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Treatment of HCV
infection in patients with advanced cirrhosis
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Hepatology
Volume 40, Issue 2, August 2004
Xavier Forns, M.D., Miquel Navasa, M.D., Juan Rodés, M.D.
Liver Unit, Hospital Clínic, Barcelona, Spain
Letter
To the Editor:
The recent AASLD Practice Guideline on Diagnosis, Management, and
Treatment of Hepatitis C dealt with the topic of antiviral therapy
in patients with decompensated cirrhosis. In their recommendations,
Strader et al.[1] suggest that antiviral therapy might be initiated
at low dose in hepatitis C virus (HCV)-infected patients with mild
degrees of hepatic compromise, preferably in patients who have been
accepted as candidates for liver transplantation. This
recommendation is essentially based on the data reported by Everson
et al. after treatment of 102 cirrhotic patients awaiting liver
transplantation.[2] We recently analyzed the safety and efficacy of
antiviral treatment in a cohort of 30 HCV-infected patients awaiting
liver transplantation.[3] Half of these patients had compensated
cirrhosis and hepatocellular carcinoma, whereas the other half had
Child-Pugh B or C cirrhosis. Our approach was completely different
from that of Everson et al.: We initiated treatment (interferon
alfa-2b, 3 MU/day; ribavirin, 800 mg/day) when the expected time for
liver transplantation was around 4 months. Our rationale to initiate
treatment when patients approached transplantation was the
assumption that most virological responders would achieve HCV-RNA
negativization by week 12. This strategy might be sufficient to
prevent infection of the graft in these patients, since the main
source of virions (the liver) will be removed. In addition, this
strategy would avoid a long treatment course in patients prone to
develop severe side effects. Interferon was administered daily to
avoid peaks and valleys of serum interferon concentrations, which
might be crucial at the time of liver transplantation. Although
pegylated interferon would have been an alternative, we were afraid
of a longer duration of hematological side effects in patients
waiting for a major surgical procedure. After a median treatment
duration of 12 weeks, 9 (30%) of 30 patients achieved on-treatment
virological response, which persisted in 6 (20%) after
transplantation. Although based on a small number of patients, our
results are comparable to those obtained by Everson et al. In fact,
we believe that a short course of antiviral therapy might be a good
alternative to treat HCV-infected patients with advanced cirrhosis
when the date of transplantation is known (living donor liver
transplantation), or in transplant programs where the waiting time
can be predicted with reasonable accuracy.
References
1 Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management,
and treatment of hepatitis C. Hepatology 2004; 39: 1147-1171. Links
2 Everson GT. Treatment of patients with hepatitis C virus on the
waiting list. Liver Transpl 2003; 9( Suppl): S90-S94. Links
3 Forns X, Garcia-Retortillo M, Serrano T, Feliu A, Suarez F, de la
MM, et al. Antiviral therapy of patients with decompensated
cirrhosis to prevent recurrence of hepatitis C after liver
transplantation. J Hepatol 2003; 39: 389-396. Links
Xavier Forns, M.D., Miquel Navasa, M.D., Juan Rodés, M.D.
Liver Unit, Hospital Clínic, Barcelona, Spain
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| http://www.natap.org/ |
Pegylated interferon
can cause serious eye problems in HIV/HCV coinfected patients, says
study
Michael Carter
Thursday, August 26, 2004 Treatment with pegylated interferon
alpha-2b (PegIntron) and ribavirin can cause serious eye
problems in individuals coinfected with HIV and hepatitis C virus
according to an article published in the September 3rd
edition of AIDS.The US investigators recommend that patients
coinfected with HIV and hepatitis C and treated with pegylated
interferon and ribarvirin receive regular ophthalmic monitoring.
Optic neuropathy, including retinal haemorrhage, cotton wool spots and
decreased colour vision have been reported in individuals receiving
interferon therapy who are monoinfected with hepatitis B or hepatitis
C. However, these are the first cases to be reported of serious eye
problems developing in HIV and hepatitis C coinfected patients
receiving therapy with pegylated interferon.
A total of 23 patients were included in the investigators’ analysis.
All had received at least twelve weeks of pegylated interferon
alpha-2b and ribavirin in an open-label, prospective trial at a
National Institutes of Health facility.
Eye examinations included visual acuity, visual field testing, and a
colour vision examination. In addition, indirect ophthalmoscopy were
performed at baseline, then at least every three months or when the
need was suggested by symptoms.
At baseline the patients had a median CD4 cell count of 553 cells/mm3,
a median HIV viral load of below 50 copies/ml and a median hepatitis C
viral load of over 1,000,000 copies/ml.
Eight individuals (35% of the study population) developed
ophthalmologic pathology during hepatitis C treatment, including six
patients who developed cotton wool spots, indicate of retinal
haemorrhage. These were detected at the week twelve ophthalmoscopy,
and "waxed and waned while [hepatitis C] therapy was continued." In
addition, two patients developed cataracts. Hepatitis C treatment was
continued in these individuals and the cataracts remained stable both
during and after therapy.
Decreases in red-green colour vision were detected in two patients.
One patient discontinued hepatitis C treatment and within ten weeks of
its cessation this individual’s colour vision had returned to normal.
Colour vision returned to normal in the other patient at week 23 of
hepatitis C treatment without any cessation of therapy.
