Is pre-treatment liver biopsy necessary for all hepatitis C genotypes?
Download PDF
Annals Of Hepatology
July-September, Vol. 10 No.3, 2011: 260-269
Kevork M. Peltekian,* Vincent G. Bain,† Samuel S. Lee,‡ Morris Sherman,§ Curtis L. Cooper, Eric M. Yoshida,¶
Paul J. Marotta,** Mel Krajden,†† Robert Balshaw,‡‡ Marc Deschênes.§§ (a)
* Division of Gastroenterology. Dalhousie University, Halifax, Nova Scotia, Canada. † Division of Gastroenterology. University of Alberta, Edmonton, Alberta, Canada.
‡ Division of Gastroenterology. University of Calgary, Calgary, Alberta, Canada. § Division of Gastroenterology. University Health Network, Toronto, Ontario, Canada.
Division of Gastroenterology. Division of Infectious Diseases of the University of Ottawa, Ottawa, Ontario, Canada.
¶ Division of Gastroenterology. University of British Columbia, Vancouver, British Columbia, Canada.
** BC Centre for Disease Control. Toronto, Ontario, Canada. †† British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
‡‡ Syreon Corporation, Vancouver, BC, Canada. §§ Division of Gastroenterology. Royal Victoria Hospital, Montreal, Quebec, Canada.
(a) On behalf of the Canadian PEGASYS Study Group.
ABSTRACT
Background. Current practice guidelines recommend liver biopsy prior to treatment of hepatitis C genotype-1 but not for genotype-2/3; this is based on expert opinion, not on published evidence.
Methods.
In retrospective analysis of a large trial database prior to the publication of recent guidelines, we compared outcomes in 985 treatment-naïve patients with hepatitis C who did or did not undergo liver biopsy before starting peginterferon alfa-2a plus ribavirin.
Results.
Physicians elected to treat 141/654 (21.6%) genotype-1 patients and 126/331 (38.1%) genotype-2/3 patients without liver biopsy. There were no differences in baseline characteristics among those with or without pre-treatment liver biopsy, except for female preponderance in genotype-1 patients with liver biopsy. The sustained viral response (SVR) rate was no different amongst genotype-2/3 patients who had a biopsy before treatment with 66.3% SVR vs. 69.8% of those treated
without biopsy (p = 0.546), but significantly higher among genotype-1 patients with pre-treatment liver biopsy at 54.6 vs. 44.0% for those treated without a liver biopsy (p = 0.029). In genotype-1 patients with liver biopsy, more patients with cirrhosis had dose adjustments (p = 0.0057) rather than drug discontinuation.
There was tendency for earlier discontinuation among patients without pre-treatment liver biopsy.
Conclusions. Pre-treatment liver biopsy was associated with better SVR amongst genotype-1 patients. This improvement may reflect ongoing commitment to completing the treatment course by both patient and physician. In genotype-2/3 patients, pre-treatment liver biopsy may not be essential to maximize SVR rates.
This study validates the recommendations of the most recent treatment guidelines for hepatitis C.
Key words. Chronic hepatitis C. Liver biopsy. Outcomes research. Practice guidelines. Antiviral therapy. Adherence. Adverse events.
INTRODUCTION
Liver biopsy has been the cornerstone for the
diagnosis and management of liver disease. Over
the past two decades, however, new tests and procedures
have increased our diagnostic ability. In particular
for liver disease due to chronic viral infections, virological
and biochemical assays, and ultrasonographic
examination of the abdomen have reduced the
uncertainty of clinical diagnosis, with progressively
greater efficiency and lower risk.1-4 Since the level of
certainty needed in decision making is a function
of the characteristics of available therapies, one may
tolerate substantial diagnostic uncertainty if the
treatment cures the disease.5-7
As progress in antiviral therapy against hepatitis
C virus (HCV) infection is made,8,9 information obtainable
from liver biopsy may have less influence on
treatment decisions. Based on these premises, the
value of a procedure with well-known risks10,11
should be critically re-examined. Because the decision
to perform a liver biopsy is firmly rooted in
physicians’ preference, past expert consensus guidelines
have recommended the routine performance of
liver biopsy before initiation of antiviral therapy for
chronic HCV.12-14
More recent guidelines have shifted the emphasis
suggesting that liver biopsy may not be necessary
for genotype-2/3 but still recommending it in patients
infected with HCV genotype-1 if treatment
is being considered. These recommendations have
been based on expert-opinion rather than published
evidence.
Patients are not always eager to have a liver
biopsy, and frequently have anticipatory anxiety,
which would be expected of a procedure that is associated
with complications and death.10
Guidelines are commonly issued by scientific committees
and often do not incorporate patients’ preference
into medical decision making. Moreover, liver
biopsy may not always be representative for stage
or grade of the liver disease, as sample bias, and
interor intra-observer variability affect the diagnostic
yield.15-18
A cost-effectiveness analysis suggested that the best
strategy in the management of patients with HCV infection
is to offer therapy to all patients and not to
biopsy,19,20 and that the histopathological diagnosis is
of little additional value for the recommendation of
treatment16 empirical treatment based on HCV-RNA
quantification, or HCV genotyping but without liver
biopsy, has acceptable cost-effectiveness.19
These conclusions, derived from mathematical simulation
based on Markov computer modeling, require
direct clinical verification before becoming
widely accepted. At minimum, patients would like to
see some evidence that a liver biopsy would make a
difference in outcomes before accepting the expert
advice. Physicians who treat HCV also would like to
see that in genotype-2/3 the decision for initiating
therapy in patients without a pre-treatment liver
biopsy would not impact the outcomes.
In this study, we compared sustained viral response
(SVR) rates after combination treatment with
peginterferon alfa-2a and ribavirin in treatmentnaïve
patients with HCV infection who underwent or
did not undergo liver biopsy prior to initiation
of therapy.
MATERIAL AND METHODS
Patients
Patients included in this retrospective analysis of
prospectively collected data were enrolled in the
open-label Canadian Pegasys Expanded Access Program
(EAP). Eligibility criteria for the program
were broad and previously described.21 Individuals
were required to have a clinical diagnosis of chronic
HCV and quantifiable HCV RNA in serum. Patients
with clinically advanced liver disease could be enrolled
only if they had compensated liver disease
(Child-Pugh class A), neutrophil count > 1.5 x 109/
L, and platelet count > 90 x 109/L. Only treatmentnaïve
patients were included in this analysis. Also
all patients with multiple genotypes or genotype-4/5/
6 were excluded.
Liver biopsy
In the second phase of EAP, there was no requirement
for a liver biopsy to enroll patients. The decision
was left to the usual clinical practice of the
participating physician. Any biopsies performed on
patients enrolled in the EAP were read by the presiding
local pathologist at each study site. For those
who underwent liver biopsy, grading of inflammation
and staging of fibrosis were analyzed according
to the METAVIR scoring system. Only the
most recent biopsy result was recorded on the case
report form. For patients who were treated
without a liver biopsy, the reason for not performing
a liver biopsy was not collected on the case
report forms
Treatment
Patients received peginterferon alfa-2a 180
μg/week plus either a low fixed dose of ribavirin
(800 mg/day) or a weight-based dose of ribavirin
(1,000 mg/day for patients with a body weight
< 75 kg; 1,200 mg/day for patients with a body
weight ≥ 75 kg) for 24 or 48 weeks (Pegasys RBV®,
Roche, Mississauga, Canada).
