Triple therapy with a PI was shown to almost double the
success rate in treatment-naive patients infected with HCV
genotype 1 from 38-44% obtained with SoC to 63-75% (Poordad
2011). The increase in SVR rate is even higher in previous
nonresponders-from 17-21% with SoC to 59-66% with triple
therapy (Bacon 2011). Nevertheless, the addition of a new agent
to an existing treatment regimen will pose substantial challenges
in terms of drug interactions and adherence, due to the
associated side effects and risk of resistance emergence.
Maximizing tolerance of future PIs based regimens will be
extremely important to achieve optimal treatment outcomes.
Telaprevir (Incivek™, Vertex Pharmaceuticals) was approved
by FDA for treatment of genotype 1 CHC in adult naive patients
with compensated liver disease, including cirrhosis, and in prior
null responders, partial responders, and relapsers, only in
combination with PegIFN/RBV.
Preliminary studies have demonstrated that 14 days
monotherapy, while inducing a VL median decline of more than
4.4 log10 units in patients with CHC G1 infection, was limited by
the appearance of resistance mutation as early as 4-7 days after
initiation. Interestingly, the mutations were subsequently
suppressed by administration of PegIFN/RBV. Consequently,
telaprevir was administered in combination with PegIFN/RBV
Searching for new antiviral therapies | 67
for 12 weeks, followed by SoC therapy alone for another 24 - 48
weeks. The recommended dose of Incivek is 750 mg orally 3
times a day.
Several phase II and III studies have assessed the efficacy and
safety of telaprevir in treatment naive G1 patients, concluding
that triple therapy yields a higher rate of SVR than current SoC
and lower rates of relapse. The SVR for patients treated with
Incivek across all studies, and across all patient groups, was
between 20 and 45% higher than the current SoC (Hézode 2009,
McHutchison 2009). RBV was shown to be an essential part of the
therapeutic regimen, playing a critical role both in achieving
superior RVR and SVR and in reducing the rates of virologic
breakthrough due to drug resistance.
The results of a response-guided therapy (RGT) study,
ILLUMINATE (Sherman 2010) support a shorter course of
treatment (from 48 to 24 weeks) for rapidly responsive naivepatients.
Sixty percent of previously untreated patients achieved
an EVR and received only 24 weeks of treatment. The SVR for
these patients was 90%. In order to identify patients who may
benefit from shorter duration of therapy, a new predictor of
treatment response was proposed: extended RVR (eRVR),
defined as undetectable HCV RNA at week 4 and 12. Among
patients who achieved an eRVR, rates of SVR were comparable
between those treated for a total duration of 24 or 48 weeks (92%
vs. 88%, respectively). Among those who did not achieve eRVR,
but continued treatment for 48 weeks, the SVR rate was lower,
but still significant (64%). More recent studies have evaluated
the use of triple therapy including telaprevir as a retreatment
option for nonresponders and relapsers to previous SoC therapy,
demonstrating synergistic effects in viral reduction and
decreased emergence of resistance. SVR rates were higher
among patients who previously experienced relapse versus
nonresponders (McHutchison 2010).
Rashes, pruritus, anemia and nausea were the most commonly
reported AEs with the use of telaprevir. AEs rates resulting in
treatment withdrawal were about 10% higher in telaprevir arms
68 | Hepatitis C Treatment
vs PegIFN/RBV, the most severe being rash, that resolved with
discontinuation of therapy. Serious skin reactions, including
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
and Stevens-Johnson Syndrome were reported in less than 1% of
subjects who received telaprevir combination treatment
compared to none who received PegIFN/RBV alone. A sequential
discontinuation of drugs was proposed for the management of
moderate or severe rash.
Boceprevir (Victrelis™, Merck) is another potent HCV NS3 PI
with antiviral activity against genotype 1 HCV. Boceprevir is FDA
approved for the treatment of CHC genotype 1 infection, in
combination with PegIFN/RBV, in patients aged 18 years of age
and older with compensated liver disease, including cirrhosis,
who are previously untreated or who have failed previous
interferon and ribavirin therapy. Boceprevir is administered
orally, at a dose of 800 mg three times daily.
