The hepatitis C epidemic is still growing in importance. While
the incidence of hepatitis C virus (HCV) infections is falling in
some countries, the burden of the disease arising from the pool
of chronic infections continues to rise. It has been estimated
that, by 2030, HCV will cause substantially higher morbidity and
mortality than HIV. Chronic Hepatitis C (CHC) occurs in 70% to
80% of those who contract the virus, 20% of whom will progress
to cirrhosis within 2-3 decades; a quarter of these will develop
decompensated liver disease, hepatocellular carcinoma (HCC)
and will need liver transplantation. A recent study has shown
that HCV infected persons have three times higher death rates
than those of age-matched general population (Brok 2010).
Excess mortality is due to both liver related causes and comorbidities
and is related to age, treatment status, the degree of
fibrosis and mean alcohol consumption.
Antiviral therapy – Standard of Care (SoC)
According to all consensus guidelines (EASL 2011, NICE 2010,
AASLD 2009), the current standard of care (SoC) for CHC is the
combination of pegylated interferon alfa (PegIFN) and
ribavirin (RBV) for 24-48 weeks, depending on the viral
genotype.
14 | Hepatitis C Treatment
The primary goal of treatment for CHC is to obtain a sustained
virological response (SVR), defined as undetectable HCV RNA
level at 6 months after treatment completion. Long-term
follow-up studies have shown that 97-100% of sustained
responders retain undetectable HCV RNA in serum, and, in many
cases, also in liver and peripheral blood mononuclear cells,
strongly suggesting that SVR is associated with eradication of
HCV infection. SVR can be also attained, even if at lower rates,
in patients with extensive fibrosis or cirrhosis, decreasing the
risk of HCC development and improving the overall survival
rates (Dieterich 2009).
The decision to treat or not to treat is made on an
individualized basis. Treatment should be considered for all
infected patients, particularly for those at risk for progression of
liver disease. However, treatment regimens and treatment
inclusion criteria have changed over time, as new therapeutic
approaches are developed and more individualized regimens are
introduced. As we will see in chapter 4, in May 2011, The US Food
and Drug Administration (FDA) has approved two new drugs –
both viral protease inhibitors – to be used in combination with
PegIFN/RBV for the treatment of CHC genotype 1 infection:
– Boceprevir (Victrelis™, Merck)
– Telaprevir (Incivek™, Vertex Pharmaceuticals Inc.)
Interferons (IFNs) are cytokines with species-specific, but nonvirus-
specific antiviral, immunomodulatory and anticellular
activities. PegIFN derives from attachment of an inert
polyethyleneglycol (Peg) chain – a unique polymer that does not
have a definite tertiary structure – to conventional IFN-alfa. This
confers an improved pharmacokinetic profile for the drug, by
slowing subcutaneous absorption, reducing degradation and
clearance and prolonging its half-life. PegIFN maintains high
sustained plasma IFN levels that allow for weekly dosing
(compared with 3 times weekly administration of standard IFN),
while also reducing its adverse side effects (AEs) and
immunogenicity.
Antiviral Therapy: The Basics | 15
There are two FDA and EMA approved formulas of PegIFN that
can be administered subcutaneously once weekly, with different
dosing regimens and pharmacokinetics (Table 1.1):
– PegIFN alfa-2a (PEGASYS™, manufactured by Hofmann La-
Roche) in which standard IFN alfa-2a is covalently linked to
a 40-kDa branched Peg molecule, administered at a fixed
dose (180 μg/week), with a plasma half-life of 80 -160 hours.
– PegIFN alfa-2b (PegIntron™, manufactured by Schering–
Plough/Merck) in which standard IFN alfa-2b is covalently
linked to a 12-kDa linear Peg molecule, dosed according to
body weight (1.5 μg/kg/week), with a mean elimination
half-life of 40 hours.
Table 1.1 – Different characteristics of the available PegIFNs*
Characteristic PegIFN alfa-2a PegIFN alfa-2b
Trade name/
Manufacturer
Pegasys/
Hoffmann-La Roche
PegIntron/
Schering Corporationnow
Merck
Structure large, branched, 40 kD small, linear, 12 kD
Volume of distribution 8-12 L 0.99 L/kg body
Clearance 60-100 mL/hr 22mL/hr/kg
Absorption half-life (hrs) 50-60 4,6
Elimination half-life (hrs) 65 40
Time to reach maximum
concentration
80 15-44
Peak to trough ratio 1.5-2 >10
Cost of combination treatment
(PegIFN + RBV) for 24 wks £ †
5019 6743
Cost of treatment 48 wks £ † 10963-11889‡ 13468
* According to data from Foster 2010
† according to British national formulary, 50th edition, excluding VAT
‡ depending on body weight
These differences do not affect significantly the treatment
outcomes. Current evidence does not allow for a definitive
recommendation of one of the two forms of PegIFNs. A Cochrane
systematic review of head-to-head randomized trials (Awad
16 | Hepatitis C Treatment
2010) suggests that PegIFN alfa-2a may be associated with an
increased benefit in terms of SVR compared to PegIFN alfa-2b,
although the largest head-to-head trial (IDEAL study) failed to
find a significant difference in SVR rates between the two PegIFN
formulations (McHutchison 2009). Nevertheless, the two
products seem to be comparable in terms of adverse effects (AEs)
leading to treatment discontinuation.