The EAP was not a randomized trial; the duration
of treatment and ribavirin dose were selected
at the investigator’s discretion. The impact of differences
in dosage has also been reported previously.
22 In this analysis, only genotype-1 patients who
were assigned to a ribavirin dose of 1,000/1,200 mg/
day and planned treatment duration of 48 weeks
were included. Among genotype-2/3 patients,
only those assigned to a ribavirin dose of 800
mg/day and planned treatment duration of 24
weeks were included.
Limiting the study to patients who received optimum
dosing and length of therapy was necessary to
avoid baseline treatment biases and allow an intention-
to-treat analysis.
Outcomes
The primary efficacy outcome was SVR, defined
as undetectable HCV RNA (< 50 IU/mL by qualitative
PCR assay, Cobas Amplicor HCV Test, v2.0, Roche
Diagnostics, Indianapolis, IN, USA) 24 weeks
following completion of therapy. Early virological
response (EVR) was defined as 2-log10 or more drop
in serum HCV RNA, or undetectable HCV RNA by
quantitative PCR assay (Cobas Amplicor HCV Monitor,
v2.0, Roche Diagnostics, Indianapolis, IN, USA;
limit of quantification 600 IU/mL) at week 12. In genotype-
1 patients those who had undetectable HCV
RNA by qualitative PCR at week 24 continued treatment
for total of 48 weeks.
End of treatment virological response (EOTVR)
was defined as undetectable HCV RNA by qualitative
PCR at the end of planned treatment (i.e., week 24
for genotypes-2/3 and 48 for genotype-1). Relapse
rate was defined as percentage of patients with
detectable HCV-RNA at 24 weeks post-treatment
from those with undetectable HCV-RNA at the end
of the treatment period.
Adverse events,
dose adjustments and drug discontinuation
Safety assessments (physical examination and laboratory
evaluations) and monitoring for adverse
events were conducted at regular intervals throughout
EAP, entered into case report forms, and captured
in the database.
In the event of clinically significant laboratory
abnormalities or adverse events, the adjustment or
discontinuation of dosage of peginterferon alpha-2a
or ribavirin was left to the individual participating
physicians who were all aware of the recommended
guidelines. All these dose adjustments and drug discontinuations
were also captured by the EAP case
report forms.
Statistical analysis
The analysis for the current study was reported
on the intention-to-treat approach. All patients registered
in the second phase of EAP who received at
least one dose of peginterferon alfa-2a and ribavirin
were included. They were grouped either having liver
biopsy or not having liver biopsy prior to treatment.
Differences between groups were evaluated by
Fisher’s exact test or Kruskal-Wallis test.
For the dose adjustment and drug discontinuation
analysis, those with pre-treatment liver biopsy
were further stratified by the presence or absence of
cirrhosis (METAVIR score 4).
Time to dose adjustment or drug discontinuation
for peginterferon alfa-2a and ribavirin was evaluated
by cumulative failure plot similar to a Kaplan
Meier survival analysis with comparison between
groups by log rank test.
Baseline factors predictive of SVR were identified
by multiple logistic regression analysis using a backward
elimination process. Factors considered in
the initial model included biopsy status (yes vs. no),
age (per 10 year increment), sex (male vs. female),
race (Caucasian vs. non-Caucasian), BMI (per unit
increase), HCV RNA level (per log10 increment) and
platelet count (< 150 vs. ≥ 150 x 109/L). All these
factors were identified a priori since they are known
to impact SVR.21
The α-level of significance for a two-tailed test
was considered to be at p of 0.05. All statistical
analyses were performed using SAS v. 9.1 (SAS Institute,
Cary, NC, USA).
RESULTS
A total of 2,702 patients were originally enrolled
into EAP at 72 centers in Canada. The first patient
was enrolled in October 2001. A total of 1,620 patients
were enrolled in the second phase of the trial
when a liver biopsy was not a prerequisite. There
were 985 treatment-naïve patients available for this
analysis including 654 genotype-1 patients assigned
to a ribavirin dose of 1,000/1,200 mg/day and treatment
duration of 48 weeks, and 331 genotype-2/3
patients assigned to a ribavirin dose of 800 mg/day
and treatment duration of 24 weeks. The baseline
characteristics of these patients are presented in
table 1.
Participating physicians elected to initiate therapy
for HCV without a pre-treatment liver biopsy in
141 (21.6%) genotype-1 infected patients and 126
(38.1%) genotype-2/3 patients. Amongst the 513 genotype-
1 infected patients and 205 genotype-2/3, the
staging of fibrosis according to METAVIR score
were comparable with 11.9% of genotype-1 patients
and 11.2% genotype-2/3 patients having cirrhosis
(METAVIR score 4).
In genotype-1 patients, except for female preponderance
in those with liver biopsy (32.6 vs. 20.6%,
p = 0.007), there were no differences in baseline characteristics
between the two groups. Female HCV
patients may have lower liver enzymes and slower
progressing liver disease both reasons for considering
liver biopsy but this database did not allow further analysis.
Download PDF
Annals Of Hepatology
July-September, Vol. 10 No.3, 2011: 260-269
Kevork M. Peltekian,* Vincent G. Bain,† Samuel S. Lee,‡ Morris Sherman,§ Curtis L. Cooper, Eric M. Yoshida,¶
Paul J. Marotta,** Mel Krajden,†† Robert Balshaw,‡‡ Marc Deschênes.§§ (a)
* Division of Gastroenterology. Dalhousie University, Halifax, Nova Scotia, Canada. † Division of Gastroenterology. University of Alberta, Edmonton, Alberta, Canada.
‡ Division of Gastroenterology. University of Calgary, Calgary, Alberta, Canada. § Division of Gastroenterology. University Health Network, Toronto, Ontario, Canada.
Division of Gastroenterology. Division of Infectious Diseases of the University of Ottawa, Ottawa, Ontario, Canada.
¶ Division of Gastroenterology. University of British Columbia, Vancouver, British Columbia, Canada.
** BC Centre for Disease Control. Toronto, Ontario, Canada. †† British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada.
‡‡ Syreon Corporation, Vancouver, BC, Canada. §§ Division of Gastroenterology. Royal Victoria Hospital, Montreal, Quebec, Canada.
(a) On behalf of the Canadian PEGASYS Study Group.
ABSTRACT
Background. Current practice guidelines recommend liver biopsy prior to treatment of hepatitis C genotype-1 but not for genotype-2/3; this is based on expert opinion, not on published evidence.
Methods.
In retrospective analysis of a large trial database prior to the publication of recent guidelines, we compared outcomes in 985 treatment-naïve patients with hepatitis C who did or did not undergo liver biopsy before starting peginterferon alfa-2a plus ribavirin.
Results.
Physicians elected to treat 141/654 (21.6%) genotype-1 patients and 126/331 (38.1%) genotype-2/3 patients without liver biopsy. There were no differences in baseline characteristics among those with or without pre-treatment liver biopsy, except for female preponderance in genotype-1 patients with liver biopsy. The sustained viral response (SVR) rate was no different amongst genotype-2/3 patients who had a biopsy before treatment with 66.3% SVR vs. 69.8% of those treated
without biopsy (p = 0.546), but significantly higher among genotype-1 patients with pre-treatment liver biopsy at 54.6 vs. 44.0% for those treated without a liver biopsy (p = 0.029). In genotype-1 patients with liver biopsy, more patients with cirrhosis had dose adjustments (p = 0.0057) rather than drug discontinuation.
There was tendency for earlier discontinuation among patients without pre-treatment liver biopsy.
