武曉麗

(山東省禹城市人民醫(yī)院 感染科， 山東 禹城 251200)

論著/病毒性肝炎

PEG-IFNα-2a與阿德福韋酯的聯(lián)用方式對(duì)HBeAg陽(yáng)性慢性乙型肝炎療效的影響

武曉麗

(山東省禹城市人民醫(yī)院 感染科， 山東 禹城 251200)

目的探討用藥順序?qū)EG-IFNα-2a聯(lián)合阿德福韋酯(ADV)治療HBeAg陽(yáng)性慢性乙型肝炎患者臨床療效的影響。方法選取2011 年9月1日-2013 年11月1日在山東省禹城市人民醫(yī)院接受治療的HBeAg陽(yáng)性慢性乙型肝炎患者86例。隨機(jī)分為A組(n=28,后期1例退出)、B組(n=29,后期2例退出)和C組(n=29,后期3例退出)，均采用PegIFNα-2a聯(lián)合ADV治療。A組同期聯(lián)合用藥；B組先給予PegIFNα-2a治療24周，再與ADV聯(lián)用；C組先給予ADV治療24周，再與PEG-IFNα-2a聯(lián)用，共治療60周，停藥后隨訪24周。對(duì)比3組的臨床療效(HBeAg消失和血清轉(zhuǎn)換率、HBsAg轉(zhuǎn)陰率、HBV DNA轉(zhuǎn)陰率、ALT復(fù)常率)與不良反應(yīng)。計(jì)量資料組間比較采用t檢驗(yàn)或方差分析；計(jì)數(shù)資料組間比較采用行×列表資料的χ2檢驗(yàn)。結(jié)果治療60周: HBeAg消失和血清轉(zhuǎn)換率3組間比較差異有統(tǒng)計(jì)學(xué)意義(85.2% vs 81.5% vs 69.2%，χ2=6.253，P<0.05)，A組和B組均高于C組(P值均<0.012 5)；HBV DNA轉(zhuǎn)陰率3組間比較差異有統(tǒng)計(jì)學(xué)意義(81.5% vs 55.6% vs 80.8%,χ2=7.409，P<0.05)，A組和C組均高于B組(P值均<0.012 5)；ALT復(fù)常率3組間比較差異有統(tǒng)計(jì)學(xué)意義(81.5% vs 80.8% vs 57.7%,χ2=7.425，P<0.05)，A組高于C組(P<0.012 5)。停藥24周時(shí)：HBeAg消失和血清轉(zhuǎn)換率3組間比較差異有統(tǒng)計(jì)學(xué)意義(81.5% vs 81.5% vs 65.4%，χ2=6.723，P<0.05)，A組和B組均高于C組(P值均<0.012 5)；ALT復(fù)常率3組間比較差異有統(tǒng)計(jì)學(xué)意義(81.5% vs 74.1% vs 53.8%,χ2=9.690，P<0.05)，A組高于C組(P<0.012 5)。不良反應(yīng)多集中于治療24周內(nèi)，主要表現(xiàn)為低熱、頭痛、肌肉酸痛等流感樣癥狀，多數(shù)患者未經(jīng)干預(yù)自行緩解；部分患者發(fā)生骨髓抑制，多表現(xiàn)為WBC、中性粒細(xì)胞及PLT減少，給予粒細(xì)胞集落刺激因子后得以緩解。結(jié)論先經(jīng)ADV 治療降低HBV DNA水平再予以PEG-IFNα-2a，與二者同時(shí)聯(lián)用效果相仿，可能對(duì)降低PEG-IFNα-2a的用藥時(shí)間和用藥量有一定的指導(dǎo)意義。

