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Alan Franciscus
Editor-in-Chief
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In This Issue:
Diagnostics
Sampling Variability of Liver
Fibrosis in Chronic Hepatitis C
Epidemiology and Natural History
Evaluation of a Prison
Outreach Clinic for the Diagnosis and Prevention of Hepatitis
C: Implications for the National Strategy
Impaired IRS-1/PI3-Kinase Signaling in Patients
with HCV: A Mechanism for Increased Prevalence of Type 2 Diabetes
Overweight and Obesity, Hepatic Steatosis, and
Progression of Chronic Hepatitis C: A Retrospective Study
on a Large Cohort of Patients in the United States
Hepatitis C Therapy
Once-Weekly Epoetin Alfa Improves Anemia and
Facilitates Maintenance of Ribavirin Dosing in Hepatitis C
Virus–Infected Patients Receiving Ribavirin plus Interferon
Alfa
High Body Mass Index Is an Independent Risk Factor
for Nonresponse to Antiviral Treatment in Chronic Hepatitis
C
Early Virologic Response to Treatment with Peginterferon
Alfa-2b plus Ribavirin in Patients with Chronic Hepatitis
C
Single-Dose Pharmacokinetics and Tolerability
of Pegylated Interferon-a2b in Young and Elderly Healthy Subjects
Antiviral Therapy of Patients with Decompensated
Cirrhosis to Prevent Recurrence of Hepatitis C after Liver
Transplantation
Infection with Chronic Hepatitis C Virus and
Liver Transplantation: A Role for Interferon Therapy before
Transplantation
Sampling
Variability of Liver Fibrosis in Chronic Hepatitis C
Pierre Bedossa, Delphine
Dargère, Valerie Paradis
Source: Hepatology 2003; 38:1449-1457
Introduction
Fibrosis is a common endpoint of clinical trials in chronic
hepatitis C, and liver biopsy remains the gold standard for
fibrosis evaluation. However, variability in the distribution
of fibrosis within the liver is a potential limitation.
Aim
The aim of this study was to assess the heterogeneity of liver
fibrosis and its influence on the accuracy of assessment of
fibrosis with liver biopsy.
Methods
Surgical samples of livers from patients with chronic hepatitis
C were studied. Measurement of fibrosis was performed on the
whole section by using both image analysis and METAVIR score
(reference value). From the digitized image of the whole section,
virtual biopsy specimens of increasing length were produced.
Fibrosis was assessed independently on each individual virtual
biopsy specimen. Results were compared with the reference
value according to the length of the biopsy specimen.
Results
By using image analysis, the coefficient of variation of fibrosis
measurement with 15-mm long biopsy specimens was 55%; and
for biopsy specimens of 25-mm length it was 45%. By using
the METAVIR scoring system, 65% of biopsies 15 mm in length
were categorized correctly according to the reference value.
This increased to 75% for a 25-mm liver biopsy specimen without
any substantial benefit for longer biopsy specimens.
Sampling variability of fibrosis is a significant
limitation in the assessment of fibrosis with liver biopsy.
Conclusion
The authors concluded that this study suggests that a length
of at least 25 mm is necessary to evaluate fibrosis accurately
with a semiquantitative score. Sampling variability becomes
a major limitation when using more accurate methods such as
automated image analysis.
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Evaluation
of a Prison Outreach Clinic for the Diagnosis and Prevention
of Hepatitis C: Implications for the National Strategy
C Skipper, J M Guy, J Parkes, P Roderkk, W M Rosenberg
Source: Gut 2003;52: 1500-1504
Introduction
Hepatitis C virus (HCV) infection is a major public health
problem recognised by the UK National Strategy that proposes
that a care pathway for assessment, diagnosis, and treatment
be established in all prisons, integrated within managed clinical
networks. A prison sentence provides the opportunity to focus
on traditionally hard to reach patients.
Aims
To evaluate the prevalence of HCV infection in a UK prison
cluster and to assess the effectiveness of a prison outreach
service for hepatitis C.
Patients
1618 male prisoners entered 3 prisons in this 1 year study
period.
