Laurie Barclay, MD
June 22, 2011 — Telaprevir added to peginterferon–ribavirin significantly improves rates of sustained virologic response in previously untreated patients with hepatitis C virus (HCV) genotype 1 infection and in those who require retreatment, according to the results of 2 randomized controlled trials reported in the June 23 issue of the New England Journal of Medicine. Most patients received only 24 weeks of therapy.
Medscape Medical News previously reported that the US Food and Drug Administration (FDA) had approved telaprevir, in combination with peginterferon alfa and ribavirin, to treat chronic HCV genotype 1 infection in patients at least 18 years old with compensated liver disease, including cirrhosis, who are previously untreated or who have been previously treated with interferon-based treatment.
Study 1: ADVANCE Study
"In phase 2 trials, telaprevir, [an HCV] genotype 1 protease inhibitor, in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients," write Ira M. Jacobson, MD, from the Weill Cornell Medical College and Center for the Study of Hepatitis C, New York, NY, and colleagues from the ADVANCE Study, an international, phase 3, randomized, double-blind, placebo-controlled trial.
Participants (n = 1088) with previously untreated HCV genotype 1 infection were randomly assigned to 1 of 3 treatment groups. The T12PR group received 12 weeks of telaprevir combined with peginterferon alfa-2a and ribavirin, followed by 12 weeks of peginterferon–ribavirin alone if HCV RNA level was undetectable at weeks 4 and 12 or by 36 weeks of peginterferon–ribavirin if HCV RNA level was detectable at either week 4 or 12.
The T8PR group received 8 weeks of telaprevir with peginterferon–ribavirin and 4 weeks of placebo with peginterferon–ribavirin, followed by 12 or 36 weeks of peginterferon–ribavirin according to the same HCV RNA criteria. The PR group received placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks of peginterferon–ribavirin. The main study outcome was the proportion of patients with sustained virologic response, defined as undetectable plasma HCV RNA levels 24 weeks after the last planned dose of study treatment.
Compared with the PR group, the T12PR and T8PR groups had significantly more patients with a sustained virologic response (75% and 69%, respectively, vs 44%; P < .001 for the T12PR or T8PR group vs the PR group). More than half (58%) of patients receiving telaprevir were eligible to receive 24 weeks of total treatment.
Compared with patients receiving peginterferon–ribavirin alone, those receiving telaprevir had higher rates of anemia, gastrointestinal tract adverse effects, and skin rashes. Overall rate of discontinuation of the study drugs because of adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.
"Telaprevir with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients," the study authors write.
Study 2: REALIZE Study
The REALIZE Study was a randomized, phase 3 trial led by Stefan Zeuzem, MD, from Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. The investigators examined the effects of adding telaprevir to peginterferon alfa-2a plus ribavirin in 663 patients with HCV genotype 1 infection who had no response or only a partial response to previous treatment, or who experienced a relapse after initially responding to treatment.
Participants were randomly assigned to the T12PR48 group (n = 266; telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks), the lead-in T12PR48 group (n = 264; 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks), or the control group (n = 132; PR48; peginterferon plus ribavirin for 48 weeks. The rate of sustained virologic response, defined as no detectable HCV RNA levels 24 weeks after the last planned dose of a study medication, was the main study outcome.
Among patients who had a previous relapse, the 2 telaprevir groups had significantly higher rates of sustained virologic response than the control group (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group). Among patients who had a previous partial response, rates were 59%, 54%, and 15%, respectively, and among patients who previously had no response, rates were 29%, 33%, and 5%, respectively (P < .001 for all comparisons). The telaprevir groups had more frequent grade 3 adverse events than the control group (37% vs 22%), and these events were mostly anemia, neutropenia, and leukopenia.
"Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase," the study authors write.
Clinical Practice Article
An accompanying Clinical Practice article, by Hugo R. Rosen, MD, at the Division of Gastroenterology and Hepatology, University of Colorado in Denver, discusses management of chronic HCV infection. He notes that liver biopsy remains the standard for assessment of hepatic fibrosis and facilitates prognostication and decision making.
Treatment goals are to prevent complications and death from HCV infection. Symptomatic extrahepatic HCV, such as cryoglobulinemia, is an indication for therapy regardless of the stage of fibrosis. On the basis of considerable evidence from randomized trials during the past decade, pegylated interferon (peginterferon) plus ribavirin became the standard of care for all HCV genotypes.
The protease inhibitors telaprevir and boceprevir were recently approved by the FDA. On-treatment viral kinetics can be used to predict the likelihood of response and to guide treatment duration.
"Although peginterferon–ribavirin is likely to remain the backbone of antiviral therapy for the foreseeable future, options for treating HCV are expected to expand rapidly in upcoming years," Dr. Rosen writes. "The optimal combination of agents (including nucleoside and nonnucleoside polymerase inhibitors, inhibitors of NS4B and NS5A proteases, modulators of the immune response, and medications that interfere with lipid metabolism, which is essential for the assembly and maturation of HCV particles) and duration of therapy will need to be defined, in order to maximize rates of sustained virologic response while minimizing the risk that resistance will develop. A recent pilot study of a combination of directly acting antiviral agents suggests the possibility of treating HCV infection with an interferon-free, oral approach."
Tibotec and Vertex Pharmaceuticals funded both studies. Financial relationships of the study authors are listed on the New England Journal of Medicine Web site with the full text of the journal articles. Dr. Rosen has disclosed no relevant financial relationships.
N Engl J Med. 2011;364:2405-2416, 2417-2428, 2429-2438.
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