The safety and efficacy of triple therapy with oral boceprevir
plus PegIFN/RBV vs PegIFN/RBV alone were demonstrated in a
phase III registration trial for treatment-naive patients, SPRINT-
2 (Poordad 2011) and in previously partial responders and
relapsers to SoC (RESPOND-2) (Bacon 2011). Boceprevir, in
combination with PegIFN/RBV has not been studied in patients
documented to be historical null responders (less than 2 log10
HCV RNA decline by treatment week 12) during prior therapy
with PegIFN/RBV.
The treatment strategy is different from telaprevir, Boceprevir
being administered in triple combination therapy for 24-44
weeks only after a 4 weeks lead-in phase with PegIFN/RBV alone.
Therefore, RVR was defined as undetectable HCV RNA at week 4
of boceprevir-containing therapy (meaning week 8 of all
therapy, including the lead-in period). In theory, a lead-in phase
may provide the additional advantage of reducing viral
replication and, consequently, the rate of resistance emergence.
However in phase III clinical trials, patients with poor response
to PegIFN/RBV, defined as <1 log10 decline after 4 weeks lead-in,
had a higher incidence of resistance mutations. Nevertheless, the
Searching for new antiviral therapies | 69
virologic response at the end of the lead-in phase is highly
predictive for the final outcome of therapy. Substantially higher
SVR rates are obtained in patients showing more than 1 log10
decline in HCV RNA at this time point. Even in patients with a
poor response to interferon, addition of boceprevir can generate
a SVR in up to 34% of the patients. This is an important
information, arguing for the utility of a lead-in phase in the
previously treated nonresponders or relapsers. For naive
patients, the lead-in period can further serve to test both
compliance and tolerability before exposure to PIs.
The most commonly reported AEs with boceprevir were anemia
(almost twice as many boceprevir recipients had Hb levels <9.5
mg/ml compared to controls) and dysgeusia (more than twice as
often in boceprevir recipients than in controls). Serious AEs were
reported in 11% of patients receiving boceprevir in combination
with PegIFN/RBV compared with 8% of patients receiving
PegIFN/RBV alone. The most common reason for dose reduction
in the trials was anemia.
success rate in treatment-naive patients infected with HCV
genotype 1 from 38-44% obtained with SoC to 63-75% (Poordad
2011). The increase in SVR rate is even higher in previous
nonresponders-from 17-21% with SoC to 59-66% with triple
therapy (Bacon 2011). Nevertheless, the addition of a new agent
to an existing treatment regimen will pose substantial challenges
in terms of drug interactions and adherence, due to the
associated side effects and risk of resistance emergence.
Maximizing tolerance of future PIs based regimens will be
extremely important to achieve optimal treatment outcomes.
Telaprevir (Incivek™, Vertex Pharmaceuticals) was approved
by FDA for treatment of genotype 1 CHC in adult naive patients
with compensated liver disease, including cirrhosis, and in prior
null responders, partial responders, and relapsers, only in
combination with PegIFN/RBV.
Preliminary studies have demonstrated that 14 days
monotherapy, while inducing a VL median decline of more than
4.4 log10 units in patients with CHC G1 infection, was limited by
the appearance of resistance mutation as early as 4-7 days after
initiation. Interestingly, the mutations were subsequently
suppressed by administration of PegIFN/RBV. Consequently,
telaprevir was administered in combination with PegIFN/RBV
Searching for new antiviral therapies | 67
for 12 weeks, followed by SoC therapy alone for another 24 - 48
weeks. The recommended dose of Incivek is 750 mg orally 3
times a day.
Several phase II and III studies have assessed the efficacy and
safety of telaprevir in treatment naive G1 patients, concluding
that triple therapy yields a higher rate of SVR than current SoC
and lower rates of relapse. The SVR for patients treated with
Incivek across all studies, and across all patient groups, was
between 20 and 45% higher than the current SoC (Hézode 2009,
McHutchison 2009). RBV was shown to be an essential part of the
therapeutic regimen, playing a critical role both in achieving
superior RVR and SVR and in reducing the rates of virologic
breakthrough due to drug resistance.
The results of a response-guided therapy (RGT) study,
ILLUMINATE (Sherman 2010) support a shorter course of
treatment (from 48 to 24 weeks) for rapidly responsive naivepatients.