“The rapid development of serious ocular pathology in our coinfected
patients demonstrates a concerning phenomenon associated with
peglyated interferon and ribavirin therapy for hepatitis C virus”
write the investigators. They add “both cotton wool spots and
cataracts developed in several patients soon after beginning therapy.
These lesions occurred in patients with high CD4 cell counts and in
patients with and without comorbidities such as diabetes and
hypertension.”
The investigators cannot say which factors led to the development of
these serious eye problems in their patients, and note that there were
no differences in the CD4 cell count, HIV viral load, or hepatitis C
viral load between the patients who did and did not develop
ophthalmologic pathologies. They note that a much larger cohort of
patients would be needed to determine if any of these factors were
significant. They also speculate that pegylated interferon could
induce an immune response leading to retinal ganglion cell toxicities
in susceptible individuals.
The investigators conclude, “routine ophthalmologic monitoring in
persons receiving pegylated interferon and ribavirin may be warranted
in order to optimize the benefit from current anti-hepatitis C virus
therapy.”
Reference
Farel C et al. Serious ophthalmic pathology compromising vision in
HCV/HIV coinfected patients treated with peginterferon alpha-2b and
ribavirin. AIDS 18: 1805-1809, 2004.
http://www.aidsmap.com/en/news/52F9ED92-DEF3-47EE-AB4D-1E298ADABA88.asp
Common Heterozygous Hemochromatosis Gene Mutations Are
Risk Factors for Inflammation and Fibrosis in Chronic Hepatitis C
Chronic hepatitis C is frequently associated with increased hepatic
iron stores. It remains controversial whether heterozygous mutations of
hemochromatosis genes affect
fibrosis progression. Therefore the aim
of the current study was to assess associations between HFE mutations and
hepatic inflammation and stage of fibrosis in German hepatitis C patients.
Liver biopsies from
166 patients were scored for inflammatory activity (A0-4) and hepatic
fibrosis (F0-4). Gene mutations were determined by LightCycler,
restriction fragment length polymorphism analysis, or direct sequencing.
Results
The frequencies of
common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the
recently described S65C substitution and the Y250X mutation in the
transferrin receptor 2 gene are very rare.
In regression
analysis, heterozygous carriers of C282Y or H63D mutations display
significantly (P<0.05) higher inflammatory activities and more advanced
fibrosis than patients without mutations.
For C282Y
heterozygous patients, the odds ratios for marked inflammatory activity
(A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6,
respectively, compared with patients carrying homozygous wild-type
alleles.
C282Y mutations are
associated with significantly (P<0.05) increased serum iron and
aminotransferase levels, whereas H63D heterozygotes display higher
transferrin saturation, serum iron, and ferritin concentrations compared
to wild-type (P<0.01).
Conclusions
In conclusion, the
authors write, "Common heterozygous hemochromatosis mutations are
associated with higher grades of inflammation and more severe hepatic
fibrosis. Our findings support a role of HFE mutations as primary risk
factors for fibrogenesis and disease progression in chronic hepatitis C."
Department of
Medicine III, University Hospital Aachen, Aachen University (RWTH), Aachen,
Germany.
08/11/04
Reference
A Geier and others. Common heterozygous hemochromatosis gene mutations are
risk factors for inflammation and fibrosis in chronic hepatitis C.
Liver International 24(4): 285-294. August 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/081104_c.html
Intercept
Pharmaceuticals Announces Publication of Study Demonstrating Its Lead
Compound Can Reverse Liver Fibrosis
- Proof-of-Principle Study Published in Gastroenterology -
NEW YORK, Aug. 12 /PRNewswire/ -- Intercept Pharmaceuticals, Inc., an
emerging specialty pharmaceutical company focused on developing small molecule
drugs for the treatment of chronic liver and metabolic diseases, today
announced publication in Gastroenterology of a major set of studies led by its
scientific co-founder, Stefano Fiorucci, M.D., demonstrating that Intercept's
lead FXR agonist, INT-747, can stop development of, and perhaps even reverse,
liver fibrosis in animal models.
Liver fibrosis is the process of chronic scarring that leads eventually to
cirrhosis and liver failure. It affects individuals with alcoholic liver
disease, chronic viral infections like hepatitis B and C, and obesity
associated non-alcoholic fatty liver disease (NAFLD), making it a major cause
of disability and death for tens of millions of people worldwide. There
currently are no approved treatments for liver fibrosis, leaving liver
transplant as the only option available for those few patients with end-stage
disease able to receive a donor organ.
"Publication of this landmark study which confirms the therapeutic
rationale underlying our lead compound for liver fibrosis is an important
milestone for our company," said Mark Pruzanski, M.D., President and CEO of
Intercept Pharmaceuticals. "Until recently, liver fibrosis and cirrhosis have
not been considered treatable, yet Dr. Fiorucci and his team have now
demonstrated in validated animal models that liver fibrosis may be slowed and
perhaps even reversed by Intercept's lead compound. Based on these
encouraging results, we plan to advance INT-747 into human clinical trials in
early 2005."
Prior work by Intercept's founders and other researchers elucidated the
role of FXR, a member of the nuclear hormone receptor family, in the
regulation of bile flow and rate of bile synthesis from dietary cholesterol.
