IFN-alfa monotherapy to 7% 9% with combination
therapy. Similarly, the incidence of dose reductions due to
anemia increased from 1% with PEG-IFN-alfa monotherapy to
22% with PEG-IFN-alfa/RBV therapy. In addition, dose reductions
due to neutropenia and thrombocytopenia were more common in
association with PEG-IFN-alfa/RBV therapy than with standard
IFN-alfa/RBV therapy.
Some of the consequences of anemia include impaired tissue
oxygenation, organ function, and quality of life, as well
as increased susceptibility to thrombocytopenic bleeding,
increased risk of postoperative mortality, and increased likelihood
that blood transfusions will be needed. In addition, anemia
may be associated with decreased survival rates among patients
with HIV infection and cancer. These clinical sequelae of
anemia indicate the importance of its treatment, especially
in patients with a chronic disease.
Strategies for Treating Hematologic Disorders in HCV-Infected
Patients
Recombinant human erythropoietin: Pharmacologic enhancement
of erythropoiesis is an effective strategy for alleviating
anemia without exposing the patient to allogeneic blood and
the accompanying risks. Epoetin alfa (Procrit; Ortho Biotech)
is the only recombinant human erythropoietin that has been
evaluated in clinical trials for the treatment of anemia in
patients with HCV.
Granulocyte colony-stimulating factor (G-CSF): Recombinant
human G-CSF (filgrastim, an agent that enhances granulopoiesis
in neutropenic patients with cancer who are receiving IFN-alfa),
stimulates production of multipotent hematopoietic progenitor
cells and mature granulocytes.
Although there are no guidelines for the use of G-CSF in the
HCV-infected population, the rationale for its use is predicated
on its success in patients with cancer who are receiving chemotherapy.
Interfeukin (IL)-11: Recombinant human IL-11 (rhIL-11; oprelvekin)
is the only currently approved agent for enhancing platelet
production, which it does by stimulating megakaryocytopoiesis.
Independent case studies have demonstrated that patients with
chronic HCV infection can develop autoimmune hemolytic anemia
in the absence of treatment with IFN-alfa. In these HCV-infected
patients, autoimmune hemolytic anemia was reversible with
prednisolone therapy. In addition, fatigue, a major symptom
of anemia, was recently reported to be the most common extrahepatic
complication in HCV-infected patients, and, in one study,
it was considered by almost one-half (48%) of all untreated
HCV-infected patients to be the initial or worst symptom.
Conclusion
Due to the slow course of HCV-related liver disease, the burden
of co-morbidities in patients chronically infected with HCV
will have a large impact over the course of the next 30 years.
The most effective treatment for HCV infection is combination
therapy with (PEG)IFN-alfa and RBV. The eradication of HCV
is possible; however, treatment adherence and dose maintenance
are essential. Both IFN-alfa and RBV induce hematologic disorders
that may exacerbate or compound an already fragile hematologic
state in the HCV-infected individual and may compromise treatment
adherence.
Therapies (e.g., epoetin alfa) to counter these disorders
(e.g., anemia) have been successful in allowing the maintenance
of critical dose levels of RBV and thus providing optimal
HCV treatment that should improve adherence and treatment
success.
Back to top
Chinese Scientists
Decode New Hepatitis B Virus Genes
by Xinhua News Agency via Pinnacor
Chinese scientists have decoded two new genes found in the
hepatitis B virus (HBV) genome. It is hoped that the discovery
will lead to a new treatment for the disease.
A research team at the No.302 Hospital of the Chinese People’s
Liberation Army found the new genes after cloning and analyzing
the gene sequencing of HBV taken from blood of HBV patients
in China, said Cheng Jun, leader of the research team, here
Wednesday.
For the past 25 years, scientists have believed that HBV genome
contained four open reading frames. The new discovery brings
the number of open reading frames to six.
The finding will not only enhance research into the HBV virus
and treatment of the disease, for instance, by helping develop
a new antigen for the virus, but also the treatment of liver
cancer, he said.
Some 350 million people worldwide are victims of hepatitis
B, only one third of whom show a favorable response to presently
available treatment. Many of the other sufferers will develop
liver cancer.
Further research will be needed to identify how far the new
genes will contribute to the treatment of hepatitis B and
liver cancer, Cheng said.
Back to top
Antioxidants May
be Beneficial For Transplant Patients
by John C. Martin, hepatitisneighborhood.com
People who undergo organ transplants may benefit by taking
supplements of both vitamins C and E, says a 2002 study by
doctors at medical institutions in Oregon and Massachusetts.
While the study focused on heart transplantation, the researchers
say patients who undergo other types of transplants, including
those of the liver, may also benefit.
“Cardiac transplantation is associated with oxidant
stress, which may contribute to the development of accelerated
coronary arteriosclerosis,” wrote researchers in the
cardiovascular division of Brigham and Women’s Hospital
in Boston. “We postulated that treatment with antioxidant
vitamins C and E would retard the progression of transplant-associated
arteriosclerosis.”
Vitamins and Transplant Oxidation
In the study, patients who received supplements of these two
antioxidant vitamins had very little coronary arteriosclerosis
associated with their transplants. Ordinarily, this is one
of the most important limitations to the long-term survival
of heart transplant patients; their arteries tend to clog
unusually fast after surgery. The condition is present in
over 70 percent of recipients within three years, according
to estimates.