Conclusions. Pre-treatment liver biopsy was associated with better SVR amongst genotype-1 patients. This improvement may reflect ongoing commitment to completing the treatment course by both patient and physician. In genotype-2/3 patients, pre-treatment liver biopsy may not be essential to maximize SVR rates.
This study validates the recommendations of the most recent treatment guidelines for hepatitis C.
Key words. Chronic hepatitis C. Liver biopsy. Outcomes research. Practice guidelines. Antiviral therapy. Adherence. Adverse events.
INTRODUCTION
Liver biopsy has been the cornerstone for the
diagnosis and management of liver disease. Over
the past two decades, however, new tests and procedures
have increased our diagnostic ability. In particular
for liver disease due to chronic viral infections, virological
and biochemical assays, and ultrasonographic
examination of the abdomen have reduced the
uncertainty of clinical diagnosis, with progressively
greater efficiency and lower risk.1-4 Since the level of
certainty needed in decision making is a function
of the characteristics of available therapies, one may
tolerate substantial diagnostic uncertainty if the
treatment cures the disease.5-7
As progress in antiviral therapy against hepatitis
C virus (HCV) infection is made,8,9 information obtainable
from liver biopsy may have less influence on
treatment decisions. Based on these premises, the
value of a procedure with well-known risks10,11
should be critically re-examined. Because the decision
to perform a liver biopsy is firmly rooted in
physicians’ preference, past expert consensus guidelines
have recommended the routine performance of
liver biopsy before initiation of antiviral therapy for
chronic HCV.12-14
More recent guidelines have shifted the emphasis
suggesting that liver biopsy may not be necessary
for genotype-2/3 but still recommending it in patients
infected with HCV genotype-1 if treatment
is being considered. These recommendations have
been based on expert-opinion rather than published
evidence.
Patients are not always eager to have a liver
biopsy, and frequently have anticipatory anxiety,
which would be expected of a procedure that is associated
with complications and death.10
Guidelines are commonly issued by scientific committees
and often do not incorporate patients’ preference
into medical decision making. Moreover, liver
biopsy may not always be representative for stage
or grade of the liver disease, as sample bias, and
interor intra-observer variability affect the diagnostic
yield.15-18
A cost-effectiveness analysis suggested that the best
strategy in the management of patients with HCV infection
is to offer therapy to all patients and not to
biopsy,19,20 and that the histopathological diagnosis is
of little additional value for the recommendation of
treatment16 empirical treatment based on HCV-RNA
quantification, or HCV genotyping but without liver
biopsy, has acceptable cost-effectiveness.19
These conclusions, derived from mathematical simulation
based on Markov computer modeling, require
direct clinical verification before becoming
widely accepted. At minimum, patients would like to
see some evidence that a liver biopsy would make a
difference in outcomes before accepting the expert
advice. Physicians who treat HCV also would like to
see that in genotype-2/3 the decision for initiating
therapy in patients without a pre-treatment liver
biopsy would not impact the outcomes.
In this study, we compared sustained viral response
(SVR) rates after combination treatment with
peginterferon alfa-2a and ribavirin in treatmentnaïve
patients with HCV infection who underwent or
did not undergo liver biopsy prior to initiation
of therapy.
MATERIAL AND METHODS
Patients
Patients included in this retrospective analysis of
prospectively collected data were enrolled in the
open-label Canadian Pegasys Expanded Access Program
(EAP). Eligibility criteria for the program
were broad and previously described.21 Individuals
were required to have a clinical diagnosis of chronic
HCV and quantifiable HCV RNA in serum. Patients
with clinically advanced liver disease could be enrolled
only if they had compensated liver disease
(Child-Pugh class A), neutrophil count > 1.5 x 109/
L, and platelet count > 90 x 109/L. Only treatmentnaïve
patients were included in this analysis. Also
all patients with multiple genotypes or genotype-4/5/
6 were excluded.
Liver biopsy
In the second phase of EAP, there was no requirement
for a liver biopsy to enroll patients. The decision
was left to the usual clinical practice of the
participating physician. Any biopsies performed on
patients enrolled in the EAP were read by the presiding
local pathologist at each study site. For those
who underwent liver biopsy, grading of inflammation
and staging of fibrosis were analyzed according
to the METAVIR scoring system. Only the
most recent biopsy result was recorded on the case
report form. For patients who were treated
without a liver biopsy, the reason for not performing
a liver biopsy was not collected on the case
report forms
Treatment
Patients received peginterferon alfa-2a 180
μg/week plus either a low fixed dose of ribavirin
(800 mg/day) or a weight-based dose of ribavirin
(1,000 mg/day for patients with a body weight
< 75 kg; 1,200 mg/day for patients with a body
weight ≥ 75 kg) for 24 or 48 weeks (Pegasys RBV®,
Roche, Mississauga, Canada).
The EAP was not a randomized trial; the duration
of treatment and ribavirin dose were selected
at the investigator’s discretion. The impact of differences
in dosage has also been reported previously.
22 In this analysis, only genotype-1 patients who
were assigned to a ribavirin dose of 1,000/1,200 mg/
day and planned treatment duration of 48 weeks
were included. Among genotype-2/3 patients,
only those assigned to a ribavirin dose of 800
mg/day and planned treatment duration of 24
weeks were included.
Limiting the study to patients who received optimum
dosing and length of therapy was necessary to
avoid baseline treatment biases and allow an intention-
to-treat analysis.
Outcomes
The primary efficacy outcome was SVR, defined
as undetectable HCV RNA (< 50 IU/mL by qualitative
PCR assay, Cobas Amplicor HCV Test, v2.0, Roche
Diagnostics, Indianapolis, IN, USA) 24 weeks
following completion of therapy. Early virological
response (EVR) was defined as 2-log10 or more drop
in serum HCV RNA, or undetectable HCV RNA by
quantitative PCR assay (Cobas Amplicor HCV Monitor,
v2.0, Roche Diagnostics, Indianapolis, IN, USA;
limit of quantification 600 IU/mL) at week 12. In genotype-
1 patients those who had undetectable HCV
RNA by qualitative PCR at week 24 continued treatment
for total of 48 weeks.
End of treatment virological response (EOTVR)
was defined as undetectable HCV RNA by qualitative
PCR at the end of planned treatment (i.e., week 24
for genotypes-2/3 and 48 for genotype-1). Relapse
rate was defined as percentage of patients with
detectable HCV-RNA at 24 weeks post-treatment
from those with undetectable HCV-RNA at the end
of the treatment period.
Adverse events,
dose adjustments and drug discontinuation
Safety assessments (physical examination and laboratory
evaluations) and monitoring for adverse
events were conducted at regular intervals throughout
EAP, entered into case report forms, and captured
in the database.
In the event of clinically significant laboratory
abnormalities or adverse events, the adjustment or
discontinuation of dosage of peginterferon alpha-2a
or ribavirin was left to the individual participating
physicians who were all aware of the recommended
guidelines. All these dose adjustments and drug discontinuations
were also captured by the EAP case
report forms.
Statistical analysis
The analysis for the current study was reported
on the intention-to-treat approach. All patients registered
in the second phase of EAP who received at
least one dose of peginterferon alfa-2a and ribavirin
were included. They were grouped either having liver
biopsy or not having liver biopsy prior to treatment.
Differences between groups were evaluated by
Fisher’s exact test or Kruskal-Wallis test.
