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original article
Telaprevir for Previously Untreated Chronic
Hepatitis C Virus Infection
Ira M. Jacobson, M.D., John G. McHutchison, M.D., Geoffrey Dusheiko, M.D.,
Adrian M. Di Bisceglie, M.D., K. Rajender Reddy, M.D., Natalie H. Bzowej, M.D.,
Patrick Marcellin, M.D., Andrew J. Muir, M.D., Peter Ferenci, M.D.,
Robert Flisiak, M.D., Jacob George, M.D., Mario Rizzetto, M.D., Daniel Shouval, M.D.,
Ricard Sola, M.D., Ruben A. Terg, M.D., Eric M. Yoshida, M.D., Nathalie Adda, M.D.,
Leif Bengtsson, B.Sc., Abdul J. Sankoh, Ph.D., Tara L. Kieffer, Ph.D.,
Shelley George, M.D., Robert S. Kauffman, M.D., Ph.D., and Stefan Zeuzem M.D.,
for the ADVANCE Study Team*
From the Weill Cornell Medical College and
Center for the Study of Hepatitis C, New
York (I.M.J.); Duke Clinical Research In-
stitute and Division of Gastroenterology,
Duke University Medical Center, Durham,
NC (J.G.M., A.J.M.); Royal Free Hospital,
Centre for Hepatology, London (G.D.);
Saint Louis University School of Medicine,
St. Louis (A.M.D.B.); Division of Gastro-
enterology, University of Pennsylvania,
Philadelphia (K.R.R.); California Pacific
Medical Center, San Francisco (N.H.B.);
Hôpital Beau jon, Service d’Hépatologie
and INSERM CRB3, Clichy, France (P.M.);
University of Vienna, Vienna (P.F.); Depart-
ment of Infectious Diseases and Hepa-
tology, Medical University of Bialystok,
Bialystok, Poland (R.F.); Storr Liver Unit,
Westmead Millennium Institute for Medi-
cal Research and Westmead Hospital, Uni-
versity of Sydney, Westmead, NSW, Austra-
lia (J.G.); Department of Gastroenterology,
University of Turin, Turin, Italy (M.R.); Liver
Unit, Hadassah–Hebrew University Hospi-
tal, Jerusalem, Israel (D.S.); Hospital del
Mar, Institut Municipal d’Investigació Méd-
ica, Universitat Autónoma de Barcelona,
Barcelona (R.S.); Hospital de Gastroen-
terología Dr. Bonorino Udaondo, Buenos
Aires (R.A.T.); University of British Colum-
bia and Vancouver General Hospital, Van-
couver, BC, Canada (E.M.Y.); Vertex Phar-
maceuticals, Cambridge, MA (N.A., L.B.,
A.J.S., T.L.K., S.G., R.S.K.); and Department
of Internal Medicine, Johann Wolfgang
Goethe University Medical Center, Frankfurt
am Main, Germany (S.Z.). Address reprint
requests to Dr. Jacobson at the Weill Cornell
Medical College and Center for the Study of
Hepatitis C, 1305 York Ave., New York, NY
10021, or at imj2001@med.cornell.edu.
* The members of the ADVANCE Study
Team are listed in the Supplementary
Appendix, available at NEJM.org.
N Engl J Med 2011;364:2405-16.
Copyright © 2011 Massachusetts Medical Society.
ABSTR ACT
Background
In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in
combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin
alone, has shown improved efficacy, with potential for shortening the duration of treat-
ment in a majority of patients.
Methods
In this international, phase 3, randomized, double-blind, placebo-controlled trial, we
assigned 1088 patients with HCV genotype 1 infection who had not received previous
treatment for the infection to one of three groups: a group receiving telaprevir com-
bined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), fol-
lowed by peginterferon–ribavirin alone for 12 weeks if HCV RNA was undetectable
at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point;
a group receiving telaprevir with peginterferon–ribavirin for 8 weeks and placebo
with peginterferon–ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks
of peginterferon–ribavirin on the basis of the same HCV RNA criteria; or a group
receiving placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks
of peginterferon–ribavirin (PR group). The primary end point was the proportion
of patients who had undetectable plasma HCV RNA 24 weeks after the last planned
dose of study treatment (sustained virologic response).
