Overview of the Current Standard of Care for Treatment of Chronic Hepatitis C

April 3, 2009

The current standard of care for the treatment of chronic hepatitis C virus (HCV) infection is combination therapy with pegylated interferon alfa-2a (Pegasys) or pegylated interferon alfa-2b (PegIntron), both in combination with ribavirin.

At the 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD) last week in Washington, DC, experts in the field of viral hepatitis were invited to present their views on various issues. Dr. Peter Ferenci of the Department of Internal Medicine, Gastroenterology and Hepatology at the Medical University of Vienna, Austria, offered an overview of the use of the 2 pegylated interferons plus ribavirin for chronic hepatitis C. Following is an edited summary of his remarks.

Current Therapies in Chronic Hepatitis C

Peginterferon-alfa in combination with ribavirin is and will remain for the next [few] years the current standard for treatment of chronic hepatitis C (1).

The primary goal of treatment for chronic hepatitis C is a sustained virologic response (SVR). Host factors including age, body weight, race, and advanced fibrosis influence outcome of treatment (1,2), but are poor predictors of response. In contrast, viral factors like the genotype and the on-treatment pattern of viral response can be used to determine the likelihood of treatment success and guide treatment duration individually and proved to be very useful in clinical practice.

Stopping Treatment in Likely Nonresponders

The absence of an early virologic response [EVR] at week 12, defined as undetectable HCV RNA (< 50 IU/mL) by qualitative PCR assay, or greater than or equal to 2-log decrease relative to the baseline value by a quantitative PCR assay, has a 98% negative predictive value in a genotype 1 patient (3).

On this basis, treatment may be discontinued in patients who do not achieve an early virologic response at week 12. Therapy should be stopped in all patients with a > 2-log decrease in HCV RNA at week 12 who have not become HCV RNA negative by week 24. Recent studies show that this information can be used to individualize the duration of therapy.

The HCV RNA status at week 4 also provides useful prognostic information that can be used to individualize the duration of therapy in genotype 1 patients (4,5). Normalization of ALT on treatment is an indicator of a therapeutic response but lacks specificity, and, thus cannot be used in place of serum HCV RNA determinations.

Individualization of Treatment

Genotypes 1 and 4

Loss of HCV RNA by week 4 of treatment documented with a commercial qualitative HCV RNA assay with a limit of detection of 50 IU/mL is an excellent predictor of sustained virologic response in patients with genotype 1 infection (3). When treated for 48 weeks with peginterferon plus ribavirin 1000 or 1200 mg/day, 87% to 91% of such patients will have a sustained virologic response (3,6).

Around 24% of European genotype 1 patients achieve an RVR [rapid virological response] (6).The level of detection of HCV has been improved by the real time PCR technique to 10 IU/mL. The impact of using more sensitive tests remains to be studied.

Shortening Treatment Duration:

The retrospective analysis of several randomized controlled trials using peginterferon-2/ribavirin have shown that the probability of achieving a sustained virologic response is similar in genotype 1 patients with rapid virologic response (RVR) treated for 24 or 48 weeks (4).

The concept of treatment shortening was addressed by prospective trials, showing that > 80% of patients with genotype 1 and 4 achieve a SVR when treated only for 24 weeks (6). Thus, it is reasonable to consider reducing the duration of combination therapy to 24 weeks in genotype 1-infected with RVR when treated with a standard peginterferon plus ribavirin regimen.

Both peginterferons have been approved in the European Union for shortened treatment duration of 24 weeks in HCV genotype 1 patients with RVR and low baseline viral load defined as <800.000 IU/ml for peginterferon alfa-2a and <600.000 IU/ml for peginterferon alfa-2b. Abbreviated therapy may not be suitable in genotype 1 patients with cirrhosis.

Extending Treatment Duration:

In patients with a slow [or partial] virologic response (pEVR), prolongation of treatment beyond 48 weeks may reduce relapse rates and thus increase SVR. Several studies investigated treatment prolongation in slow responders. Although they substantially differed in design each one has shown that extending therapy to 72 weeks increases the probability of achieving a sustained virologic response (5,7,8). There are no data on which to base a universal recommendation to treat a patient such as this for 72 weeks. In a recent study it was suggested that patients with detectable HCV at week 8 will benefit from extended treatment (5).

Genotypes 2 and 3

Patients with genotypes 2 and 3 are easier to treat than patients with genotypes 1 and 4. Peginterferon in combination with [ribavirin] 800 mg/day is sufficient. A number of studies have demonstrated comparable SVR rates between shortened (12 to 16 weeks) and 24 weeks of treatment in patients who achieve a RVR.

However, in a large randomized prospective study, among patients with an RVR, SVR rates were higher in the 24-week treatment group than in the 16-week group -- both overall and within each genotype group (9). The difference in SVR rate reflects a higher relapse rate in the 16-week group (31%) compared with the 24-week group (18%).

Like in patients with other genotypes, the presence of complete cirrhosis and a high baseline HCV RNA level are poor prognostic factors for sustained virologic response (2). Therefore abbreviation of treatment should only be offered to non-cirrhotic patients with low baseline viral load. Prolongation of treatment in patients with cirrhosis and in patients without RVR may improve the overall outcome and is currently [being] investigated by a prospective randomized trial.



Reference

CP Ferenci. Current Therapies in Hepatitis C. 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD). Washington, DC. May 20-24, 2009. Abstract SP-29.

Other Citations

1. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology 2006;130:231-264

2. Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008; 134:1699-1714.

3. Ferenci P, Fried MW, Shiffman ML et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. Journal of Hepatology 2005; 43:425-433.

4. Jensen DM, Morgan TR, Marcellin P et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43:954-960.

5. Sanchez-Tapias JM, Diago M, Escartin P et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006;131:451-460

6. Ferenci P, Laferl ,H, Scherzer TM, Gschwantler M, Andreas Maieron A, Brunner H, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008;135:451-458.

7. Berg T et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006;130:1086?1097

8. Pearlman BL et al. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology 2007;46:1688?1694

9. Shiffman ML, Suter F, Bacon BR et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. New England Journal of Medicine 2007; 357:124-134.