乙型肝炎病毒相關(guān)肝細(xì)胞癌抗病毒治療的作用和意義

黃罡 周偉平 吳孟超

·專題論壇·

乙型肝炎病毒相關(guān)肝細(xì)胞癌抗病毒治療的作用和意義

黃罡 周偉平 吳孟超

肝細(xì)胞癌(hepatocellular carcinoma，HCC)為我國(guó)常見惡性腫瘤，雖然肝臟外科技術(shù)飛速發(fā)展，但近30年來肝癌病人預(yù)后無明顯改善，大家往往重視局部治療，對(duì)肝癌病人的全身綜合治療關(guān)注不夠，尤其是忽視了對(duì)我國(guó)肝癌的最主要致病因素乙型肝炎病毒(hepatitis B virus，HBV)的研究和有效治療。結(jié)合我們自己在這一方面前期的研究結(jié)果以及國(guó)內(nèi)外近年來發(fā)表的相關(guān)文獻(xiàn)，系統(tǒng)闡述了HBV相關(guān)HCC抗病毒治療的作用和意義?？共《局委熆捎行ьA(yù)防肝癌病人HBV再激活，改善HCC病人肝臟炎癥、肝纖維化，顯著降低肝癌術(shù)后復(fù)發(fā)率，提高生存率。并討論核苷類抗病毒治療的適應(yīng)證、藥物選擇以及治療療程等相關(guān)問題。研究結(jié)果還顯示抗病毒應(yīng)答時(shí)間快慢、病毒耐藥變異等均是影響HCC術(shù)后復(fù)發(fā)的危險(xiǎn)因素，因此選擇速效、低耐藥核苷類藥物。并主張長(zhǎng)期抗病毒治療，以最大限度改善HBV相關(guān)HCC病人預(yù)后。積極有效的抗病毒治療應(yīng)該成為HBV相關(guān)HCC病人綜合治療的重要組成部分。

抗病毒治療； 肝細(xì)胞癌； 乙型肝炎病毒； 預(yù)后

肝細(xì)胞癌(hepatocellular carcinoma，HCC)，為我國(guó)常見惡性腫瘤，手術(shù)切除是可切除肝癌最有效的治療方法之一[1]，但近30年來我國(guó)HCC術(shù)后5年生存率并無明顯提高，一直維持在50%左右[2]。近年來隨著臨床和基礎(chǔ)研究的深入，發(fā)現(xiàn)乙型肝炎病毒(hepatitis B virus，HBV)不僅是肝癌發(fā)生的最重要致病因素，同樣也在肝癌的發(fā)展及預(yù)后等方面均起著關(guān)鍵的作用[3-4]。在綜合治療乙型肝炎相關(guān)肝癌的過程中，為何要給與積極抗病毒治療，如何給予有效的抗病毒治療，日益受到重視。

一、抗病毒治療預(yù)防HCC發(fā)生

HBV慢性感染是我國(guó)HCC發(fā)生的最主要病原之一，HBV持續(xù)感染，及其感染狀態(tài)是HCC發(fā)生、發(fā)展的重要危險(xiǎn)因素[5-6]。慢性乙型肝炎(chronic hepatitis B，CHB)病人HCC發(fā)生率為403～470/105[6]。導(dǎo)致HBV相關(guān)性HCC發(fā)生的病毒學(xué)因素有：HBV DNA水平、HBeAg持續(xù)陽性時(shí)間、病毒基因型、C區(qū)啟動(dòng)子變異、X基因變異等[7]。而通過長(zhǎng)期抑制HBV復(fù)制，可明顯降低HBV復(fù)制水平，這是防治HBV相關(guān)性HCC的關(guān)鍵手段[8-9]。同時(shí)抑制病毒復(fù)制可減輕肝臟炎癥活動(dòng)、逆轉(zhuǎn)肝纖維化，抗病毒還可明顯降低HBV陽性病人終末期肝病(食管靜脈曲張破裂出血、肝性腦病、原發(fā)性腹膜炎等)的發(fā)生率[10]。