Sixty percent of previously untreated patients achieved
an EVR and received only 24 weeks of treatment. The SVR for
these patients was 90%. In order to identify patients who may
benefit from shorter duration of therapy, a new predictor of
treatment response was proposed: extended RVR (eRVR),
defined as undetectable HCV RNA at week 4 and 12. Among
patients who achieved an eRVR, rates of SVR were comparable
between those treated for a total duration of 24 or 48 weeks (92%
vs. 88%, respectively). Among those who did not achieve eRVR,
but continued treatment for 48 weeks, the SVR rate was lower,
but still significant (64%). More recent studies have evaluated
the use of triple therapy including telaprevir as a retreatment
option for nonresponders and relapsers to previous SoC therapy,
demonstrating synergistic effects in viral reduction and
decreased emergence of resistance. SVR rates were higher
among patients who previously experienced relapse versus
nonresponders (McHutchison 2010).
Rashes, pruritus, anemia and nausea were the most commonly
reported AEs with the use of telaprevir. AEs rates resulting in
treatment withdrawal were about 10% higher in telaprevir arms
68 | Hepatitis C Treatment
vs PegIFN/RBV, the most severe being rash, that resolved with
discontinuation of therapy. Serious skin reactions, including
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
and Stevens-Johnson Syndrome were reported in less than 1% of
subjects who received telaprevir combination treatment
compared to none who received PegIFN/RBV alone. A sequential
discontinuation of drugs was proposed for the management of
moderate or severe rash.
Boceprevir (Victrelis™, Merck) is another potent HCV NS3 PI
with antiviral activity against genotype 1 HCV. Boceprevir is FDA
approved for the treatment of CHC genotype 1 infection, in
combination with PegIFN/RBV, in patients aged 18 years of age
and older with compensated liver disease, including cirrhosis,
who are previously untreated or who have failed previous
interferon and ribavirin therapy. Boceprevir is administered
orally, at a dose of 800 mg three times daily.
The safety and efficacy of triple therapy with oral boceprevir
plus PegIFN/RBV vs PegIFN/RBV alone were demonstrated in a
phase III registration trial for treatment-naive patients, SPRINT-
2 (Poordad 2011) and in previously partial responders and
relapsers to SoC (RESPOND-2) (Bacon 2011). Boceprevir, in
combination with PegIFN/RBV has not been studied in patients
documented to be historical null responders (less than 2 log10
HCV RNA decline by treatment week 12) during prior therapy
with PegIFN/RBV.
The treatment strategy is different from telaprevir, Boceprevir
being administered in triple combination therapy for 24-44
weeks only after a 4 weeks lead-in phase with PegIFN/RBV alone.
Therefore, RVR was defined as undetectable HCV RNA at week 4
of boceprevir-containing therapy (meaning week 8 of all
therapy, including the lead-in period). In theory, a lead-in phase
may provide the additional advantage of reducing viral
replication and, consequently, the rate of resistance emergence.
However in phase III clinical trials, patients with poor response
to PegIFN/RBV, defined as <1 log10 decline after 4 weeks lead-in,
had a higher incidence of resistance mutations. Nevertheless, the
Searching for new antiviral therapies | 69
virologic response at the end of the lead-in phase is highly
predictive for the final outcome of therapy. Substantially higher
SVR rates are obtained in patients showing more than 1 log10
decline in HCV RNA at this time point. Even in patients with a
poor response to interferon, addition of boceprevir can generate
a SVR in up to 34% of the patients. This is an important
information, arguing for the utility of a lead-in phase in the
previously treated nonresponders or relapsers. For naive
patients, the lead-in period can further serve to test both
compliance and tolerability before exposure to PIs.
The most commonly reported AEs with boceprevir were anemia
(almost twice as many boceprevir recipients had Hb levels <9.5
mg/ml compared to controls) and dysgeusia (more than twice as
often in boceprevir recipients than in controls). Serious AEs were
reported in 11% of patients receiving boceprevir in combination
with PegIFN/RBV compared with 8% of patients receiving
PegIFN/RBV alone. The most common reason for dose reduction
in the trials was anemia.
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