Adding Telaprevir Improves Sustained Response to Pegylated Interferon plus Ribavirin in Genotype 1 Chronic Hepatitis C Patients (PROVE3)

By Liz Highleyman

Since standard therapy with pegylated interferon plus ribavirin for chronic hepatitis C virus (HCV) infection produces a sustained virological response (SVR) only about half the time and can cause difficult side effects, researchers have explored several novel agents that directly target various steps of the viral lifecycle, an approach known as STAT-C.

One of the directly targeted agents furthest along in the pipeline is telaprevir (formerly known as VX-950), an HCV NS3-4A protease inhibitor being developed by Vertex. Telaprevir previously demonstrated good antiviral activity in treatment-naive genotype 1 chronic hepatitis C patients in the PROVE1 and PROVE2 trials.

At the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last week in Copenhagen, Denmark, researchers presented data from PROVE3, a Phase 2b study of 453 genotype 1 chronic hepatitis C patients in the U.S. and Europe who did not achieve sustained response with a prior course of pegylated interferon plus ribavirin.

Nearly 60% were prior non-responders who never achieved undetectable HCV RNA during previous treatment, about 35% were prior relapsers who experienced viral rebound after completing a previous course of treatment with undetectable HCV RNA, and about 7% previously experienced HCV breakthrough (viral rebound) during treatment.

At baseline, most participants (just over 90%) had HCV RNA > 800,000 IU/mL, about 40% had bridging fibrosis or cirrhosis, and 9% were black -- all factors associated with poorer response to interferon-based therapy.

Study participants were randomly assigned to receive one of the following regimens:

Telaprevir plus pegylated interferon alfa-2a (Pegasys) plus ribavirin for 12 weeks followed by pegylated interferon plus ribavirin without telaprevir for an additional 12 weeks (T12/PR24);

Telaprevir plus pegylated interferon plus ribavirin for 24 weeks followed by pegylated interferon plus ribavirin without telaprevir for an additional 24 weeks (T24/PR48);

Telaprevir plus pegylated interferon without ribavirin for 24 weeks (T24/P24);

Standard-of-care regimen of pegylated interferon plus ribavirin for 48 weeks (PR48).

Results

About half the participants (52%) completed their assigned treatment.

In an intent-to-treat analysis, 51% of patients in the T12/PR24 arm and 52% in the T24/PR48 arm achieved SVR, compared with 23% in the T24/P24 arm and just 14% in the standard-of-care PR48 arm.

Among prior non-responders, the corresponding SVR rates were 39%, 38%, 10%, and 9%, respectively.

Among prior relapsers, the rates were 69%, 76%, 42%, and 20%, respectively.

Among participants with prior HCV breakthrough during treatment, the rates were 57%, 50%, 36%, and 40%, respectively.

SVR rates were similar in patients with and without cirrhosis.

15% of patients in the T12/PR24 arm, 23% in the T24/PR48 arm, 37% in the T24/P24 arm, and 59% in the PR48 arm discontinued early due to predefined stopping criteria.

Among patients who completed treatment, 28%, 4%, 53%, and 52%, respectively, experienced HCV relapse.

Rates of early discontinuation due to adverse events were 10% in the T12/PR24 arm, 25% in the T24/PR48 arm, 9% in the T24/P24 arm, and 4% in the standard therapy arm.

The most frequent adverse events leading to discontinuation were fatigue, gastrointestinal symptoms, skin rash, pruritus (itching), anemia, and psychiatric symptoms (e.g., depression).

6% of participants in the T12/PR24 arm, 4% in the T24/PR48 arm, and 5% in the T24/P24 arm experienced grade 3 (serious) rash, compared with 1% in the standard therapy arm.

All treatment groups receiving a telaprevir-containing regimen had significantly higher SVR rates than the standard-of-care pegylated interferon/ribavirin arm, the investigators concluded. Addition of ribavirin improved efficacy compared with the telaprevir/pegylated interferon dual regimen.

While there had been some hope that adding telaprevir might allow for shorter treatment, the higher relapse rate in the T12/PR24 arm compared with the T24/PR48 arm "may warrant a total of 48 weeks of [pegylated interferon/ribavirin] in treatment-experienced patients," they added.

Medical School Hannover, Hannover, Germany; Duke University Medical Center, Durham, NC; Vertex Pharmaceuticals, Cambridge, MA; Weill Cornell Medical College, New York, NY; Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA; University of Toronto, Toronto, ON, Canada; Johann Wolfgang Goethe University Hospital, Frankfurt/Main, Germany; Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; University of California San Francisco, San Francisco, CA; Saint Louis University School of Medicine, Saint Louis, MO.

5/01/09

Reference
M Manns, A Muir, N. Adda, and others. Telaprevir in hepatitis C genotype-1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy: SVR results of the PROVE3 study. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009. Abstract 1044.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
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