"
"
More than 50% of genotype 1 and 20% of genotypes 2/3 HCVinfected
patients fail to achieve a sustained virologic response
(SVR) when treated with PegIFN/RBV. Non-sustained responders
to PegIFN/RBV comprise a heterogeneous group of patients
(non-responders, on-therapy and post-therapy relapsers)
defined by the time point when they achieved or not
undetectable viremia (see chapter 1). For these patients other
therapeutic options are clearly needed.
How to manage genotype 1 non-responders and
relapsers ?
Therapy selection: monitoring vs. retreatment
When considering further therapy for genotype 1 patients who
fail to achieve a sustained viral response (SVR) during the initial
standard-of-care (SoC) therapy, two important issues should be
considered:
– the exact classification of the initial response pattern (as
the response to subsequent therapy is strongly influenced
by the initial response),
patients fail to achieve a sustained virologic response
(SVR) when treated with PegIFN/RBV. Non-sustained responders
to PegIFN/RBV comprise a heterogeneous group of patients
(non-responders, on-therapy and post-therapy relapsers)
defined by the time point when they achieved or not
undetectable viremia (see chapter 1). For these patients other
therapeutic options are clearly needed.
How to manage genotype 1 non-responders and
relapsers ?
Therapy selection: monitoring vs. retreatment
When considering further therapy for genotype 1 patients who
fail to achieve a sustained viral response (SVR) during the initial
standard-of-care (SoC) therapy, two important issues should be
considered:
– the exact classification of the initial response pattern (as
the response to subsequent therapy is strongly influenced
by the initial response),
– the correctable factors of treatment failure during the
previous course of therapy.
Consistent with the change in HCV RNA during the previous
course of therapy, four different patterns of treatment failure
– with crucial implications for the regimen, duration and
likelihood of response to retreatment – can be distinguished:
1. Patients with less than 2 log10UI/ml decline in HCV RNA
from baseline to treatment week 12 are defined as nonresponders.
Within this group, null responders show a
minimal reduction in HCV RNA level (usually less than 1
log10UI/ml), being considered the most refractory group to
treatment with pegylated interferon alfa (PegIFN) and
ribavirin (RBV). SVR rates during retreatment rarely
surpass 15% in this population. Therefore, unless other
compelling reasons impose therapy in these patients (such
as control of extrahepatic manifestations or advanced liver
disease), the best option may be to closely monitor them
while waiting for triple therapy (PegIFN/RBV + a directacting
antiviral).
2. Patients with ≥2 log10UI/ml decline in HCV RNA from
baseline to treatment week 12, who remain HCV RNA
detectable at week 24 are partial virological responders.
3. Breakthrough is defined as detectable HCV RNA during
therapy, after an initial virologic response (HCV RNA
undetectable or ≥2 log10UI/ml decline at week 12).
4. In contrast to previous categories, relapsers are those who,
during therapy, achieved and maintained undetectable HCV
RNA (measured by a high sensitive assay), but HCV RNA
become again measurable during the first 6 months after the
end of therapy. Relapsers have the best chance of
achieving SVR during retreatment with PegIFN/RBV, with a
SVR rate of approximately 40%. Triple therapy with a
protease inhibitor further increase this rate.
Numerous host and virological factors strongly influence the
response to therapy. A complex constellation of fixed factors
related to virus, such as genotype 1 or high pre-therapeutic viral
previous course of therapy.
Consistent with the change in HCV RNA during the previous
course of therapy, four different patterns of treatment failure
– with crucial implications for the regimen, duration and
likelihood of response to retreatment – can be distinguished:
1. Patients with less than 2 log10UI/ml decline in HCV RNA
from baseline to treatment week 12 are defined as nonresponders.
Within this group, null responders show a
minimal reduction in HCV RNA level (usually less than 1
log10UI/ml), being considered the most refractory group to
treatment with pegylated interferon alfa (PegIFN) and
ribavirin (RBV). SVR rates during retreatment rarely
surpass 15% in this population. Therefore, unless other
compelling reasons impose therapy in these patients (such
as control of extrahepatic manifestations or advanced liver
disease), the best option may be to closely monitor them
while waiting for triple therapy (PegIFN/RBV + a directacting
antiviral).
2. Patients with ≥2 log10UI/ml decline in HCV RNA from
baseline to treatment week 12, who remain HCV RNA
detectable at week 24 are partial virological responders.
3. Breakthrough is defined as detectable HCV RNA during
therapy, after an initial virologic response (HCV RNA
undetectable or ≥2 log10UI/ml decline at week 12).
4. In contrast to previous categories, relapsers are those who,
during therapy, achieved and maintained undetectable HCV
RNA (measured by a high sensitive assay), but HCV RNA
become again measurable during the first 6 months after the
end of therapy. Relapsers have the best chance of
achieving SVR during retreatment with PegIFN/RBV, with a
SVR rate of approximately 40%. Triple therapy with a
protease inhibitor further increase this rate.
Numerous host and virological factors strongly influence the
response to therapy. A complex constellation of fixed factors
related to virus, such as genotype 1 or high pre-therapeutic viral
load (VL) or to the patient, such as African-American or Hispanic
race, severity of liver fibrosis/cirrhosis, hepatic steatosis or
insulin resistance (IR), negatively impact the therapeutic
outcome during a subsequent course of treatment. On the
contrary, identifying correctable factors that may have
contributed to prior treatment failure can help the decision of
retreatment and subsequent management. The most common
correctable factors that can significantly diminish the rate of
SVR include:
Dose reduction, transient discontinuation or premature
interruption of therapy, due to side effects such as anemia,
neutropenia or depression. Close monitoring and judicious
interventions (modest dose reduction, use of growth factors,
prophylactic antidepressants) could minimize these factors.
Lack of adherence to the prescribed medication regimen.
Rigorous adherence should be stressed and monitored.