These studies suggested that FXR agonists may have utility in the treatment of
a variety of cholestatic liver diseases which impair enterohepatic bile flow,
resulting in progressive damage to the liver. More recently, as reported in
the Gastroenterology paper, Intercept has uncovered the potential of FXR
agonists to directly repress the degenerative processes underlying liver
fibrosis.
"On behalf of the many researchers, clinicians and patients who have been
frustrated by our inability to treat liver fibrosis, I am encouraged to report
the positive results of our initial work with INT-747," said Stefano Fiorucci,
M.D., Professor of Gastroenterology at the University of Perugia in Italy and
a well known liver disease researcher and clinician. "Agents like INT-747 for
the first time give us the possibility of treating this often fatal condition
to preserve adequate liver function and perhaps even restore lost function. I
look forward to working with the Intercept team to rapidly advance INT-747 and
associated compounds towards human clinical testing."
Intercept's lead compound, a potent, orally bioavailable FXR agonist
formerly known as 6ECDCA, was discovered in 2001 through a collaboration
between GlaxoSmithKline and University of Perugia scientists. Worldwide
intellectual property rights to the compound and to a number of other FXR
agonists, antagonists and modulators have been assigned to Intercept. FXR is
known to be expressed in the liver, intestine and kidney, and Intercept
intends to continue to lead research efforts to fully elucidate the
therapeutic potential of this target.
About Intercept Pharmaceuticals
New York City-based Intercept Pharmaceuticals, Inc. is an emerging
specialty pharmaceutical company focused on developing small molecule drugs
for the treatment of chronic liver and metabolic diseases. The company is
currently advancing its lead drug candidate, INT-747(6ECDCA), for the
treatment of a group of life threatening fibrotic and cholestatic liver
diseases for which there are virtually no effective marketed drugs. The
company intends to lead in the advancement of drug candidates acting on FXR in
multiple indications through clinical proof-of-concept. As a ligand-regulated
nuclear hormone receptor, FXR is a member of a target class that has
consistently yielded successful marketed pharmaceuticals in a variety of
indications.
Contacts: Media:
Intercept Pharmaceuticals GendeLLindheim BioCom Partners
Mark Pruzanski, M.D. Barbara Lindheim
(917) 744-4043 (212) 918-4650
mark@interceptpharma.com
SOURCE Intercept Pharmaceuticals
News-Medical.Net
Significant advance in
the understanding of the hepatitis C virus (HCV)
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| Posted By:
News-Medical in Medical Research News |
| Published: Monday, 9-Aug-2004 |
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Researchers have made a significant
advance in the understanding of the hepatitis C virus (HCV)
by identifying new genetic factors associated with
clearing the virus spontaneously without the necessity for
additional treatment.
Hepatitis C virus infects the liver and leads to
serious permanent liver damage. The infection affects
about 170 million people worldwide and up to 500,000
people in the UK. Most people who come into contact with
HCV contract a long-term or chronic infection and, as a
consequence, run a significant risk of liver failure -
necessitating liver transplantation - or liver cancer.
The new multi-centre study was jointly led by
researchers from the
University of Southampton's School of Medicine, the
National
Genetics Institute, USA, and the
Johns
Hopkins Hospital, USA. The findings demonstrate that
natural killer (NK) cells provide a central defence
against HCV infection and that this defence is mediated by
specific inhibitory receptors expressed on NK cells and
the partners or ligands for these receptors on liver
cells.
Over 1,000 patients from the UK and the USA were
involved in the study, some of whom were chronically
infected and some who had cleared the virus. Researchers
identified a specific combination of genes in these
individuals that directly confers protection against HCV.
The genes are killer cell immunoglobulin-like receptors (KIR)
and HLA class I genes and the favourable genes identified
in the study are KIR2DL3 and group 1 HLA-C alleles.
Dr Salim Khakoo of Southampton's Infection,
Inflammation and Repair Division, who co-authored the
paper with Professor Mary Carrington of the National
Genetics Institute in the USA, commented: 'These
favourable genes control the functions of NK cells. NK
cells are part of the innate immune system, a branch of
immunity that has not been well-studied in HCV to date.
'KIR2DL3 on NK cells binds group 1 HLA-C alleles on
liver cells and our work suggests that this interaction is
more easily disturbed in HCV infection than other KIR-HLA
interactions. Simply put, as an analogy to a car, it is
like taking your foot off the brake of the natural killer
cell rather than pressing the accelerator in order to get
it going. This may then kick-start the rest of the immune
response to HCV.'
By studying how people acquired HCV infection, the
findings also suggest that the amount of virus they
received is an important factor. Data suggests that the
mechanism that researchers have discovered is more
important in people receiving lower infectious amounts of
HCV. The protective effect of genes on the virus was
observed in Caucasians and African Americans with expected
low infectious doses of HCV, but not in those with
high-dose exposure, in whom the innate immune response is
probably overwhelmed.
Dr Khakoo continued: 'We believe that this study is a
significant advance in the understanding of hepatitis C
virus infection. There are other interesting outcomes from
our research. It implicates NK cells, and the innate
immune system in general, in clearing HCV infection and
this has not previously been clearly documented. It also
suggests that the more NK cells of the protective type
that an individual has the more likely they are to clear
HCV.'
