Immunological and virological changes during treatment for hepatitis C virus infections

Abstract

Chronic HCV aff ects millions of people worldwide with major impact on the morbidity and mortality of the people aff ected. In HCV-infected patients coinfected with HIV, an 156 accelerated progression of liver fi brosis is seen, even with successful suppression of HIV due to combination antiretroviral therapy (cART). Current therapeutic regimens with pegIFN-alfa and ribavirin are only moderately successful, especially in “diffi cult to treat” patients with genotype 1 or 4 and with a HIV coinfection. Despite the lack of reliable small animal models, progress has been made with regard to the interplay between pegIFN-alfa and ribavirin on the one hand and HCV and the immune system on the other hand. The studies described in this thesis have contributed in diff erent ways to these issues. The acute HCV cohort study (chapter 3) contradicted earlier theoretical reasoning (chapter 2) about the effi cacy of pegIFN-alfa monotherapy adding important data in favor of using pegIFN-alfa in combination with ribavirin for the treatment of acute HCV in HIV-infected patients (chapter 4). The study evaluating the viral load change in the fi rst 48 hours after the start of pegIFN-alfa/ ribavirin therapy (chapter 5) generated a new hypothesis with regard to the working mechanism of pegIFN-alfa. The immunological studies evaluating the role of HCV-specifi c T-cells in both HCV mono-infected and HIV/ HCV coinfected patients demonstrated that HCV-specifi c T-cells do not seem to be involved in therapy-induced viral clearance (chapter 6 and 7). Finally, higher rates of activated caspase-3, activated caspase-8 and CD95 were observed in chronic HCV-infected patients compared to healthy controls (chapter 8) which leads to new research areas in the fi eld of T-cell apoptosis. In the next couple of years, very exciting new developments are expected in the fi eld of viral hepatitis C. The development of an immunogenic mouse models will revolutionize the research into HCV pathogenesis leading to major improvement in the understanding of HCV cell entry, immune evasion and treatment-induced viral clearance. Furthermore, the introduction of HCV protease- and polymerase-inhibitors will have major therapeutic implications revolutionizing the future anti-HCV therapy in terms of regimen and duration. This will hopefully lead to easy eradication of HCV thereby minimizing its eff ects on the human population