Therapeutical strategies
The following strategies for prior genotype 1 non-responders
and relapsers can be distinguished:
1. Retreatment with PegIFN/RBV
2. Extended treatment duration for slow virological responders
3. Increasing PegIFN dose and longer treatment duration
4. Optimizing PegIFN and RBV dosing during retreatment
5. Maintenance therapy with low-dose of PegIFN
6. Triple-combination therapy
1. Retreatment with the previous regimen (PegIFN/RBV). In
the EPIC3 study, non-responders and relapsers to previous
therapy with interferon alfa (n=1203) or PegIFN alfa-2a/2b
(n=820) with or without RBV were retreated with PegIFN alfa-2b
(1.5μg/kg/week) and weight-based RBV (800-1400 mg/day) for
48 weeks (Poynard 2009). SVR was higher in prior relapsers
vs. non-responders (38% vs. 14%) and in patients who achieved
race, severity of liver fibrosis/cirrhosis, hepatic steatosis or
insulin resistance (IR), negatively impact the therapeutic
outcome during a subsequent course of treatment. On the
contrary, identifying correctable factors that may have
contributed to prior treatment failure can help the decision of
retreatment and subsequent management. The most common
correctable factors that can significantly diminish the rate of
SVR include:
Dose reduction, transient discontinuation or premature
interruption of therapy, due to side effects such as anemia,
neutropenia or depression. Close monitoring and judicious
interventions (modest dose reduction, use of growth factors,
prophylactic antidepressants) could minimize these factors.
Lack of adherence to the prescribed medication regimen.
Rigorous adherence should be stressed and monitored.
Therapeutical strategies
The following strategies for prior genotype 1 non-responders
and relapsers can be distinguished:
1. Retreatment with PegIFN/RBV
2. Extended treatment duration for slow virological responders
3. Increasing PegIFN dose and longer treatment duration
4. Optimizing PegIFN and RBV dosing during retreatment
5. Maintenance therapy with low-dose of PegIFN
6. Triple-combination therapy
1. Retreatment with the previous regimen (PegIFN/RBV). In
the EPIC3 study, non-responders and relapsers to previous
therapy with interferon alfa (n=1203) or PegIFN alfa-2a/2b
(n=820) with or without RBV were retreated with PegIFN alfa-2b
(1.5μg/kg/week) and weight-based RBV (800-1400 mg/day) for
48 weeks (Poynard 2009). SVR was higher in prior relapsers
vs. non-responders (38% vs. 14%) and in patients who achieved
an EVR (56%) during the second course of therapy (Poynard
2008; Poynard 2009).
2. Extended treatment duration for slow virological
responders. Slow virological responders are patients with ≥2
log10 decline in HCV RNA at treatment week 12, who achieve
undetectable HCV RNA between 12 and 24 weeks of therapy. In
this group, standard 48-week course of therapy has been
associated with a high rate of virological relapse after therapy.
Despite differences in study design (different criteria of
randomization to extended therapy, different doses of RBV),
several randomized controlled trials comparing 72 weeks to 48
weeks of treatment among slow virological responders have
shown consistently that prolonged therapy significantly
improves rates of SVR (44% vs. 28% [Sanchez-Tapias 2006]; 38%
vs. 18% [Pearlman 2007]), largely by decreasing the rate of
relapse (40% vs. 64% [Berg 2006]; 20% vs. 59% [Pearlman 2007]).
However, extending therapy has been associated with a
higher rate of AEs and premature discontinuation beyond 48
weeks of treatment, a finding that temper this approach in many
patients.
3. Increasing PegIFN dose and longer treatment duration.
Trials of intensified regimen with higher fixed-dose of PegIFN
and/or longer treatment duration have demonstrated only
modest increases in SVR in prior non-responders to
PegIFN/RBV. In the REPEAT trial (Jensen 2009) prior nonresponders
received PegIFN alfa-2a higher-dose induction
(360μg/week) for 12 weeks, followed by the usual 180μg/week
for a further 60 or 36 weeks (total duration 72 and 48 weeks,
respectively) with RBV 1000-1200 mg/day. The SVR rate was
higher for those treated for 72 weeks; no difference was found
between the induction and non-induction arms. This confirms
that retreatment of non-responders with extended therapy
may improve SVR rates, while induction therapy with higher
2008; Poynard 2009).
2. Extended treatment duration for slow virological
responders. Slow virological responders are patients with ≥2
log10 decline in HCV RNA at treatment week 12, who achieve
undetectable HCV RNA between 12 and 24 weeks of therapy. In
this group, standard 48-week course of therapy has been
associated with a high rate of virological relapse after therapy.
Despite differences in study design (different criteria of
randomization to extended therapy, different doses of RBV),
several randomized controlled trials comparing 72 weeks to 48
weeks of treatment among slow virological responders have
shown consistently that prolonged therapy significantly
improves rates of SVR (44% vs. 28% [Sanchez-Tapias 2006]; 38%
vs. 18% [Pearlman 2007]), largely by decreasing the rate of
relapse (40% vs. 64% [Berg 2006]; 20% vs. 59% [Pearlman 2007]).
However, extending therapy has been associated with a
higher rate of AEs and premature discontinuation beyond 48
weeks of treatment, a finding that temper this approach in many
patients.
3. Increasing PegIFN dose and longer treatment duration.
Trials of intensified regimen with higher fixed-dose of PegIFN
and/or longer treatment duration have demonstrated only
modest increases in SVR in prior non-responders to
PegIFN/RBV. In the REPEAT trial (Jensen 2009) prior nonresponders
received PegIFN alfa-2a higher-dose induction
(360μg/week) for 12 weeks, followed by the usual 180μg/week
for a further 60 or 36 weeks (total duration 72 and 48 weeks,
respectively) with RBV 1000-1200 mg/day. The SVR rate was
higher for those treated for 72 weeks; no difference was found
between the induction and non-induction arms. This confirms
that retreatment of non-responders with extended therapy
may improve SVR rates, while induction therapy with higher
dose of PegIFN has no beneficial effect. Multiple logistic
regression analysis indicated that EVR at 12 weeks consistently
predicts SVR in retreated non-responders (Marcellin 2008).
