Enhancing the response to interferon-alpha

Background: Though initially recognized as antiviral agents, it was soon de monstrated that certain neoplasms were particularly sensitive to interferon -alpha (IFN-alpha). Indeed, the initial success of systemic IFN-alpha treat ment in AIDS-associated Kaposi's sarcoma (AIDS-KS) occurred before identifi cation of the human immunodeficiency virus (HIV) and in the absence of any coherent view of KS pathogenesis. With a more comprehensive understanding h ow KS develops and which circumstances provide an increased virulence of th is 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 availab le for patients with chronic hepatitis C (CHC). However, no more than 30% o f these patients show a sustained virological response. Initial therapy wit h a combination therapy of IFN-alpha and ribavirin turned out to be more ef fective than treatment with IFN-alpha alone. To ameliorate response rates i n 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 Virolog y (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 treatme nt options with IFN-alpha, to analyze treatment failures with this cytokine and to ameliorate future strategies of IFN-alpha therapy. It focussed on H IV-related complications as coinfection with hepatitis C virus (HCV) and AI DS-KS, respectively. Methods: A kinetic model of HCV infection based on principles established i n studying HIV-1 infection was presented which is predictive for the outcom e of IFN-alpha treatment. It involves different rates of velocity and compa res the rates of acute clearance after different dosages of IFN-alpha appli cation. Using the hypothesis to fit the changes in serum HCV RNA measured i n 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 KC V production/release. Results: Only recently clinical data revealed a greater benefit of combinat ion therapy with IFN-alpha: and ribavirin compared to IFN-alpha alone in pa tients with chronic hepatitis C. In 345 CHC patients relapsing after pretre atment with IFN-alpha monotherapy, sustained response was achieved in a 10- fold higher degree with a combination of IFN and ribavirin compared to pati ents retreated with IFN alone. In 1775 treatment-naive patients with CHC, r esponse rates to the combination therapy was significantly higher in ail pa tient groups with more than 60% of sustained virological response in patien ts 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 persiste nce and chronic viral infections is established, some similarities of HCV a nd HIV disease are striking. An unusual endogenous IFN-alpha system is asso ciated 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 fo r treatment options with IFN are a combination with ribavirin in CHC and a graduated systemic treatment schedule in AIDS-KS starting with IFN-treatmen t in early disease followed by chemotherapy in advanced stages of KS. (C) 1 999 Elsevier Science B.V. All rights reserved.