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.