Results
Significantly more patients in the T12PR or T8PR group than in the PR group had a
sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the com-
parison of the T12PR or T8PR group with the PR group). A total of 58% of the patients
treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia,
gastrointestinal side effects, and skin rashes occurred at a higher incidence among
patients receiving telaprevir than among those receiving peginterferon–ribavirin
alone. The overall rate of discontinuation of the treatment regimen owing to adverse
events was 10% in the T12PR and T8PR groups and 7% in the PR group.
Conclusions
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. (Funded by Ver-
tex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.)
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P
atients with chronic hepatitis C virus
(HCV) infection are at risk for progressive he-
patic fibrosis, cirrhosis, portal hypertension,
hepatic failure, and hepatocellular carcinoma.
1-4
For the past decade, treatment with pegylated inter-
feron (peginterferon alfa) and ribavirin has been as-
sociated with rates of sustained virologic response
of 40 to 50% among patients with HCV genotype 1
who had received no previous treatment.
5-7
At least
48 weeks of treatment is required for most of these
patients, and toxic effects may limit the extent of
treatment in some patients.
5-7
Telaprevir, a linear peptidomimetic HCV NS3/4A
serine protease inhibitor, was associated with sub-
stantial improvements in response rates in phase 2
studies when it was combined with peginterferon–
ribavirin.
8-10
Moreover, high rates of early viral sup-
pression and low rates of relapse after cessation of
telaprevir therapy suggested that therapy could po-
tentially be shortened to 24 weeks in patients who
have a rapid virologic response — that is, patients
in whom HCV RNA is undetectable at week 4 of
treatment.
8-10
A phase 3 study was conducted to
evaluate the efficacy and safety of telaprevir-based
therapy, administered in a regimen that was guided
by the patient’s response, among patients who had
received no previous treatment for HCV infection.
Methods
Patients
We enrolled patients at 123 international sites. Eli-
gible patients were 18 to 70 years of age and had
HCV genotype 1 infection with evidence of chron-
ic hepatitis, as confirmed by means of a liver biopsy
within 1 year before screening for the study; pa-
tients with compensated liver cirrhosis were eli-
gible. Additional eligibility criteria included sero-
negativity for hepatitis B surface antigen, and the
absence of antibodies against human immunode-
ficiency virus types 1 and 2, absolute neutrophil
counts of 1500 or more per cubic millimeter,
platelet counts of 90,000 or more per cubic milli-
meter, and hemoglobin levels of at least 12 g per
deciliter in the case of women or 13 g per deciliter
in the case of men. Patients were excluded if they
had decompensated liver disease, liver disease
from other causes, or hepatocellular carcinoma.
Study Design
This study was a phase 3, randomized, double-blind
trial, placebo-controlled for telaprevir. Patients were
stratified according to genotype 1 subtype (a, b,
or unknown) and baseline viral load (HCV RNA
<800,000 IU per milliliter or ≥800,000 IU per
milliliter) and were randomly assigned to one of
three treatment groups. The study was designed to
evaluate two regimens of telaprevir (Vertex Phar-
maceuticals) of different durations, combined with
peginterferon alfa-2a (Pegasys, Roche) and riba-
virin (Copegus, Roche), as compared with a regi-
men of peginterferon alfa-2a and ribavirin alone.
The total duration of treatment was either 24 or
48 weeks. During the first 12 weeks, patients as-
signed to one of the telaprevir groups received
telaprevir and peginterferon–ribavirin either for
the entire 12 weeks (T12PR group) or for 8 weeks
followed by 4 weeks of placebo and peginterferon–
ribavirin (T8PR group). Patients in the T12PR and
T8PR groups who met the criteria for an extended
rapid virologic response (defined as undetectable
HCV RNA at weeks 4 and 12) received 12 addi-
tional weeks of treatment with peginterferon–
ribavirin alone, for a total treatment period of
24 weeks. Patients in the T12PR and T8PR groups
who had detectable HCV RNA either at week 4
or at week 12 received 36 additional weeks of
treatment with peginterferon–ribavirin, for a to-
tal treatment period of 48 weeks. The group re-
ceiving peginterferon alfa-2a and ribavirin alone
(PR group) received placebo plus peginterferon–
ribavirin for 12 weeks, followed by peginterferon–
ribavirin alone for 36 additional weeks. Telaprevir
was administered orally at a dose of 750 mg every
8 hours with food, peginterferon alfa-2a by subcu-
taneous injection at a dose of 180 μg per week, and
ribavirin orally at a dose of 1000 mg per day (in
patients who weighed less than 75 kg) or 1200 mg
per day (in patients who weighed 75 kg or more).