4. Optimizing PegIFN and RBV dosing during retreatment.
When combined with PegIFN, RBV is critical to prevent
relapse after treatment cessation. A small prospective study on
10 patients with HCV genotype 1 infection and high baseline VL
(>800, 000 IU/ml) showed feasibility and high efficacy of
treatment with high RBV doses (Lindhal 2005). RBV was
calculated to achieve a steady-state concentration above 15
μmol/ml. Prophylactic and as-needed administration of
erythropoietin and blood transfusions were required in a single
patient. SVR was achieved in 9 of 10 patients without major
treatment regimen violation. RBV dosing at 13-15 mg/kg appears
to be the best balance between optimized efficacy and
intolerable hemolytic anemia that develops at high doses. SVR is
significantly diminished when RBV dose is below 11 mg/kg.
Therefore, maximizing RBV dosing, particularly in overweight
patients, has the potential to improve SVR during the second
course of therapy. In a retrospective analysis of a large database
of patients treated with PegIFN/RBV, it has been demonstrated
that RBV dose reduction led to a stepwise decrease in SVR. The
cumulative dose of RBV below 60% is associated with an evident
decline in SVR (Reddy 2007). Thus, not only maximizing RBV
dosing, but also maintaining a cumulative RBV dose higher
than 80% of the overall dose, with or without erythropoietin,
improves SVR in previous non-responders and relapsers.
Other trials (Fried 2006) demonstrated improved SVR in patients
with body weight above 85 kg treated with higher dose of
PegIFN/RBV. Patients treated with PegIFN alfa-2a, 270 μg/week
and RBV 1600 mg/day, showed an SVR of 48% versus 28% in
those treated with standard dosing regimen (relapse rates 19%
vs. 40%). However, higher dose regimen was associated with an
increased rate of hematological AEs.
regression analysis indicated that EVR at 12 weeks consistently
predicts SVR in retreated non-responders (Marcellin 2008).
4. Optimizing PegIFN and RBV dosing during retreatment.
When combined with PegIFN, RBV is critical to prevent
relapse after treatment cessation. A small prospective study on
10 patients with HCV genotype 1 infection and high baseline VL
(>800, 000 IU/ml) showed feasibility and high efficacy of
treatment with high RBV doses (Lindhal 2005). RBV was
calculated to achieve a steady-state concentration above 15
μmol/ml. Prophylactic and as-needed administration of
erythropoietin and blood transfusions were required in a single
patient. SVR was achieved in 9 of 10 patients without major
treatment regimen violation. RBV dosing at 13-15 mg/kg appears
to be the best balance between optimized efficacy and
intolerable hemolytic anemia that develops at high doses. SVR is
significantly diminished when RBV dose is below 11 mg/kg.
Therefore, maximizing RBV dosing, particularly in overweight
patients, has the potential to improve SVR during the second
course of therapy. In a retrospective analysis of a large database
of patients treated with PegIFN/RBV, it has been demonstrated
that RBV dose reduction led to a stepwise decrease in SVR. The
cumulative dose of RBV below 60% is associated with an evident
decline in SVR (Reddy 2007). Thus, not only maximizing RBV
dosing, but also maintaining a cumulative RBV dose higher
than 80% of the overall dose, with or without erythropoietin,
improves SVR in previous non-responders and relapsers.
Other trials (Fried 2006) demonstrated improved SVR in patients
with body weight above 85 kg treated with higher dose of
PegIFN/RBV. Patients treated with PegIFN alfa-2a, 270 μg/week
and RBV 1600 mg/day, showed an SVR of 48% versus 28% in
those treated with standard dosing regimen (relapse rates 19%
vs. 40%). However, higher dose regimen was associated with an
increased rate of hematological AEs.
5. Maintenance therapy with low-dose of PegIFN. Nonsustained
responders to SoC, with advanced fibrosis or cirrhosis,
have a high risk for disease progression and complications. Two
large multicentre trials have evaluated the benefits of
maintenance therapy with low-dose PegIFN in this group:
– the COPILOT study (Colchicine vs. PegIFN alfa-2b 0.5
μg/kg/week Long Term) (Afdhal 2008)
– the HALT-C study (Hepatitis C Antiviral Long-Term
Treatment Against Cirrhosis with PegIFN alfa-2a 90
μg/week) (Di Bisceglie 2008)
In the COPILOT study 555 patients with prior failure to
interferon-based therapy were randomized to receive either
PegIFN alfa-2b 0.5 μg/kg/week (n=286) or colchicine 0,6 mg twice
daily (n=269). No differences were observed between the two
groups with respect to progression of the CP score, development
of complications of portal hypertension or HCC.
The HALT-C trial was a prospective, randomized, controlled
study of long-term maintenance therapy with PegIFN alfa-2a 90
μg/week (n=517) or no treatment (n=533) for 3.5 years in
patients with chronic hepatitis C (CHC) and advanced fibrosis or
cirrhosis (Ishak score 3-6) who did not achieve SVR after
interferon-based therapy. By the end of the study period, there
was no difference between the control and treated groups in the
frequency of death, hepatic decompensation or development of
HCC. Overall, the COPILOT and HALT-C trials showed that
maintenance therapy with low-dose PegIFN alfa-2a or alfa-2b
does not reduce the rate of liver-related death, clinical
disease progression and complications over a period of up to 4
years.
6. Triple-combination therapy. Triple therapy combination of
PegIFN/RBV with a protease inhibitors (telaprevir or boceprevir)
in HCV genotype 1-experienced patients has been shown to
produce high rates of virological response in both prior relapsers
responders to SoC, with advanced fibrosis or cirrhosis,
have a high risk for disease progression and complications. Two
large multicentre trials have evaluated the benefits of
maintenance therapy with low-dose PegIFN in this group:
– the COPILOT study (Colchicine vs. PegIFN alfa-2b 0.5
μg/kg/week Long Term) (Afdhal 2008)
– the HALT-C study (Hepatitis C Antiviral Long-Term
Treatment Against Cirrhosis with PegIFN alfa-2a 90
μg/week) (Di Bisceglie 2008)
In the COPILOT study 555 patients with prior failure to
interferon-based therapy were randomized to receive either
PegIFN alfa-2b 0.5 μg/kg/week (n=286) or colchicine 0,6 mg twice
daily (n=269). No differences were observed between the two
groups with respect to progression of the CP score, development
of complications of portal hypertension or HCC.
