編者按：最近莊輝院士等發表在中華肝臟病雜誌的《B型肝炎臨床治癒：共識與爭議》[1]（相關連結）（以下簡稱為《共識與爭議》）中認可了目前臨床治癒是慢B肝治療的理想終點，然而在科學工作者不斷探索優化抗病毒治療策略的過程中，專家認為無論是聯合核苷（酸）類似物和聚乙二醇幹擾素的治療策略，還是適時終止抗病毒藥物治療，抑或是加速創新藥物的研發，目前都充滿著機遇與爭議。
針對《共識與指南》中提出的臨床治癒爭議問題，根據慢B肝臨床治癒發展歷程及相關研究，肝霖君將推出3篇系列文章，嘗試對其中的爭議問題進行討論和分析，第一篇為基於聚乙二醇幹擾素α治療優勢人群的相關爭議探討（相關連結）。今天第二篇將就基於慢B肝患者抗病毒治療停藥後能否獲得長期受益進行討論。
《共識與爭議》提出：儘管也有證據表明，適時停藥可提高患者 HBsAg 清除率，但停藥是否能給患者帶來長期獲益仍存在著爭議。
慢B肝患者抗病毒治療停藥的相關研究還是比較多的，我們將分為基於聚乙二醇幹擾素α（PEG IFNα）治療停藥和核苷類藥物（NA）治療停藥後患者的長期受益來討論。
一、抗病毒治療可顯著改善慢B肝患者的遠期結局
慢性B型肝炎防治指南（2019年版）[2]指出：非肝硬化HBV感染者的肝癌年發生率為0.5%-1.0%。而肝硬化患者肝癌年發生率達3%-6%。
以未治療的慢B肝患者作為對照組的多項研究顯示：未治療的慢B肝患者5年肝癌累積發生率高達15%左右[3-5]，有肝硬化的甚至高達19.6%[6]。
2015年《慢性B型肝炎防治指南》[7]將慢B肝的治療終點分為基本的終點（HBV DNA轉陰）、滿意的終點（HBeAg血清學轉換）及理想的終點（HBsAg清除）。隨著抗病毒治療目標的遞進，慢B肝患者的5年肝癌累積發生率遞減，從獲得基本終點時的3.6%-11.4%，下降到獲得滿意終點時的
近年來多項研究證實慢B肝患者獲得HBsAg清除後可使肝癌發生風險降到最低。2019年版《慢性B型肝炎防治指南》中治療目標中僅強調了追求臨床治癒（HBsAg清除）和降低肝癌發生風險，不再將治療目標分為三個層次。
二、基於PEG IFNα治療的慢B肝患者停藥後可獲得長期獲益
1
基於（PEG）IFNα治療慢B肝患者停藥後持久應答佳
臨床治癒是慢B肝患者抗病毒治療的理想目標，大量研究證實基於PEG IFNα治療慢B肝患者可獲得較高的臨床治癒率，其中優勢患者可達30%-80%。且通過基於（PEG）IFNα治療獲得HBsAg清除的持久性佳，復發風險低[8-11]。
而基於（PEG）IFNα治療未獲得臨床治癒的患者，實際在獲得治療應答（HBeAg血清學轉換或聯合應答）後復發率也低，其長期隨訪的持久應答率也維持在75%以上[12-15]。
2
基於（PEG）IFNα治療停藥後慢B肝患者延遲應答情況佳
PEG IFNα治療慢B肝的優勢在於其免疫調節作用，可使患者獲得停藥後持久和延遲的免疫學應答。
南方醫科大學南方醫院的相關研究發現PEG IFNα治療的慢B肝患者，治療結束時未獲得HBeAg血清學應答和聯合應答的患者中分別有18.2%和15.4%在隨訪期間獲得了HBeAg血清學應答率和聯合應答率[14]。
OSST研究中慢B肝患者基於PEG IFNα治療48周後隨訪1年，發現HBeAg血清學轉換率從治療結束時的17.7%提高至38.7%[8]。
韓國最新研究納入122例完成完整PEG IFNα治療療程的患者，其中7.4%（8/122）的患者獲得了停藥後HBsAg清除[16]。
北京大學第一醫院牽頭的相關研究4年長期隨訪結果顯示 PEG IFNα治療初治HBeAg陽性慢B肝患者HBeAg水平從治療結束時的624.6 S/CO顯著下降到隨訪4年後的59.2 S/CO，HBeAg清除率從治療結束時的19.7%顯著增加到隨訪4年後的63.8%。33.9%的無應答者在隨訪4年期間出現延遲應答[15]。
