by Liz Highleyman,
The European Association for the Study of the Liver
(EASL) International Liver Congress, held April 24-28 in Amsterdam,
confirmed expectations that the next generation of direct-acting
antiviral agents (DAAs) will be more effective, easier to take, and
better tolerated than current options, both as add-ons to
interferon/ribavirin and in interferon-free regimens. Some patients,
however, remain more difficult to treat.
Interferon-free Genotype 2 vs. 3
Interferon-sparing regimes have received the most
attention at recent conferences, and EASL 2013 was no exception. Some
combinations under study also dispense with ribavirin, which can cause
anemia and other side effects.
Gilead Science’s NS5B HCV
polymerase inhibitor sofosbuvir (formerly GS-7977) is furthest along in
the interferon-free pipeline, having been submitted in late March for
Food and Drug Administration (FDA) approval for use with ribavirin for
people with presumed “easier-to-treat” HCV genotypes 2 or 3.
A 12-week dual regimen of
sofosbuvir/ribavirin previously demonstrated 100% sustained virological
response (SVR) for previously untreated, non-cirrhotic people with
genotypes 2 or 3 in the Phase 2 ELECTRON trial. But cure rates proved
lower in larger Phase 3 trials that included 15% to 30% of participants
with liver cirrhosis.
Edward Gane (abstract 5)
presented final results from the FISSION trial, which looked at a
12-week regimen of sofosbuvir/ribavirin in 499 previously untreated
patients, 72% with genotype 3 and 28% with genotype 2. A majority (57%)
had unfavorable IL28B gene patterns and 20% had compensated cirrhosis.
Participants received either 400 mg once-daily sofosbuvir plus
1000-1200 mg/day weight-based ribavirin for 12 weeks, or else pegylated
interferon plus 800 mg/day ribavirin for 24 weeks, the current
standard of care (SoC) for genotypes 2/3.
In both arms, 99% of patients
had undetectable HCV RNA at the end of therapy and treatment failure
rates were also the same, resulting in 12-week post-treatment sustained
response (SVR12) rates of 67%.
But the most interesting finding
was the divergence in response by genotype. Among genotype 2 patients,
the SVR12 rate was 97% with sofosbuvir/ribavirin compared with 78% in
the SoC arm. Among those with genotype 3, the corresponding rates were
just 56% vs 63%, with the DAA regimen performing no better than
interferon. The difference was even more pronounced among people with
cirrhosis. Genotype 2 patients taking sofosbuvir/ribavirin had high
SVR12 rates whether they had cirrhosis (91%) or not (98%). But for
those with genotype 3, only 34% of cirrhotics were cured compared to 61%
Turning to treatment-experienced patients, the FUSION trial (abstract 6)
compared sofosbuvir plus weight-based ribavirin for 12 or 16 weeks in
201 patients (63% with genotype 3, 37% with genotype 2) who were not
cured with prior interferon-based therapy. Most (75%) were prior
relapsers, 70% had unfavorable IL28B patterns, and one-third had
All patients in both arms had
undetectable HCV RNA at the end of treatment, but relapse was common,
resulting in SVR12 rates of 50% for people taking the 12-week regimen
and 73% for those treated for 16 weeks. Again, genotype 2 patients had
high sustained response rates with both durations (86% and 94%), but
for those with genotype 3 rates fell to 30% and 62%. Almost all
non-cirrhotic genotype 2 patients were cured with either treatment
duration (96% and 100%), falling to 60% and 78% for those with
cirrhosis. But among people with genotype 3, the non-cirrhotic SVR12
rates for 12- and 16-week treatment were 37% and 63%, falling to 19%
and 61% for cirrhotics.
