A co-formulation of Gilead
Science's sofosbuvir and its investigational hepatitis C virus (HCV) NS5A
inhibitor velpatasvir taken for 12 weeks produced sustained virological
response in 95 to 99% of participants across HCV genotypes and led to
improvements in patient-reported outcomes, according to a pair of studies
presented at the 2016 Digestive Disease Week (DDW) meeting this week in San Diego.
Interferon-free therapy using direct-acting antivirals
has revolutionised treatment for chronic hepatitis C, but researchers continue
to try to optimise therapy, especially for difficult-to-treat patients. An
ideal regimen would not require ribavirin and would be pangenotypic, or active
against all HCV genotypes.
The phase 3 ASTRAL studies evaluated
sofosbuvir/velpatasvir in chronic hepatitis C patients with various HCV
genotypes.
ASTRAL-1 enrolled
740 patients with any genotype except 3. Just over half had genotype 1
(including a third with harder-to-treat subtype 1a), 17% had genotype 2, 19%
had genotype 4 and 13% had genotype 5 or 6. About 60% were men, about 80% were
white and the median age was about 54 years. A third were treatment-experienced,
19% had liver cirrhosis, and 16% had a history of
depression. Participants were randomly assigned to
receive sofosbuvir/velpatasvir or placebo for 12 weeks.
ASTRAL-2 enrolled 240 patients with HCV genotype 2. About 60% were men, 90% were
white and the median age was 57 years; 15% were treatment-experienced and 14%
had cirrhosis. Participants in this open-label study were assigned to receive
sofosbuvir/velpatasvir or sofosbuvir plus ribavirin for 12 weeks.
ASTRAL-3 enrolled 552 genotype
3 patients. Just over 60% were men, most were white and the median age was 50
years. About a quarter were treatment-experienced and 30% had cirrhosis.
Participants were randomised to receive either sofosbuvir/velpatasvir for 12
weeks or sofosbuvir plus ribavirin for 24 weeks.
Researchers presented efficacy
results from these studies at the 2015 AASLD Liver Meeting this past November.
Overall, 99% of patients in ASTRAL-1 achieved
sustained virological response, or continued undetectable viral load at 12
weeks after completion of treatment (SVR12). In
ASTRAL-2 the SVR12 rates were 99% in the sofosbuvir/velpatasvir arm and 94% in
the sofosbuvir plus ribavirin arm. SVR12 rates in ASTRAL-3 were 95% using
sofosbuvir/velpatasvir, but only 80% using sofosbuvir plus ribavirin.
Sofosbuvir/velpatasvir cure rates
were similar for previously untreated and treatment-experienced patients, and
for people with and without liver cirrhosis. Sofosbuvir/velpatasvir was generally
safe and well tolerated, with few serious adverse events or treatment
discontinuations.
At DDW 2016 Zobair Younossi of Inova
Fairfax Hospital presented additional findings on patient-reported outcomes
during and after completion of treatment in these studies.
Patient-reported outcomes were assessed using four
instruments: the 36-item Short Form Health Survey (SF-36), the FACIT fatigue
scale (FACIT-F), the Chronic Liver
Disease Questionnaire for hepatitis C (CLDQ-HCV) and the Work Productivity and Activity Impairment
questionnaire (WPAI:SHP). Testing was done at
baseline, during treatment and at up to 24 weeks of follow-up.
In ASTRAL-1 all patient-reported
outcomes were similar at baseline across treatment
arms. Patient-reported outcome scores
improved shortly after starting treatment with sofosbuvir/velpatasvir.
General health, emotional wellbeing and
all five CLDQ-HCV domains improved significantly by treatment week 4;
improvements "became even more prominent" during the remainder of
therapy, and outcomes continued to improve after completing treatment, the
researchers reported.
In the placebo arm, in contrast, patient-reported
outcome scores did not change – or in some cases
moderately decreased – during treatment.
After adjusting for sex, history of
psychiatric disorders, type 2 diabetes, cirrhosis and treatment history, using sofosbuvir/velpatasvir was independently associated with greater improvement in
most patient-reported outcomes. Achieving
SVR was also independently associated with improvement after treatment.
In ASTRAL-2 and ASTRAL-3 some patients
were randomised to receive ribavirin, which can cause more adverse events than direct-acting
antivirals and may have a detrimental effect on quality of life.
In these studies combined,
patients taking sofosbuvir/velpatasvir
saw significant improvements in 12 out of 23 patient-reported outcome domains by treatment week 4. Again, improvements
continued with further treatment.
In the groups taking sofosbuvir
plus ribavirin, about a quarter of patient-reported
outcomes improved, while the rest worsened. In a
multivariate analysis, using sofosbuvir/velpatasvir rather than sofosbuvir plus ribavirin was independently
associated with about a 3 to 10 point advantage in outcome scores at different time points during treatment.
However, after about a month on
treatment there were no remaining decrements in the sofosbuvir plus ribavirin
arms, and participants showed significant patient-reported
outcome improvements regardless of regimen –
especially those who achieved sustained response.
"The pangenotypic regimen
with a sofosbuvir/velpatasvir
fixed-dose combination has not only excellent efficacy but also a significantly
positive impact on patients’ experience during treatment and after achieving
sustained virologic response," Dr Younossi's team concluded.