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AASLD Hepatitis C Treatment Guidelines Updated to Include Boceprevir and Telaprevir

The American Association for the Study of Liver Diseases (AASLD) has updated its guidelines for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection, reflecting the advent of new direct-acting antiviral agents (DAAs).

The latest guidelines, published in the October 2011 issue of Hepatology (available free online), are also endorsed by the Infectious Diseases Society of America (IDSA), the American College of Gastroenterology, and the National Viral Hepatitis Roundtable.

The recent approval of the first 2 HCV protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), usher in a new paradigm of hepatitis C treatment. These drugs -- and many more in the development pipeline -- target specific steps of the viral lifecycle. Currently they are used in combination with interferon-based therapy (which stimulates the immune system's response against HCV), but studies of interferon-sparing, all-oral DAA combination regimens are underway.

The AASLD guidelines cover prevention, diagnosis, and treatment of chronic hepatitis C, with the latter focused on HCV genotype 1, the most prevalent type in the U.S. and the most difficult to treat. They also discuss resistance to DAAs, management of adverse events, and considerations for special populations.

"These recommendations provide a data-supported approach to establishing guidelines," they explain. Recommendations are based on a formal review and analysis of recently published international medical literature, including a MEDLINE search through June 2011, as well as the authors' considerable experience in managing hepatitis C. The guidelines "are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case," they note.

The standard of care for patients with chronic hepatitis C infection has been pegylated interferon alfa (Pegasys or PegIntron) plus ribavirin for either 48 weeks for HCV genotypes 1, 4, 5, and 6, or 24 weeks for genotypes 2 and 3. Rates of sustained virological response (SVR) -- generally regarded as a cure -- are in the range of 40%-50% for genotype 1 and about 80% for genotypes 2 and 3.

Sustained response to treatment reduces (and may in part reverse) liver fibrosis progression and lowers the risk of cirrhosis, hepatocellular carcinoma, liver transplantation and liver-related death.

The authors cite 2 major advances since the last version of the guidelines that have changed optimal therapy: the advent of DAAs for HCV genotype 1 and identification of IL28B genetic variations associated with spontaneous viral clearance and improved treatment response.

"Although [pegylated interferon and ribavirin] remain vital components of therapy, the emergence of DAAs has led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients with genotype 1 chronic HCV infection," they write.

In addition to HCV protease inhibitors such as boceprevir and telaprevir, other types of DAAs in development include HCV polymerase inhibitors and NS5A inhibitors. DAAs demonstrate greater potency and are less prone to drug resistance when agents from different classes are combined.

The new drugs necessitate revised guidelines, especially given the increasingly individualized nature of hepatitis C treatment, including complex response-guided therapy (RGT) algorithms for boceprevir and telaprevir.

Boceprevir was approved based on data from the pivotal SPRINT-2 (previously untreated) and RESPOND-2 (prior non-responders) trials. Pivotal telaprevir data came from the ADVANCE (previously untreated) and REALIZE (prior non-responders) trials.

The guideline authors emphasize, however, that information on using these new agents is still limited, especially with regard to "real world" use outside clinical trials.

Revised AASLD Recommendations

1. The optimal therapy for genotype 1 chronic HCV infection is boceprevir or telaprevir in combination with pegylated interferon alfa plus ribavirin.

2. Boceprevir and telaprevir should not be used without pegylated interferon alfa and weight-based ribavirin.

For Treatment-Naive Patients:

3. The recommended dose of boceprevir is 800 mg administered with food 3 times per day (every 7-9 hours) together with pegylated interferon alfa and weight-based ribavirin for 24-44 weeks, preceded by 4 weeks of lead-in treatment with pegylated interferon alfa and ribavirin alone.

4. Patients without cirrhosis treated with boceprevir, pegylated interferon, and ribavirin, who have undetectable HCV RNA at weeks 8 and 24 may be considered for a shortened treatment duration of 28 weeks in total (4 weeks lead-in followed by 24 weeks of triple therapy).

5. Treatment with all 3 drugs should be stopped if HCV RNA is >100 IU/mL at treatment week 12 or detectable at treatment week 24.

6. The recommended dose of telaprevir is 750 mg administered with food (not low-fat) 3 times per day (every 7-9 hours) together with pegylated interferon alfa and weight-based ribavirin for 12 weeks, followed by an additional 12-36 weeks of pegylated interferon alfa plus ribavirin alone.

7. Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, who have undetectable HCV RNA at weeks 4 and 12 should be considered for a shortened treatment duration of 24 weeks.

8. Patients with cirrhosis treated with either boceprevir or telaprevir in combination with pegylated interferon plus ribavirin should receive therapy for 48 weeks.

9. Treatment with all 3 drugs (telaprevir, pegylated interferon, and ribavirin) should be stopped if HCV RNA is > 1000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24.

For Treatment-Experienced Patients:

10. Re-treatment with boceprevir or telaprevir, together with pegylated interferon 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 conventional (non-pegylated) interferon alfa or pegylated interferon alfa and/or ribavirin.

11. Re-treatment with telaprevir, together with pegylated interferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of conventional interferon alfa or pegylated interferon alfa and/or weight-based ribavirin (pivotal trials of boceprevir did not include prior null responders).

12. Response-guided therapy for treatment-experienced patients using either a boceprevir-based or telaprevir-based regimen can be considered for relapsers and may be considered for partial responders, but cannot be recommended for null responders.

13. Patients re-treated with boceprevir plus pegylated interferon alfa and ribavirin who continue to have detectable HCV RNA > 100 IU at week 12 should be withdrawn from all therapy due to the high likelihood of developing antiviral drug resistance.

14. Patients re-treated with telaprevir plus pegylated interferon alfa and ribavirin who continue to have detectable HCV RNA > 1000 IU at weeks 4 or 12 should be withdrawn from all therapy due to the high likelihood of developing resistance.

Viral Resistance and Monitoring

15. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose.

16. Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and protease inhibitors should be discontinued if virological breakthrough occurs (>1 log increase in HCV RNA above nadir).

17. Patients who do not experience virological response, who experience virological breakthrough, or who relapse on one newly approved protease inhibitor should not be retreated with the other protease inhibitor.

Author affiliations: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Section of Hepatobiliary Disease, University of Florida, Gainesville, FL; Gastroenterology and Hepatology Division, Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, VT; Johns Hopkins Medical Institution, Baltimore, MD; The Hill Group, Bethesda, MD.

10/18/11

Reference

MG Ghany, DR Nelson, DB Strader, et al. 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. Hepatology 54(4):1433-1444 (free full text) October 2011.