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Guideline Summary
Guideline Title
An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases.
Bibliographic Source(s)
Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Disease. Alexandria (VA): American Association for the Study of Liver Diseases (AASLD); 2013 Jan 11. 10 p. [37 references]
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Genotype 1 chronic hepatitis C virus (HCV) infection

Guideline Category
Management
Treatment
Clinical Specialty
Family Practice
Gastroenterology
Infectious Diseases
Internal Medicine
Intended Users
Health Care Providers
Physician Assistants
Physicians
Guideline Objective(s)

To review what treatment for genotype 1 chronic hepatitis C virus (HCV) infection is now regarded as optimal

Target Population

Patients with genotype 1 chronic hepatitis C virus (HCV) infection

Interventions and Practices Considered
  1. Pharmacological therapy:
    • Protease inhibitors (boceprevir, telaprevir)
    • Peginterferon alfa
    • Ribavirin
    • Combination therapy
  2. Consideration of dosing and length of treatment
  3. Monitoring of hepatitis C virus (HCV) ribonucleic acid (RNA) levels using an HCV assay with a lower limit of quantification equal to or less than 25 IU/mL and a limit of HCV ribonucleic acid (RNA) detection of approximately 10-15 IU/mL
  4. Response-guided therapy of treatment-experienced patients
  5. IL28B genotype testing
Major Outcomes Considered
  • Sustained virologic response (SVR) rates
  • Hepatitis C virus (HCV) ribonucleic acid (RNA) levels
  • Adverse events
  • Drug-drug interactions

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

The recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (MEDLINE search up to June 2011); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies, including the American Association for the Study of Liver Disease (AASLD) Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines; and (4) the experience of the authors in regard to hepatitis C.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Level of Evidence

Level A Data derived from multiple randomized clinical trials or meta-analyses

Level B Data derived from a single randomized trial, or nonrandomized studies

Level C Only consensus opinion of experts, case studies, or standard-of-care

Methods Used to Analyze the Evidence
Systematic Review
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Not stated

Rating Scheme for the Strength of the Recommendations

Grading System for Recommendations

Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective

Class 2 Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment

Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy

Class 2b Usefulness/efficacy is less well established by evidence/opinion

Class 3 Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

External review was provided by Gary Davis, M.D., Chair, American Association for the Study of Liver Diseases (AASLD) Hepatitis C Virus (HCV) Special Interest Group, and the American College of Gastroenterology, the Infectious Diseases Society of America, and the National Viral Hepatitis Roundtable. Senior officials at the Division of Viral Hepatitis of the Centers for Disease Control and Prevention, the Office of HIV/AIDS Policy, U.S. Department of Health and Human Services, and the Public Health Strategic Health Care Group, U.S. Department of Veterans Affairs were provided an opportunity to review and comment on the manuscript.

This practice guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and endorsed by the Infectious Diseases Society of America, the American College of Gastroenterology and the National Viral Hepatitis Roundtable.

Recommendations

Major Recommendations

Note from the National Guideline Clearinghouse (NGC) and the American Association for the Study of Liver Disease (AASLD): On January 11, 2013, the AASLD added a new section on Use and Interpretation of HCV RNA Results During Triple Therapy to the online version of this guideline. The recommendations below include this addition.

The grading system for the classes of recommendation (1, 2, 2a, 2b, 3) and the levels of evidence (A–C) are defined at the end of the "Major Recommendations" field.

Patients Who Have Never Received Therapy (Treatment-Naive Patients)

  1. The optimal therapy for genotype 1, chronic hepatitis C virus (HCV) infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A).
  2. Boceprevir and telaprevir should not be used without peginterferon alfa and weight-based ribavirin (Class 1, Level A).
  3. The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7- 9 hours) together with peginterferon alfa and weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A).
  4. Patients without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, whose HCV ribonucleic acid (RNA) level at weeks 8 and 24 is undetectable, may be considered for a shortened duration of treatment of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks of triple therapy) (Class 2a, Level B).
  5. Treatment with all three drugs (boceprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class 2a, Level B).
  6. The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A).
  7. Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, whose HCV RNA level at weeks 4 and 12 is undetectable, should be considered for a shortened duration of therapy of 24 weeks (Class 2a, Level A).
  8. Patients with cirrhosis treated with either boceprevir or telaprevir in combination with peginterferon and ribavirin should receive therapy for a duration of 48 weeks (Class 2b, Level B).
  9. Treatment with all three drugs (telaprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24 (Class 2a, Level B).

Patients Who Have Previously Received Therapy

  1. Re-treatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class 1, Level A).
  2. Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B).
  3. Response-guided therapy of treatment-experienced patients using either a boceprevir- or telaprevir-based regimen can be considered for relapsers (Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir), may be considered for partial responders (Class 2b, Level B for boceprevir; Class 3, Level C for telaprevir), but cannot be recommended for null responders (Class 3, Level C).
  4. Patients re-treated with boceprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA >100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).
  5. Patients re-treated with telaprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA >1,000 IU at weeks 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).

Viral Resistance and Monitoring

  1. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A).
  2. Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and the protease inhibitors should be discontinued if virological breakthrough (>1 log increase in serum HCV RNA above nadir) is observed (Class 1, Level A).
  3. Patients who fail to have a virological response, who experience virological breakthrough, or who relapse on one protease inhibitor should not be re-treated with the other protease inhibitor (Class 2a, Level C).

Use and Interpretation of HCV RNA Results During Triple Therapy

  1. An HCV assay with a lower limit of quantification of equal to or less than 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL should be used for monitoring response to therapy and decision making during triple therapy (Class 2a, Level A).
  2. Response-guided therapy should only be considered when no virus is detected by a sensitive assay four weeks after initiation of the HCV protease inhibitor (Class 1, Level A ).