已有充分證據(jù)表明抗病毒治療可減少CHB、慢性丙型肝炎病人進(jìn)展至HCC的比率，多個(gè)指南均將抗病毒治療作為防治HBV相關(guān)性HCC發(fā)生的重要手段[11-13]。

二、抗病毒治療對(duì)HBV相關(guān)HCC預(yù)后的影響

1.抗病毒治療預(yù)防HBV再激活 HBV陽性的腫瘤病人在接受手術(shù)、化療、放療及免疫抑制劑治療時(shí)易引起HBV再激活，導(dǎo)致HBV-DNA水平升高，引起肝臟炎癥加重、肝功能損害甚至肝衰竭[14-15]。同樣在HBV相關(guān)HCC的手術(shù)、經(jīng)導(dǎo)管肝動(dòng)脈化療栓塞術(shù)(TACE)、消融及放療等治療中也會(huì)引起HBV再激活[14,16-17]。我們回顧性研究了1 609例術(shù)前低病毒水平的HCC病人后，發(fā)現(xiàn)即使是術(shù)前病毒水平較低的病人術(shù)后也可以發(fā)生HBV再激活，其術(shù)后12個(gè)月內(nèi)HBV再激活率高達(dá)19.1%。即使是術(shù)前HBV-DNA陰性(HBV-DNA<200 U/ml)的病人術(shù)后12個(gè)月內(nèi)也有16.7%的再激活發(fā)生率，而病毒水平>200 U/ml的病人術(shù)后12個(gè)月內(nèi)HBV再激活率高達(dá)29.4%。而其中接受術(shù)前抗病毒治療的病人，再激活發(fā)生率明顯低于未抗病毒病人(4.7%比20.6%)[16]。反復(fù)的手術(shù)、TACE、消融治療更易使HBV再激活，進(jìn)而使肝衰竭的發(fā)生率增加，這也是導(dǎo)致許多HCC病人無法繼續(xù)耐受抗腫瘤治療的原因之一。對(duì)HCC病人手術(shù)或TACE前后給予抗病毒治療，能有效預(yù)防HBV再激活，使HBV-DNA始終維持在低水平，進(jìn)而明顯減少了肝衰竭的發(fā)生率，延長(zhǎng)了病人的生存率。目前國(guó)內(nèi)外的抗HBV指南中均建議HBsAg陽性腫瘤病人在化療、放療過程中應(yīng)給予抗病毒治療以防止HBV再激活。

2.抗病毒治療改善肝癌預(yù)后 高病毒水平、HBeAg陽性及HBV再激活是HBV相關(guān)性HCC復(fù)發(fā)的危險(xiǎn)因素[15,18-19]。通過前期的回顧性研究和隨機(jī)對(duì)照研究表明抗病毒治療可明顯降低HCC術(shù)后復(fù)發(fā)率尤其是晚期復(fù)發(fā)率[20]，明顯提高HCC術(shù)后生存率[21-22]。通過更為可靠的隨機(jī)對(duì)照研究發(fā)現(xiàn)：抗病毒治療組病人其5年無瘤生存率和5年總生存率均高于未抗病毒組(分別為46.1%比27.1%；63.1%比41.5%)。并且通過多因素分析發(fā)現(xiàn)術(shù)后HBV再激活為術(shù)后腫瘤復(fù)發(fā)的獨(dú)立危險(xiǎn)因素(HR=0.651；95%CI，0.451～0.938；P=0.021)[23]。其原因有：①抗病毒治療通過抑制肝臟炎癥，改善微環(huán)境，部分阻斷或抑制“炎癥-癌癥”通路，使肝癌發(fā)生率及復(fù)發(fā)率降低；②通過降低肝癌復(fù)發(fā)率以及改善肝臟炎癥及纖維化狀態(tài)，使終末期肝病的發(fā)生率降低，從而提高了肝癌術(shù)后生存率。

三、HBV相關(guān)HCC病人抗病毒治療適應(yīng)證的選擇

HBV相關(guān)肝癌抗病毒治療的目的有以下幾方面：一是通過抑制病毒復(fù)制和再激活，改善肝功能，降低肝衰竭發(fā)生率，使病人能耐受手術(shù)、TACE及消融治療；二是通過長(zhǎng)期抗病毒治療，減輕肝臟炎癥，逆轉(zhuǎn)肝纖維化，降低終末期肝病的發(fā)生率；三是降低肝癌遠(yuǎn)期復(fù)發(fā)率，提高生存率。