Arteriosclerosis is a condition in which arteries become clogged
due to fibrosis or calcium deposits. The term is typically
used to describe several diseases associated with this condition
of the arteries.
The Culprit: Oxidation
The study found that oxidation in the body tends to contribute
to increased coronary blockage following a transplant procedure,
and the body’s natural antioxidant defenses are often
reduced. So, treatment with antioxidant vitamins appears to
have significant value in addressing this problem, the researchers
found.
Oxidants are harmful molecules that cause oxidation of cholesterol,
which results in the buildup of plaques in arteries, among
other things. Antioxidants, by contrast, are vitamins that
block the action of oxidants in the body, and prevent the
buildup of these plaques.(2)
“Like oxidants, antioxidants constitute a diverse group
of compounds with different properties. They operate by inhibiting
oxidant formation, intercepting oxidants once they have formed,
and repairing oxidant-induced injury,” wrote Diane Tribble,
Ph.D., in an advisory letter to the American Heart Association.
“In many cases, increased antioxidant intake has been
shown to be associated with reduced disease risk,” Tribble
wrote. “This generally has involved increased consumption
of antioxidant-rich foods, although some, but not all, recent
results have suggested the possible importance of supplemental
levels of antioxidants.”
According to the latest statistics, nearly a third of Americans
are taking some form of antioxidant supplement today.
Acute Oxidation After Transplantation
“Arteriosclerosis is a health condition that’s
a problem for many people, but it is much more acute and occurs
more rapidly in people who have had heart transplants,”
said Balz Frei, Ph.D., professor and director of the Linus
Pauling Institute at Oregon State University, who took part
in the study.
Forty heart transplant patients were recruited for the double-blind
research. Half received 1000 milligrams of vitamin C and 800
international units (IU) of vitamin E each day. The others
received a placebo, or dummy pill with no therapeutic value,
as a comparison.
Antioxidants’ Effect
After one year, the patients who had taken placebo saw had
increased thickening and narrowing of their coronary arteries,
but those who had received antioxidants had arterial conditions
that were relatively unchanged.
“During one year of treatment, the intimal index increased
in the placebo group by 8 percent, but did not change significantly
in the treatment group,” wrote the cardiologists. (The
intima refers to the inner layer of blood vessels.)
The research team also found that antioxidant use did not
appear to interfere with the immunosuppressive drugs that
the patients were required to take, or cause any increase
in transplant rejection.
The authors cited previous studies that tested the effect
of vitamin E alone as a supplement in patients with arteriosclerosis,
but the outcome was not as dramatic as the latest study, which
combined vitamins E and C. They may be complementary to each
other, providing more beneficial results than if either one
of them were used alone, the researchers speculate.
This type of antioxidant therapy may also have value in other
types of organ transplants, such as those of the kidney, lung
and liver, said Frei, or in medical procedures like angioplasty.
Angioplasty, in which a balloon catheter is fed into a blocked
artery to open it up, has to be repeated after several months
when arteries again become clogged.
Back to top
Risk of Cancer
Higher in Patients with Fatty Liver, Say Japanese Doctors
by John C. Martin, hivandhepatitis.com
It appears that steatosis, otherwise known as fatty liver,
increases the risk of developing hepatocellular carcinoma
(HCC), the liver cancer that sometimes results in patients
with late-stage hepatitis C (HCV).
That’s the conclusion of a group of Japanese medical
researchers who analyzed more than 100 patients to determine
whether steatosis is a cancer risk factor.(1)
“Hepatic steatosis is one of the “features of
chronic hepatitis C,” wrote Katsumi Eguchi, M.D., OF
Nagasaki University School of Medicine, and his colleagues.
“According to previous reports, the prevalence of hepatic
steatosis ranges from 31 to 72 percent.”
“The objective of this study was to determine whether
hepatic steatosis is an independent risk factor in the development
of HCC in patients with chronic HCV,” the investigators
wrote.
They launched the study based on previously reported research
that showed a protein associated with hepatitis C in mice
caused liver cancer in relation with steatosis evidence.
While steatosis is common in people with HCV, it has been
unclear about how this liver condition might affect a patient’s
risk for developing cancer. What does remain clear is that
factors such as the scarring of the liver called cirrhosis,
the strain of hepatitis C virus that a person has, and total
alcohol intake have been confirmed as higher risk factors
for liver cancer.
Origins of Liver Cancer
Hepatocellular carcinoma is the most common form of liver
cancer because it comes from hepatocytes, the main type of
liver cell. About 75 percent of primary liver cancers are
of this type.
Hepatocellular carcinoma develops using different growth patterns.
Sometimes, it begins as a single tumor that grows by expanding,
and spreads to the rest of the liver only during later stages.
A second type spreads tentacle-like growths throughout the
liver, and is not confined to a single tumor. This is the
most common pattern seen in the U.S.
In a third type, the cancer develops as nodules in several
parts of the liver.
Sometimes, however, the pattern is not clear, and the cancer
does not fit any of these profiles.
In steatosis, fat accumulates in the liver cells. Simply fatty
liver does not damage the liver, but can be identified through
a liver biopsy. Fat may accumulate in the liver in people
with extreme weight gain, those with poor diet, or with certain
illnesses. A patient has fatty liver when at least 10 percent
of the liver is made up of fat.(3)
Assessing Steatosis’ Risk For HCC
The findings of the Japanese study are based on an examination
of 161 patients who were diagnosed with chronic hepatitis
C between 1980 and 1999. All of the patients had no detectable
hepatocellular carcinoma when they enrolled in the study.
