陳潔,吳飛翔,白濤,王小波,劉軍杰,黎樂群
(廣西醫(yī)科大學(xué)附屬腫瘤醫(yī)院 肝膽外科,廣西 南寧 530021)
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術(shù)前抗病毒治療對HBV-DNA陰性的肝細(xì)胞癌患者圍手術(shù)期HBV再激活及術(shù)后肝功能的影響
陳潔,吳飛翔,白濤,王小波,劉軍杰,黎樂群Δ
(廣西醫(yī)科大學(xué)附屬腫瘤醫(yī)院 肝膽外科,廣西 南寧 530021)
目的 探討術(shù)前抗病毒治療對乙型肝炎病毒DNA(hepatitis B virus-DNA,HBV-DNA)陰性的肝細(xì)胞癌(hepatocellular carcinoma,HCC)患者圍手術(shù)期HBV再激活及術(shù)后肝功能的影響。方法 74例術(shù)前HBV-DNA陰性,首診為肝細(xì)胞癌且可行開放性肝切除術(shù)的患者,根據(jù)是否抗病毒治療分為2組:抗病毒組20例術(shù)前3天抗病毒治療,未抗病毒組54例,術(shù)前不服用抗病毒藥物,2組患者術(shù)后恢復(fù)進(jìn)食后使用抗病毒藥物。2組患者于術(shù)前、術(shù)后第3、7d檢測肝功能指標(biāo)及HBV-DNA,HBV-DNA陽性(HBV-DNA>500 IU/mL)為激活,陰性為未激活,并比較激活組與未激活組的術(shù)前、術(shù)后第3、7天的肝功能指標(biāo)變化。結(jié)果 全組患者HBV激活率為21.6%(16/74);術(shù)前未抗病毒組激活率27.7%(15/54),抗病毒組激活率5.0%(1/20),2組激活率差異有統(tǒng)計學(xué)意義(P<0.035)。Logistic回歸顯示:術(shù)前未抗病毒治療是HBV術(shù)后再激活的獨立危險因素(OR=13.952,95%置信區(qū)間:1.358~143.379,P=0.027)??共《窘M術(shù)后第3、7d白蛋白(albumin,ALB)較未抗病毒組恢復(fù)好,差異有統(tǒng)計學(xué)意義(P值分別為0.035,0.043),術(shù)后第7天激活組ALB、丙氨酸氨基轉(zhuǎn)移酶(alanine aminotransferase,ALT)較未激活組恢復(fù)較差(P值分別為0.016、0.048)。結(jié)論 術(shù)前未抗病毒治療是HBV-DNA陰性的HCC患者術(shù)后HBV再激活的獨立危險因素,術(shù)前抗病毒治療夠有效抑制術(shù)后HBV再激活,加快術(shù)后肝功能恢復(fù)。
乙型肝炎病毒DNA;肝細(xì)胞癌;再激活;抗病毒治療
原發(fā)性肝癌(primary liver cancer,PLC)在中國是常見的惡性腫瘤之一,且多為肝細(xì)胞癌(hepatocellular carcinoma,HCC)[1]。目前肝細(xì)胞癌的首選治療方法仍是手術(shù)治療,但HCC術(shù)后5年內(nèi)復(fù)發(fā)率高達(dá)50%~70%[1-2],HBV-DNA載量持續(xù)高水平是HCC術(shù)后復(fù)發(fā)的重要原因,且HBV術(shù)后再激活是HCC術(shù)后復(fù)發(fā)的獨立危險因素之一[3]。術(shù)前HBV-DNA陽性的接受肝切除手術(shù)后HBV出現(xiàn)再激活,抗病毒治療有效抑制HBV再激活[4],專家建議HBV-DNA陽性術(shù)前應(yīng)給予抗病毒治療[5]。然而HBV-DNA陰性患者接受手術(shù)后HBV能否再激活不容忽視[6],術(shù)前是否抗病毒治療國內(nèi)外指南尚無定論[7-8]。因此,本研究采用前瞻性研究方法探索HBV-DNA陰性患者接受肝切除手術(shù)后HBV是否會再激活及可能影響再激活的因素,進(jìn)一步探討抗病毒治療能否有效抑制術(shù)后HBV再激活及對圍手術(shù)期肝功能的影響,以期提高原發(fā)性肝癌患者手術(shù)后的生存率。
1.1 一般資料 選取2013年7月~2014年12月廣西醫(yī)科大學(xué)附屬腫瘤醫(yī)院肝膽外科接診肝細(xì)胞癌患者74例,男性64例,女性10例,其中抗病毒治療組20例,男性18例,女性2例,未抗病毒組54例,男性46例,女性8例。所有患者均有病理確診,符合臨床診斷標(biāo)準(zhǔn),術(shù)前檢測乙型肝炎病毒表面抗原(HBsAg)陽性,乙型肝炎病毒DNA(hepatitis B virus-DNA,HBV-DNA)陰性。本研究獲得患者知情同意,并得到醫(yī)院倫理委員會批準(zhǔn)。
