From CCO

A Practical Guide for the Use of Boceprevir and Telaprevir for the Treatment of Hepatitis C
Release Date: 9/15/11
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From CCO

A Practical Guide for the Use of Boceprevir and Telaprevir for the Treatment of Hepatitis C
Release Date: 9/15/11

With the advice of a panel of experts, this practical guide has been prepared as a consensus recommendation for how telaprevir and boceprevir should be used in the treatment of patients with HCV infection.

Learning Objectives
Upon completion of this activity, participants should be able to:

Use best practices when integrating boceprevir and telaprevir into treatment of patients with hepatitis C

Use patient-specific factors to determine if an individual with hepatitis C is a candidate for treatment with boceprevir and/or telaprevir

Counsel patients regarding efficacy and safety data with boceprevir and/or telaprevir for the treatment of hepatitis C virus infection

Manage adverse effects of treatment with boceprevir and/or telaprevir in patients with hepatitis C
Provide accurate and appropriate counsel as part of the treatment team
Provide appropriate care and counsel for patients and their families

Selecting Candidates for Treatment With Telaprevir or Boceprevir in Combination With PegIFN/RBV
At the time of writing, the FDA has approved both boceprevir and telaprevir and the EMA has approved boceprevir for the treatment of chronic genotype 1 HCV infection in combination with pegIFN/RBV in adult patients with compensated liver disease, including cirrhosis, who have not been treated for HCV or who have failed previous interferon/RBV therapy for HCV. In July of 2011, the EMA Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for telaprevir in Europe. Phase III registration trials with telaprevir included treatment of previous relapsers, partial responders, and null responders, whereas boceprevir trials did not include previous null responders.
It is the opinion of the panel that triple therapy should be considered the new standard of care in all genotype 1 HCV–infected treatment-naive and treatment-experienced patients wishing to undergo therapy for hepatitis C. Currently, pegIFN/RBV remains the standard treatment for patients infected with non–genotype 1 HCV.

Genotype 1 is the key element of candidacy for boceprevir- or telaprevir-based therapy; other important considerations in evaluating an individual patient’s likelihood of achieving SVR with triple therapy include fibrosis stage and previous treatment experience (Table 1). Fibrosis stage is also important in considering the urgency to treat; for instance, individuals with milder liver histology have a lower urgency for treatment because the risk for disease progression is low. On the other hand, these patients have higher rates of SVR, and all patients without contraindications should be considered candidates for therapy and have a data-driven discussion of the advantages and disadvantages of therapy.

On-Treatment Management: Futility Rules and Prevention of Resistance
Viral resistance with boceprevir and telaprevir occurs because of the selection of preexisting variants during the course of therapy, as a result of failure to eradicate infection on triple combination treatment.[54] In pooled analyses of subjects who had on-treatment failure or relapse during clinical trials with boceprevir or telaprevir, HCV variants emerged, which have been shown to carry several NS3 amino acid substitutions that reduce viral susceptibility to boceprevir and telaprevir (Table 10).[51,53] Extensive cross-resistance exists between the 2 drugs, one of several reasons why they should never be used together. Patterns of treatment-emergent amino acid substitutions were genotype 1 subtype specific.

Resistance was found to be more frequent among previous null responders and among those with subtype 1a HCV. The emergence of different substitutions among the subtypes can be explained by a different genetic barrier to resistance between subtype 1a and subtype 1b. For example, coding for R155K requires a single-nucleotide change in subtype 1a (AGG → AAG) but 2 nucleotide changes in subtype 1b (CGG → AAG). Thus, R155K is more likely to preexist in subtype 1a than in subtype 1b. The higher failure rates of boceprevir- or telaprevir-based therapy that are observed in treatment-experienced patients are owing to a poorer response to pegIFN/RBV than in treatment-naive patients, resulting in the subsequent outgrowth of resistant variants selected by boceprevir or telaprevir.
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