For the dose adjustment and drug discontinuation
analysis, those with pre-treatment liver biopsy
were further stratified by the presence or absence of
cirrhosis (METAVIR score 4).
Time to dose adjustment or drug discontinuation
for peginterferon alfa-2a and ribavirin was evaluated
by cumulative failure plot similar to a Kaplan
Meier survival analysis with comparison between
groups by log rank test.
Baseline factors predictive of SVR were identified
by multiple logistic regression analysis using a backward
elimination process. Factors considered in
the initial model included biopsy status (yes vs. no),
age (per 10 year increment), sex (male vs. female),
race (Caucasian vs. non-Caucasian), BMI (per unit
increase), HCV RNA level (per log10 increment) and
platelet count (< 150 vs. ≥ 150 x 109/L). All these
factors were identified a priori since they are known
to impact SVR.21
The α-level of significance for a two-tailed test
was considered to be at p of 0.05. All statistical
analyses were performed using SAS v. 9.1 (SAS Institute,
Cary, NC, USA).
RESULTS
A total of 2,702 patients were originally enrolled
into EAP at 72 centers in Canada. The first patient
was enrolled in October 2001. A total of 1,620 patients
were enrolled in the second phase of the trial
when a liver biopsy was not a prerequisite. There
were 985 treatment-naïve patients available for this
analysis including 654 genotype-1 patients assigned
to a ribavirin dose of 1,000/1,200 mg/day and treatment
duration of 48 weeks, and 331 genotype-2/3
patients assigned to a ribavirin dose of 800 mg/day
and treatment duration of 24 weeks. The baseline
characteristics of these patients are presented in
table 1.
Participating physicians elected to initiate therapy
for HCV without a pre-treatment liver biopsy in
141 (21.6%) genotype-1 infected patients and 126
(38.1%) genotype-2/3 patients. Amongst the 513 genotype-
1 infected patients and 205 genotype-2/3, the
staging of fibrosis according to METAVIR score
were comparable with 11.9% of genotype-1 patients
and 11.2% genotype-2/3 patients having cirrhosis
(METAVIR score 4).
In genotype-1 patients, except for female preponderance
in those with liver biopsy (32.6 vs. 20.6%,
p = 0.007), there were no differences in baseline characteristics
between the two groups. Female HCV
patients may have lower liver enzymes and slower
progressing liver disease both reasons for considering
liver biopsy but this database did not allow further analysis.
Click On Table 1 To Enlarge
NA: Not applicable. BMI: Body mass index. All values shown as mean ± SD (standard deviation). *All genotype-1 patients included in this analysis were assignedto receive a ribavirin dose of 1,000/1,200 mg/day and planned treatment duration of 48 weeks. †All genotype 2/3 patients included in this analysis wereassigned to receive a ribavirin dose of 800 mg/day and planned treatment duration of 24 weeks.‡Fisher’s or Wilcoxon two-sample test
The ethnic distribution amongst genotype-
2/3 patients between the two groups were different
(p = 0.041) with less Asians or Pacific
Islanders (8.8 vs. 11.1%) having undergone pre-therapy
liver biopsy. The overall number of African-Canadians
in this population was only 0.9%.
Specifically, for genotype-1, when considering the
baseline variables that usually predicted lower SVR
such as higher viral load, older age, higher BMI or
lower platelet counts (reflecting more advanced liver
disease and portal hypertension), no significant
differences could be identified between the group
who had pre-treatment liver biopsy versus the group who
did not undergo liver biopsy prior to initiation
of therapy.
Virological response
EVR rate at week 12, EOTVR rate and SVR rate
at 24 weeks following the completion of treatment
are shown in figure 1. There was no significant difference
in the proportion of genotype-2/3 patients
treated without a biopsy who achieved an SVR
(66.3%) when compared with patients treated
without a biopsy (69.8%, p = 0.546).
In contrast to the findings in genotype-2/3, 54.6%
of those with a pre-therapy biopsy achieved an SVR,
compared with 44.0% of those treated without a
biopsy (p = 0.029); this unexpected 10.6% absolute
improvement in SVR reflected 24.1% increase in
SVR in those patients whose fibrosis stage was
known before starting therapy. Further analysis revealed
that after the first 12 weeks of treatment,
there were no difference in EVR rates between the
two groups among genotype-1 patients (p = 0.28),
nor was there any difference in relapse rates with
20.4% in those with a pre-treatment biopsy vs.
22.4% in those treated without a biopsy (p = 0.687).
The major difference and contributing factor to lower
SVR was the EOTVR rate differences between
the two groups (p = 0.019).
Safety and tolerability
To further elucidate the reasons for differences in
EOTVR, we examined the number of dose adjust-
ments and early discontinuation among the groups.
baseline variables that usually predicted lower SVR
such as higher viral load, older age, higher BMI or
lower platelet counts (reflecting more advanced liver
disease and portal hypertension), no significant
differences could be identified between the group
who had pre-treatment liver biopsy versus the group who
did not undergo liver biopsy prior to initiation
of therapy.
Virological response
EVR rate at week 12, EOTVR rate and SVR rate
at 24 weeks following the completion of treatment
are shown in figure 1. There was no significant difference
in the proportion of genotype-2/3 patients
treated without a biopsy who achieved an SVR
(66.3%) when compared with patients treated
without a biopsy (69.8%, p = 0.546).
In contrast to the findings in genotype-2/3, 54.6%
of those with a pre-therapy biopsy achieved an SVR,
compared with 44.0% of those treated without a
biopsy (p = 0.029); this unexpected 10.6% absolute
improvement in SVR reflected 24.1% increase in
SVR in those patients whose fibrosis stage was
known before starting therapy. Further analysis revealed
that after the first 12 weeks of treatment,
there were no difference in EVR rates between the
two groups among genotype-1 patients (p = 0.28),
nor was there any difference in relapse rates with
20.4% in those with a pre-treatment biopsy vs.
22.4% in those treated without a biopsy (p = 0.687).
The major difference and contributing factor to lower
SVR was the EOTVR rate differences between
the two groups (p = 0.019).
Safety and tolerability
To further elucidate the reasons for differences in
EOTVR, we examined the number of dose adjust-
ments and early discontinuation among the groups.
Click On Figure 1 To Enlarge
Figure 1. Virological response rates at week 12 (EVR) the end of treatment (EOTVR) and after 24 weeks of following completion
of treatment (SVR). When comparing with patients who were treated without a biopsy, those who had pre-treatment liver
biopsy achieved 21.0% higher EOTVR and 24.1% higher SVR.
Click On Table 2 To Enlarge
Table 2. Dose adjustments and reported adverse events in treatment-naïve patients by genotype and biopsy status.
There were no statistically significant differences in
the frequency of ribavirin or peginterferon alfa-2a
dose adjustment in patients infected with genotype-1
or genotypes-2/3 who were treated with and without
a pre-treatment liver biopsy (Table 2) though there
was tendency for more peginterferon alfa-2a discontinuation
in the group that did not have pre-therapy
biopsy; this did not achieve 2-tailed significance (p
= 0.0632). Overall the incidence of non-serious adverse
events was similar in genotype-1 patients and
genotype-2/3 patients who were treated with a biopsy
vs. those patients without a biopsy (Table 2).
Among genotype-1 patients, there were no significant
differences between the two groups in the mean
overall length of therapy with either peginterferon
alfa-2a (286 vs. 270 days in patients with and
without a biopsy) or ribavirin (291 vs. 275 days,
respectively). Similarly, there were no significant
differences between the two groups in the mean overall
length of therapy with either peginterferon alfa-
2a (159 vs. 152 days, respectively) or ribavirin (165
vs. 158 days, respectively) among genotype-2/3 infected
patients.
