Boceprevir
Improves Response to Interferon-Based HCV Therapy
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| SUMMARY:
The HCV protease inhibitor boceprevir improved sustained
response rates when combined with pegylated interferon
plus ribavirin in both previously untreated patients
and prior non-responders, according to findings from
2 studies published in the March 31 New England Journal
of Medicine. |
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By
Liz Highleyman
The
advent of direct-acting antiviral agents that interfere with various
steps of the hepatitis C virus (HCV) lifecycle will usher in a
new era of treatment. The current standard of care, pegylated
interferon plus ribavirin, leads to sustained virological
response (SVR) less than half the time for hard-to-treat HCV genotype
1.
The
first of these drugs -- 2 HCV protease inhibitors currently undergoing
review by the U.S. Food and Drug Administration (FDA) -- are Merck's
boceprevir
(recently given the brand name Victrelis) and Vertex's telaprevir.
Initially they will be used in combination with standard therapy,
making it both more effective and potentially shorter.
This
week's New England Journal of Medicine featured reports
from 2 pivotal Phase 3 studies of telaprevir: SPRINT-2, which
enrolled previously untreated patients, and RESPOND-2, which enrolled
prior non-responders and relapsers. These findings were previously
presented at the American Association for the Study of Liver
Diseases (AASLD) meeting last fall.
SPRINT-2
SPRINT-2
included 1097 treatment-naive genotype 1 patients. Participants
were divided into cohorts according to race, as people of African
descent do not respond as well to interferon-based therapy. One
cohort included 159 black patients, while the other included 938
people of other racial/ethnic groups (dubbed "non-black").
All
participants started a regimen of 1.5 mcg/kg/week pegylated interferon
alfa-2b (PegIntron) plus 600-1400 mg/day weight-adjusted ribavirin
for a 4-week lead-in period. They were randomly allocated to subsequently
either continue on pegylated interferon/ribavirin plus placebo
for 44 more weeks (control group) or to add 800 mg 3-times-daily
boceprevir.
Boceprevir recipients were further randomized to receive the triple
combination either for a fixed duration of 44 more weeks or using
response-guided therapy. In the latter group participants with
undetectable HCV viral load between weeks 8 and 24 stopped boceprevir
early. People who still had detectable viral load at week 24 discontinued
all therapy due to likely futility of continued treatment.
Results
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SVR
rates 24 weeks after completion of treatment were significantly
higher in the boceprevir arms than in the standard therapy
control group. |
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In
an intent-to-treat analysis, 68% of non-black patients receiving
fixed-duration triple therapy and 67% receiving response-guided
therapy achieved SVR, compared with 40% in the control group.
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Among
black patients the corresponding SVR rates were 53%, 42%,
and 23%, respectively. |
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Relapse
rates in both fixed duration and response-guided boceprevir
arms were significantly lower than in the standard-therapy
control group. |
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Almost
all boceprevir recipients with undetectable HCV RNA during
weeks 8 through 24 went on to achieve SVR. |
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The
most common treatment-related adverse events across arms were
fatigue, headache, and nausea. |
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Anemia
and dysgeusia (odd taste sensations) were significantly more
common among boceprevir recipients. |
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Overall
rates of discontinuation due to adverse events were similar
across treatment arms. |
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More people in the boceprevir arms, however, discontinued
therapy (2% vs 1% in the control group), reduced drug doses
(21% vs 13%), or used erythropoietin (43% vs 24%) due to anemia. |
Based
on these findings, the study authors concluded, "The addition
of boceprevir to standard therapy with peginterferon/ribavirin,
as compared with standard therapy alone, significantly increased
the rates of sustained virologic response in previously untreated
adults with chronic HCV genotype 1 infection."
SVR rates were similar with 24 weeks or 44 weeks of boceprevir,
they added.
"Among non-black patients, the combination therapy with boceprevir
was associated with a relative increase of approximately 70% in
the rates of sustained virologic response over standard therapy,"
they elaborated in their discussion. "Although lower among
black patients than among non-black patients, the rates of sustained
virologic response with the boceprevir regimens were nearly double
those with the standard of care."
RESPOND-2
RESPOND-2 included 403 treatment-experienced genotype 1 patients,
both prior non-responders and relapsers; about 12% were black.
Again,
all participants initially received pegylated interferon/ribavirin
for a 4-week lead-in period. They were randomly assigned to subsequently
continue on pegylated interferon/ribavirin plus placebo for 44
more weeks or to add 800 mg 3-times-daily boceprevir.
Boceprevir recipients either stayed on triple therapy for 44 more
weeks or used response-guided therapy. The latter group stopped
boceprevir at week 36; those who had detectable HCV RNA at week
8 continued on pegylated interferon/ribavirin through week 48.
