The FUSION study enrolled 201 genotype 2
or 3 patients who had previously attempted interferon-based therapy. Again,
most were white men and the mean age was 54 years. About 63% had genotype 3,
one-third had cirrhosis, 30% had IL28B 'CC' and three-quarters were prior
post-treatment relapsers – considered more promising candidates for re-treatment
than prior null responders.
Participants were randomised to receive 400mg
once-daily sofosbuvir plus 1000 to 1200mg/day weight-based ribavirin for either 12
or 16 weeks. They were also compared against an historical control SVR rate of
25% for similar patients using interferon-based therapy.
As in FISSION, viral decline was dramatic
and rapid, with 97 to 98% achieving undetectable viral load at week 4 and 100% at
the end of either 12 or 16 weeks of treatment.
But relapse was common after completing
therapy – usually within
4 weeks, resulting in
SVR12 rates of just 50% for people taking the 12-week oral regimen and 73% for
those treated for 16 weeks.
Again, people with HCV genotype 3 fared
worse. Amongst genotype 2 patients, response rates were high for both the
12-week and 16-week regimens, at 86 and 94%, respectively. Sustained response
rates were much lower for genotype 3 patients – 30 and 62%, respectively – and treatment duration had a greater
In this study, unlike FUSION, cirrhosis
negatively affected response rates for both genotype 2 and 3 patients. Whilst
96 and 100% of non-cirrhotic genotype 2 patients treated for 12 and 16 weeks
achieved SVR12, corresponding rates fell to 60 and 78%, respectively, for
those with cirrhosis. Amongst people with genotype 3, the non-cirrhotic SVR12
rates for 12 and 16 weeks were 37 and 63%, falling to 19 and 61% for
In other words, 12-week treatment cured
37% of genotype 3 non-cirrhotics and 19% of cirrhotics, though the 16-week
regimen worked about the same for both subgroups. For people with genotype 3
overall, longer treatment doubled the response rate, but among cirrhotics, the
rate tripled, Nelson summarised.
Here again, side-effects were common
overall but serious adverse events and discontinuations for this reason were
rare across the board. There were no notable differences in frequency of any
side-effect between the 12-week and 16-week groups, indicating that the extra 4
weeks of therapy had "no significant negative impact".
The investigators concluded that
sofosbuvir plus ribavirin "provided a simple, well tolerated,
interferon-free regimen" for treatment-experienced patients with genotype
2 or 3 HCV infection. Whilst genotype 2 patients had high SVR rates with either
12 or 16 weeks of therapy, extending treatment duration to 16 weeks
"significantly increased SVR rates" in genotype 3 patients, particularly
those with cirrhosis.
Nelson said that he would feel comfortable treating
genotype 2 patients with this regimen for 12 weeks, though he would like more
data for cirrhotics. For those with genotype 3, however, "16 weeks is a
bare minimum", and an ongoing study is looking at whether 24 weeks might
be better. Unfortunately, he added, the data revealed no on-treatment
predictors of which patients are likely to relapse.
The FUSION results were published in the April 23
2013, advance online edition of the New
England Journal of Medicine, released to coincide with the conference. The
same article also described findings from POSITRON, a phase 3 placebo-controlled trial of
sofosbuvir plus ribavirin for genotype 2 or 3 patients who were
"ineligible, intolerant or unwilling" to take interferon. In this
study, SVR12 rates were 93% for patients with genotype 2 and 61% for those
with genotype 3.