all-oral dual regimen of sofosbuvir (GS-7977) plus full-dose ribavirin was
well-tolerated and produced four-week post-treatment sustained response in
approximately three-quarters of previously untreated genotype 1 chronic
hepatitis C patients in an inner-city pilot study, researchers reported at The Liver Meeting 2012, the
recent 63rd Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD) in Boston. Reducing the ribavirin dose, however,
lowered response rates.
advent of direct-acting antiviral agents that target different steps of the
hepatitis C virus lifecycle has brought about a new era of treatment. The first
such drugs must be used with pegylated interferon and ribavirin, but several
all-oral regimens now being evaluated offer the hope of a cure for people who
cannot tolerate or are reluctant to face the difficult side-effects of
controlled clinical trials do not enrol the most difficult-to-treat patients –
considering biological, demographic and socioeconomic factors –
and as such their results may look better than those seen in 'real-world'
described in a late-breaker presentation by Anu Osinusi from the US National Institute of Allergy and Infectious
Diseases, investigators with the SPARE trial tested a two-drug interferon-free
regimen of sofosbuvir plus ribavirin for difficult-to-treat patients.
Gilead Sciences' sofosbuvir (formerly GS-7977) is a
once-daily nucleotide analogue HCV polymerase inhibitor. Early data from the
ELECTRON trial showed that sofosbuvir plus 1000 to 1200mg/day weight-adjusted
ribavirin for 12 weeks produced 100% sustained virological response (SVR) at 24
weeks post-treatment for previously untreated people with easier-to-treat HCV
genotypes 2 or 3. The SVR rate fell to 60%, however, when the ribavirin dose
was reduced to 800mg/day. The response rate was also lower (68%) for
treatment-experienced genotype 2/3 patients.
1 patients receiving sofosbuvir plus ribavirin experienced an initial rapid
decline in HCV RNA and had undetectable viral load at the end of 12 weeks of
treatment, but almost
all prior null responders relapsed soon thereafter. The ELECTRON
trial went on to test sofosbuvir plus ribavirin with a third drug, Gilead's HCV
NS5A inhibitor GS-5885, in genotype 1 treatment-naive patients and prior null
responders. Results from this analysis were also
presented at the Liver Meeting, as were findings
from a study testing a promising 12-week dual regimen of
sofosbuvir plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir.
SPARE team looked at people who were previously untreated and mostly did not
have advanced liver disease, but otherwise had characteristics associated with
analysis included 60 people in
Washington, DC, where the HCV prevalence rate is estimated at about 1.8%. About
85% of participants were African-American, a group that responds poorly
to interferon. Recent research has attributed this to a lower frequency of the
favourable IL28B 'CC' gene pattern associated with interferon responsiveness.
Approximately 80% of SPARE participants had the unfavourable 'CT' or 'TT'
patterns. About half were obese and roughly one-quarter had advanced fibrosis.
at virus characteristics, 70% of participants had HCV subtype 1a, which is
harder to treat than subtype 1b. About 60% had high baseline viral load
the first part of the study, ten participants received 400mg once-daily
sofosbuvir plus 1000 to 1200mg/day ribavirin for 24 weeks. In the second part, 50
people were assigned to receive the same dose of sofosbuvir plus either the
standard 1000 to 1200mg/day full dose or a 600mg/day reduced dose of ribavirin,
both also for 24 weeks.
Among the ten participants in part 1, 90% – all
but a single participant who dropped out at week 3 – had HCV RNA below the lower
limit of quantitation at weeks 4, 12 and 24 weeks, and sustained response at 4
and 12 weeks post-treatment in an intent-to-treat analysis (100% in a modified
part 2, among full-dose ribavirin recipients, 96% – again, all but one participant
– had viral load below the lower limit at weeks 4, 12 and 24 of treatment in an intent-to-treat analysis. Some
patients relapsed after the end of therapy, however, yielding a 4-week
sustained response rate of 72% (75% in a modified intent-to-treat analysis).
who received the lower ribavirin dose also had a 96% early response rate at
week 4. Three people dropped out by week 8. The response rate was 88% at weeks
12 and 24 of treatment, but fell to 56% by 4 weeks post-treatment (64% in a
modified intent-to-treat analysis).
was not independently predicted by baseline factors including high viral load,
IL28B gene pattern, being African-American, obesity, extent of fibrosis or –
despite the lower 4-week SVR rate in the latter group –
by high versus low ribavirin dose.
clearance was associated with rapid normalisation of alanine aminotransferase
(ALT) levels. Comparison of pre- and post-treatment liver biopsies showed that
participants experienced 'significant improvement' in liver inflammation with
treatment according to histological activity index scores.
dose regimens were generally safe and well tolerated. Most side-effects were
reported by fewer than 5% of participants and there were no severe (grade 4)
adverse events or early discontinuations for this reason. However, elevated
bilirubin (11 vs 4%) and anaemia (20 vs 4%) were more common in the full-dose
compared with the low-dose ribavirin arm.
"In this inner-city population of HCV genotype
1 subjects, an interferon-free regimen of [sofosbuvir] with ribavirin was well
tolerated and effective in achieving sustained virological response," the
Whilst these findings were generally well received,
other data presented later at the meeting raised concerns. Although the effect
of lowering the dose of ribavirin did not reach statistical significance in the
SPARE study, most other research indicates that it plays an important role in
Based on the ELECTRON findings, SVR at week 4
post-treatment is too soon to declare patients cured. In that study almost all
genotype 1 prior null responders relapsed, but so did some treatment-naive
participants. Although Osinusi emphasised that the SPARE and ELECTRON
populations were too different to allow direct comparison of response rates, it
appears that adding a third oral drug – or perhaps a dual combination of direct-acting
antivirals without ribavirin –
could offer better efficacy for genotype 1 patients without necessarily
reducing tolerability to an unacceptable degree.