Ira Jacobson (abstract 61)
reported data from POSITRON, another Phase 3 trial with 278
participants, split evenly between genotypes 2 and 3, who were
ineligible, intolerant, or unwilling to take interferon. About 55% had
unfavorable IL28B variants and about 16% had cirrhosis. They were
randomized to receive sofosbuvir plus weight-based ribavirin for 12
weeks or placebo. The overall SVR12 rate for the sofosbuvir/ribavirin
arm was 78%, but again, this broke down to 93% for genotype 2 and 61%
for genotype 3. Non-cirrhotic and cirrhotic genotype 2 patients both
responded well (92% and 94%, respectively), but genotype 3
non-cirrhotics did much better than cirrhotics (68% and 21%).
generally safe and well-tolerated in all studies. There were few
serious adverse events or early treatment discontinuations for this
These results call into question
the traditional classification of genotypes 2 and 3 together as
“easy-to-treat,” mirroring the disparity that recently emerged between
HCV subtypes 1a and 1b. Viral variants that were thought to be similar
when only interferon was available may be quite different in their
response to DAAs.
Gane suggested that genotype 2
and 3 should no be longer be lumped together, as genotype 3 is
“behaving as a harder-to-treat virus.”
Interferon-free Genotype 1
The conference featured several reports of all-oral regimens for people with HCV genotype 1.
Mark Sulkowski (abstract 1417) reported
findings from a Phase 2a proof-of-concept study of sofosbuvir plus
Bristol-Myers Squibb’s NS5A inhibitor daclatasvir (formerly BMS-790062)
for 24 weeks, with or without ribavirin, for patients who did not
respond to interferon-based triple therapy containing boceprevir
(Victrelis) or telaprevir (Incivek). This open-label trial included 41
participants, most with hard-to-treat HCV genotype 1 and unfavorable
IL28B patterns. People with known cirrhosis were excluded, but most had
at least moderate fibrosis.
All patients treated with sofosbuvir/daclatasvir
and 95% treated with sofosbuvir/daclatasvir/ribavirin achieved
SVR12—close to the 100% response rate previously reported for
treatment-naïve, non-cirrhotic patients treated for 12 weeks. One person
missing from the SVR12 analysis later returned for follow-up, so SVR24
rates were 100% in both arms. This study provides some of the first
data on “rescue therapy” after failure of the current standard-of-care.
Gilead has declined to pursue this combination in
Phase 3 trials in favor of its own NS5A inhibitor, ledipasvir (formerly
GS-5885). Gane (abstract 14) presented further data from the
ELECTRON trial, confirming that sofosbuvir/ribavirin alone is not
adequate for genotype 1. Adding ledipasvir in a triple oral regimen,
however, raised the cure rate to 100% for both treatment-naïve patients
and prior null responders. Gilead announced in a press release that a
co-formulation of sofosbuvir/ledipasvir without ribavirin for eight or
12 weeks led to SVR4 and SVR8 rates of 95% to 100% for treatment-naïve
and previously treated patients in the Phase 2 LONESTAR trial, but this
is too soon to declare a cure.
A late-breaking poster (abstract 1423)
presented findings from a Phase 2a trial evaluating a three-drug regimen
containing daclatasvir, the protease inhibitor asunaprevir (formerly
BMS-650032), and two doses of the non-nucleoside polymerase inhibitor
BMS-791325, without ribavirin, for either 12 or 24 weeks. The study
enrolled 66 treatment-naïve genotype 1 patients without cirrhosis.
Three-quarters had subtype 1a and about two-thirds had unfavorable
SVR12 rates ranged from 89% to 94% in an interim
intent-to-treat analysis of the three arms that reached this endpoint.
SVR24 rates were 94% and 88% for patients treated with 75 mg BMS-791325
for 12 or 24 weeks (the 150 mg arms having not yet reached this
point), with all treatment “failures” due to missing data from
participants lost to follow-up. The regimen was generally safe and
well-tolerated, regardless of BMS-791325 dose or treatment duration,
with two serious adverse events and no discontinuations for this reason.
Bristol-Myers Squibb indicated that it plans to start a Phase 3 study
of daclatasvir, asunaprevir, and BMS-791325 in a fixed-dose
co-formulation by the end of the year.