3
基於PEG IFNα治療的慢B肝患者遠期不良結局風險極低
基於PEG IFNα的優化治療方式可大大提高慢B肝患者HBsAg清除率，且顯著高於NA。而HBsAg清除可將慢B肝患者遠期不良結局發生風險最小化[16-23]，肝霖君曾系統綜述HBsAg清除患者的肝癌發生風險極低（相關連結）。
另外，也有研究證實：採用PEG IFNα治療的患者，即便是未獲得HBsAg清除，其肝組織學均有顯著改善[16,24]，且肝癌發生風險基本與獲得HBsAg清除的患者相似（如重慶醫科大學附屬第二醫院[25]、上海瑞金醫院[26]和臺灣研究[27]等分析PEG IFNα整體治療後肝癌風險，均未區分患者是否獲得HBsAg清除）。
三、基於NA治療慢B肝患者停藥後長期受益與否仍需權衡
1
NA治療的慢B肝患者停藥後復發風險高
無論是基於PEG IFNα還是NA治療獲得HBsAg清除後的持久性也同樣很好[28-31]，但NA治療HBsAg清除率極低，且停藥後復發率高。中國《慢性B型肝炎防治指南（2019年版）》指出對於HBeAg陽性慢B肝患者NA治療 1 年若 HBV DNA 低於檢測下限、 ALT 復常和 HBeAg 血清學轉換後，再鞏固治療至少 3 年（每隔 6 個月複查 1 次）仍保持不變，可考慮停藥，延長療程可減少復發，而對於HBeAg陰性慢B肝患者NA治療後建議HBsAg消失且HBV DNA檢測不到後停藥隨訪。因此很多專家並不建議NA停藥，認為應該長期服用。
然而無論是HBeAg陰性[32-44]還是HBeAg陽性[43-46]慢B肝患者NA治療停藥後，若未獲得HBsAg清除，復發風險極高（相關連結一、相關連結二）。
2
慢B肝患者NA停藥後能否追求HBsAg清除？
HBeAg陰性慢B肝患者NA停藥後雖然面臨著復發的高風險，但是仍有研究發現，這部分人群仍然有著較高的HBsAg清除機會。如何判斷這部分人群會復發還是將會獲得更高的臨床治癒機會，肝霖君也曾系統綜述相關內容（相關連結）。
「宿主主導型」和「病毒主導型」肝炎類型對於預測NA停藥後結局有重要意義，因此區分「宿主主導型」和「病毒主導型」肝炎類型，是擬定再治療決策的關鍵。聯合HBsAg和ALT水平更好地區分病毒主導型肝炎和宿主主導型肝炎：HBsAg較前一水平（在ALT升至峰值前或接近峰值時）下降> 10%反映了宿主正在進行有效的HBV免疫清除（「宿主主導型肝炎」）；反之，如果HBsAg隨著ALT的升高而持續增加，或者在ALT峰值後仍保持高水平，則反映了宿主免疫清除的失敗（「病毒主導型肝炎」）。對於「病毒主導型肝炎」患者而言，需要再治療，若可聯合PEG IFNα治療，仍然有機會獲得HBsAg清除。
而「宿主主導型肝炎」患者，可暫不治療，但需要密切監測生化指標，避免病情加重，以追求遠期受益。
四、抗病毒治療均可降低慢B肝患者肝癌發生風險，PEG IFNα優於NA
然而根據已發表的研究，慢B肝患者經NA治療，肝癌累積發生率相比不治療有顯著降低，但依然處於較高水平[47-53]。
2020年發表的兩項研究表明：慢B肝患者經恩替卡韋或替諾福韋酯長期治療後的肝癌發生風險仍穩定存在，治療前5年和5年後的肝癌發生率無顯著變化，5年的肝癌累積發生率仍然高達9%以上[47,48]。
多年來的臨床研究結果顯示：IFNα治療包括PEG IFNα治療，可以極大降低慢B肝患者的肝癌發生風險，5年的肝癌發生風險基本為1%左右，有的甚至僅有0%[25-27,54-57]。近來年多項比較（PEG）IFNα與NA降低肝癌風險作用的研究均發現：PEG IFNα降低慢B肝患者肝癌風險顯著優於NA[25-27]。
參考文獻：（可上下滑動查看）
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