The researchers believe that the findings could
eventually lead to new treatment strategies for HCV based
around NK cells in general and KIR2DL3/HLA-C in
particular.
http://www.soton.ac.uk/ |
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NK Cell Phenotype Controls Host Response to HCV
By Karla Gale
NEW YORK (Reuters Health) Aug 05 - Only about 20% of people exposed to
hepatitis C virus (HCV) naturally clear the infection. New research suggests
that the host response depends in part on the phenotype of natural killer (NK)
cells, the lymphocytes that secrete cytokines and kill infected cells.
Senior investigator Dr. Mary Carrington and associates determined the
genotype of 1037 individuals exposed to HCV, 352 of whom resolved the
infection. Specifically, they examined the genotype of killer cell
immunoglobulin-like receptors (KIR) on NK cells and the genotype of the
corresponding human leukocyte antigen C group 1 (HLA-C1) ligand.
Ordinarily, KIR receptors suppress the action of the NK cells so they
will not attack otherwise healthy cells, the researchers explain in the
August 6th issue of Science. If the KIR-HLA interaction is weaker, the NK
cell can become activated and thus rid the body of infected cells.
"We know that NK cells enter the liver of individuals infected with HCV,
apparently to try to clear the viral infection," Dr. Carrington, a
researcher at the National Cancer Institute in Frederick, Maryland, told
Reuters Health. "Because KIR receptors regulate the activity of NK cells,
causing them to become inhibited or activated, we thought it made sense to
look at these genes among those with persistent or cleared infection."
The investigators did observe differences between groups. Individuals
homozygous for HLA-C1 and KIR2DL3 resolved HCV infection more frequently
than did those with other genotypes (odds ratio (OR) for clearance, 1.71, p
= 0.003).
The relationship was even stronger among the subset of patients who were
infected with a low inoculum of HCV, as would be found in needlestick
injuries compared with those infected by blood transfusions (in multivariate
analysis, OR = 2.24, p = 0.001).
"This combination of HLA and KIR transmits a weaker inhibitory signal to
NK cells than other combinations, which translates into stronger activation
of those cells," Dr. Carrington explained. "This says that activation of NK
cells in the liver is a good thing for clearance of HCV."
Further research will be required before these findings can be applied
clinically, she said. But eventually, "it's possible that if we could
activate NK cells in the liver after infection, maybe that could enhance
clearance of the virus."
For example, "perhaps soluble ligands could be applied in a localized
manner in the liver to enhance NK cell activation, or antibodies that would
bind to an activating receptor could be injected."
Science 2004;305:872-874.
http://www.medscape.com/viewarticle/487100
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Potential Current and Future Therapeutic Options for
Nonresponders to Antiviral Therapy for Chronic HCV
A significant proportion of chronic hepatitis C patients fails to
achieve
sustained virologic response even after
treatment with the current, more potent,
combination of pegylated interferon-alfa (IFNa)
plus ribavirin.
Such patients represent a rather heterogeneous group and may be divided
initially into relapsers and nonresponders. Both the type of previous
therapy and of previous response are very important factors for the
indication and the type of
re-treatment.
The combination
of
pegylated IFNa and ribavirin seems to
be a rational approach for patients who failed to respond to
IFNa monotherapy.
Pegylated IFNa-based
regimens appear to induce sustained responses in 40-68% of relapsers but
in only 11% of nonresponders to previous therapy with standard IFNa plus
ribavirin.
Thus, new
therapeutic approaches are needed for the latter subgroup of patients as
well as those who fail to respond to pegylated IFNa-based regimens.
Such new
approaches currently under evaluation include the triple combination of
pegylated IFNa, ribavirin, and amantadine,
alternative types of IFN, use of agents with ribavirin like activity but
lesser degrees of side-effects, inhibitors of hepatitis C virus (HCV)
replication, mainly inhibitors of NS3 protease or helicase, antisense
oligonucleotides, and ribozymes, and several immunomodulators.
Moreover,
maintenance antifibrotic therapy, mostly with low doses of pegylated
IFNa, are under evaluation in patients with advanced
fibrosis.
The authors
conclude, "Thus, even in the current era of the potent pegylated IFNa-based
regimens, the management of these difficult-to-treat patients represents
an increasingly frequent problem and perhaps the most challenging
therapeutic task in chronic hepatitis C."
Academic
Department of Medicine, Hippokration General Hospital, Athens, Greece.
08/11/04
Reference
G V Papatheodoridis and E Cholongitas. Chronic hepatitis C and no
response to antiviral therapy: potential current and future therapeutic
options. Journal of Viral Hepatitis 11(4):287-296. July 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/081104_b.html |
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Common Heterozygous Hemochromatosis Gene Mutations Are
Risk Factors for Inflammation and Fibrosis in Chronic Hepatitis C
Chronic hepatitis C is frequently associated with increased hepatic
iron stores. It remains controversial whether heterozygous mutations of
hemochromatosis genes affect
fibrosis progression. Therefore the aim of
the current study was to assess associations between HFE mutations and
hepatic inflammation and stage of fibrosis in German hepatitis C patients.
Liver biopsies from
166 patients were scored for inflammatory activity (A0-4) and hepatic
fibrosis (F0-4). Gene mutations were determined by LightCycler, restriction
fragment length polymorphism analysis, or direct sequencing.
