People
with hepatitis C who did not achieve sustained virological response with a
prior short course of direct-acting antiviral (DAA) therapy had a high
likelihood of being cured if treated again with sofosbuvir/ledipasvir standard
therapy, according to results from the SYNERGY study presented at the 2015
AASLD Liver Meeting earlier this month in San Francisco, USA. A related analysis showed
that emergence of certain drug-resistance mutations was common during very
short therapy, but this did not appear to compromise response to retreatment.
DAAs
used in interferon-free therapy can now cure more than 90% of people with
hepatitis C virus (HCV) genotype 1, but researchers continue to seek regimens
that are easier to use and less expensive. Combining agents that target
multiple steps of the HCV lifecycle can potentially shorten treatment and
reduce the risk of viral rebound and drug resistance.
Treatment using currently
approved hepatitis C therapies is typically indicated for 12 weeks, although 8 weeks works
well for easier-to-treat patients, while more challenging patients may need 24
weeks. A few studies have looked at shorter multi-drug regimens, finding that
6 weeks appears adequate for some people, but most people treated for only 4 weeks do not achieve sustained
virological response at 12 weeks post-treatment (SVR12).
Glossary
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
One such study, the US
National Institutes of Health SYNERGY trial, evaluated a variety of short multi-drug
regimens for people with HCV genotype 1 and early-stage liver fibrosis,
attempting to maximise adherence and treatment completion for an inner city
population with socioeconomic risk factors.
As previously reported, SYNERGY participants were
allocated to six treatment arms, receiving Gilead Sciences' nucleotide HCV NS5B
polymerase inhibitor sofosbuvir plus NS4A inhibitor ledipasvir (the drugs in Harvoni) either alone or in combination
with the investigational HCV protease inhibitor vedroprevir (formerly GS-9451),
the non-nucleoside polymerase inhibitor GS-9669 or both:
- 12 weeks sofosbuvir/ledipasvir (n =
20): 100% SVR12
- 6 weeks sofosbuvir/ledipasvir +
GS-9669 (n = 20): 95% SVR12
- 6 weeks sofosbuvir/ledipasvir +
vedroprevir (n = 20): 100% SVR12
- 6 weeks sofosbuvir/ledipasvir +
vedroprevir (n = 50): 76% SVR12
- 4 weeks sofosbuvir/ledipasvir +
vedroprevir (n = 25): 40% SVR12
- 4 weeks sofosbuvir/ledipasvir +
vedroprevir + GS-9669 (n = 25): 20% SVR12
In the analysis presented at the Liver
Meeting, Eleanor Wilson of the
University of Maryland School of Medicine and colleagues looked at
retreatment options for people who had relapsed in the earlier part of the
study.
"Short-course therapy can reduce cost and
increase access, but strategies are need for retreatment of patients who fail
short-course therapy," Wilson noted as background.
This single-centre phase 2a trial included 34 people
who experienced viral relapse after 4 or 6 weeks of short-course combination
therapy using three or four DAAs. All but one had previously been treated for
only 4 weeks, about half with sofosbuvir/ledipasvir plus GS9451 and half with
all four drugs.
Most participants were male (82%) and African American
(82%), with a median age of about 59 years. Most had absent to moderate liver
fibrosis (stage F0-F2) with one having advanced fibrosis (F3). People with HIV
co-infection were excluded. More than three-quarters had harder-to-treat HCV
subtype 1a. Deep sequencing showed that prior to retreatment 29 people (85%)
had NS4A resistance-associated variants (RAVs) conferring > 25-fold
resistance; just one person had an NS5B RAV conferring very low-level
resistance.
All participants in this open-label trial were
retreated with sofosbuvir/ledipasvir (400/90mg) alone for 12 weeks – the
standard regimen for first-time treatment for people with HCV genotype 1 without
cirrhosis. The median interval was 22 weeks between relapse and restarting
treatment.
A total of 32 participants (94%) completed 12 weeks of
treatment, with the other two withdrawing consent.
The overall SVR12 rate was 91%, with one relapse. The two
people who dropped out were counted as having had treatment failures in the
intention-to-treat analysis, but they later returned for follow-up and had
undetectable HCV viral load. Thus in a per protocol analysis the SVR12 rate
increased to 97%.
The individual who relapsed had the NS5A L31M RAV
comprising > 90% of the viral population before initial treatment, and L31M
and Y93H RAVs making up > 99% of virus after short-course therapy. After the
second relapse, this participant continued to have predominant L31M and Y93H
NS5A RAVs, as well as new minority S282T and V321I NS5B RAVs.
Treatment was generally safe and well-tolerated, with
no deaths and one serious adverse event deemed unrelated to treatment (chest
pain in a person who used cocaine).
Based on these findings, the study authors concluded,
"Retreatment with 12 weeks of
[sofosbuvir/ledipasvir] following initial short-course therapy with a [sofosbuvir/ledipasvir]-based
regimen is highly effective, with >90% achieving SVR12."
Wilson noted that this is the first time a high SVR
rate has been demonstrated following retreatment of people who previously
failed DAA-only therapy, adding that it is "not entirely clear" at
what point short-duration therapy puts people at risk for treatment failure.
In a related SYNERGY
analysis, Sarah Kattakuzhy of the NIH Laboratory of Immunoregulation and colleagues looked in more detail at
the evolution of RAVs conferring resistance to NS5A, NS5B and NS3/4 (though no
one took HCV protease inhibitors in this trial).
They found that 27% of the
33 patients who relapsed after 4 weeks of DAA treatment had NS5A RAVs, only 3%
had NS5B RAVs and 30% had NS3/4 RAVs. After the first viral relapse, these
proportions were 85%, 6% and 33%, respectively – indicating that about 60%
developed new NS5A RAVs during short-course therapy. Most people had only a
single RAV, but a few had as many as four.
Nevertheless, 12-week
treatment with sofosbuvir/ledipasvir was highly effective despite the presence
of RAVs, and NS5A RAVs had no apparent effect on retreatment outcomes.
"Baseline
mutations were a factor in response to ultra-short duration therapy," the
researchers concluded. "Emergent variants persisted over a mean of 22
weeks from the time of viral relapse, and were both maintained and
enriched." However, they continued, "Retreatment outcomes with
standard of care utilizing [sofosbuvir/ledipasvir] were not affected by the presence
of these RAVs."