As long as SVR is only a surrogate marker of clinical outcomes
(liver failure, HCC and mortality) and the data on the long-term
AEs are limited, both regimens seems to be equally effective in
the clinical practice.
It is important to mention that HCV has notable properties by
which it can inhibit the actions of IFNs. The HCV protease
NS3/4A blocks important proteins and enzymes within the cells
(such as IRF3, a key transcriptional regulator of the IFN
response, and retinoid-inducible gene 1- RIG1, a growth
regulator), leading to a reduction in the expression of IFNsignaling
genes (Bode 2008).
Ribavirin (RBV) has both antiviral and immunomodulatory
actions. Although RBV monotherapy has little influence against
HCV, in combination with interferon it improves dramatically
the response rates. Being a guanosine analog, RBV acts by direct
inhibition of nucleic acid elongation and of enzymes important
in viral replication, such as inosine monophosphate
dehydrogenase (IMPDH), as well as by induction of lethal
mutagenesis during the viral life-cycle. Although the specific
mechanism has not yet been completely elucidated, there is
increasing evidence of RBV acting as a true antiviral agent and
thus having a critical role in the suppression of viral replication.
RBV amplifies the effect of IFN, generating a significant decrease
in the relapse rate (Manns 2001, Fried 2002).
Adding RBV to PegIFNs was recommended by consensus in
Europe in 1999 and in the United States in 2002. Subsequently, it
has been shown that weight–dosed RBV is more effective in
acquiring a high rate of therapeutic success. In today’s regimens,
RBV is administered according to patient’s weight: 1000 mg/day
Antiviral Therapy: The Basics | 17
for patients <75 kg and 1200 mg/day for patients >75 kg. Recent
clinical trials with new antiviral compounds associated with
PegIFN/RBV have demonstrated that maintaining RBV in the
therapeutic regimen has an important additive effect.
Predictors of response before treatment
Experienced providers need to take treatment decisions on a
case-by-case basis. There are a series of virus, host and
treatment characteristics that influence the likelihood of
treatment success and are useful when assessing the benefits and
risks of therapy
the incidence of hepatitis C virus (HCV) infections is falling in
some countries, the burden of the disease arising from the pool
of chronic infections continues to rise. It has been estimated
that, by 2030, HCV will cause substantially higher morbidity and
mortality than HIV. Chronic Hepatitis C (CHC) occurs in 70% to
80% of those who contract the virus, 20% of whom will progress
to cirrhosis within 2-3 decades; a quarter of these will develop
decompensated liver disease, hepatocellular carcinoma (HCC)
and will need liver transplantation. A recent study has shown
that HCV infected persons have three times higher death rates
than those of age-matched general population (Brok 2010).
Excess mortality is due to both liver related causes and comorbidities
and is related to age, treatment status, the degree of
fibrosis and mean alcohol consumption.
Antiviral therapy – Standard of Care (SoC)
According to all consensus guidelines (EASL 2011, NICE 2010,
AASLD 2009), the current standard of care (SoC) for CHC is the
combination of pegylated interferon alfa (PegIFN) and
ribavirin (RBV) for 24-48 weeks, depending on the viral
genotype.
14 | Hepatitis C Treatment
The primary goal of treatment for CHC is to obtain a sustained
virological response (SVR), defined as undetectable HCV RNA
level at 6 months after treatment completion. Long-term
follow-up studies have shown that 97-100% of sustained
responders retain undetectable HCV RNA in serum, and, in many
cases, also in liver and peripheral blood mononuclear cells,
strongly suggesting that SVR is associated with eradication of
HCV infection. SVR can be also attained, even if at lower rates,
in patients with extensive fibrosis or cirrhosis, decreasing the
risk of HCC development and improving the overall survival
rates (Dieterich 2009).
The decision to treat or not to treat is made on an
individualized basis. Treatment should be considered for all
infected patients, particularly for those at risk for progression of
liver disease. However, treatment regimens and treatment
inclusion criteria have changed over time, as new therapeutic
approaches are developed and more individualized regimens are
introduced. As we will see in chapter 4, in May 2011, The US Food
and Drug Administration (FDA) has approved two new drugs –
both viral protease inhibitors – to be used in combination with
PegIFN/RBV for the treatment of CHC genotype 1 infection:
– Boceprevir (Victrelis™, Merck)
– Telaprevir (Incivek™, Vertex Pharmaceuticals Inc.)