Finally, Kris Kowdley (abstract 3)
reported results from the Phase 2 AVIATOR trial, testing a quadruple
oral regimen containing three DAAs developed by AbbVie (formerly
Abbott)—HCV protease inhibitor ABT450 boosted with ritonavir, NS5A
inhibitor ABT-267, and non-nucleoside polymerase inhibitor
ABT-333—taken with ribavirin for 12 or 24 weeks. AVIATOR included 438
previously untreated patients and 133 prior null responders without
cirrhosis. About 70% of naïve patients and almost all null responders
had unfavorable IL28B patterns, and 70% and 60%, respectively, had
At AASLD 2012, Kowdley reported SVR12 rates of 99%
for treatment-naïves and 93% for null responders treated for 12 weeks.
At EASL he added SVR12 findings for arms treated for 24 weeks, and
SVR24 data for all arms. Focusing on the 247 patients who received all
four drugs for 12 weeks, 96% of treatment-naïve patients and 93% of
prior null responders achieved SVR24. The corresponding rates for those
treated for 24 weeks were 90% and 95%.
This combination cured more than 90% of patients
regardless of prior treatment status, HCV subtype 1a or 1b, or IL28B
pattern, though people with cirrhosis were excluded. Treatment was
well-tolerated, with only 2% of patients discontinuing treatment due to
adverse events and none reporting serious anemia. AbbVie has selected a
12-week regimen of the three DAAs plus ribavirin for further study in
Phase 3 trials, and the FDA recently gave the combo a “breakthrough
While many patients and providers eagerly await interferon-free
regimens, some people with advanced liver disease need treatment now and
The current standard of care for genotype 1 adds
boceprevir or telaprevir to pegylated interferon and ribavirin.
First-generation triple therapy works better than interferon/ribavirin
alone, but response remains suboptimal for some patients and comes with
added side effects.
Hélène Fontaine (abstract 60) reported
data from the French CUPIC (Compassionate Use of Protease Inhibitors in
Cirrhotics) study, in which people with cirrhosis who were not cured
with interferon/ribavirin alone were retreated with protease inhibitor
triple therapy through an early access program. Among 221 patients
followed for at least 60 weeks, SVR12 rates were 41% for people treated
with boceprevir and 40% for those receiving telaprevir, but cure rates
were better for HCV subtype 1b (51% and 46%) than 1a (31% and 34%).
Just over half of patients taking either drug experienced serious
adverse events, but discontinuations were more common with telaprevir
than boceprevir (21% vs 11%). In addition, 4% of boceprevir recipients
and 7% of telaprevir recipients developed infections and 5% in both
groups experienced liver decompensation.
Karoline Rutter (abstract 65) presented
data on use of boceprevir or telaprevir triple therapy in 191 patients
in Austria, including 131 with advanced fibrosis or cirrhosis. SVR
rates were 47% for people with advanced fibrosis and 28% for those with
cirrhosis, compared to 65% for those with absent-to-moderate fibrosis.
More than one-quarter experienced serious adverse events, including 18
infections requiring hospitalization and three deaths due to sepsis.
The investigators concluded that triple therapy for people with
advanced liver disease is “feasible,” but associated with poor outcomes.
Elizabeth Verna (abstract 23) reported
findings from the CRUSH-C study, which evaluated triple therapy—mostly
using telaprevir—in 112 liver transplant recipients with recurrent HCV.
Most had moderate-to-severe fibrosis and half had previously been
treated post-transplant. Of the 43 patients with at least four weeks of
post-treatment follow-up, 65% achieved SVR4, though this rose to 93%
for those with extended rapid virological response. However, just 44%
of patients with advanced liver disease achieved SVR4, compared to 71%
of those without. Here too, adverse events were common. One-fifth
experienced serious events requiring hospitalization, 11% discontinued
due to adverse events, 4% experienced liver graft rejection, and 4%
died from liver-related causes.
This article appears in the June 2013 edition of the HCV Advocate newsletter. Part 2 will appear in the July issue of the HCV Advocate.