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Further evidence that interferon-free hepatitis C treatment safe and effective for people who inject drugs

Liz Highleyman
07 September 2016

People with hepatitis C and 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 people who inject drugs 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.


decompensated cirrhosis

The later stage of cirrhosis, during which the liver cannot perform some vital functions and complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.

The phase 3 ION trials, testing Gilead Science's sofosbuvir/ledipasvir co-formulation with 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 enrol. 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 of the 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 people with genotype 1 without cirrhosis.

Participants in ION-1 and ION-2 were randomly assigned to receive the once-daily fixed-dose co-formulation 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 three 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.

The overall SVR12 rate for people on OST was 94%, which fell within the 93 to 99% response range for the three trials as a whole. Treatment for 24 weeks was no better than 12 weeks and adding ribavirin did not improve efficacy, though it was associated with more side-effects.

People on OST were about as likely as other study participants to complete treatment (97% vs 98%, respectively) and to maintain at least 80% adherence (93% vs 92%, respectively).

Treatment was safe and well tolerated for people on OST, with no notable adverse events specific to this group; 4% of people in the OST group experienced serious adverse events, similar to the 3% rate for all trial participants.

After completion of treatment the researchers did not identify any cases of HCV reinfection among participants in the OST group during 24 weeks of follow-up.

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 Dr 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 people with all HCV genotypes except 3, ASTRAL-2 enrolled 266 people with genotype 2 and ASTRAL-3 enrolled 552 people with genotype 3. (ASTRAL-4, which looked at people with decompensated cirrhosis, and ASTRAL-5, which enrolled people with HIV/HCV co-infection, 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 three 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 one person had subtype 1b and none had genotypes 5 or 6.

The overall SVR12 rate for OST users was 96% – similar to the 95 to 99% cure rates seen across all study participants. The cure rate was also 96% for hard-to-treat genotype 3. Of the two participants on OST who did not achieve SVR12, one discontinued treatment after a single dose due to adverse events and one was lost to follow-up after 5 days of treatment.

Here too, the investigators found that OST use did not affect the likelihood of treatment completion (96% in the OST group vs > 99% in the non-OST group) or maintaining at least 90% adherence (90% vs 96%, respectively). However, people on OST with less than 90% adherence did not do as well as those with better adherence (60% vs 100% SVR12).

Again, treatment was safe and well tolerated for people on OST. There were more serious adverse events in the OST group (6% vs 2%), but the difference was not statistically significant.

No cases of HCV reinfection were observed during 24 weeks of post-treatment follow-up.

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 people who inject drugs – 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.


Grebely J 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. 23 August, 2016 (online ahead of print).

Grebely J 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. 23 August, 2016 (online ahead of print).