Background Despite much effort made to reduce hepatocellular carcinoma (HCC) over past three decades from primary to tertiary prevention in Taiwan, how to combine different levels of preventive strategies to reach the optimal benefit become an interesting subject on the prevention of HCC at population level and individual level. This is particularly relevant to the underpinnings of economic appraisal when the entire population has been intervened by universal hepatitis B vaccination administered to neonates and screening for HCC with abdominal ultrasonography together with the advent of anti-viral therapy for birth cohorts without being vaccinated. However, such a subject has been never addressed. Aims The aims of this thesis are to (1) provide empirical evidence on time trends of incidence, case-fatality, and mortality of HCC after introduction of universal vaccination against hepatitis B virus infection, national health insurance (NHI), abdominal sonography screening, and anti-viral therapy based on Taiwan experiences; (2) develop a natural history (from infection, recovery, carrier, and chronic liver disease) and prognosis of HCC model for the comparator of the following economic appraisal in the absence of intervention program; (3) develop a series of Markov decision model for accommodating how these intervention programs alter the baseline disease natural history and also subsequent prognosis of the sequelae of hepatitis virus infection, chronic liver disease, and HCC; (4) evaluate the efficacy and effectiveness of various intervention programs indicated in (1) through the simulation of a hypothetical cohort with the make-ups of demographic features, the prevalence and incidence rate of hepatitis virus infection, and incidence of HCC similar to Taiwanese scenario based on (2) ; (5) do economic appraisal of various combinations of intervention programs including universal vaccination, mass screening with abdominal sonography, and anti-viral therapy. (6) do economic appraisal of personalized surveillance schedule for those sustained virological response (SVR); (7) compare cost-effectiveness of Radiofrequency Tumor Ablation (RFA) surgery and resected surgery; Materials and Methods Overall framework of economic appraisal of intervention program of HCC from primary prevention with vaccination and anti-viral therapy, secondary prevention with abdominal sonography screening, and tertiary prevention has been proposed to unify each intervention program as a whole. Time-trend epidemiology of HCC by four age bands corresponding to the eligible birth cohort with various intervention was elucidated by using vital statistics since 1984 until 2013. Poisson regression model was used to model the effectiveness of the corresponding intervention programs. The disease natural history of HCC was develop from susceptible population, hepatitis B virus infection considering maternal vertical transmission, recovery, carrier, chronic liver disease, hepatocellular carcinoma (HCC), compensated and decompensated liver cirrhosis and until death to represent no intervention group. An analytical Markov decision model was used to model cost and effectiveness analysis of various combinations of intervention including universal vaccination, anti-viral therapy, and abdominal ultrasonography screening. Economic appraisal was also performed for personalized surveillance schedule for those who had SVR. Cost-effectiveness analysis for the comparison between RFA surgery and resected surgery was also performed. Results The overall incidence and mortality of HCC has started to decline since around 2000. Time trends in case-fatality has consistently declined since 1985 and had a dramatic decrease after 2000, five years after the introduction of national health insurance (NHI). By classifying age band into four categories, < 30 year, 30-49 years, 50-69 years, and 70+ years in accordance with the implementation of various available intervention methods for eligible birth cohorts, we found all the time trends of incidence of HCC except old age group (70+ years) have shown a declining trend due to each category of birth cohort experiencing each corresponding intervention program. For the efficacy and effectiveness of primary and secondary intervention with single modality, universal vaccination contributed to 88% (95% CI: 85%, 90%) reduction of liver diseases and deaths from HCC, which led to 15% (95% CI: 11%, 20%) reduction of all-cause of death compared with no intervention. The anti-viral therapy was associated with 16% (95% CI: 8%, 25%), 2% (95% CI: 0.2%, 5.6%), and 18% (95% CI: 10%, 23%) HCC death averted due to HBV, HCV, and both, respectively. Abdominal ultrasonography mass screening, conferred 14% (95% CI: 6%, 20%) reduction of death from HCC. The combined use of universal vaccination with anti-viral therapy, mass screening, and both made contribution to 90% (95% CI: 88%, 91%), 89% (95% CI:87%, 91%), and 91% (95% CI: 86%, 95%) reduction of death from HCC, respectively, compared to no intervention. The corresponding figures were 17% (95% CI: 7%, 28%), 13% (95% CI: 3%, 23%), and 29% (95% CI: -14%, 59%) compared with the scenario of vaccination taken as the reference group. The cost-effectiveness analysis shows that single modality of universal vaccination dominated no intervention (cost-saving). The probability of being cost-effective was 100%. Even any prevention strategy combined with vaccination resulted in dominance (cost-saving) as compared with no intervention. The incremental cost-effectiveness ratio (ICER) of single modality of anti-viral therapy of HBV and HCV, and screening was $5,137 (95% CI: $672, $22,245), and $3,323 (95% CI: -$1,339, $16,002), respectively, than no intervention. The ICERs for the combined used of vaccination with anti-viral therapy of HBV and HCV, screening, and both were $4,633 (95% CI: -$33,414, $34,875), $11,668 (95% CI: -$58,164, $31,715), and $9,102 (95% CI: -$103,320, $33,628), respectively, than universal vaccination only. However, the probability of them reached plateau to 60%-70% given the uncertainty of parameters. A personalized strategy with prolonged surveillance intervals for low risk patients with sustained virological response after interferon could reduce cost by 60% without compromise of the life-year gained. The cost-effectiveness analysis suggests that surgery cost less ($1155.37) but earned 0.6231 life-years, which suggests surgery dominated RFA (cost-saving). Conclusions This thesis has evaluated the effectiveness of reducing incidence and mortality of HCC by various intervention programs by using the empirical data on time-trend of epidemiology. Systematic economic appraisal for evaluation of various combinations of intervention programs have been done to show universal vaccination even in the combination with anti-viral therapy was always cost-saving screening. Optimal personalized surveillance for those with SVR seems available after the administration of anti-viral therapy. Such systematic economic appraisal is very helpful for the country with the same scenario of hepatitis virus infection in Taiwan when various combinations of intervention programs have been considered.