Role of IL28B Testing in Decision to Treat and Selection of Therapeutic Regimen

  1. IL28B genotype is a robust pretreatment predictor of sustained virologic response (SVR) to peginterferon alfa and ribavirin as well as to protease inhibitor triple therapy in patients with genotype 1 chronic hepatitis C virus infection. Testing may be considered when the patient or provider wish additional information on the probability of treatment response or on the probable treatment duration needed (Class 2a, Level B).

Definitions:

Grading System for Recommendations

Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective

Class 2 Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment

Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy

Class 2b Usefulness/efficacy is less well established by evidence/opinion

Class 3 Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful

Level of Evidence Description

Level A Data derived from multiple randomized clinical trials or meta-analyses

Level B Data derived from a single randomized trial, or nonrandomized studies

Level C Only consensus opinion of experts, case studies, or standard-of-care

Clinical Algorithm(s)

None available

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate and effective treatment of genotype 1 chronic hepatitis C virus (HCV) infection

Potential Harms
  • In the boceprevir (BOC) trials, anemia and dysgeusia were the most common adverse events, whereas in the telaprevir (TVR) trials, rash, anemia, pruritus, nausea, and diarrhea developed more commonly among those who received TVR than who received standard-of-care (SOC) therapy.
  • Because patients with chronic hepatitis C (CHC) frequently receive medications in addition to those used to treat hepatitis C virus (HCV) infection, and because the protease inhibitors (PIs) can inhibit hepatic drug-metabolizing enzymes such as cytochrome P450 2C (CYP2C), CYP3A4, or CYP1A, both BOC and TVR were studied for potential interactions with a number of drugs likely to be coadministered. These included statins, immune suppressants, drugs used to treat human immunodeficiency virus (HIV) coinfection, opportunistic infections, mood disorders, and drug addiction support medications. Both BOC and TVR, were noted to cause interactions with several of the drugs examined, either increasing or decreasing pharmacokinetic parameters. It is particularly important, therefore, that the medical provider review this information as listed in the package insert for each of the drugs before starting treatment for CHC.
  • Emergence of antiviral-resistant variants during PI-based therapy has been observed during all trials and is associated with virological failure and relapse.

Contraindications

Contraindications

Boceprevir (BOC) and telaprevir (TVR) are not recommended for use in children and adolescents younger than 18 years of age, because the safety and efficacy has not been established in this population.

Qualifying Statements

Qualifying Statements

Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Mobile Device Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Disease. Alexandria (VA): American Association for the Study of Liver Diseases (AASLD); 2013 Jan 11. 10 p. [37 references]
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2011 Oct (republished 2012)
Guideline Developer(s)
American Association for the Study of Liver Diseases - Nonprofit Research Organization
Source(s) of Funding

American Association for the Study of Liver Diseases (AASLD)

AASLD does not accept corporate support for the development of practice guidelines. However, AASLD gratefully acknowledges the support of Genentech and Merck for providing independent medical education grants for mobile download applications for AASLD practice guidelines.

Guideline Committee

Practice Guidelines Committee

Composition of Group That Authored the Guideline

Primary Authors: Marc G. Ghany; David R. Nelson; Doris B. Strader; David L. Thomas; Leonard B. Seeff

Committee Members: Jayant A. Talwalkar, MD, MPH (Chair); Adrian M. Di Bisceglie, MD (Board Liaison); Jeffrey H. Albrecht, MD; Hari S. Conjeevaram, MD, MS; Amanda DeVoss, MMS, PA-C; Hashem B. El-Serag, MD, MPH, David A. Gerber, MD; Christopher Koh, MD; Kevin Korenblat, MD; Raphael B. Merriman, MD, MRCPI; Gerald Y. Minuk, MD; Robert S. O'Shea, MD; Michael K. Porayko, MD; Adnan Said, MD; Benjamin L. Shneider, MD; and Tram T. Tran, MD

Financial Disclosures/Conflicts of Interest

Potential conflict of interest: Dr. Nelson receives research support from Vertex, Merck, Phamassett, Genentech/Roche, Gilead, Bristol-Myers Squibb, Tibotec, Bayer/Onyx and serves on advisory boards of Merck, Pharmassett, Genentech/Roche, Gilead, Tibotec, and Bayer/Onyx, and is a consultant for Vertex. Dr. Thomas receives research support from Merck, Gilead and serves on a Merck advisory board. Dr. Ghany, Dr. Seeff, and Dr. Strader have nothing to report.

Guideline Endorser(s)
American College of Gastroenterology - Medical Specialty Society
Infectious Diseases Society of America - Medical Specialty Society
Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the American Association for the Study of Liver Diseases Web site External Web Site Policy.

Print copies: Available from the American Association for the Study of Liver Diseases, 1729 King Street, Suite 200; Alexandria, VA 22314; Phone: 703-299-9766; Web site: www.aasld.org External Web Site Policy; e-mail: aasld@aasld.org.

Availability of Companion Documents

This guideline is available as a Personal Digital Assistant (PDA) download via the APPRISOR™ Document Viewer from www.apprisor.com External Web Site Policy.

Patient Resources

None available

NGC Status

This summary was completed by ECRI Institute on June 29, 2012. This summary was updated by ECRI Institute on April 13, 2012 following the U.S. Food and Drug Administration advisory on Incivek (telaprevir). The information was updated by the guideline developer in 2012 and updated by ECRI Institute on April 19, 2013.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the American Association for the Study of Liver Diseases' copyright restrictions.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouseâ„¢ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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