When the cumulative failure plots for dose adjustment
and drug discontinuation were reviewed
(Figure 2) for peginterferon alfa-2a or ribavirin in
genotype-1 and genotype-2/3 patients, amongst
those who underwent liver biopsy, more patients
with cirrhosis had significantly more dose adjustments
(p = 0.0057) especially during the first 12
weeks of therapy. The drug discontinuation was
comparable (p = 0.3023) to those without cirrhosis
or patients who did not undergo liver biopsy
with discontinuations occurring around week-12
due to lack of early viral response or at week-24
because of ongoing HCV viremia by qualitative
PCR testing. Also in genotype-1 patients who did
not undergo liver biopsy prior to treatment, there
was tendency for earlier drug discontinuation
compared to patients who had undergone liver
biopsy with or without cirrhosis.
Click On Figure To Enlarge
Figure 2. In genotype-2/3 there were no differences in number of patients with dose adjustments in peginterferon alfa-2a or ribavirin
Independent factors impacting SVR
We proceeded by exploring the significant difference
in SVR in genotype-1 patients. To avoid and
correct for the inherent bias in the patient population,
we conducted multiple logistic regression
analysis to see if the availability of pre-treatment liver
biopsy was independently associated with SVR.
When baseline factors were entered into the stepwise
analysis, the following were significantly associated
with SVR in genotype-1 infected patients:
• Pre-therapy biopsy (OR 1.513 vs. no biopsy, 95%
CI 1.024-2.234; p = 0.0376).
• Age (OR 0.827 per 10-year increment, 95% CI
0.685-0.998; p = 0.0473).
• Caucasian race (OR 0.435 vs. non-Caucasian
race, 95% CI 0.279-0.678; p = 0.0002).
• HCV RNA level (OR 0.663 per 1-log increase,
95%CI 0.529-0.830; p = 0.0003).
• Platelet count level (OR 0.352 for < 150 vs. ≥ 150
x109/L, 95% CI 0.215-0.570; p < 0.0001).
Only age was significantly associated with SVR
in the multiple logistic regression analysis of data
from genotype-2/3 infected patients (OR 0.739 per
10-year increment in age, 95% CI 0.576-0.948; p =
0.0173).
DISCUSSION
All patients with chronic HCV are potential candidates
for specific antiviral therapy. Originally, given
the modest response to interferon monotherapy,
treatment was recommended only in patients in
whom the impact of treatment could be greatest,
in terms of halting disease progression and preven-
ting complications. On this premise early treatment
guidelines recommended that decisions about
treatment should be made only after performing a
liver biopsy.12-14
However, in recent years we have witnessed a remarkable
improvement in the clinical effectiveness
of treatment of chronic HCV, with SVR rates of up
to 50% in genotype1- patients and up to 80% in patients
infected with genotype-2/3.8,9,22 Revision of
guidelines would be expected to follow this therapeutic
gain: as the probability of achieving an SVR increases,
the need for absolute certainty in staging
and grading chronic viral hepatitis decreases.
One would expect that a selective rather than
routine liver biopsy policy would be used to assist
in decision-making regarding therapy; possible algorithm
may include restricting the invasive procedure
to patients with a high probability of no response or
considering performing liver biopsy in non-responders
after first course of treatment.
Pretreatment liver biopsy was recommended at
the time the Canadian EAP was initiated.12-14 The
current AASLD and Canadian guidelines continue
to recommend liver biopsy prior to initiating treatment
but both make the distinction that in genotype-
2/3 treatment may be initiated without a
pre-therapy liver biopsy.23,24
This current analysis substantiates the expert
opinion that in genotype-2/3 patients, the pre-therapy
liver biopsy does not make a difference in outcomes.
A liver biopsy may be unnecessary in patients
with genotypes 2/3 HCV infection, since more than
80% of them achieve SVR with the standard-of-care
treatment.
In this analysis, genotype-1 patients achieved lower
SVR rates with an absolute difference of 10.6%
when pre-treatment liver biopsy was not performed.
If we analyzed the number-needed-to-treat, there
would be one additional subject achieving SVR for
every 10 HCV patients starting therapy in the group
with a pre-treatment liver biopsy. When we examined
this more closely, with similar EVR and relapse
rates, the difference in SVR rate was due to differences
in EOTVR rate in genotype-1.
Of course there might have been some bias in the
decision to biopsy or not biopsy prior to initiating
treatment. Using the more rigorous multiple logistic
regression analysis identified pre-treatment liver
biopsy as independent association with SVR only in
HCV-infected patients with genotype-1 but not with
genotype-2/3.
We had hypothesized that if a treating physician
suspected the patient was cirrhotic on the basis
of clinical or radiological evidence, they may
avoid a biopsy. However, in this analysis, surrogate
markers of advanced liver disease or more resistance
to treatment such as lower platelet
counts, older age, higher BMI, and higher viral
load were comparable between the groups that did
or did not undergo liver biopsy before therapy. In
fact, amongst those who underwent liver biopsy,
29.8% had advanced METAVIR fibrosis stages 3 or
4. This was no different from our own EAP phase-
1 study, when liver biopsy was an inclusion criterion,
where 34.2% had METAVIR fibrosis stages 3
or 4.21
This analysis excluded patients who had clear indications
for advanced liver disease with portal hypertension
(Child-Pugh class B or C, neutrophil count ≤
1.5 x 109/L, and platelet count ≤ 90 x 109/L). It is
likely that in those patients with stigmata of advanced
liver disease or imaging compatible with cirrhosis
or portal hypertension, treating physicians avoided
pre-treatment liver biopsy. This would imply an over
representation of cirrhotic patients in the group treated
without a liver biopsy, and therefore, lower SVR
that was seen in genotype-1 patients.
The interesting finding in the current analysis is
that similar bias should have been expected to occur
in the genotype-2/3 patients but yet similar SVR was
achieved in the group undergoing pre-treatment liver
biopsy vs. the group without pre-treatment liver
biopsy.
Adherence is an important contributor to successful
treatment of HCV. Both patient motivation and
physician treatment experience may be important
for a better adherence to combination treatment for
HCV.25 Adherence of 85% or more to peginterferon
and ribavirin treatment was associated with increased
HCV suppression.26
In this analysis, close examination of adherence
to treatment, revealed more dose adjustments in the
group of patients who had cirrhosis on the pre-treatment
liver biopsy but similar rates of dose discontinuation
as the patients who had shown no cirrhosis
on the liver biopsy.
Although data on patient’s motivation and treating
physician’s experience were not collected, it is
plausible that patients with pre-treatment liver biopsy,
especially those with more advanced disease,
may have had higher levels of commitment for completion
of therapy; furthermore in those patients
with known cirrhosis on the liver biopsy, treating
physicians tried more dose adjustment rather than
drug discontinuation to avoid failure and progression
to end-stage liver disease.
Of course there is also the possibility that patients
who did not undergo pre-treatment liver biopsy
may have been less committed to starting therapy
and to completion of longer course of therapy needed
for genotype-1 patients but not impacting genotype-
2/3 patients significantly.
The finding that SVR rates were higher in genotype-
1 patients treated after a biopsy does not resolve
the ongoing debate about whether a biopsy is
warranted for persons infected with HCV, genotype-
1, whose response to such treatment approximates
50% among Caucasians and 30% among African
Americans. A key question is whether a decision to
treat with antiviral therapy is or is not altered by
the information provided by histology.
