Interferon-Free Hepatitis C Treatment Safe and Effective for People Who Inject Drugs

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Chronic hepatitis C patients on opioid substitution therapy, including those who continue to use illicit drugs, maintained good adherence and had high sustained response rates when treated with sofosbuvir/ledipasvir (Harvoni) or sofosbuvir/velpatasvir (Epclusa), according to a pair of ad-hoc analyses published in the August online edition of Clinical Infectious Diseases.

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 have considered people who inject drugs to be poor candidates for treatment. Active drug users have typically been excluded from clinical trials of hepatitis C therapies, but some studies of the newest direct-acting antiviral agents have enrolled people using opioid substitution therapy (OST) to manage their addiction.

As recently reported, the Phase 3 C-EDGE CO-STAR trial, which was specifically designed for injection drug users on OST, found that Merck's grazoprevir/elbasvir (Zepatier) combination was well-tolerated and cured more than 90% of study participants with HCV genotype 1, 4, and 6.

The Phase 3 ION trials, testing Gilead Science's sofosbuvir/ledipasvir coformulation without or without ribavirin, and the ASTRAL trials evaluating the newer sofosbuvir/velpatasvir combination, were not specific to people who inject drugs, but people with a history of drug use on OST were allowed to enroll. However, people with clinically significant active drug use during the past year and those with positive urine tests for non-prescribed drugs at study screening were not eligible.

ION Trials

As described in the first analysis, Jason Grebely fromthe Kirby Institute at the University of New South Wales and colleagues performed an ad-hoc (unplanned in the trial design) pooled analysis of Gilead's ION trials to evaluate the impact of OST and ongoing drug use during treatment on completion of therapy, adherence, safety, and sustained virological response at 12 weeks post-treatment (SVR12).

As previously reported, ION-1 enrolled 865 previously untreated people with HCV genotype 1 with or without liver cirrhosis, ION-2 enrolled 440 genotype 1 prior non-responders with or without cirrhosis, and ION-3 enrolled 647 treatment-naive non-cirrhotic genotype 1 patients.

Participants in ION-1 and ION-2 were randomly assigned to receive the once-daily fixed-dose coformulation of sofosbuvir/ledipasvir for 12 or 24 weeks with or without ribavirin, while those in ION-3 were treated for 12 weeks without ribavirin or 8 weeks with or without ribavirin.

Of the 1952 participants in the 3 trials combined, a total of 70 (4%) were receiving OST using methadone or buprenorphine. Just over two-thirds were men, 90% were white, and the mean age was 47 years. Most (89%) were previously untreated and 10% had cirrhosis.

Results

Stored samples from the ION-1 trial were retrospectively tested for illicit drugs. Nearly a quarter of trial participants (23%) -- and not only those on OST -- were found to have used illicit drugs while being treated for hepatitis C (15% cannabis alone; 8% other drugs). There were no differences in treatment completion, adherence, sustained response, or adverse events between people who did and did not use illicit drugs during treatment.

ASTRAL Trials

A brief report in the same journal described a similar pooled analysis of the ASTRAL trials, also led by Grebely.

Unlike ledipasvir, which is active against HCV genotypes 1, 4, 5, and 6, velpatasvir is also effective against genotypes 2 and 3. Genotype 3, which is common among people who inject drugs, is considered the hardest type to treat with direct-acting antivirals.

As previously reported, ASTRAL-1 enrolled 740 hepatitis C patients with all HCV genotypes except 3, ASTRAL-2 enrolled 266 people with genotype 2, and ASTRAL-3 enrolled 552 genotype 3 patients. (ASTRAL-4, which looked at patients with decompensated cirrhosis, and ASTRAL-5, which enrolled HIV/HCV coinfected patients, were not included in this pooled analysis.)

Participants in ASTRAL-1 were randomly assigned to receive the once-daily fixed-dose sofosbuvir/velpatasvir combination or placebo for 12 weeks, ASTRAL-2 participants received sofosbuvir/velpatasvir or sofosbuvir plus ribavirin for 12 weeks, and ASTRAL-3 participants received sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus ribavirin for 24 weeks.

Among the 1035 participants treated with sofosbuvir/velpatasvir in the 3 trials, 51 (5%) were on OST using methadone or buprenorphine. Three-quarters were men, the mean age was 49 years, 22% were treatment-experienced, and 25% had cirrhosis. Nearly half (47%) had HCV genotype 3, followed by 1a (24%), 2 (16%), and 4 (12%); just 1 patient had subtype 1b and none had genotypes 5 or 6.

Results

In both of these analyses, the study authors concluded that OST during hepatitis C therapy -- and illicit drug use in the ION trials -- "did not impact treatment completion, adherence, SVR12, or safety."

These findings add to the evidence supporting treatment for injection drug users -- a population with the highest burden of hepatitis C.  

However, the researchers noted, these trials enrolled selected cohorts of people on stable OST with recent illicit drug use excluded, and therefore may not be representative of all people who inject drugs.

9/3/16

References

J Grebely, S Mauss, A Brown, et al. Efficacy and safety of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic HCV genotype 1 infection receiving opioid substitution therapy: Analysis of Phase 3 ION trials. Clinical Infectious Diseases. August 23, 2016 (online ahead of print).

J Grebely, GJ Dore, S Zeuzem, et al. Efficacy and safety of sofosbuvir/velpatasvir in patients with chronic hepatitis C virus infection receiving opioid substitution therapy: Analysis of Phase 3 ASTRAL trials. Clinical Infectious Diseases. August 23, 2016 (online ahead of print).