Grazoprevir/elbasvir hepatitis C treatment works well for people who inject drugs

Liz Highleyman
Published:
14 August 2016

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.

Reference

Dore GJ et al. Elbasvir-Grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Annals of Internal Medicine. 9 August, 2016 (online ahead of print).