Results
The frequencies of
common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently
described S65C substitution and the Y250X mutation in the transferrin
receptor 2 gene are very rare.
In regression
analysis, heterozygous carriers of C282Y or H63D mutations display
significantly (P<0.05) higher inflammatory activities and more advanced
fibrosis than patients without mutations.
For C282Y
heterozygous patients, the odds ratios for marked inflammatory activity
(A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6,
respectively, compared with patients carrying homozygous wild-type alleles.
C282Y mutations are
associated with significantly (P<0.05) increased serum iron and
aminotransferase levels, whereas H63D heterozygotes display higher
transferrin saturation, serum iron, and ferritin concentrations compared to
wild-type (P<0.01).
Conclusions
In conclusion, the
authors write, "Common heterozygous hemochromatosis mutations are associated
with higher grades of inflammation and more severe hepatic fibrosis. Our
findings support a role of HFE mutations as primary risk factors for
fibrogenesis and disease progression in chronic hepatitis C."
Department of
Medicine III, University Hospital Aachen, Aachen University (RWTH), Aachen,
Germany.
08/11/04
Reference
A Geier and others. Common heterozygous hemochromatosis gene mutations are
risk factors for inflammation and fibrosis in chronic hepatitis C. Liver
International 24(4): 285-294. August 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/081104_c.html
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A Comparison of Two Dose Regimens of Peginterferon
Alfa-2a Compared with Conventional Interferon Alfa-2ae
This study
compared the efficacy and safety of
peginterferon alfa-2a (Pegasys)
135 mg/wk, peginterferon alfa-2a 180 mg/wk and interferon alfa-2a in
patients with chronic hepatitis C.
A total of
639 patients received peginterferon alfa-2a 135 mg or 180 mg once weekly, or
interferon alfa-2a 3 MIU thrice weekly for 48 wk.
Results
Sustained virological responses (SVR)
were significantly higher with peginterferon alfa-2a than with interferon
alfa-2a 3 MIU (28% in the 135 mg and 180 mg peginterferon alfa-2a groups
vs 11% with interferon alfa-2a, p = 0.001).
The
proportion of patients with clinically significant histological improvement
was lower in the peginterferon alfa-2a 135 mg (48%) than the 180 mg group
(58%, p = 0.035 vs peginterferon alfa-2a 135 mg), but similar
to that in the interferon alfa-2a group (45%, p = 0.820 vs
peginterferon alfa-2a 135 mg and p = 0.017 vs peginterferon
alfa-2a 180 mg, respectively).
The overall
safety profiles were similar for the three treatments.
Conclusions
In patients
with chronic hepatitis C, peginterferon alfa-2a 135 mg/wk and 180 mg/wk
produced similar sustained virological response rates, both of which were
significantly higher than that achieved with interferon alfa-2a thrice
weekly.
A significantly higher
proportion of patients treated with the 180 mg dose of peginterferon alfa-2a
had clinically significant histological improvement.
08/06/04
Reference
P J Pockros and
others.
Efficacy and Safety of Two-Dose Regimens of Peginterferon Alpha-2a Compared
with Interferon Alpha-2a in Chronic Hepatitis C: A Multicenter, Randomized
Controlled Trial. The American Journal of
Gastroenterology 99(7):
1298-1305. July 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/080604_b.html
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Is There a Correlation Between HCV Viral Load and
Severity of Liver Disease?
The significance of hepatitis C virus (HCV) serum titers (HCV
viral load) has been examined in several clinical
situations. There is much evidence that patients with a lower viral load
have better response rates to anti-viral therapy compared to those with
higher levels.
Moreover, a direct
association has been observed between serum titers of HCV and transmission
rates of the virus.
The aim of the present
study was to determine if there was any correlation between HCV viral load
and the severity of
liver disease.
Fifty patients with HCV
infection were included in the study. These comprised of 34 subjects with a
history of alcohol use and 16 non-alcoholics.
Quantitative serum HCV RNA assay
was carried out using the branched DNA (bDNA) technique. Linear regression
analysis was performed between serum viral titers and liver tests.
In addition, for the
purpose of comparison, the subjects were divided into two groups: those with
low viral titers (<=50 genome mEq/mL) and high titers (>50 mEq/mL).
Results
All subjects were men,
with a mean+/-SD age of 47+/-7.8 years. The mean HCV RNA level in the blood
was 76.3X10(5)+/-109.1 genome equivalents/mL.
There was no correlation
between
HCV RNA levels and age of
the patients (r = 0.181), and the history or amount (g/d) of
alcohol consumption (r = 0.07).
Furthermore, no
correlation was observed between serum HCV RNA levels and the severity of
liver disease as judged by the
values of serum albumin (r =
0.175), bilirubin (r = 0.217),
ALT (r = 0.06) and
AST (r = 0.004) levels.
Similarly, no significant
difference was observed between patients with low viral titers and high
titers with respect to any of the parameters.
Conclusion
The authors conclude, “Our
results indicate that the severity of liver disease is independent of serum
levels of hepatitis C virus. These findings are important since they have a
direct impact on the current debate regarding the role of direct cytopathic
effect of hepatitis C virus versus immune-mediated injury in the
pathogenesis of HCV-related liver damage.”