In the past, advocates for routine biopsy prior to
treatment argued that treatment should be provided
to patients in whom the impact of treatment could
be greatest, for example those with advanced fibrosis,
rather than those patients who are less likely to
benefit, such as those with minimal or no portal fibrosis.
The main argument supporting this claim
was the slowly progressive natural history of chronic
hepatitis, with a median time from infection to
cirrhosis of roughly 30 years.27
Today the rationale is to treat all patients to reduce
the burden of liver disease. Often, physicians
use the liver biopsy to support the decision to postpone
therapy in a patient. With the newer HCV therapies
in the pipeline, the requirement of liver
biopsy prior to starting of treatment will have to be
re-examined.
Opponents of routine liver biopsy question the
view that liver-related deaths are the only serious
consequences of HCV infection. Other benefits of viral
elimination, such as a patient’s perceived lack of
cleanliness, elimination of the risk of household and
sexual transmission, and barriers to fertility, are
usually ignored by academic committees, but are given
a high priority by patients.28
Furthermore, treatment is less effective once fibrosis
has progressed to a more severe stage,29
whilst even relatively mild disease can progress to a
fibrotic event over years.30,31 Patients with mild hepatitis
may not be at greatest risk for liver-related
deaths, but might opt for treatment if available therapy
offers a high probability of ridding them of
their infection.
Since there has been significant advancements
made in assessing liver fibrosis using elastography
or serum fibrosis markers, either alone or in combination,
32 some of these issues may be revisited with
another cost-benefit analysis in genotype-1 treat
treatment-
naïve patients incorporating baseline information
from a combination of non-invasive methods for
analysis of liver histology vs. liver biopsy or considering
liver biopsy only in non-responders to antiviral
therapy
There are other reasons for considering liver
biopsy in HCV patients such as identification of patients
at high risk for development of hepatocellular
carcinoma and large esophageal varices; these were
not dealt with in this study though recent longitudinal
data reveal that techniques such as transient
elastography may be even more useful in identifying
those with cirrhosis.33
CONCLUSION
The results of the present study show that genotype-
1 patients who underwent liver biopsy had higher
SVR rates than those who did not undergo
biopsy. This might be related to better adherence
over a longer duration to the combination therapy
in more advanced liver disease.
This will require a controlled trial where genotype-
1 patients would be randomized to antiviral therapy
with or without pre-treatment staging of
fibrosis (by liver biopsy or non-invasive markers).
In contrast liver biopsy had no impact on SVR rates
in those infected with HCV genotype-2/3 challenging
the assumed need for a biopsy in these
individuals. These findings provide hard evidence
for the recommendations published by recent consensus
guidelines23,24,34-36 based only on expert-opinions.
ACKNOWLEDGEMENT
Nadia Lesnikova and Jennifer Lee of Syreon Corporation,
Vancouver, Canada assisted Dr. Balshaw
with the initial data analyses. Mr. Chris Usaty,
from Roche, Mississauga, Canada, was instrumental
in coordinate all phases of development of this manuscript.
DISCLOSURE STATEMENT
As the guarantor of the article Dr. Peltekian accepts
full responsibility for the conduct of analysis,
had full access to the data and made the final decision
to publish the article.
The first draft of the Methods
and Results and the tables were prepared by
Blair J. Jarvis MSc under the direction of Dr. Peltekian
using study reports generated by Syreon Corporation.
Dr Peltekian prepared the first drafts of
the Introduction, Discussion and the abstract. Mr.
Jarvis did this work under contract to Roche Canada.
Drs Peltekian, Bain, Lee, Sherman, Cooper, Yoshida,
Marotta, Krajden, and Deschênes were
involved in the planning and conduct of the study,
collection and interpretation of data and revising
the manuscript. Dr. Balshaw was involved in the design
and conduct of the statistical analyses and drafting
of the manuscript. All authors read and
approved the final draft submitted to the journal.
This study was funded by Roche, Mississauga, Canada.
ABBREVIATIONS
• AASLD: American Association for the Study of
Liver Disease.
• BMI: Body mass index.
• EAP: Expanded Access Program.
• EOTVR: End of therapy viral response.
• EVR: Early viral response.
• HCV: Hepatitis C virus.
• PCR: Polymerase chain reaction.
• RNA: Ribonucleic acid.
• SVR: Sustained viral response.
APPENDIX
The Canadian Pegasys Study Group also includes:
Frank Anderson MD, The Liver & Intestinal
Research Centre, Vancouver, BC; Robert Bailey MD,
Royal Alexandra Hospital, Edmonton, AB; Victor
Feinman MD, Mount Sinai Hospital, Toronto ON;
Susan Greenbloom MD, Toronto Digestive Disease
Associates Inc., Toronto ON; Nir Hilzenrat MD,
Montreal Jewish General Hospital, Montreal QC;
Kelly Kaita MD, John Buhler Research Centre, Winnipeg
MB; Linda Scully MD, The Ottawa Civic Hospital,
Ottawa ON; Bernard Willems MD, CHUM
Saint Luc Hospital, Montreal QC; Helga Witt-Sullivan
MD, Hamilton Health Sciences Corp-General
Site, Hamilton ON; Lawrence Worobetz MD, Royal
University Hospital, Saskatoon, SK.
REFERENCES
1. Sorbi D, McGill DB, Thistle JL, Therneau TM, Henry J, Lindor
KD. An assessment of the role of liver biopsies in
asymptomatic patients with chronic liver test abnormalities.
Am J Gastroenterol 2000; 95: 3206-10.
2. Andriulli A, Festa V, Leandro G, Rizzetto M. Usefulness of a
liver biopsy in the evaluation of patients with elevated
ALT values and serological markers of hepatitis viral infection:
an AIGO study. Dig Dis Sci 2001; 46: 1409-15.
3. Andriulli A, Mangia A, Niro G, Caturelli E. To biopsy or not
to biopsy. Hepatol 2001; 34: 438-39.
4. Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D,
Easley K. The role of liver biopsy in chronic hepatitis C.
Hepatol 2001; 33: 196-200.
5. Pauker SG, Kassirer JP. The threshold approach to clinical
decision making. N Engl J Med 1980; 302: 1109-17.
6. Eisenberg JM, Hershey JC. Derived thresholds. Determining
the diagnostic probabilities at which clinicians initiate
testing and treatment. Med Decis Making 1983; 3:
155-68.
7. Kassirer JP. Our stubborn quest for diagnostic certainty. A
cause of excessive testing. N Engl J Med 1989; 320: 1489-91.
8. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman
M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin
compared with interferon alfa-2b plus ribavirin for
initial treatment of chronic hepatitis C: a randomized
trial. Lancet 2001; 358: 958-65.
9. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G,
Goncales FL Jr., et al. Peginterferon alfa-2a plus ribavirin
for chronic hepatitis C virus infection. N Engl J Med
2002; 347: 975-82.
10. Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications
following percutaneous liver biopsy. A multicentre retrospective
study on 68,276 biopsies. J Hepatol 1986; 2:
165-73.
11. Myers RP, Fong A, Shaheen AA. Utilization rates, complications
and costs of percutaneous liver biopsy: a population-
based study including 4275 biopsies. Liver Int 2008;
28: 705-12.
12. National Institutes of Health Consensus Development Conference
Panel statement: management of hepatitis C. Hepatology
1997; 26: 2S-10S.