以下HCC病人應(yīng)給予抗病毒治療：①HBV-DNA可檢測(cè)病人，無論是否手術(shù)均應(yīng)抗病毒治療；②HBV-DNA不可檢測(cè)病人，在進(jìn)行手術(shù)、肝移植、TACE、放療以及消融等治療期間應(yīng)給予抗病毒治療，以防止病毒再激活；③HBV陽性合并丙氨酸轉(zhuǎn)氨酶(ALT)升高或肝纖維化者，不論HBV-DNA是否可檢測(cè)，建議抗病毒治療，因?yàn)橐延袌?bào)道顯示長(zhǎng)期抗病毒治療可明顯減輕肝臟炎癥和肝硬化；目前在抗病毒治療的適應(yīng)證方面還有不同的意見，尤其是病毒不可檢測(cè)病人的抗病毒治療，需要更多的循證醫(yī)學(xué)證據(jù)支持。

四、核苷類抗病毒治療藥物的選擇

目前國(guó)內(nèi)上市的核苷類藥物包括拉米夫定、阿德福韋酯、替比夫定和恩替卡韋。拉米夫定耐藥率很高，5年可達(dá)72%；阿德福韋酯由于腎毒性，常常要減少治療劑量，導(dǎo)致其抗病毒治療的效果較差，快速抑制病毒復(fù)制的比例較低；替比夫定與拉米夫定類似，其耐藥性較高；恩替卡韋能快速抑制病毒復(fù)制，其長(zhǎng)期使用的耐藥性很低(5年耐藥率僅1.2%)。已有研究表明恩替卡韋抗病毒療效要優(yōu)于阿德福韋酯[24]。我們的研究發(fā)現(xiàn)肝癌術(shù)后抗病毒治療早期應(yīng)答病人預(yù)后更好[25]。國(guó)外指南中推薦恩替卡韋和替諾福韋(國(guó)內(nèi)未上市)為一線用藥[13]，國(guó)內(nèi)由于各種原因仍把上述4種藥列為一線用藥?？共《局委熕幬锏倪x擇原則是速效、高效和低耐藥，根據(jù)這一原則，推薦使用恩替卡韋或替諾福韋。在抗病毒治療的過程中應(yīng)定期監(jiān)測(cè)HBV-DNA水平及肝、腎功能情況，一般建議每3個(gè)月左右檢測(cè)一次，對(duì)于在抗病毒治療過程中出現(xiàn)HBV-DNA水平升高的病人應(yīng)進(jìn)行及時(shí)復(fù)測(cè)。確認(rèn)HBV-DNA異常應(yīng)給予檢測(cè)HBV耐藥情況。根據(jù)具體檢測(cè)情況調(diào)整抗病毒藥物使用。

五、HBV相關(guān)HCC抗病毒治療的療程

已有大量證據(jù)表明長(zhǎng)期抗病毒治療可減輕肝臟炎癥，逆轉(zhuǎn)肝纖維化，降低HCC發(fā)生率，降低HBV再激活率，降低HCC術(shù)后復(fù)發(fā)率，降低終末期不良事件發(fā)生率，延長(zhǎng)HCC病人生存期，因此對(duì)于HCC病人來說，應(yīng)采用長(zhǎng)期抗病毒治療的策略，而不應(yīng)中途隨意停藥，這一點(diǎn)不同于CHB的治療，我們認(rèn)為HCC抗病毒治療的最終目的是提高病人生存率，而不僅僅是HBV-DNA和HBeAg轉(zhuǎn)陰[26]。由于HCC術(shù)后復(fù)發(fā)率高，病人往往要反復(fù)進(jìn)行TACE、消融、放療等治療，這些治療均易導(dǎo)致HBV再激活，如果中途停藥，則會(huì)使HBV再激活的比例大大提高，增加病人的病死率。另外長(zhǎng)期抗病毒治療可改善病人肝功能和肝纖維化，有利于病人耐受TACE等治療，更有效地控制腫瘤，延長(zhǎng)生存期。

