Improves Hepatitis C Treatment Response
The recently approved HCV protease telaprevir added to standard
therapy increased cure rates for both previously untreated
people and prior non-responders.
antiviral agents that target different steps of the hepatitis
C virus (HCV) lifecycle signal a new paradigm in treatment for
chronic hepatitis C, especially for people with difficult-to-treat
HCV genotype 1 and those who did not achieve sustained response
to prior treatment attempt.
The first 2 direct-acting drugs -- Merck's boceprevir
(Victrelis) and Vertex's telaprevir
(Incivek) -- were approved by the U.S. Food and Drug Administration
(FDA) last month.
Pivotal clinical trials with both treatment-naive and previously
treated patients showed that adding the new drugs to standard
therapy consisting of pegylated
interferon plus ribavirin increased the likelihood of achieving
sustained virological response (continued undetectable HCV RNA
after completion of treatment); furthermore, many people could
receive a shorter course of therapy.
data from the treatment-naive ADVANCE trial and the treatment-experienced
REALIZE trial were published in the June 23, 2011, New England
Journal of Medicine. (Boceprevir
findings from the treatment-naive SPRINT-2 and treatment-experienced
RESPOND-2 trials appeared in the March 31, 2011 issue of the same
Jacobson from Weill Cornell Medical College and a large international
team of collaborators evaluated the safety and efficacy of telaprevir
plus standard therapy for previously untreated patients. The Phase
3 ADVANCE study included 1088 treatment-naive participants with
chronic genotype 1 hepatitis C.
Participants were randomly assigned to receive 750 mg 3-times-daily
telaprevir or placebo along with 180 mcg/week pegylated interferon
alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin.
Patients received telaprevir for either 8 or 12 weeks; duration
of pegylated interferon/ribavirin (up to 48 total weeks) was determined
using a response-guided strategy based on HCV RNA declines at
weeks 4 and 12.
Investigators measured HCV viral load levels at various points
after starting treatment, including week 4 (rapid virological
response or RVR), week 12 (early virological response or EVR),
end of treatment, and 24 weeks after completion of treatment (sustained
virological response or SVR).
more participants who took telaprevir for 8 or 12 weeks achieved
SVR compared with those taking standard therapy alone (75%
and 69%, respectively, vs 44%).
treatment failure occurred more often in the 8-week telaprevir
of patients treated with telaprevir were eligible to stop
all treatment after 24 weeks using the response-guided strategy.
was generally safe and well-tolerated, with mostly mild-to-moderate
events that occurred more often in the telaprevir group than
in the standard therapy group included anemia, gastrointestinal
symptoms, and skin rash.
of patients taking telaprevir for 12 weeks and 7% taking standard
therapy discontinued treatment prematurely due to side effects.
on these findings, the study authors wrote, "Telaprevir with
peginterferon-ribavirin, as compared with peginterferon-ribavirin
alone, was associated with significantly improved rates of sustained
virologic response in patients with HCV genotype 1 infection who
had not received previous treatment, with only 24 weeks of therapy
administered in the majority of patients."
"Patients in the [8-week telaprevir] group, as compared with
those in the [12-week telaprevir] group, had a lower rate of response,
and also a slightly lower rate of discontinuation of telaprevir,"
they elaborated in their discussion. "The lower rate of virologic
failure during treatment in the [12-week] group as compared with
the [8-week] group and the more frequent emergence of wild-type
and lower-level resistant variants beyond week 12 in the [8-week]
group than in the [12-week] group are probably attributable to
more efficient elimination of these viral strains as a result
of the additional 4 weeks of telaprevir therapy in the [12-week]
researchers also noted that SVR rates "were substantially
improved with the addition of telaprevir in patients with negative
predictive factors for a response to peginterferon-ribavirin treatment,
such as bridging fibrosis or cirrhosis, older age, diabetes, and
HCV RNA levels of 800,000 IU per milliliter or more. An increase
in sustained virologic response by a factor of more than 2 occurred
with telaprevir in black patients, in whom low response rates
to interferon have been reported."
significant improvement in the rates of sustained virologic response
with telaprevir-based therapy and the capacity for response-guided
therapy to shorten the duration of exposure to peginterferon-ribavirin
among patients who have a rapid response represent important advances
in the treatment of patients with HCV genotype 1 infection,"
Zeuzem from J.W. Goethe University in Frankfurt and fellow investigators
looked at the safety and effectiveness of telaprevir in previously
treated people in the REALIZE study, another large international
Phase 3 trial.
This study included 663 genotype 1 chronic hepatitis C patients
who had no response or partial response to previous therapy, or
who relapsed after an initial response.
Again, participants were randomly assigned to receive 750 mg 3-times-daily
telaprevir or placebo along with weekly pegylated interferon alfa-2a
and daily weight-adjusted ribavirin. However, everyone in this
harder-to-treat patient population received telaprevir for 12
weeks and pegylated interferon/ribavirin for 48 weeks. Some started
with a 4-week pegylated interferon/ribavirin lead-in period before
rates were significantly higher in the 2 telaprevir groups
compared with the standard therapy control group:
relapsers: 83% with concurrent start and 88% with lead-in,
vs 24% in the standard therapy group;
partial responders: 59%, 54%, and 15%, respectively;
null responders: 29%, 33%, and 5%, respectively.
rates did not differ significantly in the telaprevir concurrent
start and lead-in arms.
most common side effects overall (reported by > 25% of
patients) were fatigue, pruritis or itching, rash, nausea,
flu-like symptoms, anemia, and diarrhea.
most common serious side effects were blood cell deficiencies
(anemia, neutropenia, leukopenia).
(grade 3) adverse events were significantly more frequent
in the telaprevir groups compared with the standard therapy
group (37% vs 22%).
of patients in the telaprevir arms experienced grade 3 rash,
skin events leading to drug discontinuation, or serious skin-related
adverse events, compared with none in the standard therapy
findings led the investigators to conclude, "Telaprevir combined
with peginterferon plus ribavirin significantly improved rates
of sustained virologic response in patients with previously treated
HCV infection, regardless of whether there was a lead-in phase."
"Among patients who have had no response or a partial response
to previous therapy, those with a high baseline viral load and
advanced liver fibrosis have disease that is particularly difficult
to cure," they explained in their discussion. "In our
study, more than 85% of patients had a high baseline viral load
(i.e., above 800,000 IU per milliliter), 26% had liver cirrhosis,
and 22% had bridging fibrosis. No specific safety and tolerability
issues were associated with the use of telaprevir in patients
with an advanced stage of liver fibrosis, and in such patients
the rates of sustained virologic response were higher in the telaprevir
groups than in the control group."
virologic failure rates during therapy were lower in patients
who had a previous relapse or a partial response than in patients
who had no response to previous therapy," they continued.
"Selection and persistence of drug-resistant variants is
a common concern in the use of direct-acting antiviral agents...strict
application of stopping rules may help to avoid the selection
and long-term persistence of HCV variants with telaprevir resistance."
more information about telaprevir, including full Prescribing
Information, see www.Incivek.com.
Jacobson, JG McHutchison, G Dusheiko, et al (ADVANCE Study Team).
Telaprevir for previously untreated chronic hepatitis C virus
New England Journal of Medicine 364(25):2405-2416 (abstract).
June 23, 2011.
Zeuzem, P Andreone, S Pol, et al (REALIZE Study Team). Telaprevir
for retreatment of HCV infection. New England Journal of Medicine
June 23, 2011.
Pharmaceuticals. New England Journal of Medicine Publishes Data
From Two Phase 3 Studies of Incivek (telaprevir) in Hepatitis
C. Press release. June 22, 2011.