抗B型肝炎病毒藥物治療之長期療效評估

Long-Term Effectiveness of Antiviral Therapy for Patients with Chronic Hepatitis B

葉怡君(Yi-Chun Yeh)

指導教授 ： 賴美淑

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/博士(2015年)

https://doi.org/10.6342/NTU.2015.10840

摘要

研究背景與目的：
B型肝炎是常見的傳染性疾病，許多末期肝病(如：肝硬化、肝癌)的發生與肝癌復發，皆與B型肝炎感染有關。因此，B型肝炎防治計畫，除了藉由疫苗防治控制B型肝炎感染外，必須透過更積極抗病毒藥品治療，控制B型肝炎病毒，舒緩肝臟發炎狀況，以期望延緩或降低肝硬化與肝癌的發生與復發。雖然過去研究業已指出抗病毒藥品降低肝硬化與肝癌發生與復發的療效，然而受限於研究樣本數，結果未有一致性。因此，本研究將評估 (1) 慢性B型肝炎病人，接受有治療期限規定之lamivudine、interferon或peg-interferon治療的長期療效，以及 (2) B型肝炎相關肝癌且接受治癒性肝癌治療病患，後續接受輔助性抗病毒治療的長期療效。
研究材料與方法：
本研究利用全民健康保險資料庫(National Health Insurance, NHI)與癌症登記資料庫(Taiwan Cancer Registry, TCR)建立世代研究，選取研究2004至2010年間，診斷為慢性B型肝炎病人，與新診斷並接受治癒性肝癌治療之B型肝炎相關肝癌病人，為研究對象。利用治療機率倒數加權(Inverse probability of treatment weighting, IPTW)以及傾向分數配對(Propensity score matching)進行校正，以Cox 比例風險模式(Cox proportional hazard model)，估計研究事件之風險比(Hazard ratios, HRs)與95%信賴區間(confidence intervals, CIs)。
研究結果：
於慢性B型肝炎病患研究中，相較於未治療組，有治療期限規定下lamivudine能有效降低肝癌 (HR, 0.46; 95%CI, 0.41-0.51)、肝臟相關疾病死亡(HR,0.68; 95%CI, 0.61-0.77)，以及全死因死亡(HR, 0.70; 95%CI, 0.64-0.76)的發生。此療效於有治療期限規定之interferon治療亦可發現相似的結果(肝癌：HR, 0.22; 95%CI, 0.15-0.31；肝臟相關疾病死亡：HR, 0.14; 95%CI, 0.07-0.27；全死因死亡：HR, 0.10; 95%CI, 0.06-0.18)。
於B型肝炎相關肝癌且接受治癒性肝癌治療病患研究中，接受輔助性抗病毒治療的病患，相較於未治療組，有較高風險的肝癌復發 (HR, 1.19; 95%CI, 1.03-1.37)，以及全死因死亡(HR, 1.22; 95%CI, 0.98-1.51)的發生。於治癒性肝癌治療後，不同時間點接受輔助性抗病毒治療，與肝癌復發及全死因死亡發生無顯著性相關。
結論：
本研究證實有治療期限規定之lamivudine, interferon與peg-interferon抗B型肝炎病毒藥品，用於治療慢性B型肝炎病患，可有效降低肝癌與死亡發生。然而，將抗B型肝炎病毒藥品，用於輔助治療B型肝炎相關肝癌且接受治癒性肝癌治療病患，則未觀察到其降低肝癌復發與死亡發生之療效。

關鍵字

慢性B型肝炎 ； B型肝炎相關肝癌 ； 抗病毒治療 ； 肝癌 ； 死亡

並列摘要

BACKGROUND AND OBJECTIVE:
Hepatitis B virus (HBV) is one of high prevalence and serious global health problem. The end-stage liver diseases incidence and hepatocellular carcinoma (HCC) incidence or recurrence may be attributed to viral hepatitis B. Therefore, HBV control programs must be augmented by active antiviral treatment among patients with chronic hepatitis B (CHB) or HBV-related HCC. The efficacy of anti-HBV treatments in mitigating the incidence or recurrence of HCC and mortality has not yet been substantiated. This study was (1) to evaluate the effects of finite-period lamivudine (LAM) and interferon (IFN) or peg-interferon (PEG-IFN) treatments on HCC development and mortality among CHB patients, as well as (2) to investigate the effect of adjuvant antiviral therapies on HCC progression and deaths in HBV-related HCC patients following curative treatment.
MATERIALS AND METHODS:
A nationwide inception cohorts of CHB patients and newly diagnosed HBV-related HCC patients who received curative HCC therapy as the first course of treatment for the years 2004 to 2010 were identified from the National Health Insurance (NHI) program and the Taiwan Cancer Registry (TCR), respectively. This study employed a Cox proportional hazards model based on inverse probability of treatment weighting (IPTW) and propensity score matching to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS:
CHB patients who underwent finite-period lamivudine treatment presented greater reductions in HCC incidence (HR, 0.46; 95%CI, 0.41-0.51), liver-related mortality (HR, 0.68; 95%CI, 0.61-0.77), and all-cause mortality (HR, 0.70; 95%CI, 0.64-0.76) than patients in the untreated group. Finite-period interferon or peg-interferon therapy resulted in similar reductions in HCC incidence (HR, 0.22; 95%CI, 0.15-0.31), liver-related mortality (HR, 0.14; 95%CI, 0.07-0.27), and all-cause mortality (HR, 0.10; 95%CI, 0.06-0.18).
HBV-related HCC patients following curative therapy who underwent adjuvant antiviral therapy demonstrated a higher risk of HCC progression (HR, 1.19; 95%CI, 1.03-1.37) and death from all causes (HR, 1.22; 95%CI, 0.98-1.51) than untreated patients. The interval length between initiation of antiviral therapy and first-line curative treatment did not show a significant association with HCC progression and all-cause mortality.
CONCLUSIONS:
Our results demonstrate the effectiveness of finite-period lamivudine, interferon, or peg-interferon anti-HBV therapy in reducing the incidence of HCC and mortality in the long-term follow-up of a large CHB patient population. However, this effect did not be found in reducing the risk of HCC progression or mortality in HBV-related HCC patients after curative therapy.

並列關鍵字

Chronic hepatitis B ； Hepatitis B Virus-related Hepatocellular carcinoma ； Antiviral therapy ； Hepatocellular carcinoma ； Mortality

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