綜上所述，抗病毒治療對(duì)降低HCC發(fā)生及預(yù)防HCC復(fù)發(fā)，提高HCC病人生存率具有非常重要的意義。HBV相關(guān)HCC的抗病毒治療已成為HCC綜合治療中非常重要的一部分，隨著對(duì)抗病毒治療重要性的認(rèn)識(shí)不斷深入，規(guī)范的抗病毒治療方法的普及，必將使HCC的生存率得到進(jìn)一步的提高。

1 European association for the study of the liver,European organisation for research and treatment of cancer.EASL- EORTC clinical practice guidelines:management of hepatocellular carcinoma.J Hepatol,2012,56:908-943.DOI: 10.1016/j.jhep.2011.12.001.

2 湯釗猷.關(guān)于肝癌治療的策略.臨床肝膽病雜志,2011,27:337-339.

3 Tseng TC,Liu CJ,Yang HC,et al.High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load.Gastroenterology,2012,142:1140-1149.e3.DOI:10. 1053/j.gastro.2012.02.007.

4 Qu LS,Jin F,Huang XW,et al.High hepatitis B viral load predicts recurrence of small hepatocellular carcinoma after curative resection.J Gastrointest Surg,2010,14:1111-1120.DOI:10.1007/s11605-010-1211-1.

5 Chen CJ,Yang HJ,Su J,et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA, 2006,295:65-73.DOI:10.1001/ jama. 295.1.65.

6 El-Serag HB.Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology,2012,142:1264-1273.DOI:10.1053/j.gastro.2011.12.061.

7 Zhao LH,Liu X,Yan HX,et al.Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.Nat Commun,2016,7: 12992.DOI: 10.1038/ncomms12992.

8 Wu CY,Lin JT,Ho HJ,et al.Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B:a nationwide cohort study.Gastroenterology, 2014,147:143-151.e5.DOI: 10.1053/j.gastro.2014.03.048.

9 Wang JP,Kao FY,Wu CY,et al.Nucleos(t)ide analogues associated with a reduced risk of hepatocellular carcinoma in hepatitis B patients:a population-based cohort study. Cancer,2015,121:1446-1455.DOI:10. 1002/cncr.29159.

10Chang TT,Liaw YF,Wu SS,et al.Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.Hepatology, 2010,52:886-893.DOI: 10.1002/hep.23785.

11Terrault NA,Bzowej NH,Chang KM,et al.AASLD guidelines for treatment of chronic hepatitis B.Hepatology,2016,63:261-283. DOI:10.1002/hep.28156.

12Liaw YF,Kao JH,Piratvisuth T,et al.Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update.Hepatol Int,2012,6:531-561.DOI:10.1007/s12072-012-9365-4.

13European association for the study of the liver.EASL clinical practice guidelines:management of chronic hepatitis B virus infection.J Hepatol,2012,57:167-185.DOI:10.1016/ j.jhep.2012.02.010.

14Jang JW,Choi JY,Bae SH,et al.A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization.Hepatology,2006,43:233-240.DOI:10.1002/hep.21024.

15Huang G,Lau WY,Shen F,et al.Preoperative hepatitis B virus DNA level is a risk factor for postoperative liver failure in patients who underwent partial hepatectomy for hepatitis B-related hepatocellular carcinoma. World J Surg,2014,38:2370-2376.DOI:10.1007/s00268-014-2546-7.

16Huang G,Lai EC,Lau WY,et al.Post-hepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survivals in patients with preoperative low HBV-DNA levels.Ann Surg,2013,257: 490-505.DOI:10.1097/SLA.0b013e318262b218.

17Dan JQ,Zhang YJ,Huang JT,et al.Hepatitis B virus reactivation after radiofrequency ablation or hepatic resection for HBV-related small hepatocellular carcinoma:A retrospective study.Eur J Surg Oncol,2013,39:865-872.DOI: 10.1016/j.ejso.2013.03.020.