1.2 方法 術(shù)前1天所有患者于空腹?fàn)顟B(tài)下抽取外周靜脈血,檢測肝功能指標(biāo),包括:總膽紅素(total bilirubin,TBI)、直接膽紅素(direct bilirubin,DBIL)、總蛋白(total protein,TP)、白蛋白(albumin,ALB)、丙氨酸氨基轉(zhuǎn)移酶(alanine aminotransferase,ALT)、天門冬氨酸氨基轉(zhuǎn)移酶(aspartate aminotransferase,AST)、凝血酶原時間(prothrombin time,PT)、HBV-DNA載量。HBV-DNA最低檢測值為500 IU/mL。術(shù)后第3天抽取空腹非抗凝外周血2 mL復(fù)測HBV-DNA載量,術(shù)后第3天、7天各抽靜脈血3 mL復(fù)查肝功能指標(biāo)。
根據(jù)是否抗病毒治療分為抗病毒組(術(shù)前3天開始抗病毒治療,術(shù)后恢復(fù)進(jìn)食后繼續(xù)抗病毒治療)和未抗病毒組(不使用任何抗病毒藥物,術(shù)后恢復(fù)進(jìn)食后使用抗病毒藥物)??共《舅幬镞x用恩替卡韋分散片(江蘇正大天晴公司,國藥準(zhǔn)字H20100019)0.5 mg/次,1次/天,口服。根據(jù)術(shù)后檢測激活指標(biāo)分為激活組(術(shù)后檢測HBV-DNA>500 IU/mL即為再激活[9])和未激活組(術(shù)后檢測HBV-DNA<500 IU/mL)。第3天肝功能差值:術(shù)后第3天肝功能指標(biāo)減去術(shù)前肝功能指標(biāo);第7天肝功能差值:術(shù)后第7天肝功能指標(biāo)減去術(shù)前肝功能指標(biāo)。
2.1 術(shù)后2組患者HBV激活率比較 術(shù)后檢測HBV-DNA載量,全組患者中,HBV激活率為21.6%(16/74),未抗病毒組激活率27.7%(15/54),抗病毒組激活率5.0%(1/20),2組激活率差異有統(tǒng)計學(xué)意義(P=0.035)。見表1。
表1 術(shù)后2組患者HBV激活率比較Tab.1 Comparison of HBV reactivation between two groups
2.2 Logistic回歸分析 術(shù)前未抗病毒治療是HBV再激活的獨立危險因素(OR=13.952,95%置信區(qū)間:1.358~143.379,P=0.027)。
2.3 肝功能差值比較
2.3.1 抗病毒組與未抗病毒組術(shù)后第3天、第7天肝功能差值比較:抗病毒組術(shù)后第3、7 d ALB較未抗病毒組恢復(fù)好,差異有統(tǒng)計學(xué)意義(P值分別為0.035,0.043),其余肝功能指標(biāo)差值差異無統(tǒng)計學(xué)意義。見表2。
表2 抗病毒與未抗病毒組術(shù)后第3、7天肝功能指標(biāo)差值比較Tab.2 Comparison of difference value of liver function indexes between antiviral therapy and non-antiviral therapy at 3rd, 7th day
2.3.2 激活組與未激活組術(shù)后第3天、第7天肝功能指標(biāo)差值比較:術(shù)后第7天激活組ALB、ALT較未激活組恢復(fù)較差(P值分別為0.016、0.048),其余肝功能指標(biāo)差值差異無統(tǒng)計學(xué)意義。見表3。
表3 激活組與未激活組術(shù)后第3、7天肝功能差值比較
近年來,隨著手術(shù)理念的轉(zhuǎn)變和設(shè)備的更新,原發(fā)性肝癌患者的預(yù)后得到改善,然而肝癌的高復(fù)發(fā)率仍然是困擾臨床醫(yī)生的一個重大問題。研究表明HBV相關(guān)HCC患者在接受化療、免疫抑制治療、放射治療過程中容易再激活[11]。HBV相關(guān)HCC接受肝動脈灌注化療栓塞術(shù),射頻消融術(shù),肝切除、肝移植同樣能夠再激活[12],阻止HBV相關(guān)HCC患者HBV術(shù)后再激活引起廣泛重視。