Patient Characteristics
| |
Overall % (3 prisons) |
| Age < 30 years |
37.2 |
| Drug offences |
19.6 |
| White |
69.7 |
| Black |
24.1 |
| Asian |
2.9 |
| Other |
3.3 |
Methods
A nurse specialist led clinic within a cluster of adult prisons
was established, offering health education on hepatitis C,
advice on harm minimisation, and HCV testing.
Infected prisoners were offered access
to a care pathway leading to treatment. Outcome measures were
uptake of the service, and diagnosis and treatment of hepatitis
C.
Results
A total of 8.5% of 1618 prisoners accepted testing: 30% had
active infection with HCV. Fifty six (97%) admitted to having
injected drugs: 19 (33%) while in prison. Forty one (71%)
were tattooed. Five (9%) reported having received a blood
transfusion prior to 1991. In one subject intranasal drug
use was the only identifiable potential exposure to HCV and
none of the inmates identified sex with an HCV positive partner
as their only exposure to the virus.
Most were ineligible for treatment due
to psychiatric illness, persisting high risk behaviours, and
failure to biopsy during their prison term. Only 7% of HCV
polymerase chain amplification positive inmates received treatment
in prison.
Conclusion
There is a large pool of HCV infected prisoners at risk of
complications, constituting a source of infection during their
sentence and after discharge. A prison outreach clinic and
care pathway was perceived as effective in delivering health
education, and reducing the burden on prison and hospital
services. It provided an opportunity for intervention but
had a limited effect in eradicating HCV in prisoners, and
it remains unclear how this might be achieved.
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Impaired
IRS-1/PI3-Kinase Signaling in Patients with HCV: A Mechanism
for Increased Prevalence of Type 2 Diabetes
Serhat Aytug, David Reich, Lawrence E. Sapiro, David Bernstein,
Najma Begum
Source: Hepatology 2003;38:1384-1392
Introduction
Patients with hepatitis C virus (HCV) infection have a greater
risk of developing type 2 diabetes mellitus. However, the
mechanism of this association is unclear.
Aim
In this study, we examined the potential defects in upstream
insulin signaling pathways in liver specimens obtained from
nonobese/nondiabetic subjects with HCV infection.
Methods
Fasting liver biopsy specimens were obtained from 42 HCV-infected
subjects and 10 non-HCV-infected subjects matched for age
and body mass index. Liver tissues were exposed to insulin
and examined for the contents and phosphorylation/activation
status of the upstream insulin signaling molecules by immunoprecipitation
and Western blot analysis.
Results
HCV infection resulted in a trend toward a 2-fold to 3-fold
increase in insulin receptor (IR) and insulin receptor substrate
(IRS)-1 contents when compared with non-HCV. In contrast,
insulin-stimulated IRS-1 tyrosine phosphorylation was decreased
by 2-fold in HCV-infected subjects compared with non-HCV-infected
subjects (P < .05).
The observed reductions in IRS-1 tyrosine
phosphorylation were accompanied by a 3.4-fold decrease in
IRS-1/p85 phosphatidylinositol 3-kinase (PI3-kinase) association
and a 2.5-fold decrease in IRS-1-associated PI3-kinase enzymatic
activity (P < .05 vs. non-HCV). This was accompanied by
a marked reduction in insulin-stimulated Akt phosphorylation
without any alterations in mitogen-activated protein kinase
(MAPK) phosphorylation. Cellular contents of the hepatic p85
subunit of PI3-kinase were comparable between HCV-infected
and non-HCV-infected subjects.
Conclusion
The authors found that (1) HCV infection leads to a postreceptor
defect in IRS-1 association with the IR, and (2) Insulin signaling
defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase
association/activation may contribute to insulin resistance,
which leads to the development of type 2 diabetes mellitus
in patients with HCV infection.
