The ELECTRON team then proceeded to test sofosbuvir in
people with more difficult-to-treat HCV genotype 1, looking at both
treatment-naive patients and null responders to previous interferon-based
They looked first at the same combination of 400mg
sofosbuvir once-daily plus 1000 to 1200mg ribavirin for 12 weeks.
reported at this year's Conference on Retroviruses and Opportunistic Infections, whilst all
participants saw a rapid decline in HCV RNA and had undetectable viral load at
the end of the 12-week course of treatment, almost all genotype 1 prior null
responders relapsed soon thereafter, resulting in a very low cure rate.
Given that sofosbuvir plus ribavirin as a dual regimen
is not adequate for this more difficult-to-treat patient population,
researchers then asked whether adding a second direct-acting agent could increase
Two additional ELECTRON arms were started to test a
12-week triple regimen of sofosbuvir plus ribavirin plus GS-5885, Gilead's HCV
NS5A replication complex inhibitor, in treatment-naive patients and prior null
responders. In studies to date GS-5885 has shown good activity against
hepatitis C as well as a favourable safety and tolerability profile.
At this week's meeting Gane presented data from the
four ELECTRON genotype 1 arms evaluated to date:
- sofosbuvir + ribavirin for 12 weeks in 25 treatment-naive
- sofosbuvir + ribavirin for 12 weeks in 10 prior null
- sofosbuvir + GS-5885 + ribavirin for 12 weeks in 25 treatment-naive
- sofosbuvir + GS-5885 + ribavirin for 12 weeks in 9
prior null responders.
About 65% of
study participants in the sofosbuvir/ribavirin arms were men; in the triple-therapy arms, only 32%
of treatment-naive patients were men, rising to 78% for prior null responders.
Across all arms most participants (80 to 100%) were white and the average age was
approximately 48 years.
of participants had difficult-to-treat HCV subtype 1a – typical of the
hepatitis C population in Australia, Gane said. None had liver cirrhosis.
Amongst treatment-naive patients assigned to either regimen, about 40% had the
IL28B 'CC' gene variant associated with good interferon response; as expected,
only 20% of null responders in the dual-therapy arm and none in the
triple-therapy arm had this favourable pattern.
regimens were generally safe and well-tolerated. Side-effects were uncommon and
mostly occurred with similar frequency across study arms.
one serious adverse event in the dual-therapy arm and two in the triple-therapy
arm – none of them judged by investigators to be drug-related – and only one
person in the latter group discontinued treatment early for this reason. No
participants had severe grade 4 laboratory abnormalities.
more common (20%) in the treatment-naive triple therapy arm – the only one
with high proportion of women – and about one-third of people in this arm had
unexplained blood in their urine. None of the null responders taking the same
regimen experienced either symptom, however.
Gane concluded that addition of
GS-5885 to sofosbuvir/ribavirin introduced "no additional safety
As seen in
the earlier ELECTRON arms, almost all participants experienced rapid
virological response (RVR), or undetectable HCV viral load by week 4 of
treatment. All patients – including the single individual who did not have RVR
at week 4 – reached HCV RNA below 15 IU/mL at week 12, for an end-of-treatment
response rate of 100% across all arms. No participants experienced viral
breakthrough during treatment.
Outcomes diverged dramatically, however,
after completing therapy. Amongst recipients of sofosbuvir/ribavirin dual
therapy, four treatment-naive people and nine out of ten prior null responders
experienced viral relapse within four weeks, yielding SVR4 rates of 88 and
One additional treatment-naive patient relapsed later, resulting in
12-week sustained virological response (SVR12) rates of 84 and 10%,
respectively. Studies indicate that SVR12 is a very good predictor of SVR24,
and regulatory authorities now consider SVR12 to represent a cure.
In contrast, the three-drug regimen containing GS-5885 continued to
work well. None of the 25 participants in the treatment-naive arm, nor
the three patients who reached this time point in the null-responder arm, had relapsed
by post-treatment week 4, so SVR4 rates remained at 100%. SVR12 rates are
Four weeks after the end of therapy is too soon to determine whether study
participants are truly cured, but these results are promising given that most
relapses in the dual-therapy arm occurred by this point.
Based on these findings, adding GS-5885 appears to prevent
post-treatment relapse amongst people who fully suppress HCV during treatment.
Ribavirin has a similar effect, though it was not adequate for genotype 1
patients in this study.
It will be interesting to see whether a dual regimen of sofosbuvir plus
GS-5885 without ribavirin will produce similar results in difficult-to-treat
patients, as the elimination of ribavirin could reduce side-effects, especially
Another study presented at the AASLD meeting showed that a dual regimen
of sofosbuvir plus a different NS5A inhibitor, Bristol-Myers Squibb's daclatasvir, also demonstrated
high sustained response rates, and the addition of ribavirin did not add to its
efficacy. Gilead indicated this past spring, however, that it would no longer
pursue studies of the sofosbuvir/daclatasvir combination.
In a press release issued to coincide with this
week's meeting, Gilead said it recently initiated a phase 3 trial,
dubbed ION-I, to evaluate a fixed-dose coformulation of sofosbuvir plus
GS-5885, with and without ribavirin, for 12 and 24 weeks duration, in
treatment-naive genotype 1 hepatitis C patients.