The average follow-up period was about 6 and a half years.
Among the analyses conducted were body mass index (the measure
of a person’s weight related to height), drinking habits,
whether the patient had diabetes, levels of a liver enzyme
known as alanine aminotransferase (ALT) that may indicate
liver disease, interferon treatment, fibrosis, and of course,
whether each patient had fatty liver or not.
The team found that the incidence of hepatocellular carcinoma
was about 24 percent five years after diagnosis, climbing
to 63 percent at 15 years. “Multivariate analysis identified
hepatic steatosis, together with aging, cirrhosis, and no
interferon treatment, as independent and significant risk
factors for [cancer],” the Japanese research team noted.
Other Associations
The doctors also found that steatosis was directly linked
to higher body mass index and with blood levels of ALT and
triglycerides. “We did not find direct effects of diabetes
or obesity on [liver cancer]. This may be attributable to
the fact that our study did not include patients who had advanced
cirrhosis at baseline and/or that the studied population included
relatively small numbers of obese patients and patients with
diabetes,” Eguchi and his team wrote.
But they added that people with HCV who lose weight may reduce
their steatosis and liver enzyme levels. “However, it
is unclear whether weight reduction leads to a favorable outcome
in patients with chronic HCV because BMI [body mass index]
had no significant effect on the development of HCC in our
study,” the team wrote.
The Bottom Line
“Patients with chronic HCV and hepatic steatosis should
be monitored carefully for [liver cancer],” they wrote,
but adding that “the factors responsible for steatosis
could not be identified clearly.”
In an accompanying editorial, Andrew Zhu, M.D., Ph.D., and
Raymond Chung, M.D., both of Massachusetts General Hospital,
wrote that steatosis might still be a risk factor for cancer
even in patients who have cleared the hepatitis virus. But
they stressed that it will be imperative to show how steatosis
may cause liver cancer before jumping to conclusions.
“Before we contemplate targeting steatosis as a strategy
to decrease the risk of HCC development in patients with chronic
HCV infection, it will be important to demonstrate that steatosis
is a critical step in the hepatocarcinogenesis pathway [origins
of liver cancer],” wrote Zhu and Chung. “Further
study to define the relation between steatosis, HCV, and fibrosis
will be essential to clarify the individual contributions
of these potentially carcinogenic factors.”
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August 27, 2003
Accelerated Schedules
for Vaccinations Against Hepatitis A and B
by hivandhepatitis.com
The availability of accelerated schedules of vaccination,
as well as the development of combination vaccines, has enhanced
the methods of protection against infectious disease, in particular
that of hepatitis A and B viruses.
The benefits of using accelerated schedules include:
(1) Enhanced adherence to and subsequent completion of vaccine
courses;
(2) Convenience for the recipient of the vaccine;
(3) Reduced administration costs of providing the vaccine;
and, most importantly,
(4) The ability to provide protection against these serious
infections to those who will be imminently exposed to the
risk and so require protection as quickly as possible.
Active immunization against both hepatitis
A and B viruses has only been recognised within the last 20
years. During this time clinical studies have demonstrated
the safety and efficacy of administering the monovalent hepatitis
B vaccine by way of accelerated schedules.
There are now several accelerated schedules of administration
of hepatitis B vaccine that can be tailored to the needs of
the individual at risk of exposure to infection.
One such schedule allows the primary course to be administered
within a period of 1 month [Emphasis added-Ed]. This schedule
of day 0, 7 and 21, with a booster at 12 months, is licensed
for use with the recombinant hepatitis B vaccine Engerix B
trade mark and results in a seroprotection rate of 65% at
day 28 which increases to 99% at month 13.
In more recent years, the development of a multivalent or
combination vaccine against hepatitis A and B (Twinrix trademark
) has been a welcome advance in the protection against viral
hepatitis, and has been of particular benefit to those who
are at risk of infection with both viruses.
The advantages of accelerated schedules have also been recognized
with this combination vaccine. The primary course may be administered
within a period of 1 month so providing protection for those
at risk and, in particular, the last minute traveler.
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High Dose Infergen
(Consensus Inter-feron) Produces Sustained Response in Low
Percentage of Nonresponders to Interferon Alfa and Ribavirin
by hivandhepatitis.com
Approximately 60% of patients with chronic hepatitis C treated
with a combination of interferon (IFN) alfa-2b and ribavirin
are nonresponders. The purpose of the present study was to
evaluate the efficacy of treatment with high dose Infergen
(consensus IFN/CIFN) 15 microgram/day in nonresponders.
Patients were administered 15 microgram CIFN/day. Treatment
was stopped in those whose serum hepatitis C virus (HCV) RNA
remained detectable at 12 weeks. Those with undetectable HCV
RNA at 12 weeks continued on 15 microgram three times per
week for a further 36 weeks.
Twenty-four patients were recruited; six (25%) withdrew before
12 weeks because of side effects. Of the 18 patients who completed
12 weeks of therapy, nine (38%) had undetectable HCV RNA.
Seven of nine patients who were HCV RNA-negative at week 12
completed 48 weeks of treatment and two withdrew because of
intolerable side effects.
At 48 weeks, HCV RNA remained undetectable in three patients.
After six months of follow-up off treatment, two patients
(8%) continued with no detectable HCV RNA in their sera.
