Boston—Discontinuation rates with boceprevir (Victrelis, Merck & Co.) and telaprevir (Incivek, Vertex Pharmaceuticals) are much higher in the real-world setting than in the clinical trials that led to the drugs’ approvals. This news comes from two studies presented at The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases.

Researchers say that treatment rates are low because of the complexity of treatment with the direct-acting antivirals (DAA) and concerns about side effects, even at experienced centers. The FDA approved boceprevir and telaprevir for the treatment of patients with hepatitis C virus (HCV) genotype 1 infection in combination with pegylated interferon and ribavirin in 2011.
Fasiha Kanwal, MD, MSHS, associate professor at Baylor College of Medicine, in Houston, who was not involved with the study, said she was not surprised by the high discontinuation rates of these two agents.

“With the addition of the new DAAs, the probability of cure is much higher (approximately 70% in clinical trials) and the duration of treatment may be half as long for some patients, but the side effect burden is significantly greater than the previous standard,” Dr. Kanwal said. “Moreover, participants in the DAA registration trials were generally much healthier than most HCV patients in routine practice, who often have physical or mental comorbidities that may complicate treatment. The fact that rates of treatment-related adverse events and resulting discontinuations are higher in these community-based patients is therefore not surprising.”

High Discontinuation Rates
In one of the studies presented at The Liver Meeting, researchers reviewed the medical charts of all adult HCV patients being treated with DAA triple regimens over a one-year period at the University of Texas Southwestern Medical Center, in Dallas, and a referral center at the University of Miami Health System, in Florida (abstract 133). All patients had at least 12 weeks of follow-up. Researchers excluded patients who were post-transplant, receiving dialysis or co-infected with HIV.

Of the 454 patients at the two centers, only 19% began triple therapy. Reasons for treatment deferral included early disease stage (19%), comorbidities (18%) and advanced liver disease (13%). The overall discontinuation rate of the triple therapy was 21% before week 12. This discontinuation rate was higher than that seen in the trials that led to the telaprevir approval, with the ADVANCE trial showing a 10% discontinuation rate and REALIZE showing a 13% discontinuation rate (Jacobson IM et al. N Engl J Med 2011;364:2405-2416; Zeuzem S et al. N Engl J Med 2011;364:2417-2428). This rate is also higher than the rates seen in the trials that led to boceprevir’s approval, which was roughly 2% in the Sprint-2 trial and 8% and 12% in the two boceprevir arms in the RESPOND-2 trial (Poordad F et al. N Engl J Med 2011;364:1195-1206; Bacon BR et al. N Engl J Med 2011;364:1207-1217).

In a second study, researchers reviewed the records of HCV patients treated with telaprevir-based triple therapy at Mount Sinai Medical Center and Montefiore Medical Center, both in New York City (abstract 1755). Patients had at least 12 weeks of follow-up. Of 157 patients who initiated the triple therapy, 32% discontinued telaprevir prematurely and 21% discontinued treatment due to adverse events. Discontinuation rates were similar in patients with stage F0-F2 and F3-F4 fibrosis. Discontinuation due to adverse events was almost 10% greater than the REALIZE trial that led to telaprevir’s approval (21% vs. 13%; P=0.01).

Dr. Kanwal said that DAAs are effective, and treatment response in clinical practice has been approximately twice as high as seen with pegylated interferon and ribavirin alone.
“Given this, I believe that the message for the clinicians is that these new agents [boceprevir and telaprevir] hold promise, particularly for patients with more advanced fibrosis or cirrhosis, where watchful waiting may not be appropriate. For patients with less advanced fibrosis, waiting for other ‘in-the-pipeline’ antivirals may be a reasonable alternative,” Dr. Kanwal said.
“Treatment decisions in this new era of DAAs may need to be informed with not only the scientific knowledge base of the treating clinician, but also patients’ perceptions of outcome expectancies, risks and benefits associated with the available options and subsequent preferences for treatment,” she added.

Drug–Drug Interactions Overlooked
In another study (abstract 136), researchers found that in the real world, HCV patients frequently use drugs that have the potential to interact with boceprevir and telaprevir. This study was presented at The Liver Meeting by Christina Mayer, PharmD, a postdoctoral research associate at the University of North Carolina at Chapel Hill’s Eshelman School of Pharmacy. Investigators identified adults with chronic HCV infection in a large commercial claims database; drugs with the potential to interact with boceprevir or telaprevir were identified using
Of the 20 most frequently filled prescriptions by 71,584 patients, six had potential for a drug–drug interaction and four had clear indications. For example, 17% of patients were using zolpidem, 14.3% were using tramadol and 11.8% were using alprazolam, all of which have interactions with both boceprevir and telaprevir. Other frequently used drugs that interact with these two DAAs included amlodipine (10.2%), escitalopram (8.1%) and bupropion (7.2%).

Drs. Kanwal and Mayer reported no relevant conflicts of interest.