Results
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In
an intent-to-treat analysis, patients in the boceprevir arms
again had significantly higher SVR rates -- 66% with fixed-duration
therapy and 59% with response-guided therapy -- than those
in the standard therapy control group (21%). |
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Among
people with undetectable HCV RNA at week 8, SVR rates were
86% after 32 weeks and 88% after 44 weeks of triple therapy.
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Among
participants who had less than a 1 log IU/mL decrease in HCV
RNA at week 4, one-third of boceprevir recipients still achieved
SVR, compared with none in the control group. |
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Here
too, the most common adverse events were fatigue, headache,
and nausea. |
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Anemia
again occurred about twice as often in the boceprevir arms
than in the control group. |
"The
addition of boceprevir to peginterferon/ribavirin resulted in
significantly higher rates of sustained virologic response in
previously treated patients with chronic HCV genotype 1 infection,
as compared with peginterferon/ribavirin alone," the investigators
concluded, noting that fixed-duration and response-guided therapy
were similarly effective.
Patients who previously relapsed after receiving standard therapy
had SVR rates of up to 75% on boceprevir triple therapy, while
previous non-responders had sustained response rates of 40% to
52%, they added in their discussion.
In
summary, they wrote, the results of this trial "show that
boceprevir, when added to peginterferon alfa-2b and ribavirin,
leads to high rates of sustained virologic response in difficult-to-treat
patients."
Editorial
In
an accompanying editorial, Donald Jensen from the University of
Chicago Medical Center wrote that, "A new era of therapy
for hepatitis C virus (HCV) infection is dawning with the development
of 2 effective HCV protease inhibitors, boceprevir and telaprevir."
While
HCV protease inhibitors represent a "major advance in our
ability to treat chronic HCV infection," he continued. "Future
therapy will be more complex, not easier, but the improvement
in the rate of sustained virologic response with boceprevir, to
nearly 70% in the SPRINT-2 trial and to more than twice the rate
in previously treated patients in HCV RESPOND-2, have been eagerly
awaited."
Investigator
affiliations:
SPRINT-2: Cedars-Sinai Med Ctr, Los Angeles, CA; Gastroenterology-Hepatology-Certified
Endoscopy Ctrs, Alexandria, VA; St Louis Univ School of Medicine,
St Louis, MO; Azienda Ospedaliera Fatebenefratelli e Oftalmico,
Milan, Italy; Hannover Medical School, Hannover, Hannover, Germany;
John Hopkins Univ School of Medicine, Baltimore, MD; Ctr for the
Study of Hepatitis C, Weill Cornell Medical College, New York,
NY; Univ of Pennsylvania, Philadelphia, PA; Inova Fairfax Hospital
and the Betty and Guy Beatty Center for Integrated Research, Falls
Church, VA; Merck, Whitehouse Station, NJ; Ctr Hosp Univ de Nancy,
Univ Henri Poincaré Nancy 1, Vandoeuvre-lès-Nancy,
France. RESPOND-2: St Louis Univ School of Medicine, St Louis,
MO; Henry Ford Hosp, Detroit, MI; Alamo Medical Research, San
Antonio, TX; Univ Paris-Diderot, Hosp Beaujon, Clichy, France;
Baylor College of Medicine, Houston, TX; Department of Medicine,
J.W. Goethe University Hospital, Frankfurt, Germany; Cedars-Sinai
Medical Ctr, Los Angeles, CA; Inova Fairfax Hospital and the Betty
and Guy Beatty Center for Integrated Research, Falls Church, VA;
Merck, Sharp & Dohme, Whitehouse Station, NJ; Hospital General
Universitario Vall d'Hebron and Centro de Investigación
Biomédica en Red de Enfermedades Hepáticas y Digestivas
del Instituto Carlos III, Barcelona, Spain.
Both
SPRINT-2 and RESPOND-2 were funded by Schering-Plough, now part
of Merck.
4/1/11
References
F
Poordad, J McCone, BR Bacon, et al. (SPRINT-2 Investigators).
Boceprevir for Untreated Chronic HCV Genotype 1 Infection. New
England Journal of Medicine 364: 1195-1206 (abstract).
March 31, 2011.
BR
Bacon, SC Gordon, E Lawitz, et al. Boceprevir for Previously Treated
Chronic HCV Genotype 1 Infection (HCV RESPOND-2 Investigators).
New England Journal of Medicine 364: 1207-1217 (abstract).
March 31, 2011.
DM
Jensen. A New Era of Hepatitis C Therapy Begins (editorial). New
England Journal of Medicine 364: 1272-1274. March 31, 2011.