The authors conclude, “High dose induction therapy with
CIFN 15 microgram/day in prior nonresponders to IFN alfa-2b
and ribavirin led to loss of detectable HCV RNA in 50% of
patients, but this response was only sustained in 8% of patients
on completion of therapy.”
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Prediction at Week 4 of Treatment
Effect with Interferon Alfa and Ribavirin in HCV Patients
Identifies One-half of All Nonresponders and Allows Them Benefit
of Early Cessation of Therapy
by hivandhepatitis.com
Treatment of chronic hepatitis C virus (HCV) infection with
interferon alfa-2b (Intron A) and ribavirin is costly in terms
of side effects, medical resources and drug costs. Furthermore,
less than 50% of patients overall have a sustained virological
response (SVR).
The objective of the current study was to determine if the
log fall in HCV RNA between baseline and week 1 (b-wk1) and
between baseline and week 4 (b-wk4) after starting treatment
could identify the nonresponders.
Sixty-three patients who had completed a full course of therapy
were identified. Quantitative measurements of HCV RNA were
analyzed from stored sera, collected prospectively.
SVR was achieved in 47.1% and 47.3% of patients in the b-wk1
and b-wk4 groups, respectively. No patients had an SVR with
a fall in HCV RNA of less than 0.35 log10 and 1.05 log10 at
week 1 and week 4, respectively. This accounted for 44.4%
and 51.7% of the nonresponders in the b-wk1 and b-wk4 groups,
respectively.
Once the decline in viral load was known, genotype, age, sex
and baseline viral load did not provide additional power in
predicting treatment responses.
The authors conclude, “A fall of 1.05 log10 in HCV RNA
at week 4 predicts those patients who will not respond, identifying
one-half of all nonresponders; this allows therapy to be stopped
early, without depriving any patient who would have an SVR
from treatment.”
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Early Response to Individualized
Weight-Based PegIntron(R) and Rebetol(R)
Hepatitis C Therapy Allows Accurate Prediction
of Treatment Success -
80 Percent of Early Responders Achieve Sustained Response
After
Full 48-Week Treatment
Early Response Can Motivate Patients to Complete Treatment
Early virologic response (EVR) in patients with chronic hepatitis
C following 12 weeks of individualised, weight-based dosing
of PegIntron® (peginterferon alfa-2b) and Rebetol®
(ribavirin) combination therapy can accurately predict the
likely outcome of a full, 48-week course of treatment, according
to a paper appearing in the current issue of Hepatology.(1)
The findings show that EVR is important to physicians in making
treatment decisions and to patients as a treatment milestone.
This analysis is consistent with the current European Union
(EU) labeling for PegIntron.
As noted in the paper, 76 percent of patients demonstrated
an EVR following 12 weeks of individualised, weight-based
dosing of PegIntron and Rebetol combination therapy, and,
of those, 80 percent of patients went on to achieve a sustained
virologic response (SVR) after full treatment. EVR is defined
as at least a 99 percent (2 log10) reduction in hepatitis
C virus (HCV) load at week 12 of therapy. SVR is defined as
the sustained undetectability of HCV six months following
48 weeks of treatment and is the accepted criterion for efficacy.
The paper also noted that, of the patients who failed to attain
an EVR at 12 weeks, none achieved an SVR (100 percent negative
predictive value). When cost was considered, it was estimated
that discontinuing treatment in early non-responders could
reduce total overall drug treatment costs nearly 20 percent.
“A 12-week EVR provides patients and physicians with
an early goal, and, for the majority of patients who attain
EVR, can motivate treatment adherence and completion to achieve
a sustained virologic response,” said Michael P. Manns,
M.D., professor, Department of Gastroenterology and Hepatology,
Medical School of Hannover, Germany. “On the other hand,
as noted in the EU labeling for PegIntron, for patients who
do not demonstrate an EVR or take longer to respond to therapy,
physicians should consider discontinuing treatment or continuing
it based on other prognostic factors,” he added.
Dr. Manns said that the positive predictive value of individualised,
weight-based dosing of PegIntron and Rebetol combination therapy
in this study is very encouraging in that, of those patients
who achieved an EVR, 80 percent went on to achieve an SVR.
He also stated that the 100 percent negative predictive value
of this combination therapy indicates that physicians can
predict, with a high degree of confidence, which patients
will not respond to further treatment, and ensure that therapy
is not prematurely discontinued for any potential responders.
PegIntron and Rebetol combination therapy is the most prescribed
treatment for hepatitis C worldwide and is indicated for the
treatment of chronic hepatitis C in patients with compensated
liver disease who have not been previously treated with interferon
alpha and are at least 18 years of age. More than 300,000
hepatitis C patients worldwide, including 150,000 U.S. patients,
have received this combination therapy since its introduction
in 2001.
About PegIntron and Rebetol Combination Therapy
PegIntron and Rebetol combination therapy for hepatitis C
was approved in the EU in March 2001. PegIntron had previously
received centralized marketing authorization in the EU and
is marketed as a monotherapy in cases of intolerance or contraindication
to ribavirin for the treatment of adult patients with chronic
hepatitis C.