Stopping rules were implemented to prevent the
continuation of treatment in patients who did
not have an adequate response. Patients receiv-
ing telaprevir who had HCV RNA levels greater
than 1000 IU per milliliter at week 4 discontin-
ued telaprevir but continued peginterferon–riba-
virin. All patients with less than a 2 log
10
de-
crease from baseline in HCV RNA levels at week
12 discontinued treatment. Patients discontinued
treatment if HCV RNA was confirmed to be de-
tectable at any time between weeks 24 and 40.
Study Oversight
The protocol was designed by Vertex Pharmaceu-
ticals and Tibotec in collaboration with one of the
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Telaprevir for Previously Untreated HCV Infection
n engl j med 364;25 nejm.org june 23, 2011
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academic authors. The protocol, which is available
with the full text of this article at NEJM.org, was
approved by an independent or institutional review
board at each participating center, and all patients
provided written informed consent before par-
ticipating in study-related activities. The corre-
sponding author prepared the first draft of the
manuscript and made the decision to submit the
manuscript for publication, and all the authors, to-
gether with an employee of the sponsor, assisted in
the revision of subsequent drafts. All the authors
reviewed and approved the final draft of the man-
uscript and assume responsibility for the accuracy
and completeness of the data and data analyses and
for the fidelity of the study to the trial protocol.
Efficacy Assessments
Plasma HCV RNA levels were measured with the
use of the COBAS TaqMan HCV RNA assay, version
2.0 (Roche), with a lower limit of quantification
of 25 IU per milliliter and a lower limit of detection
of 10 IU per milliliter. The lower limit of detec-
tion was used in the determination of extended
rapid virologic response. HCV RNA levels were
measured on day 1 and at weeks 1, 2, 3, 4, 6, 8,
10, 12, 16, 20, 24, 28, 36, 40, and 48; at follow-up
visits 4 weeks after the end of treatment; and at
weeks 60 and 72.
Evaluation of HCV Sequence
Blood samples were obtained for viral sequencing
at baseline and at every treatment and follow-up
study visit. Sequencing samples from all the pa-
tients were analyzed at baseline, and those from
patients who did not meet the criteria for a sus-
tained virologic response were analyzed at all
post-baseline time points at which HCV RNA levels
were above the limit of detection of the sequenc-
ing assay (approximately 1000 IU per milliliter).
HCV RNA was isolated from the plasma and am-
plified by reverse-transcriptase polymerase chain
reaction, and the NS3/4A region of the HCV ge-
nome was analyzed with the use of population
sequencing.
Safety Assessments
Chemical and hematologic assessments were per-
formed at the same time as the efficacy assess-
ments during the treatment period and at 4 weeks
after the last dose of the study drug was admin-
istered. Data on adverse events were collected at
each treatment visit and at the safety follow-up
assessment. Full physical examinations were per-
formed at the screening visit and at the safety
follow-up assessment. Physical examinations were
performed as needed for the assessment and treat-
ment of symptoms during treatment visits.
Because an increased rate of rash had been
observed in phase 2 studies,
8-10
guidance regarding
the grading and management of rash was incorpo-
rated into this study. Rash was classified as grade
1 (mild, localized), grade 2 (moderate, with a dif-
fuse skin eruption involving up to 50% of the body
surface), or grade 3 (severe, involving more than
50% of the body surface, or rash with the appear-
ance of substantial systemic signs or symptoms).
If a progressive grade 2 rash or any grade 3 rash
developed, telaprevir or placebo was to be discon-
tinued but the patient would continue to receive
peginterferon–ribavirin. If the rash worsened with-
in 7 days after discontinuation of telaprevir or pla-
cebo, ribavirin (with or without peginterferon) was
to be discontinued (sequential discontinuation).
Anemia was to be managed by means of re-
ductions in the dose of ribavirin in accordance
with the product labeling. Erythropoietin-stimu-
lating agents were prohibited according to the
final amended study protocol, as were reductions
in the dose of telaprevir. If ribavirin was discon-
tinued owing to anemia, discontinuation of tela-
previr (or placebo) was required.