The HALT-C trial was a prospective, randomized, controlled
study of long-term maintenance therapy with PegIFN alfa-2a 90
μg/week (n=517) or no treatment (n=533) for 3.5 years in
patients with chronic hepatitis C (CHC) and advanced fibrosis or
cirrhosis (Ishak score 3-6) who did not achieve SVR after
interferon-based therapy. By the end of the study period, there
was no difference between the control and treated groups in the
frequency of death, hepatic decompensation or development of
HCC. Overall, the COPILOT and HALT-C trials showed that
maintenance therapy with low-dose PegIFN alfa-2a or alfa-2b
does not reduce the rate of liver-related death, clinical
disease progression and complications over a period of up to 4
years.
6. Triple-combination therapy. Triple therapy combination of
PegIFN/RBV with a protease inhibitors (telaprevir or boceprevir)
in HCV genotype 1-experienced patients has been shown to
produce high rates of virological response in both prior relapsers
and, to a lesser extent, prior non-responders in phase III trials. A
detailed presentation of the newly aproved direct-acting
antivirals (DAAs) is given in chapter 4.
Prove-3 trial evaluated triple-combination therapy with
telaprevir in treatment-experienced patients (~60% nonresponders
and ~40% relapsers) (McHutchison 2010). Patients
were randomized on four treatment arms in order to assess the
impact of different durations of triple therapy, different total
treatment duration and the importance of RBV for this difficultto-
treat population. Prior relapsers treated with 24 weeks of
triple therapy followed by 24 weeks of PegIFN/RBV (total
duration of therapy 48 weeks) had a SVR rate of 76%, while prior
non-responders had lower rates of SVR (~40% ).
RESPOND-2 evaluated triple therapy combination with
boceprevir in non-responders and relapsers (Bacon 2011). The
results indicate that 75% of prior relapsers and 52% of prior nonresponders
treated with a fixed triple therapy boceprevir
regimen achieved SVR. In the response-guided arm, SVR was 69%
in prior relapsers and 40% in prior non-responders.
Curent available data clearly show that that triple therapies
including a protease inhibitor provide higher chance of SVR
for relapsers and non-responders. The benefits of these novel
treatment regimens for each individual patient must be weighed
against the side effects, costs and potential of developing viral
resistance.
Practical approach to retreatment
When deciding retreatment of previous non-sustained
responders to standard therapy, the following practical issues
should be considered:
– Patient’s motivation for another course of therapy. Lower
likelihood of SVR in treatment-experienced patients, side
effects, poor QoL should be discussed with the patient;
– Severity of liver disease (clinical, biochemical,
histological). Patients with minimal-to-moderate fibrosis
detailed presentation of the newly aproved direct-acting
antivirals (DAAs) is given in chapter 4.
Prove-3 trial evaluated triple-combination therapy with
telaprevir in treatment-experienced patients (~60% nonresponders
and ~40% relapsers) (McHutchison 2010). Patients
were randomized on four treatment arms in order to assess the
impact of different durations of triple therapy, different total
treatment duration and the importance of RBV for this difficultto-
treat population. Prior relapsers treated with 24 weeks of
triple therapy followed by 24 weeks of PegIFN/RBV (total
duration of therapy 48 weeks) had a SVR rate of 76%, while prior
non-responders had lower rates of SVR (~40% ).
RESPOND-2 evaluated triple therapy combination with
boceprevir in non-responders and relapsers (Bacon 2011). The
results indicate that 75% of prior relapsers and 52% of prior nonresponders
treated with a fixed triple therapy boceprevir
regimen achieved SVR. In the response-guided arm, SVR was 69%
in prior relapsers and 40% in prior non-responders.
Curent available data clearly show that that triple therapies
including a protease inhibitor provide higher chance of SVR
for relapsers and non-responders. The benefits of these novel
treatment regimens for each individual patient must be weighed
against the side effects, costs and potential of developing viral
resistance.
Practical approach to retreatment
When deciding retreatment of previous non-sustained
responders to standard therapy, the following practical issues
should be considered:
– Patient’s motivation for another course of therapy. Lower
likelihood of SVR in treatment-experienced patients, side
effects, poor QoL should be discussed with the patient;
– Severity of liver disease (clinical, biochemical,
histological). Patients with minimal-to-moderate fibrosis
may wait for triple therapy while patients with advanced
fibrosis should be treated immediately with available
regimens;
– Virological response during the initial course of therapy.
Null and partial responders achieve lower SVR rates as
compared with relapsers, irrespective of therapeutic
regimen. Slow virological responders who have relapsed
may benefit from extending duration of therapy;
– Previous dose regimen and adherence assessment.
Optimizing RBV dosing, minimizing dose reductions by use
of growth factors and avoiding premature discontinuations
are important issues during retreatment;
– Correctable factors that may affect the subsequent
response to therapy: steatosis, insulin-resistance, chronic
alcohol consumption etc.
How to manage genotype 2 and 3 non-responders
and relapsers ?
Nonresponders/relapsers infected with HCV G2/3
Genotype 2 or 3 infected patients are easier to treat and require
only 24 weeks of therapy with PegIFN and low-dose of RBV (800
mg/day) (Zeuzem 2004). Patients who are intolerant of a planned
24-week course of therapy can discontinue the antiviral therapy
between weeks 12 and 16 without a negative impact on SVR, if
they have achieved a RVR (Mangia 2005).
Treatment failure is uncommon in genotype 2 and 3 patients.
