Up to 170 million people are infected with Hepatitis C Virus worldwide. Chronic HCV infection is the leading cause of fibrosis, cirrhosis and liver cancer. Treatment options are currently limited to interferon based therapies alone or in conjunction with direct acting antivirals (DAA) such as viral protease inhibitors. While the implementation of DAAs has increased the effective cure rate of HCV infected individuals, treatment is far from being complete or ideal. New DAAs with unique modes of action will be necessary to compliment our current repertoire of anti-HCV therapies. Previously our lab identified three dihydropyridines (DHP) as potent HCV replication inhibitors. We investigated and characterized the anti-HCV properties of nine additional DHP compounds. We also show that DHP compounds inhibit IRES dependent translation in full-length HCV. This inhibition of two separate steps of the viral life cycle may be a unique feature of DHPs making them superior DAAs. Among these DHPs, efonidipine emerged as the most effective HCV replication and translation inhibitor with the least toxicity. Using a real-time evolution strategy, we developed and characterized a mutant virus which was resistant to DHPs and several other drugs which modify intracellular calcium stores. Our results further the understanding of DHP inhibition of HCV providing a solid basis for investigation of more structurally related compounds as potent inhibitors of HCV.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Freiburg i. Br., Universiẗat, Diss., 2009.

Zugl.: Giessen, Universiẗat, Diss., 2005.

Berlin, Freie University, Diss., 2005. / Dateiformat: zip, Dateien im PDF-Format.

This thesis examines the effect of hepatitis C virus infection (HCV) on health-related quality of life (HRQOL) to define burden of disease at individual and population levels. A systematic review of HCV HRQOL studies was undertaken with translation of Short Form-36 (SF-36) Health Survey data into community-weighted health state utilities using three different methods. Derived estimates of health utilities were 0.87 for HCV treatment-induced sustained virological response (SVR); 0.81 for pre-cirrhosis; 0.76 for compensated cirrhosis; 0.69 for decompensated cirrhosis; 0.67 for hepatocellular carcinoma (HCC); and 0.77 for liver transplant. The HCV health state utilities varied considerably from expert estimates, with relatively lower estimates for early liver disease and higher estimates for advanced liver disease, but were comparable to direct patient-elicited utilities. A study utilising data from population-based health surveys incorporating HCV screening among prisoners at Australian correctional centres in 1996 and 2001 showed no measurable effect of HCV on HRQOL, including that attributable to HCV viraemia. Compared to uninfected Australian norms, prisoners had lower HRQOL irrespective of HCV status. Several non-HCV factors such as age, co-morbidity, severity of depressive symptoms, and medical care utilization influenced HRQOL. A prospective study of health outcomes among HCV monoinfected and HIV/HCV coinfected individuals conducted at Sydney tertiary level hepatitis clinics between 2003 and 2005 found similar cognitive function, mood, and HRQOL patterns in these two HCV groups in the context of pegylated interferon (PEG-IFN) alfa-2a and ribavirin therapy. The HCV groups had similar levels of pre-treatment HRQOL impairment, further on-treatment deterioration, and posttreatment improvements. SVR was associated with significant HRQOL improvements, but mental HRQOL improvement was also seen in individuals not achieving an SVR. The impact of HCV treatment uptake on HCV-related burden of disease at a population level in Australia was examined using a mathematical model. The model estimated that in 2004, there were ~181,500 cases of chronic HCV infection, 7,020 with HCV-related cirrhosis, and annual incidence of 238 cases of HCV-related liver failure and 70 cases of HCV-related HCC. Compared to no treatment, current treatment levels (~1% of HCV-infected individuals per annum) would reduce projected HCV-related cirrhosis and advanced liver disease numbers by ~30% at 2020 and a gain of ~122,200 Quality-Adjusted Life Years (QALYs). Even with a five-fold increase from current treatment levels, advanced liver disease numbers will continue to increase through 2020 but will be reduced by ~55% and a gain of ~483,200 QALYs.

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Thesis (M.Sc. (Hons.)) -- University of Western Sydney, 2007. / A thesis submitted towards the degree of Master of Nursing (Honours) in the University of Western Sydney, College of Health and Science, School of Nursing. Includes bibliographical references.

No description available.