HCV
Protease Inhibitor Boceprevir Improves Response for Treatment-Naive and
Non-responders
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| SUMMARY:
Merck's investigational hepatitis C
virus (HCV) protease inhibitor boceprevir
improved sustained response rates when combined with pegylated
interferon plus ribavirin in both previously untreated patients
and those who were non-responders or relapsers after prior
therapy, according to 2 Phase 3 studies presented at the 18th
Conference on Retroviruses and Opportunistic Infections (CROI
2011) this month in Boston. |
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By
Liz Highleyman
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Mark
Sulkowski
(Photo:
Liz Highleyman)
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The advent
of direct-acting antiviral agents that interfere with various steps
of the HCV lifecycle will usher in a new era of treatment for chronic
hepatitis C. The current standard-of-care, pegylated
interferon (Pegasys or PegIntron) plus ribavirin, leads to sustained
virological response (SVR), or a cure, less than half the time for individuals
with hard-to-treat HCV genotype 1.
The first
such drugs -- boceprevir and Vertex's HCV protease inhibitor telaprevir
-- are expected to be approved this year. Initially, they will be used
in combination with standard-of-case therapy, but all-oral regimens
without interferon are currently being studied.
At CROI,
researchers presented final data 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 results were
previously
presented at the American Association for the Study of Liver Diseases
(AASLD) meeting this past fall.
SPRINT-2
and RESPOND-2 did not include people with HIV -- making these presentations
unusual for CROI -- but HIV specialists recognize the need to get up
to speed on hepatitis C treatment, since many HIV positive people are
coinfected with HCV. As recently
reported, the conference also featured the first data on telaprevir
for HIV/HCV coinfected individuals.
SPRINT-2
SPRINT-2 included 1097 treatment-naive HCV genotype 1 patients (about
60% men). 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 ("non-black"). Most
had high HCV viral load and nearly 10% had advanced liver fibrosis.
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. After this, they were randomly
assigned to continue on pegylated interferon/ribavirin, either alone
or in combination with 800 mg boceprevir 3-times-daily.
Boceprevir
recipients were further allocated to receive either the triple combination
for a fixed duration of 48 total weeks or response-guided therapy. In
the latter arm, all participants stopped boceprevir at week 28. Those
with undetectable HCV RNA during weeks 8-24 stopped all drugs, while
those with continued detectable HCV viral load stayed on pegylated interferon/ribavirin
through week 48.
Results
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In
an intent-to-treat analysis, SVR rates were significantly higher
in the boceprevir arms -- 66% with fixed-duration treatment and
63% with response-guided therapy -- compared with the standard therapy
arm (38%). |
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In
all arms, white patients had higher response rates than blacks:
68% vs 53% in the fixed duration boceprevir arm, 67% vs 42% in the
response-guided therapy arm, and 40% vs 23% in the standard therapy
arm. |
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The
relapse rate was 9% in both boceprevir arms, compared with 22% in
the standard therapy group. |
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Almost all boceprevir recipients with undetectable HCV RNA during
weeks 8-24 achieved SVR: 96% with fixed-duration boceprevir, 97%
with response-guided therapy. |
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Among
boceprevir participants who had detectable HCV viral load at least
once during weeks 8-24, still 74% achieved SVR in both arms. |
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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 more common in the boceprevir
groups than in the standard therapy group. |
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Rates
of discontinuation due to adverse events, however, were similar
across arms: 16% in the standard therapy arm, 16% in the boceprevir
fixed-duration arm, and 12% in the response-guided therapy arm. |
Based on
these findings, the researchers concluded that a regimen of boceprevir
plus pegylated interferon/ribavirin "significantly increased SVR"
compared with standard therapy alone, and HCV RNA at week 8 could be
used to determine duration of pegylated interferon/ribavirin.
RESPOND-2
RESPOND-2 enrolled 400 treatment-experienced genotype 1 patients, both
prior non-responders and relapsers (undetectable at the end of treatment
followed by viral rebound). About two-thirds were men, 12% were black,
and 12% had liver cirrhosis.