本研究共納入74例HBV-DNA陰性的HCC患者,均接受肝癌切除手術(shù),術(shù)后出現(xiàn)HBV再激活16例,其中未抗病毒組激活率27%(15/54),抗病毒組激活率5.0%(1/20),2組激活率存在顯著差異。術(shù)前是否需要抗病毒治療等問題,專家建議:HBV相關(guān)性HCC患者檢測HBV-DNA陽性,均應(yīng)給予NAs抗病毒治療。HBV相關(guān)性HCC檢測HBV-DNA陰性患者接受經(jīng)導(dǎo)管動脈化療栓塞、放射治療或全身化療時,應(yīng)高度重視HBV 的再激活,并密切監(jiān)測HBV-DNA[13]。
手術(shù)打擊能夠使HBV再激活,然而引起HBV再激活是多因素作用的結(jié)果,研究發(fā)現(xiàn)腫瘤直徑、門靜脈癌栓、肝纖維化程度、手術(shù)方式、創(chuàng)傷程度、麻醉方式、術(shù)中輸血、術(shù)后抗病毒治療等指標(biāo)與術(shù)后再激活有關(guān)[14-17]。多因素分析顯示未抗病毒治療是術(shù)后HBV再激活的可能獨立危險因素。抗病毒治療是HBV再激活的保護(hù)因素。
HBV再激活加重肝功能損傷,增加肝功能衰竭風(fēng)險[18-19],影響術(shù)后肝功能恢復(fù),且增加肝癌術(shù)后復(fù)發(fā)率,縮短患者生存期。近年來圍手術(shù)期抗病毒開始被重視,恩替卡韋以其快速,強效的抗病毒作用,已成為專家建議及指南推薦圍手術(shù)期用藥[20],多項研究表明術(shù)前應(yīng)用恩替卡韋能夠有效抑制乙肝病毒再激活,改善術(shù)后肝功能,降低腫瘤復(fù)發(fā),延長生存期[21]。
本實驗研究發(fā)現(xiàn)2組患者術(shù)后第3天肝功能差值指標(biāo)差異無統(tǒng)計學(xué)意義,術(shù)后第7天ALB差值(P=0.016)、ALT差值(P=0.048) 差異存在統(tǒng)計學(xué)意義。激活組較未激活A(yù)LB及ALT恢復(fù)較差??紤]術(shù)后3天ALT變化主要與手術(shù)打擊有關(guān)[22],術(shù)后3天內(nèi)給予外源性人血白蛋白支持治療,影響術(shù)后3天統(tǒng)計結(jié)果。術(shù)后乙肝病毒再激活影響ALB及ALT的恢復(fù)??共《窘M與未抗病毒組術(shù)后第7天ALB差值差異存在統(tǒng)計學(xué)意義(P=0.043),抗病毒組術(shù)后白蛋白(ALB)恢復(fù)較好,抗病毒治療加快術(shù)后肝功能恢復(fù)。
本研究表明HBV-DNA陰性的HCC患者術(shù)后HBV能夠再激活,術(shù)前未抗病毒治療是HBV-DNA陰性的HCC患者術(shù)后再激活的獨立危險因素。術(shù)前抗病毒治療使用恩替卡韋能夠有效抑制術(shù)后HBV再激活,加快術(shù)后肝功能恢復(fù),不同抗病毒藥物的作用已有不少研究[23-24],本次研究因樣本量不大未做比較,可以在以后的研究中進(jìn)行完善。
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(編校:王儼儼)
Effect of preoperative antiviral therapy on HBV reactivation and postoperative liver function in perioperative patients with HBV-DNA-negative hepatocellular carcinoma
CHEN Jie, WU Fei-xiang, BAI Tao, WANG Xiao-bo, LIU Jun-jie, LI Le-qunΔ
(Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China)
ObjectiveTo explore the effect of preoperative antiviral therapy on hepatitis B virus (HBV) reactivation and postoperative liver function in perioperative patients with HBV-DNA-negative hepatocellular carcinoma(HCC).Methods74 patients with preoperative HBV-DNA-negative scheduled which were analyzed. Patients were divided into two groups according to antiviral therapy or not: 20 cases in antiviral treatment group received