An independent data and safety monitoring
committee conducted regular planned reviews of
the safety data to evaluate safety and side effects
of the study regimens. The analyses and prepa-
ration of the safety data for each review of the
committee were performed by a statistical group
that was independent of the sponsor (Parexel In-
ternational). No interim analyses were planned or
conducted.
End Points
The primary end point was the proportion of pa-
tients who had undetectable plasma HCV RNA
24 weeks after the last planned dose of study
treatment (sustained virologic response). Second-
ary efficacy end points included the proportion of
patients with undetectable HCV RNA at week 72;
at week 4, week 12, or both weeks 4 and 12; at the
end of treatment; and 12 weeks after the last
planned dose of treatment. A patient was consid-
ered to have had a relapse if he or she had unde-
tectable HCV RNA levels at the end of the treat-
ment period but had confirmed detectable HCV
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RNA levels sometime between the end of treatment
and 24 weeks after the last study dose.
Statistical Analysis
The analysis of the primary end point was based
on a logistic-regression model, with sustained viro-
logic response as the dependent variable and treat-
ment, genotype 1 subtype, and baseline HCV RNA
plasma level as factors. The primary end point was
also evaluated by an analysis of the consistency
of the treatment effect in prespecified subgroups
according to 10 baseline variables (see the statis-
tical analysis plan provided with the protocol at
NEJM.org). We estimated that with a sample size
of 350 patients in each treatment group, the study
would have 92% power to show a significant dif-
ference among the treatments, with the use of a
two-sided, continuity-corrected chi-square test, at
an overall significance level of 5% (adjusted for
multiple comparisons), assuming a 50% response
rate in the control (PR) group and a 64% response
rate in a telaprevir group. Efficacy and safety anal-
yses included data from all patients who underwent
random assignment and received at least one dose
of any study drug.
Results
Study Patients
Of the 1095 patients enrolled in the study, 1088
received at least one dose of a study drug and
were included in the data set for the full analysis
(Fig. 1). Patients were well balanced with respect
to major baseline demographic and disease char-
acteristics (
Table 1
). A total of 58% of the patients
were men, 9% were black, 11% were Hispanic,
and 21% had bridging fibrosis or cirrhosis.
Efficacy
A significantly greater proportion of patients in
each of the two groups receiving telaprevir than in
the group receiving peginterferon–ribavirin alone
met the criteria for a sustained virologic response
(undetectable plasma HCV RNA 24 weeks after
the last planned dose of study treatment): 75% in
the T12PR group and 69% in the T8PR group, as
compared with 44% in the PR group (P<0.001 for
the comparison of either telaprevir group with the
PR group) (
Table 2
). A total of 73% of patients in
the T12PR group, 67% in the T8PR group, and 44%
in the PR group had undetectable HCV RNA 72
weeks after starting treatment (P<0.001 for the
comparison of either telaprevir group with the PR
group); 68%, 66%, and 9% in the three groups,
respectively, had undetectable HCV RNA at week
4 (rapid virologic response); and 58%, 57%, and 8%
in the three groups, respectively, had undetectable
HCV RNA at weeks 4 and 12 (extended rapid viro-
logic response). Among the patients with extended
rapid virologic response assigned to receive a total
of 24 weeks of therapy, 89% in the T12PR group
and 83% in the T8PR group met the criteria for
sustained virologic response. Mean HCV RNA lev-
els during treatment are shown in Figure 2 in the
Supplementary Appendix, available at NEJM.org.
Analyses of subgroups according to various
characteristics showed that there were higher rates
of sustained virologic response with telaprevir than
with peginterferon–ribavirin alone (Fig. 2, and
Fig. 1 in the Supplementary Appendix). A sustained
virologic response occurred in 71% of the patients
with HCV genotype 1a and 79% with genotype
1b in the T12PR group, in 66% and 74% of the
patients with genotype 1a and genotype 1b, re-
spectively, in the T8PR group, and in 41% and 48%
in of the patients with genotype 1a and genotype
1b, respectively, in the PR group. Among black
patients, 62% in the T12PR group and 58% in the
T8PR group had a sustained virologic response,
as compared with 25% in the PR group. Among
patients with HCV RNA levels of 800,000 IU per
milliliter or more at baseline, those who received
telaprevir had a higher rate of response than did
those who received peginterferon–ribavirin alone
(74% of the patients in the T12PR group and 66%
in the T8PR group vs. 36% in the PR group).