Primary non-response to PegIFN/RBV is a very rare event, while
partial response or virological relapse after therapy withdrawal
may be detected in a subgroup of patients. Factors that have
been associated with suboptimal response to SoC in HCV
genotypes 2/3 patients include hepatic steatosis, obesity and IR
(Zeuzem 2004, Poustchi 2008), advanced fibrosis (Dalgard 2004)
and high pretreatment viremia (Shiffman 2007).
In most clinical trials, SVR rates in patients with HCV genotype 2
or 3 chronic infection, considered as a single group, exceed 80%
fibrosis should be treated immediately with available
regimens;
– Virological response during the initial course of therapy.
Null and partial responders achieve lower SVR rates as
compared with relapsers, irrespective of therapeutic
regimen. Slow virological responders who have relapsed
may benefit from extending duration of therapy;
– Previous dose regimen and adherence assessment.
Optimizing RBV dosing, minimizing dose reductions by use
of growth factors and avoiding premature discontinuations
are important issues during retreatment;
– Correctable factors that may affect the subsequent
response to therapy: steatosis, insulin-resistance, chronic
alcohol consumption etc.
How to manage genotype 2 and 3 non-responders
and relapsers ?
Nonresponders/relapsers infected with HCV G2/3
Genotype 2 or 3 infected patients are easier to treat and require
only 24 weeks of therapy with PegIFN and low-dose of RBV (800
mg/day) (Zeuzem 2004). Patients who are intolerant of a planned
24-week course of therapy can discontinue the antiviral therapy
between weeks 12 and 16 without a negative impact on SVR, if
they have achieved a RVR (Mangia 2005).
Treatment failure is uncommon in genotype 2 and 3 patients.
Primary non-response to PegIFN/RBV is a very rare event, while
partial response or virological relapse after therapy withdrawal
may be detected in a subgroup of patients. Factors that have
been associated with suboptimal response to SoC in HCV
genotypes 2/3 patients include hepatic steatosis, obesity and IR
(Zeuzem 2004, Poustchi 2008), advanced fibrosis (Dalgard 2004)
and high pretreatment viremia (Shiffman 2007).
In most clinical trials, SVR rates in patients with HCV genotype 2
or 3 chronic infection, considered as a single group, exceed 80%
(Zeuzem 2008). However, in a meta-analysis (Andriulli 2008), an
overall SVR rate of 80-89% for HCV genotype 2, but only 66-80%
for genotype 3 was reported, with an estimated 8.7% difference
in SVR rates between the two genotypes after a 24-week course
of PegIFN alfa-2b plus RBV. Reduced response in genotype 3 is
associated with a higher incidence and degree of steatosis and
higher rate of post-treatment relapse.
Retreatment of HCV genotype 2 and 3 patients
Retreatment with PegIFN/RBV for 48-52 weeks in genotype 2 or
3 patients, who have failed previous therapy, can achieve SVR in
more than 60% of previous relapsers and in more than 30% of
previous non-responders (Zeuzem 2008, Shiffman 2007). On the
basis of these findings, retreatment with a 48-52 week course
of PegIFN/RBV is clearly recommended in genotypes 2/3
relapsers, partial responders or non-responders to the
previous 24-weeks course of SoC.
Recently, it has been suggested that patients with genotype 3
HCV infection and advanced liver fibrosis or cirrhosis should be
treated from the very beginning for at least 48 weeks, based on
the observation than many of them relapse after therapy
discontinuation when treated for only 24 weeks (Mangia 2009).
Despite the fact that most DAAs against HCV have been designed
to target patients with genotype 1 infection (the largest pool of
patients who fail to respond to currently available therapies),
some of these new compounds may be active also on non-1
genotypes. For example, telaprevir and other investigational
protease inhibitors (for details, see chapter 4) have been recently
shown to have significant antiviral activity against genotype 2,
but not genotype 3.
overall SVR rate of 80-89% for HCV genotype 2, but only 66-80%
for genotype 3 was reported, with an estimated 8.7% difference
in SVR rates between the two genotypes after a 24-week course
of PegIFN alfa-2b plus RBV. Reduced response in genotype 3 is
associated with a higher incidence and degree of steatosis and
higher rate of post-treatment relapse.
Retreatment of HCV genotype 2 and 3 patients
Retreatment with PegIFN/RBV for 48-52 weeks in genotype 2 or
3 patients, who have failed previous therapy, can achieve SVR in
more than 60% of previous relapsers and in more than 30% of
previous non-responders (Zeuzem 2008, Shiffman 2007). On the
basis of these findings, retreatment with a 48-52 week course
of PegIFN/RBV is clearly recommended in genotypes 2/3
relapsers, partial responders or non-responders to the
previous 24-weeks course of SoC.
Recently, it has been suggested that patients with genotype 3
HCV infection and advanced liver fibrosis or cirrhosis should be
treated from the very beginning for at least 48 weeks, based on
the observation than many of them relapse after therapy
discontinuation when treated for only 24 weeks (Mangia 2009).
Despite the fact that most DAAs against HCV have been designed
to target patients with genotype 1 infection (the largest pool of
patients who fail to respond to currently available therapies),
some of these new compounds may be active also on non-1
genotypes. For example, telaprevir and other investigational
protease inhibitors (for details, see chapter 4) have been recently
shown to have significant antiviral activity against genotype 2,
but not genotype 3.
Special categories of patients
Given the increased prevalence of HCV infection among special
populations there is a stringent need to broaden the spectrum of
patients eligible for therapy.
Injecting drug users (IDUs)
CHC is hyperendemic among IDUs. There are several
challenging aspects that have to be considered before effective
antiviral therapy can be provided to this group of patients (Roy
2002):
– uptake of antiviral therapy is low in these patients,
depending on the phase of addiction (active/regular IDUs,
on maintenance therapy with methadone; past users;
abstinence)
– adherence to therapy is low
– side effects are frequent and difficult to manage in the
context of drug dependency
– there is a risk of relapse to drug use in patients who are
currently abstinent or on maintenance therapy even after
HCV therapy is started
– even after successful HCV eradication, there is a high risk of
reinfection in IDUs (Backmund 2001)
When treatment is indicated in IDUs, it should be provided as
soon as possible and during any phase of drug addiction, with
the same regimen (dose, duration) delivered to the non-drug
users. Treatment uptake and adherence to therapy is usually low
in active IDU and reinfection may occur. Treatment should
preferably be postponed until the patient is stabilized on
maintenance (methadone) therapy. Treatment of abstinent/past
users is associated with excellent adherence, being as effective as
in non-drug users (Wilkinson 2009). Psychiatric illnesses are
common among IDU and high awareness and early intervention
for psychiatric side effects during HCV treatment is important
Given the increased prevalence of HCV infection among special
populations there is a stringent need to broaden the spectrum of
patients eligible for therapy.
