Enhancing the response to interferon-alpha.

Abstract

BACKGROUND: Though initially recognized as antiviral agents, it was soon demonstrated that certain neoplasms were particularly sensitive to interferon-alpha (IFN-alpha). Indeed, the initial success of systemic IFN-alpha treatment in AIDS-associated Kaposi's sarcoma (AIDS-KS) occurred before identification of the human immunodeficiency virus (HIV) and in the absence of any coherent view of KS pathogenesis. With a more comprehensive understanding how KS develops and which circumstances provide an increased virulence of this neoplasm in HIV-infected persons, a more subtle rationale for IFN-alpha treatment arose regarding the disorder of the endogenous IFN-system in HIV-positive individuals. Until recently IFN-alpha was the only therapy available for patients with chronic hepatitis C (CHC). However, no more than 30% of these patients show a sustained virological response. Initial therapy with a combination therapy of IFN-alpha and ribavirin turned out to be more effective than treatment with IFN-alpha alone. To ameliorate response rates in antiviral IFN-therapy a profound understanding of viral dynamics, as well as immunological conditions associated with viral persistence, seems to be essential. Within a conference of the European Society of Clinical Virology (ESCV), which took place in Hamburg from August 30 to September 2, 1998, and was entitled 'Progress in Clinical Virology IV', a satellite symposium was organized to evaluate the clinical results of special antiviral treatment options with IFN-alpha, to analyze treatment failures with this cytokine and to ameliorate future strategies of IFN-alpha therapy. It focussed on HIV-related complications as coinfection with hepatitis C virus (HCV) and AIDS-KS, respectively. METHODS: A kinetic model of HCV infection based on principles established in studying HIV-1 infection was presented which is predictive for the outcome of IFN-alpha treatment. It involves different rates of velocity and compares the rates of acute clearance after different dosages of IFN-alpha application. Using the hypothesis to fit the changes in serum HCV RNA measured in a set of patients, it was found that 5 mIU daily dosing on average blocks 81% of HCV production/release, whereas 10 or 15 mIU blocks about 95% of HCV production/release. RESULTS: Only recently clinical data revealed a greater benefit of combination therapy with IFN-alpha and ribavirin compared to IFN-alpha alone in patients with chronic hepatitis C. In 345 CHC patients relapsing after pretreatment with IFN-alpha monotherapy, sustained response was achieved in a 10-fold higher degree with a combination of IFN and ribavirin compared to patients retreated with IFN alone. In 1775 treatment-naive patients with CHC, response rates to the combination therapy was significantly higher in all patient groups with more than 60% of sustained virological response in patients with genotype 2 and 3, while patients with genotype 1 (poorer prognosis) benefit from extended combination treatment duration from 24 to 48 weeks (17 versus 29% of sustained virological response), respectively. CONCLUSIONS: As viral dynamics on one side and host immune response on the other feature as two landmarks on which the manifestation of viral persistence and chronic viral infections is established, some similarities of HCV and HIV disease are striking. An unusual endogenous IFN-alpha system is associated with both infections and is a negative prognostic factor to response to treatment with IFN-alpha in CHC as well as AIDS-KS. The consequences for treatment options with IFN are a combination with ribavirin in CHC and a graduated systemic treatment schedule in AIDS-KS starting with IFN-treatment in early disease followed by chemotherapy in advanced stages of KS.