肝細胞癌的初級、次級和三級預防策略之成本效益分析

Abstract

前言： 儘管台灣在過去三十年中，透過初級至三級預防性策略降低肝細胞癌發生，已有顯著成效，然而如何結合不同層級的預防策略，應用族群和個人層次之預防策略以獲得最佳效果是目前肝癌防治相當有趣的議題。尤其當經濟觀點評估應用於施行全面性新生兒Ｂ型肝炎疫苗施打後及對於未接種疫苗的出生世代結合腹部超音波篩檢與抗病毒治療之議題，截至目前為止尚未有相關研究進行深入探討。 本研究目的如下： (1) 利用台灣實證資料，呈現並探討全面性接種B型肝炎病疫苗、全民健康保險實施（NHI）、腹部超音檢查及抗病毒治療之後，以長期資料探討台灣肝癌發生率、死亡率和致死率之時間趨勢之經驗。 (2) 在無任何介入模式下，發展肝癌自然病史模型（從病毒感染、健康復原、帶原者及慢性肝病）及肝癌預後模式進行經濟評估之比較。 (3) 發展一系列馬可夫決策模型，以肝癌疾病自然史為基礎，包含不同介入性策略及肝炎病毒感染、慢性肝病和肝癌之後續病程變化及預後。 (4) 根據本研究目的(2)所呈現台灣目前情況下之肝炎病毒感染盛行率和發生率以及肝癌發生率等參數，以模擬該人口之假設性世代，進一步以(1)中呈現各種不同介入性計畫進行效益和效用評估。 (5) 針對合併不同介入性計畫之不同策略組合進行經濟評估，包括全面性B型肝炎疫苗接種、大規模腹部超音波篩檢及抗病毒治療等。 (6) 根據肝炎患者對於抗病毒治療後之病毒反應（sustained virological response ,SVR）不同而提供個人化監控計畫進行經濟評估。 (7) 比較肝癌治療之射頻燒灼術(Radiofrequency Ablation, RFA)及外科切除手術之成本效益分析。 材料與方法： 本研究透過整合B型肝炎疫苗接種和抗病毒治療之初級預防性策略、次級預防之腹部超音波篩檢及三級預防性策略，提出了將上述若干預防方案整合為一的整體經濟評價之總體框架。從1984年到2013年，藉由使用生命統計資料來闡明經由各種預防措施相對應的符合條件的四個年齡段出生世代，所產生肝癌時間趨勢流行病學。利用波以松回歸模型估計相對應介入措施的效益。 根據肝癌疾病自然史，本研究從易感受性人口，考量孕婦垂直傳播引起的Ｂ型肝炎感染、恢復或帶原者、慢性肝病、肝細胞癌、補償性和失代償性肝硬化，直到死亡作為無預防性介入組。利用馬可夫決策模型模擬各種不同組合介入措施之成本效益分析，包括全面性B型肝炎疫苗接種、抗病毒治療和腹部超音波篩檢。 對於具有SVR的病患也進行個人化監控計畫的經濟評估。此外，也進行肝癌接受RFA手術與切除手術的成本效益分析比較。 結果： 從2000年以來，肝癌的整體發生率和死亡率已經開始下降。自1985年以來，個案致死率持續下降，尤其在2000年後，即全民健康保險（NHI）實施五年後，下降幅度更加明顯。根據各類與介入計畫接觸的出生世代，將年齡分為四類：<30歲、30-49歲、50- 69歲、70歲以上，我們發現除了老年人（70歲以上）以外，各類年齡層的肝癌發生率呈下降趨勢。 就單一模式的初級和次級預防的效用和效益來看，普遍接種疫苗有效降低88％（95％CI：85％，90％）肝臟疾病和因肝癌所導致死亡，亦導致所有個案的死亡比例降低15％（95％CI： 11％，20％）。透過抗病毒治療可避免16％（95％CI：8％，25％）因HBV所造成肝癌死亡、可避免2％（95％CI：0.2％，5.6％）因HCV所造成肝癌死亡和可避免18％（95％CI：10％，23％）因HBV和HCV所造成肝癌死亡。大規模腹部超音波篩檢，相較於沒有介入組，可減少約14％（95％CI：6％，20％）的肝癌死亡個案。相較於沒有介入組，合併使用全面免疫接種與抗病毒治療、大規模篩檢、兩者皆使用者則分別減少約90％（95％CI：88％，91％）、89％（95％CI：87％，91％）和91％（95％CI：86％，95％）肝癌死亡。若以全面性疫苗接種策略作為參考組，合併使用全面免疫接種與抗病毒治療、大規模篩檢、前兩者皆使用者，其分別可以降低17％（95％CI：7％，28％），13％（95％CI：3％，23％）和29％（95％CI：-14％，59％）肝癌死亡。 成本效益分析結果顯示，單一模式的全面性免疫接種較無介入措施組顯著優勢（節約成本），達成本效益的機率是100％。任何預防性介入策略與疫苗接種組合，較無介入措施組為優勢（節省成本）。單一模式HBV和HCV的抗病毒治療、篩檢介入策略，相較於無介入措施組的增加成本效益比（ICER）分別為5,137美元（95％CI：672美元，22,245美元）和3,323美元（95％CI： - 1,339美元，16,002美元）。 合併使用全面性疫苗接種與HBV和HCV的抗病毒治療、篩檢策略、前兩者皆使用者相較於全面疫苗接種的ICER分別為4,633美元（95％CI：- 33,414美元，34,875美元），11,668美元（95％CI：- 58,164美元，31,715美元）和9,102美元(95％CI：- 103,320美元，33,628美元)。然而，在考量參數的不確定性下，成本效益的機率達到了60％-70％。針對使用干擾素治療後之持續性病毒反應的低風險患者，藉由個人化策略延長監測的間隔可以將降低60％成本，而不損害生命年。成本效益分析結果顯示，手術成本較低（1155.37美元），且獲得了0.6231的壽命年，這說明手術比RFA為優勢（節省成本）。 結論： 本論文透過流行病學時間趨勢的實證證據，評估了各種預防策略降低肝癌發生率和死亡率的實證效益。進一步針對各種介入措施的不同組合，進行了系統性的經濟評估，評估結果顯示全面施打疫苗策略，即使與各種抗病毒治療組合，也是節省成本。另外，對於進行抗病毒治療後的SVR患者，可以提供個人化的最佳監測策略可行性相當高。在考慮各種介入措施的不同組合下，進行系統的經濟評估，對於與台灣有類似肝炎病毒感染情況相同的國家是非常有幫助的。

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.