Digestive Diseases Section (111D), VA
Medical Center, 2002 Holcombe Blvd. Houston, Texas.
08/06/04
Reference
B S Anand and M
Velez. Assessment of correlation between serum titers of hepatitis c virus
and severity of liver disease.
World Journal of
Gastroenterology
10(16):2409-12411. August 15, 2004.
http://www.hivandhepatitis.com/hep_c/news/2004/080604_a.html
Hepatitis C Virus Infection in
Cocaine Users: A Silent Epidemic; study suggests snorting cocaine is
transmission risk
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Source: Medical College of Wisconsin
Researchers at the Medical College of Wisconsin have found that up to
one-third of cocaine users who thought they were healthy may be infected
with hepatitis C. Hepatitis C can lead to chronic hepatitis, cirrhosis
of the liver and even liver cancer. There is no cure or vaccine.
It has been suggested by some researchers that Hepatitis C infection may
be the major cause of liver disease in the United States. The use of
alcohol may make the effects of Hepatitis C on the liver more severe.
"Our observations suggest a significant epidemic in an unsuspecting
population with little regular access to health care," notes study
author Harold H. Harsch, MD, Associate Professor of Psychiatry at the
Medical College. "These individuals also form a large pool for the
continued transmission of Hepatitis C to the general population. As this
reservoir of virus increases, even what may be minor transmission
channels, such as sexual activity, ear piercing and tattooing will
become more significant."
The study screened cocaine users who volunteered for a study of how the
brain reacts to cocaine. Of the 144 people screened, 47 were found to
have Hepatitis C, while only seven tested positive for Hepatitis B and
only two for HIV. Of the 144, 56% were African-American, 81% were male,
75% were never-married, and 55% were unemployed. The average age was 36.
None of the subjects had ever received a blood transfusion.
Twenty-nine percent who tested negative for Hepatitis C reported
intravenous drug use, while 77% of those testing positive for the
disease reported IV drug use. Those who tested positive for Hepatitis C
tended to be three to four years older than Hepatitis C-free patients.
One of the most surprising findings was that about 14% of those with
Hepatitis C said they had never used intravenous drugs. This suggests
that there are other ways for the spread of the disease among cocaine
users, such as sharing straws to snort cocaine, particularly if
nosebleeds occur. For Hepatitis C to be spread, the virus generally must
enter the bloodstream through the skin or mucous membranes. Hepatitis C
does not spread as easily through sexual contact as Hepatitis B or HIV.
A recent study of blood donors who tested positive for Hepatitis C found
that intranasal cocaine use, sexual promiscuity, intravenous drug use,
history of transfusion and ear piercing among men were risk factors.
It was only in the late 1980s that a test was developed to identify
Hepatitis C. While screening for Hepatitis B and HIV has become routine
at hospitals, drug centers and blood banks, Hepatitis C is sometimes
overlooked. The Medical College study suggests it may be widespread
among cocaine users, including those who smoke crack cocaine.
The Medical College study appeared in the June 2000 issue of Community
Mental Health Journal. Co-authors of the study are John Pankiewicz, MD;
Alan S. Bloom, PhD; Charles Rainey, MD; Jung-Ki Cho, MD; Lori Sperry,
PhD; and Elliott A. Stein, PhD.
http://healthlink.mcw.edu/article/971122496.html
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Mt Sinai School of Medicine Press
Release on APRICOT COINFECTION STUDY RESULTS
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New England Journal of Medicine Publishes Results from
Landmark Study Reporting the Highest Response Rates Ever Achieved for
the Treatment of Hepatitis C in Co-infected Patients
Press Release from Mt Sinai School of Medicine
Study findings offer new hope for the estimated 300,000 Americans
co-infected with hepatitis C and HIV
New York, NY (July 28, 2004) -- A landmark study published in this
week's New England Journal of Medicine reveals the highest efficacy
rates ever reported among patients co-infected with hepatitis C and HIV
treated with pegylated interferon and ribavirin.
Here is link to full reports of the two coinfection studies (ACTG 5071 &
APRICOT) published in the NEJM & to an accompanying article in NEJM on
treating HCV in difficult to treat patients including HIV:
(ACTG 5071)-
http://www.natap.org/2004/HCV/072904_03.htm
APRICOT-
http://www.natap.org/2004/HCV/072904_02.htm
'Difficult to Treat Patients/HIV'-
http://www.natap.org/2004/HCV/072904_01.htm
The multinational APRICOT (AIDS PEGASYS• Ribavirin International
CO-infection Trial) study found that the drug combination of Pegasys• (peginterferon
alfa-2a) and Copegus (ribavirin) was much more effective than the
previous generation of hepatitis C therapy standard interferon and
ribavirin. Efficacy was measured as the sustained virological response (SVR)
rate, which is defined by the absence of detectable HCV RNA in the serum
for at least six months after treatment.
HCV and HIV are the two most prevalent blood-borne infections in the
United States. Of the nearly one million people estimated to have HIV in
the U.S., approximately 300,000 are believed to be co-infected with HCV.
It can take 10 to 20 years following infection with hepatitis for a
person to progress to end stage liver disease. However, in patients with
HIV, the disease progresses far more quickly. With advances in HIV
therapy prolonging the life expectancy of HIV patients, hepatitis C is
now a major threat to people with HIV.
