The rise and fall of new treatment options for chronic hepatitis C

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic liver disease. It is a life-shortening disease associated with liver cirrhosis and hepatocellular carcinoma. The main goal of treatment for chronic hepatitis C (CHC) is to prevent liver-related morbidity and mortality. In this thesis, new treatment options and their unsuccessful outcome for CHC (“rise and fall”) are described. HCV replication is a continuous process with a high turnover rate of hepatitis C virions allowing the generation of a heterogeneous quasi-species population which are negatively associated with responsiveness to interferon alpha therapy. Interferon alpha induces a bi-phasic decline in HCV load. The decline in the first phase is dose-dependent, suggesting that high dosing can induce a more pronounced decline. Beneficial effects of amantadine on HCV have been reported in previous non-responders. Addition of amantadine to (PEG-) interferon alpha and ribavirin was studied in 297 treatment-naive CHC patients. Amantadine did not enhance SVR and had no effect on primary non-response, breakthrough or relapse rates. Severity, potential risk factors for and underlying mechanisms of anemia during anti-HCV therapy were evaluated in 44 patients. Anemia occurred in 98% of patients. Decrease of Hb was associated with higher baseline Hb, ribavirin dose >15mg/kg bodyweight/day and lower pre-treatment platelet levels. No differences in membrane phospholipid composition between erythrocytes of anemic patients and healthy controls were found. The erythrocytes of CHC patients on antiviral treatment were not more susceptible to osmotic or bile-salt induced stress than the erythrocytes of healthy persons. We identified possible risk factors for more pronounced anemia during anti-HCV treatment and evaluated endogenous erythropoietin response in 145 naive CHC patients on PEG-interferon/ribavirin treatment. More pronounced anemia was associated with older age, lower baseline creatinine clearance, higher baseline hemoglobin levels, a deeper decrease in hemoglobin levels after 2 weeks and higher serum ribavirin concentrations at week 24 of antiviral therapy. Hb decrease was not associated with the final treatment result. Erythropoietin levels increased during antiviral treatment. Comparison of rise in erythropoietin levels in our study population with the normal response to anemia, showed a suboptimal endogenous EPO response in CHC patients during PEG-interferon/ribavirin treatment. Alpha-1-antitrypsin (A1AT) deficiency has been reported to be more common in CHC patients with advanced liver disease than in healthy controls. The prevalence of A1AT alleles heterozygosity and its effect on anti-HCV treatment outcome were retrospectively studied in 1048 patients. A1AT heterozygosity was found in 6% of patients and did not affect SVR rates. The effect of extracorporeal whole body hyperthermia (EWBH) was studied in 13 CHC patients. 62% of patients reached the primary endpoint of viral reduction of at least 90%. However, within one day, levels of HCV RNA returned to pre-treatment levels and the decrease in viral load was not sustained in any of the patients. EWBH induced 359 adverse and 42 serious adverse events (SAE). The most adverse events were mild to moderate side effects which resolved without persistent sequelae. Most of the SAEs were related to muscle and liver cell damage and recovered in all patients.