PegIntron is a longer-acting form of Intron® A (interferon
alfa-2b, recombinant) Injection that uses proprietary PEG
technology developed by Enzon, Inc. (NASDAQ: ENZN) of Bridgewater,
N.J. PegIntron, recombinant interferon alfa-2b linked to a
12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly
therapy dosed according to patient body weight that is designed
to achieve an effective balance between antiviral activity
and elimination half-life. Schering-Plough holds an exclusive
worldwide license to PegIntron.
Rebetol is an oral formulation of ribavirin, a synthetic nucleoside
analog with broad-spectrum antiviral activity. It is approved
worldwide for use in combination with PegIntron or Intron
A for the treatment of adult patients with chronic hepatitis
C. Schering-Plough has rights to market oral ribavirin for
hepatitis C in all major world markets through a licensing
agreement with ICN Pharmaceuticals, Inc. (NYSE: ICN) of Costa
Mesa, Calif.
Schering-Plough Europe, based in Brussels, Belgium, is part
of Schering-Plough Corporation (NYSE: SGP) of Kenilworth,
N.J., USA, a research-based company engaged in the discovery,
development, manufacturing and marketing of pharmaceutical
products worldwide.
Note to Editors: PegIntron and Rebetol are licensed to Aesca
in Austria, Essex Pharma in Germany and Essex Chemie in Switzerland.
References
(1) Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J,
Albrecht J. Early virologic response to treatment with peginterferon
alfa-2b plus ribavirin in patients with chronic hepatitis
C. Hepatology, Vol. 38, No. 3, 2003, pp. 645-652.
FOR FURTHER INFORMATION PLEASE CONTACT:
Schering-Plough Corporation
Robert J. Consalvo
(908) 298-7409
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August 28th, 2003
Early Virologic Response to Treatment
in Patients with Chronic Hepatitis C
by gastrohep.com
Patients with chronic hepatitis C who fail to achieve early
virologic response will not clear the virus even if an additional
9 months of therapy is received, find researchers in the September
issue of Hepatology (Hepatology 2003; 38:
645-52).
Interferon-based therapy for patients with
chronic hepatitis C is increasingly effective. The virus may
be eradicated in over half of cases. The early identification
of non-responding patients is desirable as it allows treatment
to be stopped.
In this study, a team from the United States
examined differing degrees of viral inhibition during early
treatment (early virologic response [EVR]) with pegylated
interferon alpha-2b and ribavirin (PEG/R). The team’s
aim was to identify patients who would not respond to therapy.
They considered that the best definition
of EVR was a reduction in hepatitis C virus (HCV) RNA by at
least 2 logs after the first 12 weeks of treatment when compared
to baseline.
The team found that up to 76% of patients
achieved this threshold, depending on the treatment regimen.
A sustained virologic response (SVR) was achieved in 67% to
80% of these patients.
The researchers determined that patients
who did not reach EVR did not respond to further therapy.
Up to 76% of patients achieved early virologic response.
Furthermore, they calculated that if treatment was stopped
in patients without EVR, drug costs would be reduced by more
than 20%.
Dr Gary Davis’s team concluded, “Early
confirmation of viral reduction following initiation of antiviral
therapy for chronic hepatitis C is worthwhile”, “It
provides a goal to motivate adherence during the first months
of therapy and a milepost at which to reassess the need for
continued treatment”. “Most patients who are able
to complete the first 12 weeks of therapy achieve EVR and
have a high probability of SVR”. “Patients who
fail to achieve EVR will not clear virus even if an additional
9 months of therapy is received”. “Therapy can
be confidently discontinued in those cases”.
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August 29th, 2003
Outcomes and Indicators
of Upper Digestive Bleeding in Cirrhosis
by gastrohep.com
Prognosis of digestive bleeding in cirrhosis has much improved
over the past 2 decades, find researchers in the September
issue of Hepatology.
There are several treatments which are for variceal bleeding
in patients with cirrhosis.
In this study, a team of physicians assessed how these treatments
are used in clinical practice. They also evaluated the posttherapeutic
prognosis and prognostic indicators of upper digestive bleeding
in patients with cirrhosis.
The researchers included a training set of 291 and a test
set of 174 bleeding cirrhotic patients in this study.
The treatments were allocated according to the preferences
of each center.
There was a follow-up period of 6 weeks.
5-day failure rate was 13%.
The team developed predictive rules for
5-day failure (uncontrolled bleeding, rebleeding, or death)
and 6-week mortality using a logistic model in the training
set. These rules were validated in the test set.
They established that initial treatment controlled bleeding
in 90% of patients. Therapy included vasoactive drugs in 27%
of patients, endoscopic therapy in 10%, combined endoscopic
and vasoactive treatment in 45%, balloon tamponade alone in
1%, and none in 17%.
They determined that the 5-day failure rate was 13%, 6-week
rebleeding was 17%, and mortality was 20%.
The physicians found that for 5-day failure, variceal bleeding
occurred in 15%, compared to nonvariceal bleeding in 7%. For
6-week rebleeding 19% was variceal and 10% nonvariceal, and
when mortality occurred 20% of bleeding was variceal and 15%
nonvariceal.
They determined that active bleeding on endoscopy, hematocrit
levels, aminotransferase levels, Child-Pugh class, and portal
vein thrombosis were significant predictors of 5-day failure.
However, alcohol-induced etiology, bilirubin, albumin, encephalopathy,
and hepatocarcinoma were predictors of 6-week mortality.
Prognostic reassessment including blood transfusions improved
the predictive accuracy.
The team found that all the developed prognostic models were
superior to the Child-Pugh score.
