A throwback regimen of sofosbuvir (Sovaldi),
ribavirin and pegylated interferon taken for 12 weeks cured 93% of people
with hepatitis C virus (HCV) genotype 3 – substantially more than sofosbuvir
plus ribavirin alone taken for 16 or 24 weeks, according to results from the
BOSON study presented on Saturday at the European Association for the Study of the
Liver (EASL) 50th International Liver Congress in Vienna, Austria.
Interferon-containing therapy for three months was described as
"surprisingly well-tolerated".
The advent of direct-acting antiviral agents has brought about a
revolution in treatment for chronic hepatitis C. As direct-acting antivirals (DAAs)
were developed they were first tested in combination with pegylated interferon
and ribavirin, the old standard of care. But researchers soon discovered that
most people could be cured of hepatitis C using all-oral regimens without interferon, which
must be injected and often causes difficult side-effects.
However, people with HCV genotype 3 do not respond as well to available
interferon-free regimens, and those with liver cirrhosis and non-responders to
prior therapy are particularly in need of more effective treatment options.
Glossary
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- 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.
Graham Foster of Queen Mary's University of London and fellow
investigators conducted the BOSON study to explore whether returning to an
interferon-containing regimen could raise cure rates for people with hard-to-treat genotype
2 and 3 HCV.
Prior clinical trials showed that sofosbuvir plus ribavirin taken for 12
weeks cured 82% of people with HCV genotype 2 who had cirrhosis, Foster noted as
background. Among people with genotype 3, this dual combination taken for 24
weeks cured only 68% of people with cirrhosis. These rates fall well below the 95% or
greater sustained response rates that are now expected for people with easier-to-treat HCV.
The phase 3 BOSON trial (GS-US-334-0153) included 592 people – 48
with genotype 2 and 544 with genotype 3 – enrolled in the UK, North
America,
Australia and New Zealand. All participants with genotype 2 were both
treatment-experienced and had compensated cirrhosis. Among the
participants with genotype 3, about half were prior non-responders and
about a third had cirrhosis.
Overall, 67% of participants were men, the mean age was 50 years, most
were white and 13% were Asian. More than two-thirds had unfavourable IL28B gene
variants associated with poor interferon response and the mean baseline HCV
viral load was 6.3 log10.
Participants were randomly assigned to receive extended-duration therapy
with 400mg once-daily sofosbuvir plus 1000-1200mg weight-based ribavirin for
either 16 or 24 weeks, or else sofosbuvir and ribavirin with 180mcg
once-weekly pegylated interferon for 12 weeks. The primary endpoint was
sustained virological response, or HCV RNA below the lower limit of
quantification (<15 IU/ml) at 12 weeks after the end of treatment (SVR12).
Looking first at the hard-to-treat genotype 2 patients, SVR12 rates were
87% for sofosbuvir plus ribavirin for 16 weeks, 100% for the dual regimen for
24 weeks, and 94% for sofosbuvir plus ribavirin with pegylated interferon for
12 weeks.
Turning to the larger group of participants with genotype 3, sustained response
rates were 71% for sofosbuvir plus ribavirin for 16 weeks and 84% for 24 weeks,
but rose to 93% for sofosbuvir plus ribavirin with pegylated interferon – the highest cure rate
observed to date for this challenging population in a phase 3 study.
Within the genotype 3 group, SVR12 rates were 80%, 87% and 95%,
respectively, for people without cirrhosis. The most dramatic improvement in
response was seen for people with cirrhosis: 51% with sofosbuvir and
ribavirin for 16 weeks, 79% for 24 weeks and 88% with interferon. Among
previously untreated patients, SVR12 rates were 77%, 88% and 95%, respectively.
A big improvement was also seen when adding interferon for
treatment-experienced patients: 64%, 80% and 91%, respectively.
Focusing on the patients Foster described as the "toughest of the
tough" – genotype 3 prior non-responders with cirrhosis – the cure rate
rose from just 47% for sofosbuvir plus ribavirin taken for 16 weeks to 86% for the
interferon-containing regimen taken for 12 weeks. All other subgroups had SVR12
rates above 80% using the interferon-free dual regimen for 24 weeks, confirming that this
is the preferred duration for difficult-to-treat patients.
Poor tolerability is a major reason for avoiding interferon, but the
short interferon-containing regimen in this study was "by and
large very well-tolerated," Foster said. The most frequently reported adverse events
across all treatment arms were fatigue, headache, insomnia and nausea. Flu-like
illness and fever were more common with the interferon-containing regimen.
While almost all participants in all treatment arms reported some
adverse events, grade 3-4 (moderate to severe) events were uncommon: 6% with
sofosbuvir plus ribavirin for 16 weeks, 4% with the dual regimen for 24 weeks
and 8% with the interferon-containing regimen for 12 weeks. Serious adverse
events (4%, 5% and 6%, respectively) and treatment discontinuations due to
adverse events (2%, 1% and <1%) were rare and occurred with similar
frequency across treatment arms. Grade 3-4 laboratory abnormalities, however,
were more than twice as common in the interferon-containing arm (15%, 15% and
38%, respectively) owing to anaemia and reduced platelet counts.
The surprisingly good tolerability of pegylated interferon in this study
may be attributable to its short duration, Foster suggested. Before the advent
of direct-acting antivirals, the usual course of pegylated interferon/ribavirin
was 24 weeks for HCV genotypes 2 and 3 or 48 weeks for genotypes 1 and 4.
Based on these results, treatment-experienced people with genotype 2
who had
cirrhosis had "high SVR12 rates with all regimens," while people with
genotype 3 had "higher SVR12 rates with sofosbuvir plus pegylated
interferon/ribavirin than with sofosbuvir plus ribavirin for 16 or 24
weeks," the researchers concluded. They added that all three regimens
were
"well-tolerated with a low rate of treatment discontinuation due to
adverse events."
While most people with hepatitis C and health professionals seek to avoid
interferon-containing therapy in the direct-acting antiviral era, Foster said
that "interferon may still have a role to play" for niche patient
populations.
"I don't think any of us are happy going back to
interferon and ribavirin, but these are patients who can't wait for the next
generation [of antivirals]," he said. "It is an interim solution – I
don't think any of us are pretending this is a prefect long-term option."
Asked about using sofosbuvir/ledipasvir (Harvoni) for this patient population,
Foster explained that ledipasvir "doesn't have much activity" against
HCV genotype 3. Sofosbuvir plus Bristol-Myers Squibb's HCV NS5A inhibitor
daclatasvir (Daklinza) is a potential
interferon-free alternative. Gilead Sciences, which produces sofosbuvir and Harvoni, is also working on a
pangenotypic NS5A inhibitor (GS-5816) with more potent activity against
genotype 3.