At least 95% of newly treated people with genotype 1
hepatitis C and prior non-responders achieved sustained virological
response using a fixed-dose combination of sofosbuvir plus ledipasvir, with or
without ribavirin, according to findings from the LONESTAR study presented at The Liver Meeting 2013,
the 64th annual meeting of the American Association for the Study of Liver
Diseases (AASLD) in Washington, DC. While response rates were high overall, the
two relapsers in the trial were not taking ribavirin.
The advent of direct-acting antiviral
agents has revolutionised treatment of chronic hepatitis C. While these agents
were initially tested as add-ons to interferon-based therapy, many people with
hepatitis C virus (HCV) and their care providers are awaiting all-oral regimens that dispense with
pegylated interferon and its difficult side-effects.
Eric Lawitz of the Texas Liver Institute
reported results from the phase 2 LONESTAR study, which evaluated a fixed-dose
combination pill containing Gilead Sciences' HCV polymerase inhibitor
sofosbuvir (formerly GS-7977) plus the NS5A inhibitor ledipasvir (formerly
GS-5885), taken with or without ribavirin for 8 or 12 weeks.
Glossary
- IL28B
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.
LONESTAR enrolled two cohorts at a single
centre in the United States. Cohort 1 included 60 treatment-naive
individuals (people who had not taken treatment before) who did not have
liver cirrhosis. Cohort 2 included 40 people, about half with
cirrhosis, who did not achieve a cure with the current standard of care:
triple
therapy with the approved HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivo or Incivek) plus pegylated interferon/ribavirin.
Overall, two-thirds of participants were
men, 9% were black and the mean age was 50 years. Most (87%) had
harder-to-treat HCV genotype 1a and only 15% had the favourable IL28B CC gene
variant associated with interferon responsiveness. In Cohort 2, 55% had
cirrhosis at study entry. Just over half (55%) had previously been treated with
boceprevir while 45% had used telaprevir. All experienced prior virological
failure; people who stopped previous therapy due to adverse events were
excluded.
Participants in Cohort 1 were randomly
assigned (1:1:1) to receive the once-daily fixed-dose tablet containing 400mg
sofosbuvir and 90mg ledipasvir either with or without 1000-1200mg/day
weight-based ribavirin for 8 weeks, or without ribavirin for 12 weeks.
Treatment-experienced patients were randomised to receive sofosbuvir/ledipasvir
either with or without ribavirin for 12 weeks.
All participants completed therapy except
for one who withdrew consent. In Cohort 1, 95% of treatment-naive patients
treated with sofosbuvir/ledipasvir for either 8 or 12 weeks achieved sustained
virological response, or continued undetectable HCV RNA at 12 weeks
post-treatment (SVR12). The SVR12 rate was 100% in the 8-week
sofosbuvir/ledipasvir plus ribavirin arm.
In Cohort 2, SVR12 rates were 95% for
sofosbuvir/ledipasvir and 100% for sofosbuvir/ledipasvir plus ribavirin given
for 12 weeks. All patients without cirrhosis achieved sustained response, as did
all but one of the people with cirrhosis (91%).
Response rates for all arms remained the
same at 24 weeks post-treatment (SVR24). These results compared favourably to historical
SVR24 rates of about 70% for people without cirrhosis and 44% for people with cirrhosis
in pivotal trials of boceprevir or telaprevir plus pegylated
interferon/ribavirin.
The 95% response rates reflected three
people who did not achieve SVR12/24. One patient in Cohort 1 who received
sofosbuvir/ledipasvir alone for 8 weeks and one in Cohort 2 who received
sofosbuvir/ledipasvir for 12 weeks experienced viral relapse, while one person
in Cohort 1 who received sofosbuvir/ledipasvir for 12 weeks was lost to
follow-up after reaching SVR8. Both relapsers had HCV genotype 1a. No one who
took ribavirin relapsed.
Seven of the nine people with NS5A
resistance mutations and all 28 people with NS3/4A (protease) resistance
mutations at baseline nevertheless achieved sustained response. One patient had
evidence of the S282T mutation and multiple NS5A resistance mutations at the
time of relapse at week 8. This individual was retreated with
sofosbuvir/ledipasvir plus ribavirin for 24 weeks and went on to achieve SVR12.
Sofosbuvir/ledipasvir was generally safe
and well-tolerated with or without ribavirin. Two people receiving
sofosbuvir/ledipasvir alone and two receiving ribavirin experienced serious
adverse events, but no one discontinued treatment for this reason. Grade 3 to 4
adverse events (0 vs 14%) and grade 3 to 4 laboratory abnormalities (7 vs 14%)
were more common among those taking ribavirin. Anaemia was seen only in the
ribavirin arms (19%).
Asked whether ribavirin is still important, Lawitz said these results
confirm that "for a large proportion of patients we can remove ribavirin
without impacting SVR," and "outside clinical trials, anything we can
do to improve compliance is a benefit".
The phase 3 ION trials are currently
underway, testing sofosbuvir/ledipasvir with or without ribavirin for 8, 12 or
24 weeks in treatment-naive patients with genotype 1 and prior non-responders,
Lawitz noted.
Results from the phase 2 ELECTRON trial, also
reported at the Liver Meeting, showed that Gilead's non-nucleoside polymerase inhibitor
GS-9669 as a third agent instead of ribavirin also led to SVR12 rates of 100%
for difficult-to-treat genotype 1 patients.