antiviral therapy for three days, 54 cases in non-antiviral teatment group did not receive antiviral therapy, and both groups received antiviral therapy after post-operative resuming to diets. The indicators of liver function and HBV-DNA levels were detected on pre-operative, post-operative 3rdand 7thday in two groups, and HBV-DNA-positive (HBV-DNA>500 IU/mL) was defined as reactivation, conversely as inactivation. The indicators of liver function on pre-operative, post-operative 3rdand 7thday were compared between reactivation group and inactivation group.ResultsThe reactivative rate was 21.6%(16/74) in all patients; 27.7%(15/54) in pre-operative non-antiviral teatment group, 5.0%(1/20) in antiviral teatment group, and there was significant differences in reactivative rate between two groups (P=0.035). The results of Logistic regression showed that pre-operative nonantiviral therapy was an independent risk factor of post-operative HBV reactivation (OR=13.952,95% confidence interval[CI]:1.358-143.379,P=0.027). The recovery of albumin (ALB) on post-operative 3rd, 7thdays in antiviral treatment group was faster than those in nonantiviral treatment group,respectively (P=0.035,0.043). The recovery of ALB and alanine aminotransferase (ALT) on post-operative 7thday in reactivation group were slower than those in inactivation group, respectively (P=0.016, 0.048).ConclusionThe pre-operative nonantiviral therapy is an independent risk factor of post-operative HBV reactivation in patients with HBV-DNA-negative HCC. The pre-operative antiviral therapy could inhibit post-operative HBV reactivation effectively and accelerate the post-operative recovery of liver function.
hepatitis B virus-DNA; hepatocellular carcinoma; reactivation; antiviral therapy
國家自然科學(xué)基金(81260088);廣西科技廳資助項目(GK2013-13-b-01);廣西衛(wèi)計委自籌課題(Z2015570)
陳潔,男,博士,講師,研究方向:肝膽胰疾病的診斷與治療,E-mail:903488911@qq.com;黎樂群,通信作者,男,博士、博士生導(dǎo)師、教授,研究方向:肝膽胰疾病的診斷與治療,E-mail:lilequn2012@163.com。
R735.7
A
1005-1678(2015)11-0049-04