Drs Gennaro D’Amico and Roberto De Franchis concluded
that the, “Prognosis of digestive bleeding in cirrhosis
has much improved over the past 2 decades”.
“Initial treatment stops bleeding in 90% of patients”.
“Accurate predictive rules are provided
for early recognition of high-risk patients”.
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Factors Influencing the Outcome
of Liver Retransplantation
by gastrohep.com
Liver retransplantation is associated with a greater rate
of complications, and lower patient and graft survival, find
physicians in the September issue of Liver Transplantation
(Liver Transpl 2003; 9: 897-904).
Whether the outcome of liver retransplantation is dependent
on the indication for retransplantation or the cause of liver
disease is unknown.
In this study, physicians from Baltimore, Maryland, compared
the outcome of retransplantation in adults with that of primary
liver transplantation (PLT). They assessed whether the outcome
of retransplantation was dependent on its indication.
The research team used data from the United Network for Organ
Sharing from 1988 to 2001.
Hepatitis C virus infection is an independent predictor of
mortality after liver retransplantation.
Overall, the team identified 34,267 patients who met their
inclusion criteria. Of these, 761 patients underwent liver
retransplantation for primary graft nonfunction (PGNF) (group
1), 3428 patients underwent retransplantation for other reasons
(group 2), and 30,078 patients underwent PLT (group 3).
The researchers identified a greater incidence of PGNF and
regrafting in the retransplant groups when compared with the
PLT group.
In addition, analysis showed significantly lower short- and
long-term patient and graft survival in the retransplant groups
compared with the PLT group.
Furthermore, the team found that patients in group 1 had lower
patient and graft survival compared with group 2.
However, when data was analyzed using Cox regression they
found that graft survival not patient survival was lower in
group 1. The team also found that patients with hepatitis
C virus (HCV) infection who underwent retransplantation had
lower patient and graft survival compared with those without
HCV infection.
HCV was identified as an independent predictor of mortality
after liver retransplantation.
Dr Hwan Yoo’s team concluded, “Retransplantation
was associated with a greater rate of complications and lower
patient and graft survival compared with PLT”.
“Retransplantation for PGNF and HCV infection was associated
with lower patient and graft survival compared with retransplantation
for other causes”.
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Britain Says It Will Pay Hepatitis
C Victims
by Richard Woodman
Thousands of Britons infected with the hepatitis C virus as
a result of contaminated blood products and transfusions are
to receive compensation, Health Secretary John Reid said on
Friday.
The details of the payments have yet to be worked out but
a Department of Health spokesman said the sums involved could
range from 20,000 to 45,000.
Many thousands of people, especially hemophiliacs, were infected
during the 1970s and early 1980s before the hepatitis C virus
could be detected in blood and before blood products were
heat-treated.
Reid said in a statement a financial assistance scheme would
be introduced for people infected with the virus as a result
of being given blood products by the National Health Service.
“I looked at the history of this issue and decided on
compassionate grounds that this is the right thing to do in
this situation. I have therefore decided in principle that
English hepatitis C sufferers should receive ex-gratia payments
from the Department of Health.”
The ministry spokesman said compensation schemes were also
planned in Scotland, Wales and Northern Ireland.
Between 3000 and 5000 people might be eligible for the payments,
he said. Possible ballpark figures were 20,000 for people
who had not cleared the virus from their system and 45,000
for people with liver damage.
The Hemophilia Society urged the government last year to make
52.6 million available annually for people with hemophilia
who were infected with hepatitis C through contaminated blood
products.
The charity said that from 1969 to 1985, 95% of people with
hemophilia were treated with blood products carrying a high
risk of infection with hepatitis C. As a result, 2,829 hemophiliacs
alive in the country today were infected with the virus.
It argued that annual payments were needed because of loss
of earnings, difficulties in obtaining travel, life and medical
insurance, pensions and mortgages, and the progressive impact
of hepatitis C on the health of hemophiliacs.
Hundreds of British hemophiliacs have already received government
compensation for being infected with HIV via blood products.
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Patients with HBV Genotype B Infection
Have More Severe Exacerbations of Disease and Higher Risk
of Hepatic Decompensation and Mortality Compared with Patients
with HBV Genotype C Infection
by hivandhepatitis.com
There is growing evidence that hepatitis B virus (HBV) genotypes
may play some role in causing different disease profiles in
chronic hepatitis B (CHB). Among Asians, who constitute >75%
of the worldwide population of individuals with CHB, genotypes
B and C are the 2 most common HBV genotypes.
Though genotype B can be subdivided into genotype Bj, representing
genotype B found among infected individuals from Japan, and
genotype Ba, representing genotype B found among individuals
from the rest of Asia, most infected non-Japanese Asians have
genotype Ba only. In this article, references to genotype
B refer to genotype Ba unless otherwise noted.
A study from Taiwan shows that young patients with hepatocellular
carcinoma are more likely to be infected with HBV genotype
B than genotype C, whereas patients with more-advanced liver
disease are more likely to be infected with genotype C than
genotype B.
Other studies demonstrate that, compared with patients with
genotype C infection, patients with genotype B infection have
more serious liver disease. Recent studies show that patients
with genotype B achieve hepatitis B e antigen (HBeAg) seroconversion
a decade earlier than do patients with genotype C. Regarding
responsiveness to treatment, there is some evidence that patients
with genotype B respond better to IFN-alfa when compared with
patients with genotype C.