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Overweight
and Obesity, Hepatic Steatosis, and Progression of Chronic
Hepatitis C: A Retrospective Study on a Large Cohort of Patients
in the United States
Ke-Qin Hu,* kqhu@uci.edu
, Namgyal L. Kyulo 1, Eric Esrailian 2, Kevin Thompson 3,
Resa Chase 4, Donald J. Hillebrand 5 and Bruce A. Runyon 5
1 Division of Gastroenterology/Hepatology, University of California,
Irvine, Orange, CA, USA; 2 Department of Medicine, USC Keck
School of Medicine, Los Angeles, CA, USA;
3 Department of Pathology, Loma Linda University Medical Center,
Loma Linda, CA, USA; 4 Department of Pathology, Jerry L. Pettis
Memorial VA Medical Center, Loma Linda, CA, USA; 5 Division
of Gastroenterology / Hepatology, Loma Linda University Medical
Center, Loma Linda, CA, USA
Source: Journal of Hepatology, Vol. 40 (1)
2004 pp 147-154
Introduction
Hepatic steatosis has been associated with chronic hepatitis
C (CHC), but its prevalence, risk factors, and clinical significance
remain to be determined.
Aims
The present study determined the frequency of, and risk factors
for hepatic steatosis and its association with activity and
progression of chronic hepatitis C in a large cohort of U.S.
patients.
Methods
This is a retrospective study that utilized systematic chart
review and statistical analyses to investigate 324 U.S. patients
with chronic hepatitis from a university medical center and
a regional VA medical center.
Results
The frequency of hepatic steatosis was 66.0%. We demonstrated
that not only being obese, but also overweight (i.e. body
mass index 25 kg/m2) was independently associated with hepatic
steatosis. In our cohort of patients with chronic hepatitis
C, hepatic steatosis, especially grade II/III steatosis was
significantly associated with elevated aspartate aminotransferase
at entry, persistently elevated alanine aminotransferase,
and stage III/IV fibrosis. Grade II/III steatosis, was significantly
associated with a higher histology activity index as well.
Multivariate analysis indicated that steatosis, especially
grade II/III steatosis, was independently associated with
stage III/IV fibrosis.
Conclusion
The authors concluded that being overweight/obese serves as
an independent risk factor for hepatic steatosis in U.S. patients
with chronic hepatitis C. Steatosis accelerates activity and
progression of chronic hepatitis C, and is independently associated
with stage III/IV hepatic fibrosis in these patients.
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Once-Weekly
Epoetin Alfa Improves Anemia and Facilitates Maintenance of
Ribavirin Dosing in Hepatitis C Virus–Infected Patients
Receiving Ribavirin plus Interferon Alfa
Douglas T. Dieterich, M.D., Ronald Wasserman, M.D., Norbert
Brau, M.D., Tarek I. Hassanein, M.D., Edmund J. Bini, M.D.,
Peter J. Bowers, M.D., and Mark S. Sulkowski, M.D.
Mount Sinai School of Medicine, New York University School
of Medicine and New York VA Medical Center, New York, New
York; Bronx VA Medical Center, Bronx, New York; Hepatitis
Resource Center, Walnut Creek, California; University of California
at San Diego, San Diego, California; Ortho Biotech Products,
Bridgewater, New Jersey; and Johns Hopkins University, Center
for Viral Hepatitis, Baltimore, Maryland
Source: Am J Gastroenterol 2003;98
Introduction
Interferon and ribavirin are associated with decreased Hb
levels, which can result in anemia. Approximately 26% of HCV-infected
patients receiving standard IFN monotherapy experience decreases
in Hb levels of 2 g/dl or more. Ribavirin causes a dose-dependent,
reversible hemolytic anemia in most patients. Combination
therapy with standard interferon plus ribavirin therapy has
been associated with severe decreases in Hb levels, to less
than 10 g/dl in 8% to 9% of patients.
The standard of care for the management
of ribavirin/interferon associated anemia has been to dose
reduce ribavirin. However, recent data suggest that lower
doses of ribavirin decrease the likelihood of a sustained
virological response.
Objective
The aim of this study was to determine the efficacy of epoetin
alfa in alleviating anemia and minimizing ribavirin (RBV)
dose reductions in patients with chronic hepatitis C virus
(HCV) infection receiving combination ribavirin/interferon
alfa (IFN) therapy.
