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Triple Therapy for Chronic Hepatitis C Virus Infection

Adding boceprevir to standard peginterferon and ribavirin therapy dramatically improved sustained virologic response.

Triple therapy with peginterferon, ribavirin, and a direct antiviral agent is considered the next therapeutic regimen for patients with chronic hepatitis C virus (HCV) infection. To evaluate the potential benefit of adding boceprevir — a protease inhibitor that binds to the nonstructural 3 active site of the virus — to standard peginterferon and ribavirin, investigators conducted two industry-sponsored, phase III, randomized, controlled studies involving treatment-naive or treatment-experienced patients with HCV genotype 1 infection. The primary endpoint in both studies was sustained virologic response (SVR; undetectable viral count 24 weeks after completion of therapy).

In the first study, 1097 treatment-naive patients (159 black and 938 nonblack patients) received a 4-week lead-in regimen of standard-of-care (SOC) peginterferon alfa-2b (1.5µg/kg/weekly) and ribavirin (600–1400 mg daily by body weight). Patients were then randomized to receive SOC plus placebo for 44 weeks (SOC group); triple therapy with peginterferon, ribavirin, and boceprevir (800 mg three times daily) for 24 weeks, plus an additional 20 weeks in patients with detectable viral count between weeks 8 and 24 (group 2); or triple therapy for 44 weeks (group 3).

SVR was higher in groups 2 and 3 than in the SOC group in the nonblack cohort (67% and 68%, respectively, vs. 40%; P<0.001 for both comparisons) as well as in the black cohort (42% and 53% vs. 23%; P=0.004 for both). Among nonblack patients in group 2, 47% received shorter-duration triple therapy (28 weeks). Dose reduction because of anemia was required by more triple-therapy recipients than SOC recipients (21% vs. 13%), as was the use of erythropoietin (43% vs. 24%). Rates of dysgeusia were twofold higher in triple-therapy recipients than SOC recipients. Boceprevir resistance-associated variants were found in 17% and 15% of patients in groups 2 and 3, respectively.

In the second study, 403 treatment-experienced patients received SOC during a 4-week lead-in period. Patients were then randomized to receive SOC plus placebo for 44 weeks (SOC group); triple therapy with peginterferon, ribavirin, and boceprevir for 32 weeks, plus an additional 12 weeks in patients with detectable viral count at week 8 (group 2); or triple therapy for 44 weeks (group 3).

SVR was higher in groups 2 and 3 than in the SOC group overall (59% and 66% vs. 21%; P<0.001 for both) as well as in patients with prior relapse (69% and 75% vs. 29%; P<0.001 for both), in patients with prior nonresponse (40% and 52% vs. 7%), and in those with poor response to SOC at week 4 (33% and 34% vs. 0%). Among patients in group 2, 46% were able to receive shorter-duration therapy (36 weeks). Boceprevir resistance-associated variants were noted in 44% of patients without SVR in the triple-therapy groups. Safety data were similar to that in the first study.

Comment: These two companion studies demonstrate the superiority of boceprevir triple-therapy regimens over peginterferon and ribavirin alone, with SVR rates in the >65% range among nonblack treatment-naive patients and those with previous relapse. In addition, the boceprevir regimens consistently achieved SVR rates of approximately 40% to 50% among the more difficult-to-treat patients, such as blacks and previous nonresponders. However, excitement over these impressive results needs to be tempered by the complexity of the regimens, the high rates of anemia requiring erythropoietin use in >40% of patients, and the development of boceprevir resistance-associated variants, especially among treatment-experienced patients. To realize the high SVR rates promised by these new regimens, clinicians will need to develop and implement HCV-treatment programs that will improve compliance, minimize and manage adverse effects, and employ rules for stopping therapy to minimize resistance.

— Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology March 30, 2011

Citation(s):

Poordad F et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011 Mar 31; 364:1195.

• Medline abstract (Free)

Bacon BR et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011 Mar 31; 364:1207.

• Medline abstract (Free)

Jensen DM. A new era of hepatitis C therapy begins. N Engl J Med 2011 Mar 31; 364:1272.

• Medline abstract (Free)

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