The results of this study are groundbreaking news for the hundreds of
thousands of Americans who are living with both hepatitis C and HIV,"
said Dr. Douglas Dieterich, Professor of Medicine, Mount Sinai School of
Medicine, New York City and co-lead investigator of the APRICOT study.
"These are patients who have fought long and hard to control their HIV
-- for them to ultimately be defeated by a manageable disease like
hepatitis C is unacceptable."
Results from the study report 40 percent overall efficacy among
co-infected patients and, when analyzed by genotype, 62 percent efficacy
in patients with genotypes 2 and 3, and 29 percent in those with
genotype 1. Genotype 1 is typically the most difficult strain of HCV to
treat.
Four times more genotype 1 patients cleared the hepatitis C virus with
Pegasys in combination with Copegus than with those treated with
standard interferon/ribavirin combination therapy (29% vs. 7%
respectively).
Additionally, Pegasys monotherapy showed superior efficacy to treatment
with standard interferon and ribavirin (20 percent vs. 12 percent),
which is important for patients who cannot tolerate ribavirin.
The randomized, partially blinded international trial had a total of 868
HCV/HIV co-infected patients in 19 countries, and is currently, the
largest study conducted among this patient population. All patients were
HCV positive, had compensated liver disease, a CD4+ count greater than
100 cells/mL, and stable HIV disease, with or without antiretroviral
therapy.
Patients were randomized to 48 weeks of treatment with interferon three
times a week plus 800 mg/day of ribavirin, 180 mcg of Pegasys once
weekly plus placebo, or 180 mcg of Pegasys once weekly with 800 mg/day
of Copegus. Sustained virological response (SVR) was accessed at the end
of 24 weeks of treatment-free follow up (week 72).
Negative predictability ranged from 98 to 100 percent at 12 weeks.
Negative predictability means that patients can determine by week 12 if
they are unlikely to respond to therapy with Pegasys so decisions about
the continuance of treatment can be made in that time. In addition, HIV
viral levels were not negatively impacted by treatment with Pegasys and
Copegus combination therapy, and no new safety concerns were reported
with this study.
Pegasys is a well-tolerated medication, even with the addition of full
doses of ribavirin. In this study, the most commonly reported side
effects were fatigue, fever and headache.
Co-authors on the study include J. Torriani, University of California,
San Diego, CA; J. Rockstroh, University of Bonn, Bonn, Germany; M.
Rodriguez-Torres, Fundacion de Investigacion de Diego, Santurce, Puerto
Rico; E. Lissen, Virgen del Rocío University Hospital, Seville, Spain;
J. González, Hospital La Paz, Madrid, Spain; A. Lazzarin, San Raffaele
Vita-Salute University, Milan, Italy; G. Carosi, University of Brescia,
Italy; J. Sasadeusz, Royal Melbourne Hospital, Australia; C. Katlama,
Groupe Hospitalier de la Pitie Salpetriere, Paris, France; J. Montaner,
University of British Columbia, Vancouver, Canada; H. Sette, Instituto
de Infectologia Emilio Ribas, Sao Paulo, Brazil; F. Duff, Roche, Nutley,
NJ, USA , J. DePamphilis, Roche, Nutley, NJ, USA; U. M. Schrenk, Roche,
Basel; Switzerland. The study was funded by Roche, the developers of
Pegasys.
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www.natap.org
Infection with
hepatitis C
genotype 3 often clears spontaneously,
which can spare the patient unnecessary treatment, according to German
doctors.1Scientists at Hannover
Medical School in Hannover, Germany and their colleagues who initiated a
study on this topic say 15 to 50 percent of untreated patients may
experience this type of spontaneous clearance. "Therefore, factors are
needed to identify patients prior to therapy who have a higher or lower
risk for developing a chronic course to avoid unnecessary
treatment," wrote the researchers, headed
by Heiner Wedemeyer, M.D., in Hannover Medical School's department of
Gastroenterology, Hepatology and Endocrinology.
A Mounting Infection
According to experts, hepatitis C infection has reached epidemic
proportions around the world, accounting for more than 1 million new cases
each year. Four million people in the U.S. alone are infected, and 30,000
new infections are estimated to occur each year. The hepatitis C virus is
classified into various groups, or strains, known as genotypes and
subtypes. Genotype 1, subtype b (genotype 1b) is thought to be more
closely associated with severe
liver disease, and a more aggressive
course than the other HCV genotypes.2
It is also well known that treatment in patients with HCV
genotype 1 is more often unsuccessful compared to patients with genotypes
2 and 3.3 That's why genotype testing is part of a standard
protocol when designing an individual treatment regimen for hepatitis
patients, said Wedemeyer, in an e-mail interview with Priority Healthcare.
This study led to "important new data for the management
of acute HCV," he said.
Homing in on Genotype 3
To further understand the course of hepatitis infection based on genotype,
Wedemeyer and his team evaluated 1,176 inmates at a German prison,
screening them for anti-HCV antibodies. Ninety-two of them tested
positive, the scientists reported. Of those, nearly all reported using IV
drugs for an average of 3 years prior to imprisonment.
