Merck's grazoprevir/elbasvir coformulation cured hepatitis C infection in 92% of injecting drug users
receiving opioid substitution therapy in the C-EDGE CO-STAR study, according to
a presentation on Sunday at the 2015 AASLD Liver Meeting in San Francisco. Participants maintained good adherence and had a
high cure rate even though many continued to use illicit drugs.
Hepatitis C virus (HCV) is easily transmitted through
sharing drug injection equipment, and current and former injecting drug users
have high rates of infection (50% to 80% in some studies). But many providers
and insurers still consider people who inject drugs (PWID) to be poor
candidates for treatment and active drug users have been excluded from most
trials of new direct-acting antiviral agents.
Gregory Dore of the Kirby Institute at the University
of New South Wales presented findings from the phase 3 C-EDGE CO-STAR trial, which
evaluated Merck's HCV NS3/4A protease inhibitor grazoprevir and HCV NS5A
inhibitor elbasvir in PWID receiving opioid agonist therapy using methadone or buprenorphine. This combination has
previously demonstrated cure rates of 90% or better in non-PWID populations.
CO-STAR enrolled 301 previously untreated people with
HCV genotypes 1, 4 or 6 (including 76% with hard-to-treat HCV subtype 1a).
About three-quarters were men, about 80% were white and the median age was 48
years. About one in five had liver
cirrhosis and 7% were co-infected with HIV. Just over half had high HCV viral
load at baseline (> 2,000,000 IU/ml).
Participants were required to be on stable opioid
agonist therapy (mostly methadone) for at least three months and to have
consistently kept at least 80% of their appointments. Urine screens were
done to test for non-prescribed drug use – with nearly 60% testing
positive at study
entry – but people were not excluded or removed from the study on this
Participants were randomly assigned (2:1) to receive either
immediate treatment with grazoprevir/elbasvir as a once-daily fixed-dose co-formulation
(100mg/50mg) or placebo for 12 weeks. At that point the study was unblinded and
placebo recipients were also given active treatment on an open-label basis.
The researchers looked at
both a full analysis population that included all participants, and a modified
population that excluded people who discontinued the study for
non-treatment-related reasons (such as loss to follow-up) or who became reinfected
with a different viral type after HCV clearance. The primary study endpoint was
sustained virological response, or continued undetectable viral load at 12
weeks post-treatment (SVR12), in the modified population.
The overall SVR12 rate for people who received
immediate treatment in the full analysis population was 91.5%, rising to 95.5%
in the modified population. Overall, seven patients relapsed, five were reinfected,
two discontinued for treatment-related reasons and three did so for other
reasons or were lost to follow-up.
SVR12 rates were similar for people with HCV genotypes 1a, 1b and 4 (96.1%,
96.6% and 100%, respectively, in the modified population). Only five people had
genotype 6, of whom two relapsed and two were re-infected, giving SVR12 rates
of 20% for the full population or 60% for the modified population. Dr Dore
cautioned that this subgroup was too small to draw definitive conclusions.
The SVR12 rate was the same for people who had
positive urine drug screens and those who had consistently negative screens
(95.5% and 95.4%, respectively).
Response rates were also similar for men and women,
for people over or under age 50, for people with high or low baseline viral
load, and for participants with or without cirrhosis.
Use of illicit drugs during hepatitis C treatment was
common, and the proportion of people who had positive urine drug screens
remained stable during the 12 weeks of therapy. About 60% used any drugs
(including cannabis, opiates, benzodiazepines, cocaine, amphetamines, barbiturates,
phencyclidine or propoxyphene), falling to under half if cannabis was excluded.
Almost all participants completed therapy and
adherence was good, with most people taking all their treatment doses. Everyone
taking grazoprevir/elbasvir achieved over 80% adherence (> 67 doses) and 96.5%
achieved over 95% adherence (> 79 doses).
Grazoprevir/elbasvir was generally safe and
well-tolerated. Overall adverse events (83%) and serious adverse events (4%)
occurred equally often in the immediate treatment and placebo groups. Two
people in each arm discontinued due to adverse events. The most common side-effects in both groups were fatigue, headache,
nausea and diarrhoea.
Based on these findings the researchers
concluded that grazoprevir/elbasvir "demonstrated high efficacy
in genotype 1 and 4-infected patients receiving opiate agonist therapy."
The sustained response rates and adherence levels seen
in C-EDGE CO-STAR compare favourably to those of people who were not injecting
drug users in the C-EDGE Treatment-naive and C-EDGE Treatment-experienced studies.
"The safety and high efficacy convincingly
demonstrate the benefits of treating HCV within this population," said Dr
Dore. "Such evidence should enhance access to new HCV therapies, including
removal of restrictions to access in many settings based on illicit drug use.
This study offers reassurance to providers who are concerned that patients who
actively use illicit drugs will not be adherent to their chronic HCV
Dr Dore noted that the CO-STAR study has been extended
to follow participants for two years to evaluate longer-term outcomes. He said Kirby
Institute researchers are looking at drug injection networks to further
understand and try to prevent HCV reinfection.