For people who can wait a bit longer, several studies at EASL
showed good outcomes when adding more effective and better-tolerated
second-generation DAAs to interferon-based therapy.
evaluated the HCV protease inhibitor faldaprevir (formerly BI 201335)
plus pegylated interferon/ribavirin in 656 previously untreated
patients. Two-thirds had subtype 1b, about 60% had unfavorable IL28B
patterns, and 6% had cirrhosis. They were randomly allocated to receive
120 mg or 240 mg once-daily faldaprevir for 12 or 24 weeks, with
pegylated interferon/ribavirin continued for 24 or 48 weeks based on
early treatment success, or else interferon/ribavirin alone for 48
patients taking 120 mg faldaprevir and 80% taking 240 mg achieved
SVR12, compared with 52% in the control arm. Most (88%) had early
treatment success and stopped all treatment at week 24; of these, 86%
and 89% achieved SVR12. People with HCV 1a did not respond as well as
those with 1b due to more relapses (69% vs 84% taking 120 mg, 76% vs
83% taking 240 mg). Patients with favorable IL28B also did better.
Treatment was generally safe and well-tolerated, with 4% to 5%
discontinuing therapy due to adverse events. While the two faldaprevir
doses had similar overall efficacy, the lower dose was better tolerated
and caused less bilirubin elevation.
evaluated once-daily simeprevir added to pegylated
interferon/ribavirin in 391 treatment-naive patients; 40% had subtype
1a, 30% had the favorable IL28B CC pattern, and 8% had cirrhosis. The
study found that 81% of simeprevir recipients achieved SVR12, compared
with 50% of those using interferon/ribavirin alone. Most (91%) met
response-guided therapy criteria allowing them to finish treatment at
24 weeks. The simeprevir SVR12 rate reached 96% for patients with
favorable IL28B, but fell to 65% for people with cirrhosis.
showed similar response rates, but more difference between HCV
subtypes 1a and 1b (71% vs 90%). Adverse event and discontinuation
rates were similar with both regimens, indicating that simeprevir does
not reduce the tolerability of interferon-based therapy.
which enrolled 327 previously untreated patients with HCV genotypes 1
(89%), 4 (9%), 5, or 6. Most (70%) had unfavorable IL28B variants and
17% had cirrhosis. Everyone was treated for 12 weeks with no
for genotype 4, and 100% for the seven patients with genotypes 5 or 6.
Cirrhosis, unfavourable IL28B, and higher baseline viral load predicted
poorer response, but all achieved SVR12 rates of at least 80%, which
presenter Eric Lawitz noted “is the highest reported in cirrhosis yet.”
Treatment was safe and well-
tolerated with only 1% reporting serious adverse events.
second-generation protease inhibitor MK-5172 increased sustained
response rates in a Phase 2 study of 332 previously untreated genotype 1
patients without cirrhosis (abstract 66). About 60% had
subtype 1a and 73% had unfavorable IL28B patterns. Participants were
randomly assigned to receive once-daily MK-5172 at doses of 100, 200,
400, or 800 mg with pegylated interferon/ribavirin for 12 weeks,
continuing pegylated interferon/ribavirin alone through week 24 or 48
depending on early response. The control group received the latest
standard-of-care, boceprevir plus pegylated interferon/ribavirin.
86% to 92%, with no clear dose-response effect, compared with 54% in
the control group (many of whom were still undergoing follow-up).
Focusing on the 100 mg dose selected for further development, 91% of
recipients were eligible for shorter response-guided therapy, and in
this group 90% achieved SVR24. IL28B genotype had a minimal effect and
HCV subtype had a small influence. Rates of serious adverse events were
similar in the combined MK-5172 arms and the boceprevir arm (9% vs
8%), but MK-5172 recipients were half as likely to discontinue therapy
due to adverse events (7% vs 14%). Some patients taking MK-5172
developed elevated bilirubin or transaminase levels, and a data safety
board recommended that people in the 400 and 800 mg arms lower their
dose for this reason.
vaniprevir (formerly MK-7009), also increased pegylated
interferon/ribavirin cure rates for a more challenging group,
previously treated genotype 1 patients with compensated cirrhosis (abstract 106).
The cirrhotic cohort in this Phase 2b study had 74 patients, including
25% prior null responders, 42% with subtype 1a, and 80% with
unfavorable IL28B. They were randomly allocated to five treatment arms,
receiving 300 mg or 600 mg twice-daily vaniprevir plus pegylated
interferon/ribavirin for 24 or 48 weeks, or pegylated
interferon/ribavirin alone for 48 weeks.
77%, compared with just 14% in the control arm. These were somewhat
lower than the 67% to 84% seen in a previous cohort of non-cirrhotic
patients. The lower vaniprevir dose and shorter treatment duration were
less effective. HCV subtype had a notable effect, with 83% of 1b
patients but just 50% of 1a patients achieving SVR24 in the combined
vaniprevir 600 mg arms. Vaniprevir was generally safe and
well-tolerated, with 4% to 7% experiencing serious adverse events,
comparable to the frequency in the control arm.
evaluated adding once-daily daclatasvir to pegylated interferon and
fixed-dose ribavirin for 12 or 16 weeks in 151 treatment-naive
patients. One-third of genotype 2 patients and 40% with genotype 3 had
the favorable IL28B CC pattern, and nearly 25% of genotype 3 patients
(but only one with genotype 2) had cirrhosis.
better than those with genotype 3. In the genotype 2 group, 83% in both
the 12-week and 16-week arms achieved SVR24, compared with 63% who
received pegylated interferon/ribavirin alone for 24 weeks. In the
genotype 3 group, however, more patients relapsed, resulting in SVR24
rates of 69%, 67%, and 59%, respectively. Adding daclatasvir was
generally safe and well-tolerated, with few serious adverse events or
early discontinuations for this reason.
Treat or Wait?
In summary, several next-generation DAAs added to pegylated
interferon produce cure rates in the 80% to 90% range, can often
shorten treatment to three to six months (down from six months to a
year), and generally do not cause more side effects than pegylated
interferon and ribavirin alone.
Secretary General Mark Thursz said at a press conference kicking off
the congress, but “interferon is not dead yet.”
to treat now with available but poorly tolerated approved DAAs, wait
for more effective and better tolerated second-generation add-ons to
interferon/ribavirin, or hold out even longer for interferon-free
disease], lots of physicians are recommending their patients wait,”
Thursz explained. “For those with more advanced disease, treating with
the standard of care is probably the way to go—unless they have very
advanced disease,” in which case they have “significant risk of dying
from septic complications” if treated with current triple therapy.
weeks of an interferon-based triple regimen will be “tolerable for a
large number of patients,” he continued. “Many are perfectly happy with
that, and it may be better than waiting another year for a suitable
all-oral regimen.” Within two to four years, however, “the pressure to
use all-oral regimens will become overwhelming.”