13 EASL International Consensus Conference on Hepatitis C.
Paris, 26-28, February 1999, Consensus Statement. European
Association for the Study of the Liver. J Hepatol
1999; 30: 956-61.
14. Grant A, Neuberger J. Guidelines on the use of liver biopsy
in clinical practice. British Society of Gastroenterology.
Gut 1999; 45(Suppl. 4): IV1-IV11.
15. Soloway RD, Baggenstoss AH, Schoenfield LJ, Summerskill
WH. Observer error and sampling variability tested in evaluation
of hepatitis and cirrhosis by liver biopsy. Am J Dig
Dis 1971; 16: 1082-86.
16. Pagliaro L, Rinaldi F, Craxi A, Di PS, Filippazzo G, Gatto G,
et al. Percutaneous blind biopsy versus laparoscopy with
guided biopsy in diagnosis of cirrhosis. A prospective,
randomized trial. Dig Dis Sci 1983; 28: 39-43.
17. Maharaj B, Maharaj RJ, Leary WP, Cooppan RM, Naran AD,
Pirie D, et al. Sampling variability and its influence on the
diagnostic yield of percutaneous needle biopsy of the liver.
Lancet 1986; 1: 523-25.
18. Intraobserver and interobserver variations in liver biopsy
interpretation in patients with chronic hepatitis C. The
French METAVIR Cooperative Study Group. Hepatology
1994; 20: 15-20.
19. Wong JB, Koff RS. Watchful waiting with periodic liver
biopsy versus immediate empirical therapy for histologically
mild chronic hepatitis C. A cost-effectiveness analysis.
Ann Intern Med 2000; 133: 665-75.
20. Wong JB, Bennett WG, Koff RS, Pauker SG. Pretreatment
evaluation of chronic hepatitis C: risks, benefits, and
costs. JAMA 1998; 280: 2088-93.
21. Lee SS, Bain VG, Peltekian K, Krajden M, Yoshida EM,
Deschenes M, et al. Treating chronic hepatitis C with
pegylated interferon alfa-2a (40 KD) and ribavirin in
clinical practice. Aliment Pharmacol Ther 2006; 23:
397-408.
We proceeded by exploring the significant difference
in SVR in genotype-1 patients. To avoid and
correct for the inherent bias in the patient population,
we conducted multiple logistic regression
analysis to see if the availability of pre-treatment liver
biopsy was independently associated with SVR.
When baseline factors were entered into the stepwise
analysis, the following were significantly associated
with SVR in genotype-1 infected patients:
• Pre-therapy biopsy (OR 1.513 vs. no biopsy, 95%
CI 1.024-2.234; p = 0.0376).
• Age (OR 0.827 per 10-year increment, 95% CI
0.685-0.998; p = 0.0473).
• Caucasian race (OR 0.435 vs. non-Caucasian
race, 95% CI 0.279-0.678; p = 0.0002).
• HCV RNA level (OR 0.663 per 1-log increase,
95%CI 0.529-0.830; p = 0.0003).
• Platelet count level (OR 0.352 for < 150 vs. ≥ 150
x109/L, 95% CI 0.215-0.570; p < 0.0001).
Only age was significantly associated with SVR
in the multiple logistic regression analysis of data
from genotype-2/3 infected patients (OR 0.739 per
10-year increment in age, 95% CI 0.576-0.948; p =
0.0173).
DISCUSSION
All patients with chronic HCV are potential candidates
for specific antiviral therapy. Originally, given
the modest response to interferon monotherapy,
treatment was recommended only in patients in
whom the impact of treatment could be greatest,
in terms of halting disease progression and preven-
ting complications. On this premise early treatment
guidelines recommended that decisions about
treatment should be made only after performing a
liver biopsy.12-14
However, in recent years we have witnessed a remarkable
improvement in the clinical effectiveness
of treatment of chronic HCV, with SVR rates of up
to 50% in genotype1- patients and up to 80% in patients
infected with genotype-2/3.8,9,22 Revision of
guidelines would be expected to follow this therapeutic
gain: as the probability of achieving an SVR increases,
the need for absolute certainty in staging
and grading chronic viral hepatitis decreases.
One would expect that a selective rather than
routine liver biopsy policy would be used to assist
in decision-making regarding therapy; possible algorithm
may include restricting the invasive procedure
to patients with a high probability of no response or
considering performing liver biopsy in non-responders
after first course of treatment.
Pretreatment liver biopsy was recommended at
the time the Canadian EAP was initiated.12-14 The
current AASLD and Canadian guidelines continue
to recommend liver biopsy prior to initiating treatment
but both make the distinction that in genotype-
2/3 treatment may be initiated without a
pre-therapy liver biopsy.23,24
This current analysis substantiates the expert
opinion that in genotype-2/3 patients, the pre-therapy
liver biopsy does not make a difference in outcomes.
A liver biopsy may be unnecessary in patients
with genotypes 2/3 HCV infection, since more than
80% of them achieve SVR with the standard-of-care
treatment.
In this analysis, genotype-1 patients achieved lower
SVR rates with an absolute difference of 10.6%
when pre-treatment liver biopsy was not performed.
If we analyzed the number-needed-to-treat, there
would be one additional subject achieving SVR for
every 10 HCV patients starting therapy in the group
with a pre-treatment liver biopsy. When we examined
this more closely, with similar EVR and relapse
rates, the difference in SVR rate was due to differences
in EOTVR rate in genotype-1.
Of course there might have been some bias in the
decision to biopsy or not biopsy prior to initiating
treatment. Using the more rigorous multiple logistic
regression analysis identified pre-treatment liver
biopsy as independent association with SVR only in
HCV-infected patients with genotype-1 but not with
genotype-2/3.
We had hypothesized that if a treating physician
suspected the patient was cirrhotic on the basis
of clinical or radiological evidence, they may
avoid a biopsy. However, in this analysis, surrogate
markers of advanced liver disease or more resistance
to treatment such as lower platelet
counts, older age, higher BMI, and higher viral
load were comparable between the groups that did
or did not undergo liver biopsy before therapy. In
fact, amongst those who underwent liver biopsy,
29.8% had advanced METAVIR fibrosis stages 3 or
4. This was no different from our own EAP phase-
1 study, when liver biopsy was an inclusion criterion,
where 34.2% had METAVIR fibrosis stages 3
or 4.21
This analysis excluded patients who had clear indications
for advanced liver disease with portal hypertension
(Child-Pugh class B or C, neutrophil count ≤
1.5 x 109/L, and platelet count ≤ 90 x 109/L). It is
likely that in those patients with stigmata of advanced
liver disease or imaging compatible with cirrhosis
or portal hypertension, treating physicians avoided
pre-treatment liver biopsy. This would imply an over
representation of cirrhotic patients in the group treated
without a liver biopsy, and therefore, lower SVR
that was seen in genotype-1 patients.
The interesting finding in the current analysis is
that similar bias should have been expected to occur
in the genotype-2/3 patients but yet similar SVR was
achieved in the group undergoing pre-treatment liver
biopsy vs. the group without pre-treatment liver
biopsy.
Adherence is an important contributor to successful
treatment of HCV. Both patient motivation and
physician treatment experience may be important
for a better adherence to combination treatment for
HCV.25 Adherence of 85% or more to peginterferon
and ribavirin treatment was associated with increased
HCV suppression.26
In this analysis, close examination of adherence
to treatment, revealed more dose adjustments in the
group of patients who had cirrhosis on the pre-treatment
liver biopsy but similar rates of dose discontinuation
as the patients who had shown no cirrhosis
on the liver biopsy.
