B型肝炎與相關長期慢性病預防措施經濟評估

Abstract

背景 B型肝炎病毒感染是全球性重要的健康問題。要能預防B型肝炎病毒感染必須了解其傳染途徑，但往往很難直接觀察到，所以數學模式的推估提供另一條了解的途徑。包含疫苗、免疫球蛋白的施打及在懷孕後期的婦女身上預防性投以干安能等有許多預防策略可阻斷其傳染，目前缺乏同時評估這些預防策略的成本效用分析，尤其是考量到B型肝炎病毒感染造成的長期慢性病變所造成的影響。本論文包含三大主題：(1) 用隨機過程來模擬B型肝炎病毒感染的動態過程，並同時考量到垂直感染與水平感染不同的比例； (2) 統整過去文獻，整合分析(meta-analysis)干安能的使用對阻斷B型肝炎病毒垂直感染的效益； (3) 使用決策分析來評估全面施打疫苗及孕婦預防性使用干安能的長期效用及成本效益。 研究方法 包含易感受期、潛伏期、活動期、帶原期及復原期的五階段的隨機模式被用來模擬B型肝炎病毒感染的過程，並同時考量到垂直感染與水平感染。使用貝式的方法來整合分析過去發表的三個研究關於孕婦在懷孕後期預防性使用干安能的效益。使用決策分析來比較1984年全面性疫苗施打與不施打疫苗的成本效用及2008年外加於現今全面施打疫苗，懷孕後期預防性使用干安能的成本效用。成本效用分析所使用的馬可夫過程定義為一連串的狀態，包含：急性B型肝炎病毒感染、無症狀帶原者、慢性肝炎、肝硬化、失去代償性肝硬化、肝癌及死亡。成本效用分析以3%折扣率來計算每品質調整後人年和所減少的急性感染個數的增加成本效益比。藉由指定一連串特定的分布給不同的參數，蒙第卡羅模擬產生5000個增加成本效益比模擬值並以之做隨機性成本效用分析。 結果 在五階段的模式中，每年易感受期轉換到潛伏期的速率估計為1.1-3.5%，每年潛伏期到活動期估計為0.072-1.112，每年活動期到帶原期則為0.119-0.184，而且活動期及帶原期回到復原期分別為每年1.4-2.4%和4.8-8.8%。在受感染的個體中估計其中41.4-80.2%是藉由垂直感染得到。在同時考量到不同研究的異質性情況下，孕婦在懷孕後期預防性使用干安能相對於未使用者在統計學上顯著的可見約減少一半的垂直感染 (相對危險性=0.52；95%信賴區間：0.24-0.94)。全面性施打疫苗估計約可減少86%肝癌及死亡的個案。平均每人可藉由全面施打疫苗多增加3.9年的壽命。成本效用分析顯示全面施打疫苗比不施打疫苗整體花費更少且效益更好。根據文獻回顧顯示，干安能的使用可降低血中98.3%的B型肝炎病毒脫氧核糖核酸(DNA)及減少48%的垂直感染。相對於目前的疫苗政策外加預防性使用干安能，就健康照顧提供者的角度其邊際成本效用比為$47,059，而就整體社會層面來看則是花費更少且效益更好。 結論 B型肝炎病毒垂直感染占全部傳染途徑的比例在同一國家的不同地區也有所不同，在台灣南部地區較高(80%)，而在北部地區較低(41%)。根據整合過去的研究顯示，預防性干安能的使用可減少約一半的垂直感染。成本效用分析顯示全面施打疫苗比不施打疫苗整體花費更少且效益更好。相對於目前的疫苗政策外加預防性使用干安能，就健康照顧提供者的角度其增加成本效用比為$47,059，而就整體社會層面來看則是花費更少且效益更好。這些發現顯示，就目前全面性施打疫苗的政策下，如能外加在高危險性母親身上預防性投予干安能可望能改善疫苗所不及之處並且此一政策是具成本效益的。