However, the effect of HBV genotypes on HBV disease exacerbations
has not been studied. We aimed to investigate, in a cross-sectional
study, the relationship of HBV genotypes to the probability
and severity of HBV disease exacerbations among Chinese patients
with CHB.
During the period 2000-2001, 73 patients (group I) who were
admitted to Queen Mary Hospital, The University of Hong Kong,
Hong Kong, with severe exacerbations of hepatitis B disease
and symptoms of hepatitis were recruited for our study. All
73 patients had tested positive for hepatitis B surface antigen
for >6 months.
“Severe exacerbation” of disease was defined as
an increase of alanine aminotransferase (ALT) levels to >10
times the upper limit of normal (ULN). Patients with evidence
of other hepatotrophic virus infection, checked by testing
with antibodies to hepatitis A, C, D, and E, were excluded.
Patients with a history and clinical features of drug-induced
hepatitis, alcoholic hepatitis, and steatohepatitis were also
excluded.
There were no differences in the median age, sex ratio, proportion
of HBeAg to antibody to HBeAg positivity, proportion of patients
with ultrasonographic evidence of cirrhosis, and median HBV
DNA level between the 4 groups of patients. Group I patients
(i.e., with severe exacerbations) had a significantly higher
median ALT level, lower median albumin level, and higher median
bilirubin level compared with the other 3 groups (all P <
.001).
There were no significant differences in the prevalence of
genotype B and genotype C between the 4 groups (all P = NS).
In total, there were 102 patients with single genotype B infection
and 183 patients with single genotype C infection.
Infection with genotype B was associated with a higher prevalence
of precore mutations (84 [82.4%] of 102 patients), compared
with infection with genotype C (54 [29.5%] of 183). In contrast,
infection with genotype C was associated with a higher prevalence
of core promoter mutations (165 [90.2%] of 183 patients),
compared with infection with genotype B (35 [34.3%] of 102;
P < .001).
All patients with exacerbations of disease (groups I, II,
and III) were categorized according to whether they were infected
with HBV genotypes B or C. Patients infected with genotype
B had a higher median ALT level, higher median bilirubin level,
and lower median albumin level during periods of exacerbation,
compared with patients infected with genotype C. This means
that patients infected with genotype B had more severe exacerbations
compared with those had by patients infected with genotype
C.
Because nearly all patients we studied with HBV infection
in the Chinese population became infected during the perinatal
period or within the first 1-2 years of life, it is unlikely
that there is any difference in the duration of infection
for patients infected with genotypes B and C.
The higher rates of hepatic decompensation and mortality among
patients infected with genotype B compared with patients infected
with genotype C suggests that HBV genotype B may be more immunogenic
and hence cause more severe immune-system-mediated damage.
Studies have shown that patients infected with genotype B
have earlier HBeAg seroconversion, compared with patients
with genotype C.
Infection with genotype B was associated with precore mutations
and infection with genotype C was associated with core promoter
mutations.
The present study suggests that patients with HBV genotype
B infection had more severe exacerbations of disease and a
higher risk of hepatic decompensation and mortality due to
severe exacerbations, compared with patients with HBV genotype
C infections.
Previous longitudinal studies of acute exacerbations in patients
with chronic HBV infection have demonstrated convincingly
that acute exacerbations are usually not associated with infection
with viral genotypes other than the original genotype. Further
longitudinal studies should be designed to follow up a large
population of patients with CHB and define the impact of the
difference in exacerbations of disease among patients infected
with genotypes B and C on the progression of the disease and
the development of complications.
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Clinical Features and Outcome in
HCV-positive Patients with Aggressive Non-Hodgkin's Lymphoma
by hivandhepatitis.com
The clinical features and outcome of 25 previously untreated
aggressive non-Hodgkin’s lymphoma (NHL) patients with
hepatitis C virus (HCV) infection were evaluated retrospectively
by researchers at the Yokohama City University School of Medicine,
Yokohama, Japan.
The patients included 18 males and 7 females with a median
age of 66 years. The median observation period for survivors
was 32 months. Although there were no patients with hepatocellular
carcinoma during the follow-up period, 7 patients had cirrhosis
(LC) at the initiation of therapy for NHL. Seventeen patients
(68%) had initial extranodal involvement including 2 cases
with liver involvement.
Results
The 5-year overall survival (OS) rate in the whole group was
46%, and the 5-year relapse-free survival (RFS) rate of patients
with complete response (CR) was 48%.
Patients with non-cirrhosis (n = 18) experienced better OS
(P = 0.04) compared with patients with LC (n = 7) and 5-year
OS rates were 55 and 21%, respectively. Fourteen patients
died in the whole group; 4 of NHL and 2 of liver failure in
the LC group and 8 of NHL in the non-cirrhotic group. Among
the latter 8 patients, cumulative dose (CD) of doxorubicin
(ADR) and cyclophosphamide (CPA) were significantly lower
than those of survivors with non-cirrhosis.
The authors conclude, “Patients with HCV-positive, aggressive
NHL have a similar prognosis as HCV-negative aggressive NHL.
In non-cirrhotic patients, attention should be paid to the
CD of drugs required to cure the aggressive NHL.”
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Retreatment with Interferon Is Effective
in Some Partial Responders and Nonresponders with Chronic
Hepatitis C
by hivandhepatitis.com
Chronic hepatitis C can progress to end-stage liver cirrhosis
or hepatocellular carcinoma. Interferon (IFN) therapy is effective
in clearing the hepatitis C virus and in improving liver histology.