Methods
HCV-infected patients who had Hb levels of 12 g/dl or less
during the first 24 weeks of combination RBV/IFN therapy (n
= 64) were randomized to treatment with epoetin alfa (40,000
units) s.c. q.w. or to standard of care (SOC) for anemia management
(ribavirin dose reduction or discontinuation, transfusions).
Primary and secondary efficacy endpoints were changes in Hb
level and ribavirin dosage, respectively, from baseline to
week 16 of epoetin alfa therapy.
Results
Based on intent-to-treat analysis, the mean changes from baseline
Hb levels at week 16 were ±2.8 g/dl for epoetin alfa
versus ±0.4 g/dl for SOC (p<0.0001), and the mean
changes in ribavirin dosage were -34 mg/day for epoetin alfa
versus -146 mg/day (p=0.060) for SOC. The mean Hb level at
week 16 in the epoetin alfa group (13.8 g/dl) was significantly
(p<0.0001) higher than that of the SOC group (11.4 g/dl).
At week 4 and subsequently, significantly
more patients in the epoetin alfa group did not have ribavirin
dosage reductions (p< 0.011).
At study end, 83% of epoetin alfa–treated
patients maintained ribavirin dosages of at least 800 mg/day,
compared with 54% of patients receiving SOC (p< 0.022).
Epoetin alfa was well tolerated.
Conclusion
In anemic HCV-infected patients treated with ribavirin/interferon,
epoetin alfa increases Hb levels and maintains RBV dosing.
Based on these results, epoetin alfa seems to be promising
in the treatment of HCV treatment–related anemia. Further
research is warranted to determine the potential impact on
outcomes, including quality of life and sustained viral response
rate.
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High
Body Mass Index Is an Independent Risk Factor for Nonresponse
to Antiviral Treatment in Chronic Hepatitis C
Brian L. Bressler, Maha Guindi, George Tomlinson, and
Jenny Heathcote
Source: Hepatology, Vol. 38, No3, 2003
Introduction
Several factors have been shown to influence response to interferon/ribavirin
therapy.
Some studies have found that in patients with chronic hepatitis
C, the degree of hepatic steatosis and fibrosis correlate
with body mass index (BMI) and reduce the rate of sustained
virological response to anti-viral therapy.
Aim
The aim of this study was to determine if body mass index
(BMI) was an independent predictor of response to antiviral
treatment in patients with chronic hepatitis C.
Methods
A retrospective review was performed of all patients at a
single center with chronic hepatitis C treated with antiviral
medication from 1989 to 2000. A sustained response was defined
as either negative hepatitis C virus (HCV) RNA by polymerase
chain reaction and/or normal alanine aminotransferase (ALT)
level (only in those treated before availability of HCV RNA
testing) 6 months following completion of therapy.
All patients were classified into one of 3 groups according
to BMI:
1. Normal, <25 kg/m2 overweight,
2. 25-30 kg/m2 obese,
3. >30 kg/m2
A total of 253 patients were treated with
either interferon (IFN) monotherapy or interferon in combination
with ribavirin. Patients were excluded if predetermined clinical
characteristics were unavailable.
Results
Using logistic regression, and after adjusting for the examined
variables (age, sex, history of alcohol consumption >50
g/d, cirrhosis on pretreatment biopsy, and BMI), likelihood
ratio tests showed significant differences in response to
treatment according to BMI group (P = .01), genotype (P <
.01), and cirrhosis (P < .01).
Those with genotypes 2 or 3 had an odds
ratio (OR) for success of 11.7 compared with those with genotype
1, cirrhotic patients had an OR of 0.15 compared with noncirrhotic
patients, and obese patients had an OR of 0.23 compared with
normal and overweight patients.
Hepatic steatosis was not an independent
risk factor for response to antiviral treatment.
Conclusion
The authors concluded that obesity, only when defined as a
BMI greater than 30 kg/m2 is an independent (of genotype and
cirrhosis) negative predictor of response to hepatitis C treatment.
