People on opiate substitution therapy can be successfully treated with grazoprevir/elbasvir (Zepatier), leading to improvements in some aspects of quality of life, according to findings from the C-EDGE CO-STAR study presented at the 2016 International Liver Congress last month in Barcelona. However, the same study saw several cases of hepatitis C virus (HCV) reinfection after a cure, suggesting a greater emphasis on prevention may be warranted.
HCV is easily transmitted through shared drug injection equipment, and current and former injection drug users have high rates of infection. However, some providers and insurers still consider people who inject drugs (PWID) to be poor candidates for hepatitis C treatment and active drug users have been excluded from most trials of direct-acting antiviral agents.
Gregory Dore from the Kirby Institute at the University of New South Wales and colleagues conducted the phase 3 C-EDGE CO-STAR trial to evaluate Merck's HCV NS3/4A protease inhibitor grazoprevir and HCV NS5A inhibitor elbasvir for PWID receiving opioid agonist substitution therapy using methadone or buprenorphine. The grazoprevir/elbasvir co-formulation 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. About three-quarters were men, the median age was 48 years, 20% had liver cirrhosis and 8% had HIV/HCV co-infection. Participants were required to be on stable opioid agonist therapy (mostly methadone) for at least three months. They were randomly assigned to receive either grazoprevir/elbasvir or placebo once daily for 12 weeks, at which point the study was unblinded and placebo recipients were also given active treatment on an open-label basis.
As Prof Dore reported at the 2015 AASLD Liver Meeting last November, the overall sustained virological response rate at 12 weeks post-treatment (SVR12) for people randomised to grazoprevir/elbasvir was 92%, rising to 96% in a modified population that excluded people who discontinued the study for non-treatment-related reasons or became reinfected after HCV clearance. Treatment was generally safe and well tolerated. Urine screens showed that non-prescription drug use continued throughout the study.
In a poster at the EASL meeting Dore's team reported results from an exploratory analysis looking at the impact of hepatitis C treatment on health-related quality of life (HRQoL).
Health-related quality of life was assessed using the SF-36v2 health survey, which participants completed on their own at baseline, at treatment week 4, at the end of treatment at week 12 and at post-treatment follow-up weeks 4 and 12. Researchers looked at eight health domain scores, and individual domain scores were used to calculate physical component summary and mental component summary scores.
Almost all participants (98%) in both the grazoprevir/elbasvir and placebo groups completed the baseline and at least one follow-up HRQoL assessment. At baseline mean HRQoL scores were comparable between the two groups.
During treatment there were no significant mean improvements within each treatment group in the eight health domains or in the physical or mental summary scores during treatment. In general, mean changes in HRQoL score were more favourable in the grazoprevir/elbasvir group than in the placebo group, but there were no significant differences in mean change scores between the groups at treatment week 12.
At post-treatment follow-up week 4, the grazoprevir/elbasvir group saw significant improvements from baseline in two domains – general health and vitality – while the placebo group saw a decline in the mental health domain. Again, mean changes were generally more favourable in the grazoprevir/elbasvir group than in the placebo group, and at this point significant differences in mean change scores were noted, with the grazoprevir/elbasvir group seeing more improvement in general health, vitality, mental health and mental component summary scores.
However, in the final assessment at follow-up week 12, only the general health score showed significant improvement in the grazoprevir/elbasvir group.
The researchers noted that HRQoL scores among participants in this study were lower than those observed in studies of grazoprevir/elbasvir in people with hepatitis C who did not inject drugs. This lower health-related quality of life may be due to the high rates of co-morbidities among CO-STAR participants or to ongoing drug use, they suggested.
The CO-STAR investigators also looked at the incidence of HCV reinfection among study participants who had undetectable HCV RNA at end of treatment.
People with recurrent viremia following the end of treatment underwent viral population sequencing and phylogenetic analysis of the HCV NS3 and NS5A regions in baseline and post-treatment blood samples to distinguish between relapse and reinfection.
Among 296 treated participants with post-treatment HCV viremia, six probable cases of HCV reinfection were identified. Of these, five cases occurred by follow-up week 12 in the randomised grazoprevir/elbasvir group and one more by follow-up week 24 in the placebo-delayed treatment group. The estimated incidence of reinfection from the end of treatment through 24 weeks of follow-up was 8.4 per 100 person years.
"Several HCV reinfection cases were detected among PWID on opiate agonist therapy following successful [grazoprevir/elbasvir] therapy," the researchers wrote in their published study abstract. "Further follow-up is required to determine the natural course of HCV reinfection in the setting of interferon-free HCV treatment, and the impact of viral persistence following reinfection on long-term response rates in this population."
Arduino JM et al. C-EDGE CO-STAR: favorable impact of elbasvir and grazoprevir on health-related quality of life in treatment-naive HCV-infected persons who inject drugs receiving opioid agonist therapy. International Liver Congress, Barcelona, abstract THU-225, 2016.
Dore G et al. C-EDGE CO-STAR: risk of reinfection following successful therapy with elbasvir and grazoprevir in persons who inject drugs (PWID) receiving opioid agonist therapy (OAT). International Liver Congress, Barcelona, abstract SAT-163, 2016.