Merck's grazoprevir/elbasvir
hepatitis C regimen was well tolerated and cured more than 90% of people who inject drugs receiving opioid substitution therapy, according to results from the
C-EDGE CO-STAR study published in the 9 August online edition of Annals
of Internal Medicine. The investigators reported that adherence was good even though many study participants continued to use
illicit drugs.
Hepatitis C virus (HCV) is easily transmitted through
shared equipment for drug injection, and current and former injection drug
users have high rates of infection. But many providers and insurers still
consider people who inject drugs poor candidates for treatment and active drug
users have been excluded from many trials of the new direct-acting antiviral
agents (DAAs).
Gregory Dore of the Kirby Institute at the University
of New South Wales and colleagues conducted the phase 3 C-EDGE CO-STAR trial to
evaluate the HCV NS3/4A protease inhibitor grazoprevir plus the NS5A inhibitor
elbasvir for injection drug users receiving opioid substitution therapy. This
combination previously demonstrated cure rates
of 90% or better in other populations.
CO-STAR enrolled 301 previously untreated chronic
hepatitis C patients in Australia, Canada, France, Germany, Israel, the
Netherlands, New Zealand, Norway, Spain, Taiwan, the UK and the US.
Three-quarters were men, about 80% were white and the
median age was approximately 48 years. Most (76%) had hard-to-treat HCV subtype
1a, followed by 1b (15%), 4(6%) and 6 (3% or 9 people). About 20% had liver
cirrhosis, 7% had co-infection with HIV and over half had high HCV viral load
at baseline (> 2,000,000 IU/ml).
Entry criteria included stable opioid agonist therapy
(80% methadone, 20% buprenorphine) for at least 3 months and keeping at least
80% of appointments. Nevertheless, nearly 60% tested positive for non-prescribed drug use on
baseline urine screens – including about 20% positive for opioids – but they
were not excluded from the study.
Participants were randomly assigned to receive either
immediate treatment with grazoprevir/elbasvir given as a once-daily fixed-dose
co-formulation (100mg/50mg) or placebo for 12 weeks. At that point the study was
unblended, and after 4 weeks the placebo recipients were also given
grazoprevir/elbasvir on an open-label basis.
The primary endpoint was sustained virological
response, or undetectable HCV RNA at 12 weeks post-treatment (SVR12) – usually
considered a cure. In the primary analysis people who were apparently re-infected
with HCV after initial response were considered treatment failures. Dore previously presented these findings in part at the
2015 AASLD Liver Meeting.
The overall SVR12 rate was 91.5% for people assigned
to immediate treatment with grazoprevir/elbasvir and 89.5% for those who
switched from placebo. Among participants followed through 24 weeks
post-treatment, the overall cure rate (SVR24) was 84.6% in the immediate
treatment arm and 85.3% for those who switched.
SVR12 rates in the immediate treatment arm were similar for people with
HCV genotypes 1a, 1b and 4 (93.5%, 93.3% and 91.7%, respectively), but fell to
20.0% for the small number of people with genotype 6.
In total, at 24 weeks post-treatment, ten people
relapsed, two experienced viral breakthrough, six appeared to have probable HCV
reinfection, 25 were lost to follow-up and two discontinued for other reasons.
The incidence of reinfection was 4.6 per 100
person-years through 24 weeks of post-treatment follow-up. In four cases, patients with reinfection had a different HCV genotype, and in all six cases they had distinct
strains according to phylogenetic analysis. Counting people with probable reinfection
as sustained responders pushed the SVR12 rate in the immediate treatment arm up
to 94.0% overall and 60.0% for genotype 6 (a group with two relapses and two reinfections).
At baseline 43% of people with HCV subtype 1a and
10.3% with 1b had evidence of NS3 resistance-associated variants (RAVs), and
2.0% and 10.3%, respectively, had baseline NS5A RAVs, but these did not affect
treatment response.
Around 96% of people in both the immediate and
delayed treatment arms reported better than 95% adherence. About 60% of
participants used non-prescribed or illicit drugs during the study, falling to
around half if cannabis was excluded. However, illicit drug use at
baseline or during treatment did not affect treatment response or adherence to
therapy.
Grazoprevir/elbasvir was generally safe and well tolerated,
with one person experiencing serious drug-related adverse events and one
discontinuing due to adverse events while on this regimen. Overall adverse
events (82.6% vs 83.0%) and serious adverse events (3.5% vs 4.0%) occurred with
similar frequency in the immediate treatment arm and the placebo phase of the
delayed arm. The most common side-effects in both arms were fatigue, headache, and
nausea.
"Patients with HCV infection who were receiving
[opiate agonist therapy] and treated with elbasvir-grazoprevir had high rates
of SVR12, regardless of on-going drug use," the study authors concluded.
"These results support the removal of drug use as a barrier to
interferon-free HCV treatment for patients receiving [opiate agonist
therapy]."
The researchers cautioned that these findings may not
be generalisable to people who inject drugs who are not receiving opiate agonist
therapy, and they do not apply to individuals with HCV genotype 3, which is
a common strain among people who inject drugs.
They noted in their discussion that high levels of HCV
reinfection might compromise the benefits of treatment from both an individual
patient and a public health perspective. In this study three of the six
people with probable reinfection subsequently cleared HCV RNA without
additional treatment, "indicating that not all reinfection cases develop
viral persistence and drawing attention to the possible role of an augmented
HCV-specific immune response after DAA therapy," they wrote. An ongoing
extension of this study will look at drug use behaviour and the incidence and
outcome of HCV reinfection over a three-year period after treatment.