However, few patients maintain a sustained response (SR) after
IFN withdrawal.
Immediate retreatment with IFN is therefore considered to
be both effective and necessary, especially for patients who
do not respond to the initial course of IFN therapy.
All 145 patients included in the present study, conducted
at the Fukuyama National Hospital, Hiroshima, Japan, underwent
liver biopsy, followed by a first treatment course with various
IFN’s (alfa-2a, alfa-2b, OIF, or beta).
If hepatitis C virus (HCV) RNA was positive after the first
treatment, the patient was assigned to one of 3 groups, depending
on whether his or her alanine transaminase (ALT) level was
normalized (incomplete response, IR), partially responsive(PR),
or non-responsive (NR).
After an observational interval of 6 to 76 months, a second
IFN treatment was initiated with a higher dose or the same
dose of the same IFN for the IR group, and with a different
IFN for the PR and NR groups.
Results
At 6 months after retreatment with IFN, the overall efficacy
of the retreatment was 29.7%. In the case of the IR group,
who received the same IFN, the overall efficacy was 45.2%.
In patients identified as non-SR after the first treatment,
who received a different type of IFN for retreatment, the
overall efficacy was 18.6%. Anti-IFN antibody was not detected
in most of the breakthrough cases. For some IR patients, retreatment
with the same IFN was effective.
Anti-IFN antibody was mostly negative, indicating that the
same IFN can be used in both the first treatment and retreatment
to obtain an SR.
Switching to a different IFN was effective for some PR and
NR patients, suggesting that changing IFN for such cases is
a good therapeutic choice.
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September 1st, 2003
Finding the Right Combination to
Fight Hepatitis C
Linda Marsa
Of the millions of Americans infected with hepatitis C, only
half respond to treatment. The others live with the constant
threat that their health may suddenly, and fatally, deteriorate.
A new drug could improve those odds. When used with the antiviral
drug interferon, a medication called Zadaxin may help thousands
of patients better fight the disease.
“This medication looks promising for people who don’t
respond to other drugs,” says Dr. Sammy Saab, a liver
specialist at UCLA’s David Geffen School of Medicine.
“It may also be used as part of a combination drug cocktail
for all hepatitis C sufferers, since it seems to work by a
different mechanism of action than other medications.”
About 4 million Americans are infected with hepatitis C, and
about 2.7 million of those have an active infection, in which
the liver is inflamed. Infection is insidious, however. People
can be symptom-free for years, but the virus can quietly incubate,
causing cirrhosis of the liver, liver cancer or even liver
failure. Hepatitis C, which kills 10,000 people a year, is
the leading reason for liver transplants in the U.S.
The current treatment—a combination of two antiviral
medications, interferon and Ribavirin—helps only about
half of those with active infections and less than a third
who are infected with the more prevalent and more dangerous
form of hepatitis C, known as genotype 1.
The drugs also have serious side effects, leading many people
to stop taking them. Ribavirin can cause anemia, which leaves
patients feeling extremely fatigued, while interferon can
cause flu-like symptoms and birth defects if taken by pregnant
women. These side effects “can result in having to reduce
the dose and therefore decrease the efficacy of the drugs,”
says Dr. Adrian Di Bisceglie, a liver specialist at St. Louis
University School of Medicine in Missouri.
Zadaxin has no apparent side effects. It is a synthetic version
of thymosin alpha 1, a naturally occurring protein that circulates
in the body and stimulates the production of certain immune
system cells. Zadaxin is approved for sale in 30 countries
as an antiviral drug to treat hepatitis B but in only a few
countries to combat hepatitis C.
Results of a 2002 U.S. study of the drug as a hepatitis C
therapy were encouraging. The test involved 31 patients who
had high levels of genotype 1 and who hadn’t responded
to standard medications. Zadaxin, used in combination with
interferon, greatly reduced levels of the virus in up to 36%
of the patients.
The findings were especially significant because patients
who don’t respond to the initial round of treatment
seldom benefit from subsequent therapy.
“We purposely chose the most difficult of the most-difficult-to-treat
patients,” says Di Bisceglie, who conducted this research.
The drug is in the final phase of U.S. trials.
About the disease
Hepatitis C is one of five identified viruses—hepatitis
A, B, C, D and E—that attack and damage the liver. Hepatitis
C, however, is considered the most grave and is spread mostly
through contact with infected blood.
Before a test was available for hepatitis C, some people were
unwittingly infected through blood transfusions. Others acquired
it by injecting illegal drugs, receiving organs from donors
whose blood contained the virus, getting pricked with a needle
that had infected blood on it, snorting cocaine using shared
equipment, getting a tattoo or body piercing with non-sterile
instruments or through sexual activity.
Although Zadaxin may help treat the virus, other drugs—which
aren’t as far along in development—may ultimately
vanquish it. Among the more promising are hepatitis C protease
inhibitors, which work by blocking the action of a key enzyme
that the virus needs to replicate. Drugs that have a similar
mechanism of action, disabling protease, revolutionized AIDS
treatment.
Other experimental medications include a monoclonal antibody
that latches onto the surface of the HCV (HCV-AB68), preventing
the virus from entering the cells, and a fusion protein (albuferon),
which may enhance the action of interferon.
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