Injecting drug users (IDUs)
CHC is hyperendemic among IDUs. There are several
challenging aspects that have to be considered before effective
antiviral therapy can be provided to this group of patients (Roy
2002):
– uptake of antiviral therapy is low in these patients,
depending on the phase of addiction (active/regular IDUs,
on maintenance therapy with methadone; past users;
abstinence)
– adherence to therapy is low
– side effects are frequent and difficult to manage in the
context of drug dependency
– there is a risk of relapse to drug use in patients who are
currently abstinent or on maintenance therapy even after
HCV therapy is started
– even after successful HCV eradication, there is a high risk of
reinfection in IDUs (Backmund 2001)
When treatment is indicated in IDUs, it should be provided as
soon as possible and during any phase of drug addiction, with
the same regimen (dose, duration) delivered to the non-drug
users. Treatment uptake and adherence to therapy is usually low
in active IDU and reinfection may occur. Treatment should
preferably be postponed until the patient is stabilized on
maintenance (methadone) therapy. Treatment of abstinent/past
users is associated with excellent adherence, being as effective as
in non-drug users (Wilkinson 2009). Psychiatric illnesses are
common among IDU and high awareness and early intervention
for psychiatric side effects during HCV treatment is important
Hemodialysis patients
Due to the early nosocomial spread of HCV within hemodialysis
units (Fabrizi 2007), the infection is highly prevalent in this
setting and the treatment of CHC in this population remains a
challenge to clinicians.
A meta-analysis on the impact of HCV infection on mortality in
the dialysis population (seven observational studies enrolling
11,589 subjects on maintenance hemodialysis) showed a
detrimental impact of HCV on survival in patients with chronic
kidney disease (Fabrizi 2008). Positive anti-HCV serological
status after kidney transplantation is implicated in the
pathogenesis of acute glomerulopathy, “de novo” graftassociated
nephropathy, new-onset diabetes mellitus, and
increased incidence of infections.
There are good data to support antiviral therapy in the
pretransplant patients (see chapter 5). The decision to treat such
a difficult subgroup of patients should be based on liver
histology, age, comorbidities, and ability to tolerate therapy. In a
meta-analysis of patients on maintenance hemodialysis, the
overall SVR was 37% in the whole group and 30% in patients with
HCV genotype 1 (Fabrizi 2008). The viral response to
monotherapy with standard interferon in maintenance
hemodialysis patients is higher than that observed in patients
with CHC and normal kidney function (7-16%), due to the
following factors: lower VL, milder histological forms of liver
injury, a decreased interferon clearance, and an increase in
endogenous interferon release from circulating white blood cells
during hemodialysis procedures.
Data on PegIFN monotherapy and PegIFN/RBV therapy in
hemodialysed patients are limited. Very low amounts of RBV are
removed via dialysis, leading to drug accumulation and
exacerbating hemolysis in this population, already at significant
risk for anemia. Therefore, the decision to use combination
therapy in hemodialysed patients should take into consideration
several precautions: 1) use of very low RBV doses (200 mg x
Due to the early nosocomial spread of HCV within hemodialysis
units (Fabrizi 2007), the infection is highly prevalent in this
setting and the treatment of CHC in this population remains a
challenge to clinicians.
A meta-analysis on the impact of HCV infection on mortality in
the dialysis population (seven observational studies enrolling
11,589 subjects on maintenance hemodialysis) showed a
detrimental impact of HCV on survival in patients with chronic
kidney disease (Fabrizi 2008). Positive anti-HCV serological
status after kidney transplantation is implicated in the
pathogenesis of acute glomerulopathy, “de novo” graftassociated
nephropathy, new-onset diabetes mellitus, and
increased incidence of infections.
There are good data to support antiviral therapy in the
pretransplant patients (see chapter 5). The decision to treat such
a difficult subgroup of patients should be based on liver
histology, age, comorbidities, and ability to tolerate therapy. In a
meta-analysis of patients on maintenance hemodialysis, the
overall SVR was 37% in the whole group and 30% in patients with
HCV genotype 1 (Fabrizi 2008). The viral response to
monotherapy with standard interferon in maintenance
hemodialysis patients is higher than that observed in patients
with CHC and normal kidney function (7-16%), due to the
following factors: lower VL, milder histological forms of liver
injury, a decreased interferon clearance, and an increase in
endogenous interferon release from circulating white blood cells
during hemodialysis procedures.
Data on PegIFN monotherapy and PegIFN/RBV therapy in
hemodialysed patients are limited. Very low amounts of RBV are
removed via dialysis, leading to drug accumulation and
exacerbating hemolysis in this population, already at significant
risk for anemia. Therefore, the decision to use combination
therapy in hemodialysed patients should take into consideration
several precautions: 1) use of very low RBV doses (200 mg x
3/week), 2) weekly monitoring of hemoglobin levels, and 3) use
of high erythropoietin doses to treat anemia (Bruchfeld 2006).
Patients with psychiatric comorbidities
A prevalence of 60% psychiatric comorbidities has been reported
in patients with CHC. On the other side, neuropsychiatric side
effects occur in up to 50% of patients receiving treatment with
PegIFN/RBV, the commonest being depression. Prospective
clinical trials suggest that patients with HCV infection and
psychiatric comorbidities can be safely treated with interferonbased
antiviral regimens by both hepatologists and mental
health professionals as part of a multidisciplinary team (Knott
2006). An expert psychiatric assessment is required before the
decision about the management of HCV infection in this group of
patients. Through close collaboration between hepatologist and
psychiatrist, a significant proportion of patients with CHC and
well controlled psychiatric comorbidity can safely and
effectively receive antiviral treatment.
