HCV Drug Effective in Patients With Drug Addiction

The combination drug elbasvir/grazoprevir (Zepatier, Merck) reduced viral load in patients with chronic hepatitis C virus (HCV) infection being treated for opioid addiction in a randomized controlled trial.

The favorable outcomes, reported by Gregory J. Dore, MBBS, PhD, FRACP, MPH, from the Kirby Institute, University of New South Wales in Sydney, Australia, and colleagues in an article published online August 9 in the Annals of Internal Medicine, suggest the treatment is safe and effective for patients with HCV receiving opioid agonist therapy, a population that has had limited access to treatment despite its high prevalence of HCV infection.

The US Food and Drug Administration approved elbasvir/grazoprevir in January 2016 for chronic HCV genotypes (GTs) 1 and 4 infections, as reported by Medscape Medical News. "These findings should dispel notions that patients with recent histories of drug use can't adhere HCV treatment and can't be cured," according to Arthur Y. Kim, MD, director of Viral Hepatitis Clinic at Massachusetts General Hospital in Boston, who was not involved in the study.

"The opioid problem in our country is a major driver of new HCV infections, but due to restrictive policies, many of these patients have been unable to access these curative medications," Dr. Kim told Medscape Medical News. "Coupling addiction treatment and curative HCV therapies has been predicted to reduce overall transmission and burden of this deadly infection. Now we have evidence that these predictions can come true."

For the current study, investigators with the phase 3 C-EDGE CO-STAR trial evaluated the drug in treatment-naive patients with chronic HCV GT 1, GT 4, or GT 6 who were at least 80% adherent to opioid-agonist therapy visits.

Of 301 patients enrolled in the trial from September 2, 2014, through December 9, 2014, 201 were randomly assigned to an immediate-treatment group that received 12 weeks of once-daily oral treatment with the study drug, and 100 were randomly assigned to deferred treatment, which included 12 weeks of placebo followed by 4 weeks of follow-up, then 12 weeks of open-label therapy with the study drug.

Of the full population, 20.6% of had cirrhosis and 7.0% had HIV coinfection. With respect to opioid-agonist therapy, 79.4% were receiving methadone and 20.3% were receiving buprenorphine at baseline. The researchers conducted both a full analysis of the entire population and a modified analysis, excluding patients who discontinued the trial for reasons unrelated to the treatment and counting patients who had HCV reinfection as treatment successes.

The study's primary efficacy end points were the proportion of patients in the immediate treatment group who achieved a sustained viral response HCV RNA level less than the lower limit of quantitation (<15 IU/mL) at 12 weeks after treatment and safety.

In the immediate-treatment group, 91.5% (95% confidence interval [CI], 86.8% - 95.0%) of patients achieved sustained virologic response at week 12 (SVR12), as did 89.5% (95% CI, 81.5% - 94.8%) of patients in the active phase of the delayed treatment protocol, the authors write.

Among the 17 patients who did not reach the efficacy endpoint, failure was attributed to viral recurrence in 12 patients (seven relapses and five probable reinfections) and to nonvirologic causes in five, including discontinuation resulting from an adverse event (one patient), and an administrative reason (one patient), and loss to follow-up (three patients).

In the modified analysis counting the five patients who had a reinfection as treatment successes, the SVR12 rate was 94.0%, the authors write.

Over the course of 24 weeks, there were two additional relapses, and 12 more patients were lost to follow-up.

In subgroup analyses, high virologic response rates were observed in patients with cirrhosis and those with positive urine drug screens, whereas worse outcomes were observed among patients of Asian ethnicity, the authors report.

When considered by HCV GT, 93.5%, 93.3%, and 91.7% of patients with GT 1a, GT 1b, or GT 4 achieved SVR12 compared with only 20.0% of those with GT 6, although the latter group comprised only five patients.

"In the few patients with [GT 6] infection, the SVR12 rate was much lower than in those with any other GT," the authors observe, noting that the GT 6 strain is found primarily in individuals of Asian descent, which explains the poorer response rates observed in patients of Asian ethnicity.

The treatment was safe and well tolerated, with serious adverse events reported in 3.5% of the immediate treatment group and in 4% of the delayed treatment group. Only one patient in each of the two groups discontinued treatment because of a drug-related adverse event, the authors report.

The most common adverse events included fatigue (15.9% in the immediate treatment group and 20.0% in the delayed treatment group), headache (12.4% and 13.0%), and nausea (10.9% and 9.0%).

Treatment adherence, a major concern in patients who use drugs, was excellent, "despite ongoing drug use among most participants," the authors report, with 96.5% of patients in the immediate treatment group and 95.8% of patients in the active phase of the delayed treatment protocol achieving adherence greater than 95%.

The adherence rates were similar to those observed in other trials of interferon-free direct-acting antiviral therapies in the general HCV population that excluded drug-using patients, the authors write. Further, drug use did not appear to compromise the efficacy of the therapy, suggesting "access to interferon-free [direct-acting antiviral] therapy should be expanded to patients receiving [opioid agonist treatment], including the removal of drug use–based restrictions, providing further support for international guidelines," they state.

The study findings may not be generalizable to the broader drug using population, "most of whom are not in addiction treatment programs," the authors explain. "The generalizability is also limited regarding GTs other than GT1 and GT4." Additional studies of interferon-free direct-acting antiviral treatment are warranted in patients with GT2, GT3, GT5, and GT6 infections, they write.

The incidence of HCV reinfection after successful treatment in high-risk populations (six cases of early posttreatment reinfections in this study) "might compromise benefit from both the individual patient and public health perspectives," the authors write.

Of the six reinfections observed, four patients tested positive for opioids during follow-up, suggesting injection drug use was the probable source of reinfection, according to the authors. Drug use behaviors and HCV reinfection will be evaluated in the ongoing extension of this study, they note.

The study was supported by Merck. The study authors disclosed financial relationships with Merck, Gilead, AbbVie, Bristol-Myers Squibb, and Janssen. Dr. Kim previously served on the advisory boards of AbbVie and Bristol-Myers Squibb.