An interferon-free combination of the
experimental polymerase inhibitor GS-7977 plus ribavirin potently and rapidly
reduced hepatitis C virus (HCV) levels, but almost all patients experienced
viral rebound after they stopped treatment, researchers reported on 6 March at the 19th Conference on
Retroviruses and Opportunistic Infections in Seattle.
Approval of the
first direct-acting hepatitis C drugs has ushered in a new era of treatment,
but many patients and clinicians eagerly await therapy that does not require
interferon and its difficult side-effects.
(formerly PSI-7977) is a uridine nucleotide analogue HCV polymerase inhibitor
that has demonstrated potent antiviral activity, good safety, and a high
barrier to resistance in early studies. In contrast with the two currently approved
HCV protease inhibitors, GS-7977 can be taken once daily with no food
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
from Auckland City Hospital in New Zealand presented the latest data from the
ELECTRON trial. As reported at the Liver Meeting in Boston last autumn, 100% of
previously untreated patients with easier-to-treat HCV genotypes 2 or 3
virological response (RVR) using a dual combination of GS-7977 plus ribavirin for 12
weeks. All went on to achieve sustained virological response (SVR) at 12 and 24
weeks after the end of treatment, generally regarded as a cure.
promising results, ELECTRON investigators added new study arms to see if people
with more difficult-to-treat HCV genotype 1
– both treatment-naive and prior null responders
– might see similar benefits.
This analysis included 10 genotype 1 null responders
who previously had less than a 2-log reduction in HCV RNA with a prior course
of pegylated interferon plus ribavirin. All were treated with 400mg once-daily
GS-7977 plus 1000 or 1200mg weight-based ribavirin for 12 weeks.
A majority of participants (65%) were men, 90% were
Caucasian and the average age was 48 years. Most had HCV genotype 1a; 20% of
prior null responders and 44% of treatment-naive patients had the favourable
IL28B CC gene pattern.
treatment-naive people and null responders experienced rapid viral suppression,
with all of them reaching undetectable HCV RNA (< 15 IU/mL) by week 4, as was
seen previously in the genotype 2/3 group. All genotype 1 participants maintained
viral suppression at the end of 12 weeks of therapy.
1 null responders followed past the end of treatment, however, results began to
diverge from those of the genotype 2/3 patients. All but one null responder
experienced viral relapse soon after stopping therapy. The sole sustained
responder had a highly favourable profile of response predictors: a young woman
with the IL28B CC pattern and minimal liver fibrosis. (Data for genotype 1
treatment-naive patients will be presented later this year.)
GS-7977/ribavirin combination continued to show good tolerability. There were
no serious adverse events and no premature discontinuations. No viral
breakthroughs occurred while still on treatment, confirming the drug's high
barrier to resistance.
Based on these
findings, the researchers concluded that, in future studies of GS-7977 for genotype
1, prior null responders are likely to require longer treatment duration or
addition of another direct-acting antiviral agent.
"Interferon-free treatment is not a dream", Gane stated at an
accompanying press conference. "It's a reality and I think it will be here within the
next five years."