POLARIS-1 AND POLARIS-4 evaluated sofosbuvir/velpatasvir/voxilaprevir as 'salvage therapy' for people
who were not previously cured with prior DAA regimens.
Stephan Zeuzem of JW Goethe
University Medical Centre presented results from POLARIS-4, which enrolled 333
people with all HCV genotypes who had previously been treated with DAAs, but
had not used an NS5A inhibitor or an older HCV protease inhibitor plus
Again most were white men with an average age of 57
years. About 30% had HCV genotype 1a, about 13% had 1b, about 19% had genotype
3, 32% had genotype 3, and about 5% had genotype 4; no one had genotypes 5 or
6. Nearly half had cirrhosis and the mean baseline viral load was 6.3 log10
IU/ml. The majority (69%) had previously used sofosbuvir and a quarter had used
an NS5B inhibitor plus an HCV protease inhibitor (including discontinued
genotypes 1-3 were randomly assigned to receive either sofosbuvir/velpatasvir/voxilaprevir or sofosbuvir/velpatasvir for 12
weeks, while everyone with genotype 4 got the triple
SVR12 rates were 97% in
the triple therapy arm and 90% in the dual therapy arm, showing that the
was statistically superior. There was one relapse in the triple therapy
and one viral breakthrough and 14 relapses in the dual therapy arm. Cure
for people with cirrhosis were 96% and 86%, respectively (98% vs 94% for
people without cirrhosis). People with genotype 1b or 2 had high
response rates on both
regimens, but those with genotype 1a (98% vs 89%) and 3 (94% vs 85%) did
on the triple compared to the dual regimen.
Of the 22 patients with
NS5B resistance-associated substitutions at baseline, all achieved SVR12. The
relapser in the triple therapy arm had no treatment-emergent RASs, but 10 of
the 15 people with virological failure in the dual therapy arm developed Y93
Again treatment was
generally well tolerated with no serious drug-related adverse events, and
diarrhoea (20% vs 5%) and nausea (12% vs 8%) were more common with
voxilaprevir. But Prof. Zeuzem stressed that in nearly 90% of cases the diarrhoea
was grade 1 – meaning no more that two soft stools per day – and the rest
were grade 2.
Prof. Zeuzem concluded that sofosbuvir/velpatasvir/voxilaprevir "is a
highly effective salvage therapy for non-NS5A-experienced patients."
Finally, turning to
individuals who had previously used NS5A inhibitors, Marc Bourlière of
Saint Joseph presented findings from POLARIS-1, which compared
sofosbuvir/velpatasvir/voxilaprevir for 12 weeks against a placebo.
The study included 415 people,
again mostly white men, with a mean age of 58 years. In the triple therapy arm
38% had genotype 1a, 17% had 1b, 2% had genotype 2, 30% had genotype 3, 8% had
genotype 4, and about 3% had genotypes 5 or 6. Only people with genotype 1a
(77%) or 1b (20%) were assigned to the placebo arm. 46% in the triple therapy
arm and 34% in the placebo arm had cirrhosis and the mean viral load was 6.3
All participants had
previously received NS5A inhibitors including ledipasvir (51%), daclatasvir (27%),
ombitasvir as part of the AbbVie "3D" regimen (11%) or others (13%).
The SVR12 rate in the triple
therapy arm was 96%, while no one in the placebo arm achieved sustained
response. There was one viral breakthrough in a patient thought to be
non-adherent and six relapses. Cure rates were 96% for genotype 1a, 100%
1b, 2, 5 and 6, 95% for genotype 3, and 91% for genotype 4. Ninety-nine
per cent of people without cirrhosis and 93% of those with cirrhosis
achieved SVR12, and all
relapsers had cirrhosis.
People with and without resistance-associated substitutions at baseline had similar response
rates (96% and 98%); however, those with only NS5A RASs did a bit worse (94%).
None of the relapsers developed treatment-emergent RASs.
Here too, treatment was
generally well tolerated with no serious drug-related adverse events. The
frequency of diarrhoea in the triple therapy arm (18%) was within the range
seen in the other POLARIS trials – but this side-effect was actually more
common in the placebo arm (13%) than in the dual therapy arm of the other
experienced patients, treatment with sofosbuvir/velpatasvir/voxilaprevir for 12
weeks resulted in a 96% SVR rate in difficult-to-cure patients with multiple
unfavourable characteristics," the researchers concluded.
"We now have near 100% cure rate options for all
the patients we come across," Prof. Foster said.
Gilead recently indicated that it plans to request US Food and
Drug Administration approval of the sofosbuvir/velpatasvir/voxilaprevir
co-formulation by the end of 2016.