Marc Bourlière of Hôpital Saint Joseph in Marseilles, France, reported
findings from a French study of Gilead Sciences' nucleotide HCV polymerase
inhibitor sofosbuvir and NS5A inhibitor ledipasvir given as a once-daily
fixed-dose co-formulation, recently approved and marketed as Harvoni in
Europe and the US.
Participants were randomly assigned to take either sofosbuvir/ledipasvir
plus a ribavirin-like placebo for 24 weeks, or else placebo alone for 12 weeks
followed by sofosbuvir/ledipasvir plus ribavirin for 12 weeks. This enabled
patients treated for either 12 or 24 weeks to finish therapy and follow-up at
the same time, and allowed a direct comparison of adverse events between
sofosbuvir/ledipasvir and placebo. The primary endpoint was sustained
virological response at 12 weeks post-treatment (SVR12), which is considered a
cure.
The study included 155 participants with HCV genotype 1 who did not achieve
SVR after sequential treatment with pegylated interferon/ribavirin followed by
pegylated interferon/ribavirin plus an HCV protease inhibitor (PI).
Three-quarters of participants were men, most were white and the mean age
was 56 years. A majority had harder-to-treat HCV subtype 1a and more than 90%
had unfavourable IL28B gene variants. Compensated cirrhosis was an entry
criterion, but one-quarter had stomach or oesophagus varices (distended veins),
a sign of decompensation. The mean MELD score was 7, indicating a low mortality
risk, but some patients had biomarker levels showing serious liver function
impairment.
With regard to prior treatment, 59% had previously used telaprevir (Incivo
or Incivek), 37% had used boceprevir (Victrelis) and one each had
tried simeprevir (Olysio) and faldaprevir (discontinued). Nearly
three-quarters had NS3/4A protease resistance-associated viral variants at
baseline and 16% had NS5A resistance variants. Participants were stratified
according to whether they had ever achieved undetectable HCV viral load during
previous treatment (relapsers, viral breakthroughs and partial responders) or
not (null responders).
SVR12 rates were 96% for people taking sofosbuvir/ledipasvir plus ribavirin
for 12 weeks and 97% for those taking sofosbuvir/ledipasvir alone for 24 weeks.
All treatment failures were due to relapses, with three in the 12-week arm
and two in the 24-week arm. All relapsers were men with unfavourable IL28B
variants, two of whom had HCV subtype 1a while three had subtype 1b. Four were
prior null responders while the fifth had a prior breakthrough during
treatment.
SVR12 rates were similar for people with or without NS3/4A protease
resistance-associated variants at baseline (96 vs 97%, respectively). However,
the cure rate was a bit lower for people with NS5A resistance-associated
variants at baseline (92 vs 98%, respectively).
Albumin levels increased and ALT and bilirubin levels decreased following
treatment – all signs of improvement – but INR (a measure of blood clotting
ability) remained stable.
Sofosbuvir/ledipasvir was generally safe and well-tolerated. Of the 155
participants, 154 completed treatment and follow-up. The remaining patient
discontinued treatment early due to an adverse event while taking only placebo.
Just one person experienced a serious adverse event considered to be
treatment-related (anaemia).
The most common side-effects were weakness, headache, itching, insomnia,
nausea and fatigue, mostly mild or moderate in severity. Only headache and
fatigue occurred more often in the sofosbuvir/ledipasvir arm compared with
placebo. Four people taking sofosbuvir/ledipasvir plus ribavirin and one taking
sofosbuvir/ledipasvir alone developed moderate or severe anaemia.
"Twelve weeks of [sofosbuvir/ledipasvir] with ribavirin results in high
SVR rates among treatment-experienced patients with cirrhosis who have failed a
prior PI-based regimen," the researchers concluded. SVR12 rates were
similar after 12 weeks of sofosbuvir/ledipasvir with ribavirin compared with 24
weeks of sofosbuvir/ledipasvir alone.
Bourlière explained that there was no 12-week treatment arm without
ribavirin because the aim of the study was to obtain the maximum possible
sustained response rates, and when the study was designed researchers did not
think the shorter duration without ribavirin would be sufficient.
In terms of cost, adding ribavirin for
12 weeks would be substantially less expensive than doubling the duration
of sofosbuvir/ledipasvir to 24 weeks without ribavirin.