Background Hepatitis B virus infection is a major health problem worldwide. Understanding the mode of HBV transmission route is important but it is difficult to observe directly so mathematical modeling is an alternative approach. There are multi-level prevention strategies for perinantal transmission including immunization, immunoglobulin injection and maternal lamivudine prophylaxis use in third gestation trimester. Moreover, there is lacking of evaluation, particularly long-term follow-up, of the cost and effectiveness of these prevention strategies simultaneously for the hepatitis B virus infection and its related sequelae. The current thesis focused on three major themes, including (1) modeling the dynamics of HBV infection with a stochastic process making allowance for the mixture proportion of vertical transmission and horizontal transmission; (2) assessing the efficacy of lamivudine use in arresting perinatal transmission through a meta-analysis of literatures; (3) economic evaluation of long-term effectiveness and cost-effectiveness of universal vaccination and lamivudine use. Method For transmission mode, a five-state stochastic model, including susceptible, latent period, active viral replication, carrier and recovery, was use to quantify the dynamics of HBV infection with the consideration of vertical transmission and horizontal transmission. By including three studies on maternal lamivudine use in late pregnancy, a meta-analysis using a Bayesian approach was conducted. A decision analysis was performed to compare total costs and effectiveness between the prevention strategies: universal vaccination and no-vaccination in the year of 1984 and maternal lamivudine use and universal vaccination in the year of 2008. The Markov process was defined as a series of states including acute hepatitis B virus infection, asymptomatic carrier, chronic hepatitis, compensated and decompensated cirrhosis, hepatoma, and death. The incremental cost-effectiveness ratio per quality-adjusted life years gained and acute infection averted calculated at a 3% discount rate. By assigning a series of specific distributions to each parameter, a probabilistic cost-effective analysis using Monte Carlo simulation was conducted to yield 5000 incremental cost-effectiveness ratio replicates. Result In five-state model, the transmission parameter of annual infection rate for susceptible subjects was estimated to be 1.1-3.5% and 0.072-1.112 per year from latent period to active viral replication. Approximately with rate of 0.119-0.184 per year active viral replication may leave as chronic carrier. Annual recovery rates were 1.4-2.4% and 4.8-8.8% for carrier and transient viremia, respectively. Approximately 41.4-80.2% infected subjects were derived from vertical transmission. After allowing for heterogeneity, the efficacy of the maternal lamivudine use statistically significantly halves perinatal transmission compared with the untreated group (RR= 0.52, 95% CI: 0.24-0.94). The effectiveness of a universal vaccination program for reducing hepatocellular carcinoma cases and deaths was approximately 86% compared to no vaccination. The average life years gained per subject as a result of such a universal vaccination was 3.9. The vaccination program dominated over a no-vaccination program (less cost and more effectiveness). Given literature review on the application of lamivudine, the overall efficacy in reducing Hepatitis B virus DNA level was 98.3 % and 48 % in reducing vertical transmission with outcomes measured by HBsAg or Anti-HBc. The incremental cost-effectiveness ratio for prophylactic strategy versus routine active-passive immunoprophylaxis was $47,059 from health care payer perspective whereas dominance has been noted for societal viewpoint. Conclusion Prophylactic lamivudine use can reduce 50% chance of perinatal transmission related to hepatitis B virus infection based on integrated empirical data. The proportion of vertical transmission among all HBV infection varies even in different areas of the same country, which was higher in southern area (80%) and lower in northern area (41%) of Taiwan. The vaccination program dominated over a no-vaccination program (less cost and more effectiveness). The incremental cost-effectiveness ratio for prophylactic maternal lamivudine use versus routine universal vaccination was $47,059 from health care payer perspective whereas dominance has been noted for societal viewpoint. These findings suggest the administration of lamivudine to mothers with high HBV viremia added to current vaccination strategy may improve the vaccination breakthrough and seem to be cost-effective.