18Hung IF,Poon RT,Lai CL,et al.Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection.Am J Gastroenterol,2008,103:1663-1673.DOI:10.1111/j. 1572-0241.2008.01872.x.

19Huang Y,Wang Z,An S,et al.Role of hepatitis B virus genotypes and quantitative HBV DNA in metastasis and recurrence of hepatocellular carcinoma.J Med Virol,2008, 80:591-597.DOI: 10.1002/jmv.21117.

20Wu CY,Chen YJ,Ho HJ,et al.Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection.JAMA,2012,308:1906-1913.DOI:10.1001/ 2012.jama.11975.

21Lee TY,Lin JT,Zeng YS,et al.Association between nucleos(t)ide analog and tumor recurrence in hepatitis B virus-related hepatocellular carcinoma after radiofrequency ablation.Hepatology,2016,63: 1517-1527.DOI:10.1002/hep.28266.

22Chan AC,Chok KS,Yuen WK,et al.Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma.Arch Surg,2011,146:675-681.DOI:10.1001/ archsurg.2011.125.

23Huang G,Lau WY,Wang ZG,et al.Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma A randomized controlled Trial.Ann Surg,2015,261:56-66.DOI:10.1097/ SLA.0000000000000858.

24Liaw YF,Raptopoulou-Gigi M,Cheinquer H,et al.Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation:a randomized,open-label study.Hepatology,2011,54:91-100.DOI:10.1002/ hep.24361.

25Huang G,Yang Y,Shen F,et al.Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load.Ann Surg Oncol,2013,20:1482-1490.DOI: 10.1245/s10434-012-2803-7.

26Huang G,Lau WY,Zhou WP,et al.Prediction of hepatocellular carcinoma recurrence in patients with low hepatitis B virus DNA levels and high preoperative hepatitis B surface antigen levels.JAMA Surg,2014,149:519-527.DOI:10.1001/jamasurg.2013.4648.

Application and evaluation of antiviral therapy in the treatment of HBV related hepatocellular carcinoma

HuangGang,ZhouWeiping,WuMengchao.

TheThirdDepartmentofHepaticSurgery,EasternHepatobiliarySurgeryHospital,SecondMilitaryMedicalUniversity,Shanghai200438,China

ZhouWeiping,Email:ehphwp@126.com

Hepatocellular carcinoma (HCC) is the most common cancer in our country. Hepatitis B virus (HBV) infection is a major risk factor for HCC. Surgical resection is the first-line therapeutic option for patients with resectable tumors and preserved liver function. However, a significant proportion of patients develop tumor recurrence, which together with concomitant hepatic decompensation in a background of cirrhosis, is the main causes of death on long-term follow-up. Thus, the long-term prognosis after liver resection remains unsatisfactory, and prevention of recurrence via adjuvant treatments is important, though unmet medical need, in patients with HCC. HBV infection is responsible for many cases of HCC in our country. Antiviral therapy plays a significant role in the comprehensive treatment of HBV related HCC. Studies showed that antiviral therapy can suppress the replication and reactivation of HBV, reduce inflammation of the liver, improve hepatic fibrosis, reduce late recurrence after hepatectomy and improve overall survival significantly. So it is very important to choose fast effective and low resistant nucleotide. HCC patients need repeated treatment such as operation, TACE, radiation and radiofrequency ablation, so long-term antiviral therapy which can prevent the reactivation of HBV is needed. Nucleotide antiviral therapy is an important part of comprehensive treatment of HBV-related HCC patients, which can reduce the late postoperative recurrence and improve the overall survival.

Antiviral therapy; Hepatocellular carcinoma; Hepatitis B virus; Prognosis

國(guó)家科技重大傳染病專項(xiàng)(2012ZX10002010, 2012ZX10002016)，國(guó)家自然科學(xué)基金創(chuàng)新研究群體項(xiàng)目(81221061)，上海市科委醫(yī)學(xué)引導(dǎo)項(xiàng)目(14411967800)

200438 上海，第二軍醫(yī)大學(xué)附屬東方肝膽外科醫(yī)院肝臟外科

周偉平，Email：ehphwp@126.com

R735.7

A

10.3969/j.issn.1003-5591.2017.02.004

2017-02-06)