Although data on patient’s motivation and treating
physician’s experience were not collected, it is
plausible that patients with pre-treatment liver biopsy,
especially those with more advanced disease,
may have had higher levels of commitment for completion
of therapy; furthermore in those patients
with known cirrhosis on the liver biopsy, treating
physicians tried more dose adjustment rather than
drug discontinuation to avoid failure and progression
to end-stage liver disease.
Of course there is also the possibility that patients
who did not undergo pre-treatment liver biopsy
may have been less committed to starting therapy
and to completion of longer course of therapy needed
for genotype-1 patients but not impacting genotype-
2/3 patients significantly.
The finding that SVR rates were higher in genotype-
1 patients treated after a biopsy does not resolve
the ongoing debate about whether a biopsy is
warranted for persons infected with HCV, genotype-
1, whose response to such treatment approximates
50% among Caucasians and 30% among African
Americans. A key question is whether a decision to
treat with antiviral therapy is or is not altered by
the information provided by histology.
In the past, advocates for routine biopsy prior to
treatment argued that treatment should be provided
to patients in whom the impact of treatment could
be greatest, for example those with advanced fibrosis,
rather than those patients who are less likely to
benefit, such as those with minimal or no portal fibrosis.
The main argument supporting this claim
was the slowly progressive natural history of chronic
hepatitis, with a median time from infection to
cirrhosis of roughly 30 years.27
Today the rationale is to treat all patients to reduce
the burden of liver disease. Often, physicians
use the liver biopsy to support the decision to postpone
therapy in a patient. With the newer HCV therapies
in the pipeline, the requirement of liver
biopsy prior to starting of treatment will have to be
re-examined.
Opponents of routine liver biopsy question the
view that liver-related deaths are the only serious
consequences of HCV infection. Other benefits of viral
elimination, such as a patient’s perceived lack of
cleanliness, elimination of the risk of household and
sexual transmission, and barriers to fertility, are
usually ignored by academic committees, but are given
a high priority by patients.28
Furthermore, treatment is less effective once fibrosis
has progressed to a more severe stage,29
whilst even relatively mild disease can progress to a
fibrotic event over years.30,31 Patients with mild hepatitis
may not be at greatest risk for liver-related
deaths, but might opt for treatment if available therapy
offers a high probability of ridding them of
their infection.
Since there has been significant advancements
made in assessing liver fibrosis using elastography
or serum fibrosis markers, either alone or in combination,
32 some of these issues may be revisited with
another cost-benefit analysis in genotype-1 treat
treatment-
naïve patients incorporating baseline information
from a combination of non-invasive methods for
analysis of liver histology vs. liver biopsy or considering
liver biopsy only in non-responders to antiviral
therapy
There are other reasons for considering liver
biopsy in HCV patients such as identification of patients
at high risk for development of hepatocellular
carcinoma and large esophageal varices; these were
not dealt with in this study though recent longitudinal
data reveal that techniques such as transient
elastography may be even more useful in identifying
those with cirrhosis.33
CONCLUSION
The results of the present study show that genotype-
1 patients who underwent liver biopsy had higher
SVR rates than those who did not undergo
biopsy. This might be related to better adherence
over a longer duration to the combination therapy
in more advanced liver disease.
This will require a controlled trial where genotype-
1 patients would be randomized to antiviral therapy
with or without pre-treatment staging of
fibrosis (by liver biopsy or non-invasive markers).
In contrast liver biopsy had no impact on SVR rates
in those infected with HCV genotype-2/3 challenging
the assumed need for a biopsy in these
individuals. These findings provide hard evidence
for the recommendations published by recent consensus
guidelines23,24,34-36 based only on expert-opinions.
ACKNOWLEDGEMENT
Nadia Lesnikova and Jennifer Lee of Syreon Corporation,
Vancouver, Canada assisted Dr. Balshaw
with the initial data analyses. Mr. Chris Usaty,
from Roche, Mississauga, Canada, was instrumental
in coordinate all phases of development of this manuscript.
DISCLOSURE STATEMENT
As the guarantor of the article Dr. Peltekian accepts
full responsibility for the conduct of analysis,
had full access to the data and made the final decision
to publish the article.
The first draft of the Methods
and Results and the tables were prepared by
Blair J. Jarvis MSc under the direction of Dr. Peltekian
using study reports generated by Syreon Corporation.
Dr Peltekian prepared the first drafts of
the Introduction, Discussion and the abstract. Mr.
Jarvis did this work under contract to Roche Canada.
Drs Peltekian, Bain, Lee, Sherman, Cooper, Yoshida,
Marotta, Krajden, and Deschênes were
involved in the planning and conduct of the study,
collection and interpretation of data and revising
the manuscript. Dr. Balshaw was involved in the design
and conduct of the statistical analyses and drafting
of the manuscript. All authors read and
approved the final draft submitted to the journal.
This study was funded by Roche, Mississauga, Canada.
ABBREVIATIONS
• AASLD: American Association for the Study of
Liver Disease.
• BMI: Body mass index.
• EAP: Expanded Access Program.
• EOTVR: End of therapy viral response.
• EVR: Early viral response.
• HCV: Hepatitis C virus.
• PCR: Polymerase chain reaction.
• RNA: Ribonucleic acid.
• SVR: Sustained viral response.
APPENDIX
The Canadian Pegasys Study Group also includes:
Frank Anderson MD, The Liver & Intestinal
Research Centre, Vancouver, BC; Robert Bailey MD,
Royal Alexandra Hospital, Edmonton, AB; Victor
Feinman MD, Mount Sinai Hospital, Toronto ON;
Susan Greenbloom MD, Toronto Digestive Disease
Associates Inc., Toronto ON; Nir Hilzenrat MD,
Montreal Jewish General Hospital, Montreal QC;
Kelly Kaita MD, John Buhler Research Centre, Winnipeg
MB; Linda Scully MD, The Ottawa Civic Hospital,
Ottawa ON; Bernard Willems MD, CHUM
Saint Luc Hospital, Montreal QC; Helga Witt-Sullivan
MD, Hamilton Health Sciences Corp-General
Site, Hamilton ON; Lawrence Worobetz MD, Royal
University Hospital, Saskatoon, SK.
REFERENCES
1. Sorbi D, McGill DB, Thistle JL, Therneau TM, Henry J, Lindor
KD. An assessment of the role of liver biopsies in
asymptomatic patients with chronic liver test abnormalities.
Am J Gastroenterol 2000; 95: 3206-10.
2. Andriulli A, Festa V, Leandro G, Rizzetto M. Usefulness of a
liver biopsy in the evaluation of patients with elevated
ALT values and serological markers of hepatitis viral infection:
an AIGO study. Dig Dis Sci 2001; 46: 1409-15.
3. Andriulli A, Mangia A, Niro G, Caturelli E. To biopsy or not
to biopsy. Hepatol 2001; 34: 438-39.
4. Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D,
Easley K. The role of liver biopsy in chronic hepatitis C.
Hepatol 2001; 33: 196-200.
5. Pauker SG, Kassirer JP. The threshold approach to clinical
decision making. N Engl J Med 1980; 302: 1109-17.
6. Eisenberg JM, Hershey JC. Derived thresholds. Determining
the diagnostic probabilities at which clinicians initiate
testing and treatment. Med Decis Making 1983; 3:
155-68.
7. Kassirer JP. Our stubborn quest for diagnostic certainty. A
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