Those inmates who tested positive were then genotyped,
and Wedemeyer and his colleagues found that genotype 3 prevalence was
"significantly higher" among inmates who had cleared HCV spontaneously
compared to those who were diagnosed with chronic infection. Specifically,
86 percent of the prisoners with that genotype spontaneously cleared the
virus, compared to 36 percent of those who had chronic infection.
Further, 93 percent of the inmates exposed to HCV
genotype 1 went on to develop chronic infection, compared to just under
two-thirds of those exposed to genotype 3, the researchers noted.
Researchers: Avoid Unnecessary
Treatment
"Thus, acute infection in young Caucasian men with HCV genotype 3 leads
more often to spontaneous clearance than infection with HCV genotype 1,"
the scientists wrote.
Individual treatment strategies for patients with
different genotypes is probably appropriate, based on these findings, said
Wedemeyer. While
chronic infection emerges in the "vast
majority" of genotype 1 cases, unnecessary treatment might be avoided in
those with genotype 3, he said.
"Considering also the high chance of successful
treatment of chronic HCV genotype 3 infection with
pegylated interferon in combination with
ribavirin, we suggest not to treat acute hepatitis C genotype 3 infection
early, but rather to wait at least 3 months after the onset of symptoms
when chronicity becomes likely," wrote Wedemeyer and his team.
It's not exactly known why genotype 3 patients tend to
spontaneously clear the virus compared to other genotypes, Wedemeyer
explained. "It is mostly likely due to the higher sensitivity to type 1
interferons, as we know already for chronic hepatitis C," he said.
1. Lehman M, Meyer MF, Monazahian M, Tillmann HL, Manns
MP, Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C
virus genotype 3 infection. J Med Virol 2004 Jul;73(3):387-91.
2. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin
Microbiol Rev 2000 Apr;13(2):223-35.
3. Viral Hepatitis C. National Center for Infectious Diseases. Centers for
Disease Control and Prevention (CDC).
John Martin is a long-time health journalist and an
editor for Priority Healthcare. His credits include coverage of health
news for the website of Fox Television's The Health Network, and articles
for the New York Post and other consumer and trade publications.
http://www.hepatitisneighborhood.com/content/in_the_news/archive_2019.aspx
Certain Genes Fight Hepatitis
C Better
By LAURAN NEERGAARD
..c The Associated Press
WASHINGTON (AP) - Scientists may have figured out why some people
infected
with liver-destroying hepatitis C essentially cure themselves: Their
genes
seem to unleash a faster immune attack.
The research, reported Thursday in the journal Science, may point to new
ways
to prevent or treat hepatitis C, widely considered the most serious of a
family of liver viruses.
About 20 percent of people infected with hepatitis C somehow clear the
virus
from their bodies without treatment. But about 3 million Americans and
180
million people worldwide remain chronically infected, at risk of
eventually
developing liver cancer or failure. The virus claims 10,000 to 12,000
U.S.
lives annually.
Doctors have long hoped that learning why some people are lucky enough
to
spontaneously recover might help them create a vaccine to prevent
hepatitis C.
Now research by a team of U.S. and British scientists suggests one key
to that
recovery is genes that take the brakes off the body's front-line immune
defense, so-called natural killer cells.
The work won't benefit patients any time soon.
However, ``It brings us closer to understanding how the virus works,''
said
Dr. Chloe Thio of Johns Hopkins University, who co-authored the study
with
researchers from Britain's Southampton University and the U.S. National
Cancer
Institute.
``In the long term, whether we can use this information to modulate the
body's
immune system to improve therapeutics or vaccine design - that is the
ultimate
goal,'' she said.
Hepatitis C studies in chimpanzees suggested natural killer cells were
more
active in animals that recovered. To find the genes involved in that
immune
response, the researchers analyzed the DNA of 1,037 hepatitis C
patients, 352
of whom spontaneously recovered.
Natural killer cells are continually poised to attack if a virus
strikes.
Inhibitory receptors called KIRs (pronounced ``keers'') keep them in
check
between infections, to ensure they don't attack healthy tissue.
The scientists discovered a particular gene combination that controls
one KIR
receptor, and the molecule attached to it was twice as common in
recovered
patients than in the still-infected.
But how would an immune-inhibiting system fight hepatitis?
When the body senses viral infection, it has to activate the natural
killer
cells by switching off inhibiting receptors, Thio explained. This KIR
combination seems weak, ``so it's easier to overcome,'' she said.
There's a caveat: The genetic protection was found only in patients
thought to
have received an initial low dose of hepatitis C, because they were
infected
by contaminated drug or tattoo needles instead of a blood transfusion.
It may
be that the extra virus from tainted blood - long a common cause of
hepatitis
C - was simply too much for those patients' first-line defenses to
handle,
Thio said.
Since 1992, the U.S. blood supply has been strictly tested for hepatitis
C, so
new transfusion-related cases have plummeted. Today the disease is most
commonly spread here through injecting drug use.
Other factors also play a role in spontaneous hepatitis C recovery, Dr.
Peter
Parham of Stanford University said in an accompany editorial.
But he noted that doctors already help treat a type of leukemia by
releasing
natural killer cells from a different KIR receptor, so the question now
is
whether a similar strategy could be developed for hepatitis.
On the Net:
08/05/04 14:54 EDT
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