Predictors of Response to Therapy in Chronic Hepatitis C
an excerpt from Advances in Hepatitis C: Promising Clinical Management and Treatment Options*

Therapy of chronic hepatitis C (CHC) with interferon a (IFN a) is problematic and only effective in a small proportion of patients; however, combination therapy with IFN a and ribavirin has taken treatment to the next plateau. Presently, the identification of patients who are likely to respond to either IFN a monotherapy or combination therapy may represent the best way to further improve treatment success. The next generation of therapeutic agents (eg, pegylated IFN a) are likely to improve responses in carefully selected patients as well, and are also being evaluated in clinical trials using these same criteria. Such identification is possible with the application of the widely accepted baseline predictors of treatment outcome viral load and hepatitis C virus (HCV) genotype.

Combination therapy has resulted in sustained virological responses in approximately 60% (double that of IFN a alone) of patients infected with HCV genotypes 2 or 3, independent of pretreatment HCV titers, and in 35% of patients with HCV genotype 1 and viral loads less than 2 x 106 copies/mL (vs 5% with IFN a monotherapy). In patients with HCV genotype 1 and viral loads above 2 x 106 copies/mL, the sustained response depends on the duration of therapy (12 months treatment is superior to 6 months treatment), but in those patients with HCV genotype 1 and viral loads less than 2 x 106 copies/mL, and in patients with HCV genotypes 2 or 3, the sustained response is independent of treatment duration. Thus, HCV genotyping and a single definitive HCV-RNA quantification performed before treatment should be adopted as standard practice in the management of CHC.

Further gains with combination therapy may possibly be achieved by monitoring HCV-RNA serum levels during the early weeks of treatment; early response predicts eventual outcome^[1] and can in the case of nonresponders, spare the patient continuation of ineffectual treatment. Evidence supporting this notion has recently been presented at the 10th International Symposium on Viral Hepatitis and Liver Disease. Britten and Cassidy determined in 20 CHC patients that a 10-fold decrease in HCV RNA by week 12 of combination therapy was predictive of sustained virological response at the end-of-treatment (24 weeks). Normalization of alanine aminotransferase at week 12 was not similarly predictive.^[2]

Failure to clear HCV RNA from the serum at week 12 of IFN a monotherapy may also predict the nonresponse to combination retreatment. Naylor et al found that those patients who failed to respond to induction regimens of IFN a at week 12 failed to respond to combination therapy as well.^[3] The absence of the ability to clear serum HCV RNA to undetectable levels at week 8 in relapsers retreated with combination therapy has a high negative predictive value (94%) for nonresponse.^[4] Recent improvement in the standardization of quantitative assays allows the use of quantification of HCV viral load in the management of patients undergoing therapy^[5] to assess the predictive value of HCV-RNA titers during treatment.

References

1. Civeira MP, Prieto J. Early predictors of response to treatment in patients with chronic hepatitis C. J Hepatol 1999;31 (suppl 1):.

2. Britten E, Cassidy W. Predicting end level response to interferon therapy by 12 week levels of HCV-RNA (PCR) quantitative and ALT levels. Antiviral Therapy 2000;5(suppl 1):abstract C186.

3. Naylor PH, Kinzie JL, Ehrinpreis MN, et al. Retreatment of interferon failures with combination therapy: Log drop after 12 weeks of monotherapy predicts ETR to combination therapy. Antiviral Therapy 2000;5(suppl 1):abstract C191.

4. Marcellin P, Hezode C, Castelnau C, et al. Randomized controlled trial of combination therapy with interferon (IFN) alfa-2a and ribavirin, in patients with chronic hepatitis C who relapsed after interferon therapy. Hepatology 1999;30:abstract 92A.

5. Martinot-Peignoux M, Boyer N, Le Breton V, et al. A new step toward standardization of serum hepatitis C virus-RNA quantification in patients with chronic hepatitis C. Hepatology 2000;31:. 

* Reprinted with permission from Advances in Hepatitis C © 2000 Adis International, Inc.