Patients with inherited anemias
CHC is common in patients with thalassemia major or sickle cell
disease, as a result of regular or intermittent red blood
transfusions. In addition to HCV injury, progression of liver
fibrosis is influenced by the degree of hepatic iron overload, with
high rates of cirrhosis and hepatocellular carcinoma (Angelucci
2002). With PegIFN/RBV combination, SVR has been reported in
40-70% of patients with thalassemia. Patients with thalassemia
major are at increased risk of AEs of interferon and careful
monitoring for side effects, iron chelation (with liver iron
maintained between 2-7 mg/g dry weight), and regular
transfusions may be necessary. These patients should be
managed preferably by a hepatologist and a hematologist, in a
joint clinic.
of high erythropoietin doses to treat anemia (Bruchfeld 2006).
Patients with psychiatric comorbidities
A prevalence of 60% psychiatric comorbidities has been reported
in patients with CHC. On the other side, neuropsychiatric side
effects occur in up to 50% of patients receiving treatment with
PegIFN/RBV, the commonest being depression. Prospective
clinical trials suggest that patients with HCV infection and
psychiatric comorbidities can be safely treated with interferonbased
antiviral regimens by both hepatologists and mental
health professionals as part of a multidisciplinary team (Knott
2006). An expert psychiatric assessment is required before the
decision about the management of HCV infection in this group of
patients. Through close collaboration between hepatologist and
psychiatrist, a significant proportion of patients with CHC and
well controlled psychiatric comorbidity can safely and
effectively receive antiviral treatment.
Patients with inherited anemias
CHC is common in patients with thalassemia major or sickle cell
disease, as a result of regular or intermittent red blood
transfusions. In addition to HCV injury, progression of liver
fibrosis is influenced by the degree of hepatic iron overload, with
high rates of cirrhosis and hepatocellular carcinoma (Angelucci
2002). With PegIFN/RBV combination, SVR has been reported in
40-70% of patients with thalassemia. Patients with thalassemia
major are at increased risk of AEs of interferon and careful
monitoring for side effects, iron chelation (with liver iron
maintained between 2-7 mg/g dry weight), and regular
transfusions may be necessary. These patients should be
managed preferably by a hepatologist and a hematologist, in a
joint clinic.
African Americans
CHC in African Americans shows a more favorable course
characterized by lower serum ALT level, less inflammation on
biopsies, less trend to progress to cirrhosis, but a greater than
threefold higher risk of HCC as compared with whites.
African Americans have lower SVR when treated with
PegIFN/RBV (Jeffers 2004). In WIN-R trial, African Americans
have a significant higher SVR when treated with PegIFN alfa-2b
and weight-based RBV doses ranging between 800 and 1400
mg/day as compared with fixed RBV dose of 800 mg/day (21% vs.
10%, p=0.004) (Jacobson 2004). Despite advances in HCV therapy,
African Americans have decreased SVR with PegIFN/RBV, even
when optimized dosing is used and this may be explained partly
by the high distribution of unfavorable genetic predictors of SVR
(such as genotype 1 (McHutchison 2000) and unfavorable allele
CT and TT of IL28B (Ge 2009) as compared with other ethnic
groups (see also chapter 1).
HIV-HCV coinfection
Because of shared risk factors, HCV co-infection is common (10-
40%) among HIV-infected persons. HIV infection accelerates the
progression to advanced fibrosis and cirrhosis and increases the
risk for liver-related complications, including hepatocellular
carcinoma compared with HCV monoinfected patients. As a
result of the effectiveness of highly active antiretroviral
(HAART) therapy, the longevity of HIV-infected patients has
increased and HCV infection emerged as a major cause of
morbidity and mortality among this population.
A significant proportion of HIV-HCV coinfected patients (with
stable HIV infection, no AIDS, mean CD4 counts greater than
400x106/L and compensated liver disease) can be treated
successfully with PegIFN/RBV. SVR to PegIFN/RBV is lower in
HIV-HCV coinfected patients, ranging between 26% and 44%
(Torriani 2004, Carrat 2004).
CHC in African Americans shows a more favorable course
characterized by lower serum ALT level, less inflammation on
biopsies, less trend to progress to cirrhosis, but a greater than
threefold higher risk of HCC as compared with whites.
African Americans have lower SVR when treated with
PegIFN/RBV (Jeffers 2004). In WIN-R trial, African Americans
have a significant higher SVR when treated with PegIFN alfa-2b
and weight-based RBV doses ranging between 800 and 1400
mg/day as compared with fixed RBV dose of 800 mg/day (21% vs.
10%, p=0.004) (Jacobson 2004). Despite advances in HCV therapy,
African Americans have decreased SVR with PegIFN/RBV, even
when optimized dosing is used and this may be explained partly
by the high distribution of unfavorable genetic predictors of SVR
(such as genotype 1 (McHutchison 2000) and unfavorable allele
CT and TT of IL28B (Ge 2009) as compared with other ethnic
groups (see also chapter 1).
HIV-HCV coinfection
Because of shared risk factors, HCV co-infection is common (10-
40%) among HIV-infected persons. HIV infection accelerates the
progression to advanced fibrosis and cirrhosis and increases the
risk for liver-related complications, including hepatocellular
carcinoma compared with HCV monoinfected patients. As a
result of the effectiveness of highly active antiretroviral
(HAART) therapy, the longevity of HIV-infected patients has
increased and HCV infection emerged as a major cause of
morbidity and mortality among this population.
A significant proportion of HIV-HCV coinfected patients (with
stable HIV infection, no AIDS, mean CD4 counts greater than
400x106/L and compensated liver disease) can be treated
successfully with PegIFN/RBV. SVR to PegIFN/RBV is lower in
HIV-HCV coinfected patients, ranging between 26% and 44%
(Torriani 2004, Carrat 2004).
