A large number of patients with chronic hepatitis C have been treated with alpha interferon with or without ribavirin since the 1997 Consensus Development Conference. Unfortunately, a majority of these patients probably did not achieve a sustained virologic response (SVR). As new therapies are developed for  continue to arise. Recommendations regarding retreatment should be based upon several factors: (1) the previous type of response, (2) the previous therapy and the difference in potency of the new therapy, (3) the severity of the underlying liver disease, (4) viral genotype and other predictive factors for response, and finally (5) tolerance of previous therapy and compliance. ⁽¹⁾

Types of Non-Response

Patients who fail to achieve SVR can be categorized as either relapsers or non-responders. In general, relapsers are more likely to achieve SVR during retreatment with a more potent regimen than are non-responders. Yet among patients referred to as non-responders, there is the subset who have a marked reduction without disappearance of HCV RNA (1–2 log units or more) during therapy. These partial responders may also be good candidates for retreatment, if a more potent regimen of therapy is being applied, such as the currently recommended combination of peginterferon and ribavirin. In at least one study of retreatment, only non-responders who had a decline in HCV RNA to an absolute titer <100,000 copies/ml during previous treatment with interferon alone achieved SVR when retreated with interferon and ribavirin. ⁽²⁾

Retreatment of Non-Responders

The likelihood that non-responder patients will respond to retreatment depends in large part upon the previous therapy. Retreatment of non-responders with the same therapy will not result in viral clearance, whereas retreatment with a more potent regimen can result in SVR in a proportion of patients. Thus, preliminary results suggest that up to 30 percent of non-responders to the standard interferon/ribavirin combination became HCV RNA negative on retreatment using the peginterferon/ribavirin combination. ^(3,4) Higher rates occurred in patients with HCV genotypes 2 or 3 compared to genotype 1. Unfortunately, relapse was common once therapy was discontinued, so that the rate of SVR was only 15–20 percent overall.

Retreatment of Relapsers

Several studies have shown that patients with prior relapse have a high rate of SVR when retreated with more effective therapy. Thus, 50 percent of patients who relapsed following treatment with interferon alone achieved SVR when retreated with interferon/ribavirin combination. ⁽⁵⁾ The ability to achieve SVR following retreatment with peginterferon/ribavirin in 47 patients who relapsed following interferon monotherapy or standard interferon/ribavirin therapy is currently being evaluated. The majority of relapsers become HCV RNA negative during retreatment, even when the regimen is the same. When the same regimen is used, however, virtually all patients relapse again after treatment is stopped. Extending the duration of retreatment without changing the dose or regimen may reduce relapse, but this has not been prospectively proven.

Severity of Liver Disease and Retreatment

Knowledge of the severity of the underlying liver disease is important in recommending retreatment of chronic hepatitis C. Patients with no or minimal fibrosis probably have an excellent long-term prognosis and low risk for developing cirrhosis or complications of chronic hepatitis C. These patients, therefore, could forgo retreatment and await further advances in therapy. On the other hand, patients with advanced fibrosis or cirrhosis are at increased risk for developing hepatic decompensation and should be considered for retreatment, especially if the previous treatment was interferon alone. For patients with intermediate degrees of fibrosis and disease activity, recommendations for retreatment should weigh the type of initial response, the improvement in treatment regimen, factors such viral genotype, initial titer of HCV RNA, as well as tolerance of therapy.

Non-Responders to Combination Therapy With Peginterferon and Ribavirin

Patients who fail to respond even to the current optimal therapy with peginterferon/ ribavirin are a great challenge for management, particularly those with advanced fibrosis or cirrhosis. In several studies of standard interferon, up to 40 percent of non-responders developed evidence of a histological response despite persistence of HCV RNA. ^(6,7) These histological responses occurred largely among patients with a partial virological response as shown by a significant reduction in HCV RNA titer. In a prospective, randomized controlled trial, these histological improvements were shown to be maintained by continuation of interferon monotherapy. ⁽⁸⁾ The possible role of maintenance therapy with peginterferon alone in preventing further progression of cirrhosis, clinical decompensation, or development of hepatocellular carcinoma is currently the focus of a large-scale, multi-center U.S. trial, referred to as HALT-C.

Until the results of that study or similar studies are available, the role of long-term, continuous therapy with peginterferon (or ribavirin or both) for non-responder patients must be considered experimental.

Tolerance and Compliance

An important reason for relapse and non-response to interferon therapy of hepatitis C is non-compliance. Non-compliance can be the result of severe side effects or lack of commitment by the patient, but also can be due to poor counseling regarding side effects and inadequate management. If the causes of non-compliance can be corrected or lessened, retreatment can be successful. In contrast, if side effects are intolerable despite adequate counseling and management, retreatment is unlikely to be successful and should not be encouraged.

References

1. Shiffman ML. Management of interferon therapy non-responders. Clin Liver Dis 2001;5:1025–43.

2. Shiffman ML, Hofmann CM, Gabbay J, et al. Treatment of chronic hepatitis C in patients who failed interferon monotherapy: Effects of higher doses of interferon and ribavirin combination therapy. Am J Gastroenterol 2000;95:2928–35.

3. Minuk GY, Reddy KR, Lee SS, et al. Enhanced virologic response to treatment with 40KDA peginterferon-alpha-2a (Pegasys) in patients previously unresponsive to treatment with interferon-alpha-2a. Hepatology 2001;34:330A.

4. Shiffman ML, for the HALT-C trial investigators. Retreatment of interferon and interferon-ribavirin non-responders with peginterferon-alpha-2a and ribavirin: Initial results from the lead-in phase of the HALT-C trial. Hepatology 2001;34:243A.

5. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Eng J Med 1998;339:1493–9.

6. Shiffman ML, Hofmann CM, Thompson EB, et al. Relationship between biochemical, virologic and histologic response during interferon treatment of chronic hepatitis C. Hepatology 1997;26:780–5.

7. Shiffman ML. Histologic improvement in response to interferon therapy in chronic hepatitis C. Viral Hepatitis Reviews. 1999;5:27–43.

8. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon for treatment of chronic hepatitis C non-responders. Gastroenterology 1999;117:1164–72.