open access: Nature Reviews: Key Advances in Medicine

GASTROENTEROLOGY & HEPATOLOGY
HEPATITIS C IN 2011
A new standard of care and the race towards
IFN-free therapy
Wolf Peter Hofmann and Stefan Zeuzem
Chronic HCV infection is a leading cause of liver-related morbidity and mortality. In 2011, treatment options for
patients infected with HCV genotype 1 changed dramatically with the approval of two nonstructural protein 3
protease inhibitors—boceprevir and telaprevir—by the FDA and the European Medicines Agency.
Hofmann, W. P. & Zeuzem, S. Nat. Rev. Gastroenterol. Hepatol. 9, 67–68 (2012); published online 20 December 2011; doi:10.1038/nrgastro.2011.249
In phase III clinical trials, the combination
of boceprevir or telaprevir with PEG-
IFN-α–ribavirin has been shown to result
in increased sustained virological response
(SVR) rates compared with PEG-IFN-α–
ribavirin (67–75% and 38–44%, respectively)
in therapy-naive patients. 1,2 As
these new triple therapies also resulted in
increased rapid virological response (RVR;
undetectable levels of HCV RNA at week 4
of triple therapy) rates, response-guided
therapy to shorten the duration of treatment
from 48 weeks to 24–28 weeks is now
possible for a large proportion of patients.
Additional phase III clinical trials showed
that many patients who did not respond
RVR and SVR (%)
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
RVR
SVR
0 –
BMS-790052 +
BMS-650032
BMS-790052 +
BMS-650032 +
PEG-IFN-α–RBV
well to previous PEG-IFN-α–ribavirin
therapies also benefited from re-treatment
with PEG-IFN-α–ribavirin and boceprevir
or telaprevir. 3,4 Patients who had previously
relapsed achieved SVR rates of 69–88%
when re-treated, and previous partial
responders showed SVR rates of 40–59%.
In those who had a previous null response,
SVR rates following re-treatment were still
poor (33% for telaprevir). 4
Despite these encouraging achievements
for patients infected with HCV genotype 1,
the low tolerability, particularly for PEG-
IFN-α, and the emergence of resistant
variants associated with treatment failure
of triple therapies that include boce previr
BMS-790052 +
BMS-650032
PSI-7977 PSI-7977 +
RBV12
or telaprevir are still major drawbacks.
Furthermore, current dosing schedules are
complex and the pill burden is high, which
might result in suboptimal adherence to
treatment. Combination therapies with two
direct-acting antiviral agents (DAAs) that
have different modes of action, and an alloral
IFN-free DAA therapy should overcome
resistance, reduce the incidence of adverse
events and improve treatment adherence.
Different substance classes with anti-HCV
activity include nonstructural protein (NS)
3 protease inhibitors, NS5A inhibitors, and
nucleoside inhibitors and non-nucleoside
inhibitors of the HCV NS5B polymerase.
Results of several trials of DAA combination
PSI-7977 +
RBV12 +
PEG-IFN-α (4)
PSI-7977 +
RBV12 +
PEG-IFN-α (8)
PSI-7977 +
RBV12 +
PEG-IFN-α (12)
Study 1 Study 2 Study 3
Figure 1 | The effectiveness of an all-oral IFN-free therapy for patients with HCV has been demonstrated in some study arms of three recent trials.
Patients in study 1 had HCV genotype 1a or 1b infection and previously a null response to PEG-IFN-α–RBV. 8 These patients received 200 mg of the
protease inhibitor BMS-650032 twice a day plus 60 mg of the NS5A inhibitor BMS-790052 once a day with or without PEG-IFN-α–RBV for 24 weeks.
Patients with viral breakthrough during dual therapy received PEG-IFN-α–RBV and achieved SVR thereafter (not shown). Patients in study 2 all had HCV
genotype 1b and had previously had a null response to PEG-IFN-α–RBV. 9 These patients received 200 mg of the protease inhibitor BMS-650032 twice
a day and 60 mg of the NS5A inhibitor BMS-790052 once a day for 24 weeks. Patients in study 3 had HCV genotypes 2 or 3 and were treatment
naive. 10 These patients all received 400 mg of the nucleoside inhibitor PSI-7977 once a day as monotherapy or with RBV for 12 weeks. Three arms
also received PEG-IFN-α for 4, 8 or 12 weeks. Abbreviations: RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response.
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