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Early
Virologic Response to Treatment with Peginterferon Alfa-2b
plus Ribavirin in Patients with Chronic Hepatitis C
Gray L. Davis, John D.. Wong, John G. McHutchison, Michael
P. Manns, Joann Harvey,Janice Alhrecht
Source: Hepatology 2003; 38: 645-652
Introduction
Interferon-based regimens for the treatment of chronic hepatitis
C have become increasingly effective and are able to eradicate
virus in more than one half of cases. Early identification
of patients who will not respond is desirable because treatment
might be stopped, thereby avoiding the expense and inconvenience
of unnecessary therapy.
Objective
We examined the accuracy of different degrees of viral inhibition
during the early weeks of treatment early virologic response
(EVR) with pegylated interferon alfa-2b and ribavirin (PEG/R)
in identifying patients who would not respond to therapy.
The best definition of early virologic response was a reduction
in hepatitis C virus (HCV) RNA by at least 2 logs after the
first 12 weeks of treatment compared with baseline.
Results
Between 69% and 76% of patients achieved this threshold, depending
on the treatment regimen, and sustained virologic response
(SVR) occurred in 67% to 80% of these patients. Patients who
did not reach early virologic response did not respond to
further therapy.
If treatment had been stopped in patients
without early virologic response, drug costs would have been
reduced by more than 20%.
Conclusion
The authors concluded that early confirmation of viral reduction
following initiation of anti-viral 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
early virologic response and have a high probability of a
sustained virologic response. Patients who fail to achieve
an early virologic response 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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Single-Dose
Pharmacokinetics and Tolerability of Pegylated interferon-a2b
in Young and Elderly Healthy Subjects
Samir K. Gupta, Paul Glue, Sheila Jacobs, Donna Belle
& Melton Affrime
Schering Research Institute, Kenilworth, NJ, USA
Source: British Journal of Clinical Pharmacology
2003;56:131-134
Introduction
A sizeable minority of patients infected with hepatitis C
are of an advanced age, which could potentially alter drug
disposition.
Objective
The objective of this study was to determine the effect of
increasing age on the pharmacokinetics of PEG-Intron.
Methods
In this parallel design study, a single 1 µg PEG-Intron
dose was given subcutaneously to 24 subjects in the age groups
20-45, 65-69, 70-74 and 75- 80 years (n = 6/group). Blood
sampling and tolerability assessments were performed up to
168h post dose.
Results
The pharmacokinetic parameters were similar in all age groups.
The elderly to young subject ratios for Cmax were 91.1, 79.5,
and 107% for the 65-69 years, 70-74 years and 75-80 years
groups, respectively.
The corresponding values for AUC and CL/F
were 111, 102 and 108%, and 82.5. 95.8 and 86.4%, respectively.
Mean differences from the 20 to 45 years group and the 65-69
years, 70-74 years and 75-80 years groups for PEG-Intron Vd/F
were 108, 128 and 104% respectively.
None of these differences was statistically
significant based on ANOVA. Results from a Dunnett’s
test (as post hoc assessment) confirmed that the pharmacokinetic
parameters of Group II, Group III or Group IV were not different
from those of Group I. Almost all (23/24; 96%) subjects reported
typical interferon a a side-effects (flu-like symptoms, headache).
One elderly patient had a myocardial infarction 12 h postdose,
but recovered fully.
Conclusions
The authors concluded that there are no pharmacokinetic reasons
for initial dose adjustment of PEG-Intron based on age and
that age does not affect PEG-Intron clearance. They also noted
that further controlled studies involving single or multiple
dosing are required to confirm these preliminary findings.
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Antiviral
Therapy of Patients with Decompensated Cirrhosis to Prevent
Recurrence of Hepatitis C after Liver Transplantation
Xavier Forns, Montserrat Garcia-Retortillo, Trinidad Serrano,
Anna Feliu, Francisco Suarez, Manuel de la Mata, Juan Carlos
Garcia-Valdecasas, Miquel Navasa,
Antoni Rimola, Juan Rodés -Liver Unit, Hospital Clinic,
Institut de Malalties Digestives, IDIBAPS, Escala 7, 3 pis.,
Villarroel 170, Barcelona 08036, Spain, Liver Transplantation
Unit, Hospital Clinico, Zaragoza, Spain, Transplantation Unit,
Hospital Juan Canalejo, La Coruña, Spain, Transplantation
Unit, Hospital Reina Sofia, Córdoba, Spain, Surgery
and Transplantation Unit, Hospital Clinic, Institut de Malalties
Digestives, IDIBAPS, Barcelona, Spain
Source: Journal of Hepatology 39 (2003) 389-396
Background/Aims
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 of the possible strategies to prevent HCV
infection recurrence is to eradicate HCV before liver transplantation.
