An 8-week triple combination of Gilead Sciences'
sofosbuvir, velpatasvir and GS-9857 showed a high sustained response rate in a
phase 2 study of people with difficult-to-treat hepatitis C virus (HCV),
including treatment-experienced people with HCV genotype 3 and liver cirrhosis,
according to results presented on Sunday at the 2015 AASLD Liver Meeting in San
Francisco, USA. A 6-week regimen appeared inadequate, however, and
more than 8 weeks may be needed for people who have previously used
Interferon-free direct-acting antiviral (DAA) therapy
has revolutionised treatment for chronic hepatitis C, but there is still room
to optimise therapy for difficult-to-treat patients, enabling them to take
advantage of shorter-duration, ribavirin-sparing regimens like those currently
available for easier-to-treat people. Ideally, such a regimen would be pan-genotypic,
meaning it could be routinely prescribed without the need for genotype testing.
Edward Gane of Auckland Clinical Studies in New Zealand presented
final results from a phase 2 trial (NCT02202980) evaluating a three-drug regimen consisting of the
HCV NS5B polymerase inhibitor sofosbuvir, the pan-genotypic NS5A inhibitor velpatasvir
(formerly GS-5816) and the pan-genotypic NS3/4A protease inhibitor GS-9857.
Combining drugs that attack HCV at three different steps of its lifecycle may improve
efficacy and enable shorter treatment.
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
This study included 157 participants divided into seven
cohorts with various characteristics predicting good or poor treatment response.
All were treated with the triple regimen for 4, 6 or 8 weeks. Sofosbuvir and
velpatasvir were taken as a once-daily fixed-dose co-formulation (400/100mg); GS-9857
(100mg) was also taken once daily.
The easiest-to-treat group – previously untreated people
with HCV genotype 1 and without cirrhosis – were randomly assigned to receive
the combination for 4 or 6 weeks. Treatment-naive people with genotype 1 and
with cirrhosis and people with prior DAA failure (with or without cirrhosis)
were all treated for 6 weeks.
Gane presented results for these first three cohorts at the EASL International Liver Congress earlier this year. Response
rates ranged from 67% to 93% in the 6-week arms, but fell to a dismal 27% in
the 4-week arm.
At the AASLD meeting, Gane presented findings for the
final four cohorts of harder-to-treat patients:
- Genotype 1 pegylated interferon/ribavirin-experienced
with cirrhosis (n = 17)
- Genotype 1 protease inhibitor-experienced with
or without cirrhosis (n = 28)
- Genotype 3 treatment-naive with cirrhosis (n = 18)
- Genotype 3 pegylated interferon/ribavirin-experienced
with cirrhosis (n = 19)
Both genotype 1 cohorts were treated for 8 weeks. The
genotype 3 treatment-naive and treatment-experienced groups received 6 and 8
weeks of therapy, respectively.
In these four cohorts, a majority of participants were
men (56% to 82%), most were white (67% to 95%) and mean ages ranged from 52 to
58 years. A third had the favourable IL28B CC gene
pattern. In the protease inhibitor-experienced cohort 39% had
All participants in all four cohorts completed
treatment with no discontinuations.
The sustained virological response rate at 12
weeks-post-treatment (SVR12) for genotype 1 treatment-experienced patients with
cirrhosis was 100%. The overall SVR12 rate in the genotype 1 protease
inhibitor-experienced cohort was 89%. In this group, people with cirrhosis
uncharacteristically responded better than people without cirrhosis (94% vs
82%), but the numbers were small. All three genotype 1 patients without SVR12
Turning to the genotype 3 cohorts, the SVR12 rate was
83% in the cohort of treatment-naïve people with cirrhosis who were treated for
6 weeks, with two relapses and one withdrawal of consent. In the
treatment-experienced cohort of people with cirrhosis treated for 8 weeks, 100%
Looking more closely at the five participants who
relapsed, there was no consistent pattern of drug resistance-associated
variants (RAVs) at baseline or at the time of relapse. At baseline, three
people had NS3 RAVs (R155K x 2, I170T, V36M, T54S and Q168K) while two had NS5A
RAVs (M28V and L31M). At relapse, two had NS3 RAVs and two had NS5A RAVs. One
relapser had no RAVs at either baseline or relapse. The presence of NS3 RAVs at
baseline appeared to have more influence on treatment response (88% with RAVs
vs 96% without) than baseline NS5A RAVs (90% vs 95%, respectively).
Treatment with the triple regimen was generally safe
and well-tolerated. Only three of the 82 participants in these four cohorts experienced
serious adverse events and no one discontinued treatment for this reason. The
most common side-effects were headache, fatigue, nausea and diarrhoea.
Sofosbuvir/velpatasvir for 8 weeks "resulted in high
SVR12 rates in difficult-to-cure, treatment-experienced populations," the
researchers concluded. "Baseline RAVs reduced SVR rates among
PI-experienced patients" and "treatment-emergent RAVs were uncommon."
The 8-week triple regimen was "very robust" and "looks
highly efficacious" for people with previous pegylated
interferon/ribavirin failure, including people with cirrhosis, Gane said. But for
DAA-experienced people, "I think you have to go beyond 8 weeks," and
future data will tell whether that needs to be 10 or 12 weeks.