Among patients with bridging fibrosis or cirrho-
sis, 62% of patients in the T12PR group and 53%
in the T8PR group, as compared with 33% in the
PR group, had a sustained virologic response.
Among patients who had undetectable HCV
RNA levels after the last dose of study treatment,
relapse occurred in 9% in the T12PR group, 9% in
the T8PR group, and 28% in the PR group. Recipi-
ents of a telaprevir-based regimen who were as-
signed to 24 weeks of treatment and who met
the criteria for sustained virologic response were
assessed for relapse beyond 24 weeks after the last
study dose. One of 357 patients evaluated through
week 72 (<1%) had a confirmed late relapse after
early discontinuation of the T8PR regimen at
week 12. Three others had detectable HCV RNA
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Telaprevir for Previously Untreated HCV Infection
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2409
below 25 IU per milliliter; in 2 of these patients,
HCV RNA was subsequently undetectable, and
in 1, there was no available confirmation of HCV
RNA level. One patient had HCV RNA of more
than 20 million IU per milliliter, but the se-
quencing assay (limit of detection, approximately
1000 IU per milliliter) was unsuccessful, raising
the possibility of a sample error.
A patient was considered to have virologic fail-
ure during the treatment period if he or she met
the criteria for a stopping rule, had HCV RNA
greater than 1000 IU per milliliter at week 12 even
if the HCV RNA decline was greater than 2 log
10
,
or had detectable HCV RNA at the end of treat-
ment (week 24 or 48). The rate of virologic failure
during the treatment period was lower among pa-
tients who received telaprevir than among those
who received peginterferon–ribavirin alone (8% in
365 Were assigned to the T12PR
group
363 Received at least one dose
of study drugs
2 Did not receive study drugs
271/363 (75%) Had SVR
210 Were assigned to
24 wk of treatment
195 Completed
treatment
15 Discontinued
treatment
9 Had adverse
event
1 Had virologic
failure
5 Had other
reason
153 Were assigned to
48 wk of treatment
73 Completed
treatment
80 Discontinued
treatment
27 Had adverse
event
4 Were lost to
follow-up
37 Had virologic
failure
12 Had other
reason
202 Completed treatment
159 Discontinued treatment
26 Had adverse event
1 Died
4 Were lost to follow-up
2 Withdrew consent
118 Had virologic failure
8 Had other reasons
158/361 (44%) Had SVR
1095 Patients underwent randomization
207 Were assigned to
24 wk of treatment
191 Completed
treatment
16 Discontinued
treatment
10 Had adverse
event
1 Was lost to
follow-up
5 Had other
reason
157 Were assigned to
48 wk of treatment
69 Completed
treatment
88 Discontinued
treatment
27 Had adverse
event
2 Were lost to
follow-up
1 Withdrew
consent
40 Had virologic
failure
18 Had other
reason
250/364 (69%) Had SVR
365 Were assigned to the T8PR group
364 Received at least one dose
of study drugs
1 Did not receive study drugs
365 Were assigned to the PR (control)
group
361 Received at least one dose
of study drugs
4 Did not receive study drugs
Figure 1. Randomization and Sustained Virologic Response (SVR) in Study Patients.
The T12PR group was assigned to receive telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks, followed by peg-
interferon–ribavirin alone for 12 weeks if hepatitis C virus (HCV) RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA
was detectable at either time point; the T8PR group was assigned to receive telaprevir with peginterferon–ribavirin for 8 weeks and tela-
previr-matched placebo plus peginterferon–ribavirin for 4 weeks, followed by peginterferon–ribavirin alone for 12 weeks if HCV RNA
was undetectable at weeks 4 and 12 or by peginterferon–ribavirin for 36 weeks if HCV RNA was detectable at either time point; the PR
(control) group was assigned to receive telaprevir-matched placebo plus peginterferon–ribavirin for 12 weeks, followed by peginterfer-
on–ribavirin alone for 36 weeks. Of the 1095 patients who underwent randomization, 1088 received at least one dose of the study drugs
and 7 did not receive any study drugs. In the T12PR group, 3 patients had an extended rapid virologic response but were assigned to the
48-week treatment group, and 1 patient who did not have an extended rapid virologic response was assigned to receive 24 weeks of
treatment; however, this patient also met the week-12 stopping rule and discontinued treatment after the week-12 visit.
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