Methods
The authors evaluated the efficacy and safety of antiviral
therapy to prevent HCV recurrence in 30 HCV-cirrhotic patients
awaiting liver transplantation. At the time of inclusion 15
patients were Child-Pugh A and 15 Child-Pugh B/C.
The infecting genotype was lb in 25 patients.
Treatment with interferon a-2b 3 MU/day and ribavirin 800
mg/day was initiated when the expected time for liver transplantation
was less than 4 months and continued until liver transplantation.
The median duration of treatment was 12 weeks.
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 = 2 log during treatment. A viral load
decrease = 2 log at week 4 of treatment was the strongest
predictor of virological response.
All nine virological responders have already
undergone liver transplantation; six patients remain free
of infection after a median follow-up of 46 weeks and HCV
infection recurred in three patients after liver transplantation.
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.
Conclusions
The authors concluded that their data supported the utilization
of antiviral therapy in HCV-infected patients awaiting liver
transplantation as one of the strategies to prevent hepatitis
C recurrence after transplantation.
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Infection
with Chronic Hepatitis C Virus and Liver Transplantation:
A Role for Interferon Therapy Before Transplantation
Ryan M Thomas, John J.. Brems, Grace Guzman-Hartman, Sherri
Yong, Patricia Cavaliere, and David H. Van Thiel
Source: Liver Transplantation, Vol 9, No
9 (September), 2003: pp905-915
Introduction
An analysis of the National Institute of Diabetes and Digestive
and Kidney Diseases Liver Transplant Registry data shows that
the greater the viral load at the time of transplantation,
the more rapidly clinically evident post-transplantation hepatitis
C virus (HCV) disease recurs. These data suggest that aggressive
pretransplantation treatment of HCV might delay recurrent
posttransplantation HCV disease and enhance posttransplantation
survival.
Objective/Methods
We have taken an aggressive approach to treating HCV infection
pretransplantation with the use of high-dose (5 MU) daily
interferon-a 2b in an effort to clear the virus before transplantation.
Patients
A total of 27 patients with HCV-induced cirrhosis were seen
and underwent transplantation at Loyola University Medical
Center (Maywood, IL) between February 1997 and December 2001.
There were 22 men and five women, with a mean age of 56 ±
2 years. The majority had genotype 1 disease (67%). Of the
27 patients, 7 had a baseline platelet count <50,000/mm
and were excluded from interferon therapy. The remaining 20
were treated for a mean of 14 ± 2.5 (range, 0.5 to
33.5) months before orthotopic liver transplantation (OLT).
Results
Twelve (60%) responded to the therapy with serologic clearance
of HCV before OLT. The mean time from initiation of therapy
to the first negative qualitative polymerase chain reaction
was 4.5 ± 1.5 (range, 0.5 to 12) months. Four of the
12 patients in whom the virus cleared did not have evidence
of HCV recurrence after OLT, representing 20% of those treated
and 33% of those who had HCV clearance before OLT. The duration
of post-OLT freedom from HCV infection in these individuals
has been 33.6 ± 11.3 (range, 0 to 47.4) months.
Conclusion
The authors concluded that with careful supervision cirrhotic
patients can tolerate high-dose interferon. In addition, a
viral clearance can be achieved in a significant number of
cirrhotic patients with high-dose interferon. One third of
patients, in whom the HCV cleared before OLT, did not have
evidence of disease recurrence after OLT.
It is thus anticipated that with early and aggressive pre-OLT
HCV therapy, possibly with the use of pegylated interferon,
even better results may be obtained.
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