Hepatitis - The Naive Patient

Interferon mono therapy was the first antiviral regimen approved for chronic hepatitis C. Sustained response lates with IFN mono therapy were similar among the 3 approved IFNs. Sustained response rates for IFN-alfa-2b administered at a dose of 3 million units 3 times per week for 6 or 12 months were 8 % and 12%, respectively. The sustained response rate associated with IFN-alfa con-I given at a dose of 9 mcg 3 times per week for 6 months was 12.1%. Higher doses of (FN mono therapy were associated with increased end-of-treatment responses but without any improvement in sustained response. Induction trials using IFN mono therapy have not shown any increased efficacy over standard 3-times weekly dosing. Therefore, IFN mono therapy is currently recommended only for those patients who do not tolerate combination .therapy with IFN and ribavirin.

Patients should be followed on IFN mono therapy, with serial testing of alanine aminotransferase and HCV-RNA levels. Therapy should be discontinued in those patients who fail to demonstrate undetectable viral levels at week 12 of treatment.

Several factors are associated with a favorable response to therapy with IFN mono therapy. The most important of these factors include the lack of cirrhosis on liver biopsy, the presence of either HCV genotype 2 or 3, and low HCV-RNA levels pretreatment.

Interferon is associated with numerous side effects. The most common of these is flu- like illness that occurs in the first 4 weeks of therapy and which generally resolves on its own. After the first month of therapy, late side effects such as fatigue, headache, and neuropsychiatric changes may occur. Depressionis also a common side effect of IFN, and patients with prior history of depression shoulcibe carefully monitored. Other less common adverse events may include hypothyroidism, hyperthyroidism, arthralgias, rash, and reversible alopecia. Neutropenia, and especially thrombocytopenia, may occur in patients on IFN therapy and can be managed with dose reduction.

Combination therapy: the naive patient. Two large, randomized controlled trials compared combination IFN-alfa-2b plus ribavirin with IFN-alfa-2b mono therapy, given for 24 or 48 weeks to previously untreated hepatitis C patients (see Figure 4).r6970 Individuals treated with the combination regimen had sustained virologic responses at 24 and 48 weeks of 33% and 41%, respectively. This outcome compared favorably with the 6% and 16% sustained response rates achieved with 24 and 48 weeks, respectively, of IFN mono therapy.

ETR = end-of-treatment response; SVR = sustained virologic response

Careful analysis of these trials revealed the importance of genotype in both predicting response to therapy and determining duration of therapy. Genotype 1 patients treated with combination therapy had sustained response rates at 24 and 48 weeks of 17% and 29%, respectively. Genotype 2 and 3 patients had sustained response rates at 24 and 48 weeks of 66% and 65%, respectively. Based on these data, it seems reasonable to treat genotype 2 and 3 patients for a total of 24 weeks. The presence of bridging fibrosis or cirrhosis resulted in reduced response rates in patients treated with combination therapy for 6 months, but not in those treated with combination therapy for 12 months. Genotype 1 patients with high viral loads were the least likely to respond to combination therapy.

The sustained response to 24 weeks of therapy with combination IFN and ribavirin vs IFN mono therapy was evaluated in 112 noncirrhotic hepatitis C patients infected with genotype 4. The sustained response rate in the combinatioji-therapy group was 42% compared with only 8% in the mono therapy group.

Although the prevalence of the hepatitis C antibody is 2-3 times greater among blacks than whites in the United States, blacks have been underrepresented in the many large published hepatitis C treatment trials. In these trials, blacks are reported to have a lower response rate than whites to IFN mono therapy. Of the 1744 patients enrolled in the 2 large, multicenter trials evaluating IFN plus ribavirin for the treatment of previously untreated hepatitis C patients, 53 were classified as black. Among these 53 patients, 96% were genotype 1. The sustained response of these patients to 24 and 48 weeks of combination therapy were 20% and 23%, respectively. None of the black patients treated with IFN mono therapy had a sustained response.

Five independent factors have been identified as predictors of sustained response in patients treated with combination therapy. These factors are genotype 2 or 3, baseline viral load < 3.5 million copies/ml, minimal fibrosis, female sex, and age <40 years. Early loss of HCV RNA while on therapy may also be predictive of a sustained response.

Common side effects of ribavirin include anemia, depression, fatigue, irritability, rash, cough, shortness of breath, and insomnia. The anemia is the result of a dose-dependent hemolysis of red blood cells and occurs in nearly 100% of patients, with patients frequently showing a drop of 2-3 g from baseline hemoglobin. Therefore, ribavirin must be used with caution in patients with pre-existing anemia, diabetes, or coronary artery disease. Also important to note is that ribavirin is teratogenic, so patients and their sexual partners must be carefully counseled prior to initiation of therapy.

Hepatitis - Treatment of the Non responder

Non response to antiviral therapy is defined as the persistence of detectable HCV RNA throughout therapy, with detectable serum HCV RNA at the end of the therapeutic course. The sustained response to re-treatment of non responders to any form of antiviral therapy has been disappointing.

Re-treatment of non responders to IFN mono therapy was evaluated in several small studies. In the consensus interferon trial, non responders to IFN mon otherapy showed a 13% sustained virologic response rate at 48 weeks of therapy with IFN-alfa con-1. The use of combination IFN and ribavirin therapy in FN non responders has resulted in sustained response rates ranging from 0% to 15%. Of interest, a recent trial reported a 42% sustained response to intravenous recombinant IFN-bEIA in previous IFN non responders.

Approximately 60% of all patients treated with combination IFN and ribavirin are non responders. The approach to this group represents a growing challenge to the treating clinician. Although it seems reasonable that higher doses of IEN plus ribavirin or a weight-based system of ribavirin dosing should improve response to treatment in these patients, there are little if any published data to support such an approach. The peginterferons may, however, prove useful in combination with IFN and ribavirin, and clinical trials designed to test this notion are currently ongoing.

Virologic non responders to antiviral therapy may derive some benefit from re-treatment that is aimed at preventing histologic disease progression. Patients with underlying bridging fibrosis or cirrhosis are at a greater risk for developing complications of cirrhosis than are those without fibrosis. In addition to its antiviral effect, IFN was shown to have anti proliferative and anti fibrotic activity through its down regulation of transforming growth factor b. Recent studies showed improvement in underlying histology in non responders to antiviral therapy. Several studies have also demonstrated a significant reduction in the relative risk of developing HCC among non responders to IFN mono therapy.

These studies have brought the issue of IFN maintenance therapy for prevention of fibrotic progression to the fore. Shiffman and colleagues’95’ reported that a 2-year course of IFN mono therapy administered to non responders stabilized fibrosis and improved inflammation on serial biopsies. This concept has now led to the launch of a National Institutes of Health-sponsored trial -- the Hepatitis C Antiviral Long-term Treatment against Cirrhosis or HALT-C trial -- to evaluate the effect of long-term peginterferon-alfa2a therapy in patients with advanced fibrosis or cirrhosis who did not respond to combination pegylated IEN plus ribavirin.