Again, all
participants initially received pegylated interferon/ribavirin standard
therapy for a 4-week lead-in period. They were then randomly assigned
to continue on pegylated interferon/ribavirin either alone or in combination
with 800 mg 3-times-daily boceprevir.
Boceprevir recipients were assigned to either stay on triple therapy
through week 48 or use response-guided therapy. In the latter group,
participants stopped boceprevir at week 36; those with undetectable
HCV RNA at week 8 stopped all treatment, while those with detectable
viral load continued on pegylated interferon/ribavirin through week
48.
Results
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In
an intent-to-treat analysis, patients in the boceprevir arms had
significantly higher SVR rates -- 67% with fixed-duration therapy
and 59% with response-guided therapy -- than those in the standard
therapy arm (21%). |
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People
with undetectable HCV RNA at week 8 had high SVR rates in all arms:
88% with fixed-duration boceprevir, 86% with response-guided boceprevir,
and 100% with standard therapy. |
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People
taking boceprevir, however, were about 6 times more likely to have
undetectable HCV RNA at week 8 (46%-52% vs 9%). |
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In all arms, previous relapsers had higher SVR rates than prior
non-responders: 75% vs 52% with fixed-duration boceprevir, 40% vs
69% with response-guided boceprevir, and 29% vs 7% with standard
therapy. |
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Here
too, the most common adverse events were fatigue, headache, and
nausea. |
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Anemia
occurred about twice as often in the boceprevir arms: 46% with fixed-duration
boceprevir, 43% with response-guided boceprevir, and 20% with standard
therapy. |
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Serious
adverse events likewise occurred about twice as often in the boceprevir
arms: 14%, 10%, and 5%, respectively. |
The investigators
concluded that boceprevir added to pegylated interferon/ribavirin "significantly
increased SVR."
They added that boceprevir could be used to treat patients with all
types of interferon non-responsiveness, and that fixed-duration and
response-guided therapy were "equally effective."
Investigator affiliations:
Abstract 115: John Hopkins Univ School of Medicine, Baltimore, MD;
Cedars-Sinai Med Ctr, Los Angeles, CA; Gastroenterology/Hepatology/Certified
Endoscopy Ctrs, Alexandria, VA; St Louis Univ School of Medicine, St
Louis, MO; AO Fatebenefratelli e Oftalmico, Milan, Italy; Hannover Medical
School, Hannover, Germany; Ctr for the Study of Hepatitis C, Weill Cornell
Medical College, New York, NY; Univ of Pennsylvania, Philadelphia, PA;
Merck, Whitehouse Station, NJ; Ctr Hosp Univ de Nancy, Univ Henri Poincaré
Nancy 1, Vandoeuvre-lès-Nancy, France.
Abstract 116: Henry Ford Hosp, Detroit, MI; St Louis Univ School of
Medicine, St Louis, MO; Alamo Medical Research, San Antonio, TX; Univ
Paris, Hosp Beaujon, Clichy, France; Baylor College of Medicine, Houston,
TX; Universitätsklinikum des Saarlandes, Homburg/Saar, Germany;
Cedars-Sinai Med Ctr, Los Angeles, CA; Merck, Whitehouse Station, NJ;
Hosp Univ Vall d'Hebrón, Barcelona, Spain.
3/15/11
References
M Sulkowski,
F Poordad, J McCone, et al. BOC Combined with P/R for Treatment-naive
Patients with HCV Genotype-1: SPRINT-2 Final Results. 18th Conference
on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February
27-March 2, 2011. Abstract
115.
S Gordon,
B Bacon, E Lawitz, et al. HCV RESPOND-2 Final Results: High Sustained
Virologic Response among Genotype-1 Previous Non-responders and Relapsers
to pegIFN/RBV when Re-treated with BOC + PEGINTRON/RBV
18th Conference on Retroviruses and Opportunistic Infections (CROI 2011).
Boston. February 27-March 2, 2011. Abstract
116.