肝炎， 乙型， 慢性； 干擾素α-2a； 阿德福韋酯

慢性乙型肝炎(CHB)是一個(gè)全球性的健康問(wèn)題，2012年數(shù)據(jù)[1]調(diào)查顯示，中國(guó)內(nèi)地現(xiàn)有HBV攜帶者高達(dá)9300 萬(wàn)，CHB患者約為2000萬(wàn)，每年相關(guān)死亡人數(shù)接近50萬(wàn)。研究[2]表明HBV持續(xù)復(fù)制導(dǎo)致肝纖維化、肝硬化和肝細(xì)胞癌是引發(fā)死亡的最主要原因，因此治療該病的關(guān)鍵在于清除HBV感染。目前，臨床治療HBeAg陽(yáng)性CHB的有效藥物有2大類：核苷類似物和干擾素。前者抗病毒能力強(qiáng)，起效迅速，但HBeAg血清轉(zhuǎn)換率低，且易產(chǎn)生耐藥性，停藥后易復(fù)發(fā)；后者通過(guò)提高免疫功能發(fā)揮抗病毒作用，能夠?qū)崿F(xiàn)較為持久和穩(wěn)定的應(yīng)答率，但副作用明顯，且價(jià)格較高，長(zhǎng)期用藥加重了部分患者的經(jīng)濟(jì)負(fù)擔(dān)[3]。近幾年，核苷類似物和干擾素聯(lián)合給藥成為臨床研究的熱點(diǎn)，其中PEG-IFNα-2a和阿德福韋酯(adefovir dipivoxil，ADV)在HBeAg陽(yáng)性CHB的臨床治療中顯示出較好的應(yīng)用前景[4]。但目前其聯(lián)用方式尚不統(tǒng)一，療程、劑量及應(yīng)用時(shí)機(jī)尚需進(jìn)一步探索，以優(yōu)化聯(lián)用效果。本研究重點(diǎn)考察二者應(yīng)用時(shí)間順序?qū)Ο熜У挠绊?，為完善其臨床聯(lián)用方案提供參考。

1 資料和方法

1.1 研究對(duì)象 選取本院肝病科2011 年9月1日-2013 年11月1日收治的HBeAg陽(yáng)性CHB患者86例。納入標(biāo)準(zhǔn)：(1)符合2010 年《慢性乙型肝炎防治指南》[5]中HBeAg陽(yáng)性CHB的診斷標(biāo)準(zhǔn)，基線包括：血清HBsAg、HBeAg陽(yáng)性，抗-HBe陰性，HBV DNA陽(yáng)性，ALT持續(xù)或反復(fù)升高，或肝組織學(xué)檢查有肝炎病變；(2)血清HBeAg陽(yáng)性且抗HBe陰性；(3)血清HBV DNA≥105拷貝/ml；(4)簽署知情同意書。排除標(biāo)準(zhǔn)：(1)肝硬化或癌變；(2)合并有其他類型的肝炎病毒；(3)甲狀腺功能異常；(4)自身免疫性疾病史；(5)合并神經(jīng)、精神類疾病；(6)妊娠期或哺乳期；(7)6個(gè)月內(nèi)有激素、實(shí)驗(yàn)相關(guān)藥物應(yīng)用史；(8)合并腎臟疾病。所有患者按照HBV DNA水平由低到高編號(hào)，以隨機(jī)數(shù)字表分為A組(n=28)、B組(n=29)和C組(n=29)。

1.2 治療方法 基本藥物：PEG-IFNα-2a(上海羅氏公司)，用量為180 μg/周，皮下注射，1次/周；ADV(葛蘭素史克)用量為10 mg/d，口服。用藥策略：A組于治療第1天同時(shí)使用PEG-IFNα-2a和ADV，連續(xù)使用60周；B組先以PEG-IFNα-2a治療24周，再與ADV聯(lián)合應(yīng)用36周，共治療60周；C組29例先給予ADV治療24周，再與PEG-IFNα-2a聯(lián)合應(yīng)用36周，共治療60周。

1.3 觀察指標(biāo) 治療60周時(shí)和停藥后24周進(jìn)行療效評(píng)估：(1)HBeAg消失率和血清轉(zhuǎn)換率：采用ARCHITECT i2000SR化學(xué)發(fā)光免疫檢測(cè)儀(美國(guó)雅培)和乙型肝炎五項(xiàng)定量檢測(cè)試劑盒(美國(guó)雅培)測(cè)定HBeAg和抗-HBe。HBeAg消失率和血清轉(zhuǎn)換率=[HBeAg陰性(≤1.0 s/co)或抗HBe陽(yáng)性(>1.0 s/co)的患者數(shù)量/該組患者數(shù)量]×100%。(2)HBsAg轉(zhuǎn)陰率：采用化學(xué)發(fā)光免疫檢測(cè)儀和乙型肝炎五項(xiàng)定量檢測(cè)試劑盒測(cè)定HBsAg。HBsAg轉(zhuǎn)陰率=(HBsAg<0.05 IU/ml的患者數(shù)量/該組患者數(shù)量)×100%。(3)HBV DNA轉(zhuǎn)陰率：采用實(shí)時(shí)定量PCR儀(Applied BiosystemsTM)和HBV DNA定量試劑盒(上海羅氏公司)檢測(cè)病毒載量。HBV DNA轉(zhuǎn)陰率=(HBV DNA<15 IU/L的患者數(shù)量/該組患者數(shù)量)×100%。(4)ALT復(fù)常率：采用AU5800全自動(dòng)生化免疫分析儀(德國(guó)貝克曼庫(kù)爾特公司)和試劑盒測(cè)定ALT，測(cè)定原理為乳酸脫氨酶法；ALT復(fù)常率=(ALT<50 U/L的患者數(shù)量/該組患者數(shù)量)×100%。