Interferons (IFNs) are cytokines with species-specific, but nonvirus-
specific antiviral, immunomodulatory and anticellular
activities. PegIFN derives from attachment of an inert
polyethyleneglycol (Peg) chain – a unique polymer that does not
have a definite tertiary structure – to conventional IFN-alfa. This
confers an improved pharmacokinetic profile for the drug, by
slowing subcutaneous absorption, reducing degradation and
clearance and prolonging its half-life. PegIFN maintains high
sustained plasma IFN levels that allow for weekly dosing
(compared with 3 times weekly administration of standard IFN),
while also reducing its adverse side effects (AEs) and
immunogenicity.
Antiviral Therapy: The Basics | 15
There are two FDA and EMA approved formulas of PegIFN that
can be administered subcutaneously once weekly, with different
dosing regimens and pharmacokinetics (Table 1.1):
– PegIFN alfa-2a (PEGASYS™, manufactured by Hofmann La-
Roche) in which standard IFN alfa-2a is covalently linked to
a 40-kDa branched Peg molecule, administered at a fixed
dose (180 μg/week), with a plasma half-life of 80 -160 hours.
– PegIFN alfa-2b (PegIntron™, manufactured by Schering–
Plough/Merck) in which standard IFN alfa-2b is covalently
linked to a 12-kDa linear Peg molecule, dosed according to
body weight (1.5 μg/kg/week), with a mean elimination
half-life of 40 hours.
Table 1.1 – Different characteristics of the available PegIFNs*
Characteristic PegIFN alfa-2a PegIFN alfa-2b
Trade name/
Manufacturer
Pegasys/
Hoffmann-La Roche
PegIntron/
Schering Corporationnow
Merck
Structure large, branched, 40 kD small, linear, 12 kD
Volume of distribution 8-12 L 0.99 L/kg body
Clearance 60-100 mL/hr 22mL/hr/kg
Absorption half-life (hrs) 50-60 4,6
Elimination half-life (hrs) 65 40
Time to reach maximum
concentration
80 15-44
Peak to trough ratio 1.5-2 >10
Cost of combination treatment
(PegIFN + RBV) for 24 wks £ †
5019 6743
Cost of treatment 48 wks £ † 10963-11889‡ 13468
* According to data from Foster 2010
† according to British national formulary, 50th edition, excluding VAT
‡ depending on body weight
These differences do not affect significantly the treatment
outcomes. Current evidence does not allow for a definitive
recommendation of one of the two forms of PegIFNs. A Cochrane
systematic review of head-to-head randomized trials (Awad
16 | Hepatitis C Treatment
2010) suggests that PegIFN alfa-2a may be associated with an
increased benefit in terms of SVR compared to PegIFN alfa-2b,
although the largest head-to-head trial (IDEAL study) failed to
find a significant difference in SVR rates between the two PegIFN
formulations (McHutchison 2009). Nevertheless, the two
products seem to be comparable in terms of adverse effects (AEs)
leading to treatment discontinuation.
As long as SVR is only a surrogate marker of clinical outcomes
(liver failure, HCC and mortality) and the data on the long-term
AEs are limited, both regimens seems to be equally effective in
the clinical practice.
It is important to mention that HCV has notable properties by
which it can inhibit the actions of IFNs. The HCV protease
NS3/4A blocks important proteins and enzymes within the cells
(such as IRF3, a key transcriptional regulator of the IFN
response, and retinoid-inducible gene 1- RIG1, a growth
regulator), leading to a reduction in the expression of IFNsignaling
genes (Bode 2008).
Ribavirin (RBV) has both antiviral and immunomodulatory
actions. Although RBV monotherapy has little influence against
HCV, in combination with interferon it improves dramatically
the response rates. Being a guanosine analog, RBV acts by direct
inhibition of nucleic acid elongation and of enzymes important
in viral replication, such as inosine monophosphate
dehydrogenase (IMPDH), as well as by induction of lethal
mutagenesis during the viral life-cycle. Although the specific
mechanism has not yet been completely elucidated, there is
increasing evidence of RBV acting as a true antiviral agent and
thus having a critical role in the suppression of viral replication.
RBV amplifies the effect of IFN, generating a significant decrease
in the relapse rate (Manns 2001, Fried 2002).
Adding RBV to PegIFNs was recommended by consensus in
Europe in 1999 and in the United States in 2002. Subsequently, it
has been shown that weight–dosed RBV is more effective in
acquiring a high rate of therapeutic success. In today’s regimens,
RBV is administered according to patient’s weight: 1000 mg/day
Antiviral Therapy: The Basics | 17
for patients <75 kg and 1200 mg/day for patients >75 kg. Recent
clinical trials with new antiviral compounds associated with
PegIFN/RBV have demonstrated that maintaining RBV in the
therapeutic regimen has an important additive effect.
Predictors of response before treatment
Experienced providers need to take treatment decisions on a
case-by-case basis. There are a series of virus, host and
treatment characteristics that influence the likelihood of
treatment success and are useful when assessing the benefits and
risks of therapy
No comments:
Post a Comment