Several trials recommended 48 weeks of PegIFN/RBV in coinfected
patients, regardless of HCV genotype (Iorio 2010). The
SVR in HIV-HCV infected patients can be predicted by the so
called “Prometheus index” that associates HCV genotype, degree
of fibrosis, HCV VL, IL28B genotype (Medrano 2010).
Safety, tolerability and adherence to combination therapy are
important issues in the coinfected patients, with 12% to 42%
discontinuation rates. HAART can be associated with anemia,
thrombocytopenia, neutropenia and hepatotoxicity, ranging
from elevation in aminotransferases level to hepatic
decompensation and mitochondrial toxicity (i.e., acute
pancreatitis and lactic acidosis which occur especially in patients
receiving didanosine).
Autoantibody (ANA, ASMA, anti-LKM) seropositivity in the
setting of CHC is common, but does not impact on disease
progression, nor on response to antiviral therapy. It is important
to recognize an autoimmune component (high autoantibody
titer ANA>1:160 or ASMA>1:80, elevated liver enzymes (more
than 5-10 times UNL and specific features on LB) before starting
therapy, as PegIFN-based regimens may exacerbate underlying
autoimmune hepatitis. If immunosuppression for autoimmune
component is required, aminotransferases should be followed
closely during the first weeks of therapy.
Obesity and metabolic syndrome are common in patients with
CHC and associated with lower probability of achieving SVR with
antiviral therapy. Insulin resistance is one mechanism by which
response to antiviral therapy is reduced. Interventions targeting
at reducing obesity or/and IR may improve SVR rates. It is
important to stress that body weight-adjusted dosing regimens
improve rates of SVR.
patients, regardless of HCV genotype (Iorio 2010). The
SVR in HIV-HCV infected patients can be predicted by the so
called “Prometheus index” that associates HCV genotype, degree
of fibrosis, HCV VL, IL28B genotype (Medrano 2010).
Safety, tolerability and adherence to combination therapy are
important issues in the coinfected patients, with 12% to 42%
discontinuation rates. HAART can be associated with anemia,
thrombocytopenia, neutropenia and hepatotoxicity, ranging
from elevation in aminotransferases level to hepatic
decompensation and mitochondrial toxicity (i.e., acute
pancreatitis and lactic acidosis which occur especially in patients
receiving didanosine).
Autoantibody (ANA, ASMA, anti-LKM) seropositivity in the
setting of CHC is common, but does not impact on disease
progression, nor on response to antiviral therapy. It is important
to recognize an autoimmune component (high autoantibody
titer ANA>1:160 or ASMA>1:80, elevated liver enzymes (more
than 5-10 times UNL and specific features on LB) before starting
therapy, as PegIFN-based regimens may exacerbate underlying
autoimmune hepatitis. If immunosuppression for autoimmune
component is required, aminotransferases should be followed
closely during the first weeks of therapy.
Obesity and metabolic syndrome are common in patients with
CHC and associated with lower probability of achieving SVR with
antiviral therapy. Insulin resistance is one mechanism by which
response to antiviral therapy is reduced. Interventions targeting
at reducing obesity or/and IR may improve SVR rates. It is
important to stress that body weight-adjusted dosing regimens
improve rates of SVR.
Outlook
A large proportion of patients with genotype 1 CHC will not
respond to standard of care treatment (SoC). Patients with
treatment failure to PegIFN can be classified into null
responders, partial responders, patients with breakthrough and
relapsers. Multiple fixed and correctable factors identified
during the previous course of treatment must be considered
when counseling about retreatment. The kinetic in HCV RNA
during a prior course of therapy has important implications for
the likelihood of response to retreatment. Triple combination
regimens including a protease inhibitor, such as telaprevir or
boceprevir, proved to be a good option for prior non-sustained
responders.
Treatment failure is uncommon in patients with genotypes 2/3
HCV infection. Retreatment in these patients should be
considered, as response rates are reasonable, particularly with
prolonged duration of therapy.
There is an increased prevalence of HCV infection among special
populations (IDUs, comorbidities, HIV-infected patients, African
Americans) and their management requires special
consideration.
Links
– International clinical trials registry platform:
http://www.who.int/ictrp/en
– US clinical trials registry: http://clinicaltrials.gov
– Cochrane Database of Systematic Reviews
– http://www2.cochrane.org/reviews
– HCV Drug Dose and Response Decision Support Tool –
Clinical Care Options
http://www.clinicaloptions.com/Hepatitis/Management
– Nature Reviews Gastroenterology & Hepatology
http://www.nature.com/nrgastro/journal/v8/n5/index
A large proportion of patients with genotype 1 CHC will not
respond to standard of care treatment (SoC). Patients with
treatment failure to PegIFN can be classified into null
responders, partial responders, patients with breakthrough and
relapsers. Multiple fixed and correctable factors identified
during the previous course of treatment must be considered
when counseling about retreatment. The kinetic in HCV RNA
during a prior course of therapy has important implications for
the likelihood of response to retreatment. Triple combination
regimens including a protease inhibitor, such as telaprevir or
boceprevir, proved to be a good option for prior non-sustained
responders.
Treatment failure is uncommon in patients with genotypes 2/3
HCV infection. Retreatment in these patients should be
considered, as response rates are reasonable, particularly with
prolonged duration of therapy.
There is an increased prevalence of HCV infection among special
populations (IDUs, comorbidities, HIV-infected patients, African
Americans) and their management requires special
consideration.
Links
– International clinical trials registry platform:
http://www.who.int/ictrp/en
– US clinical trials registry: http://clinicaltrials.gov
– Cochrane Database of Systematic Reviews
– http://www2.cochrane.org/reviews
– HCV Drug Dose and Response Decision Support Tool –
Clinical Care Options
http://www.clinicaloptions.com/Hepatitis/Management
– Nature Reviews Gastroenterology & Hepatology
http://www.nature.com/nrgastro/journal/v8/n5/index
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