2 結(jié)果

2.1 一般資料 86例患者中男47例，女39例，年齡27～73歲，平均(41.2±12.6)歲，A、B、C組間一般資料比較差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值均<0.05)(表1)。

2.2 臨床療效 治療過(guò)程中，A、B、C組分別有1例、2例、3例退出實(shí)驗(yàn)。治療60周:HBeAg消失和血清轉(zhuǎn)換率3組間比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，A組和B組均高于C組(P值均<0.012 5)；HBV DNA轉(zhuǎn)陰率3組間比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，A組和C組均高于B組(P值均<0.012 5)；ALT復(fù)常率3組間比較差異有統(tǒng)計(jì)學(xué)意(P<0.05)，A組高于C組(P<0.012 5)。停藥24周時(shí)：HBeAg消失和血清轉(zhuǎn)換率3組間比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，A組和B組均高于C組(P值均<0.012 5)；ALT復(fù)常率3組間比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，A組高于C組(P<0.012 5)(表2)。

2.3 不良反應(yīng) 不良反應(yīng)多集中于治療24周內(nèi)，主要表現(xiàn)為低熱、頭痛、肌肉酸痛等流感樣癥狀，多數(shù)患者未經(jīng)干預(yù)均可自行緩解；部分患者發(fā)生骨髓抑制，多表現(xiàn)為WBC、中性粒細(xì)胞及PLT減少，給予粒細(xì)胞集落刺激因子后得以緩解，未影響用藥治療。各組不良反應(yīng)發(fā)生情況如表3所示，各不良反應(yīng)組間差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值均>0.05)。

表1 各組患者一般資料基線水平比較

注：與A組比較，1)P<0.012 5；與B組比較，2)P<0.012 5

表3 各組不良反應(yīng)發(fā)生率比較[例(%)]

3 討論

CHB的發(fā)病機(jī)制十分復(fù)雜，現(xiàn)有研究已證實(shí)免疫機(jī)制占主導(dǎo)作用，患者自身對(duì)HBV的特異性免疫反應(yīng)弱，不足以清除病原體，以致HBV在體內(nèi)持續(xù)復(fù)制，誘發(fā)肝炎、肝纖維化、肝硬化甚至肝癌[6]。目前，用于CHB臨床治療的藥物主要有干擾素及核苷酸類藥物，其代表藥物分別是PEG-IFNα-2a和ADV。PEG-IFNα-2a具有抗病毒和調(diào)節(jié)免疫雙重作用，是CHB的一線用藥，其典型優(yōu)勢(shì)在于HBeAg 血清學(xué)轉(zhuǎn)換率高，且有良好的后續(xù)效應(yīng)，療程相對(duì)較短，停藥后不易復(fù)發(fā)。但PEG-IFNα-2a并非對(duì)所有患者均敏感，且價(jià)格昂貴，存在一定的副作用[7-8]。ADV通過(guò)競(jìng)爭(zhēng)性抑制HBV DNA多聚酶活性直接抑制HBV DNA復(fù)制，其典型優(yōu)勢(shì)是起效迅速、作用強(qiáng)勢(shì)，但該藥療程較長(zhǎng)，期間可能出現(xiàn)耐藥問(wèn)題，停藥后復(fù)發(fā)率也高[9-10]?？梢姡吒饔欣?，均未達(dá)到理想的治療效果。個(gè)體化的用藥固然能夠事半功倍，但臨床并不易實(shí)施。近年，越來(lái)越多的研究[11-12]支持PEG-IFNα-2a和ADV聯(lián)合給藥的治療方案，并指出二者的協(xié)同作用對(duì)于提高早期應(yīng)答率、縮短療程具有積極作用。

目前，關(guān)于PEG-IFNα-2a和ADV的聯(lián)用方案尚無(wú)確明確規(guī)范。安紅杰等[13]指出，PEG-IFNα-2a對(duì)低病毒載量的CHB應(yīng)答效果更佳，先以ADV降低HBV DNA水平再給予PEG-IFNα-2a可能取得更好的療效。與此同時(shí)，筆者考慮到先給予一定療程的PEG-IFNα-2a 促進(jìn)HBeAg轉(zhuǎn)陰，對(duì)降低ADV的用藥時(shí)間，減少耐藥性可能會(huì)有一定的作用?；谝陨峡紤]，本研究對(duì)PEG-IFNα-2a和ADV的用藥時(shí)機(jī)做適當(dāng)調(diào)整，分析用藥時(shí)間順序?qū)Ο熜Ш筒涣挤磻?yīng)的影響，以期為臨床用藥提供依據(jù)。

2012年歐洲肝病年會(huì)[14]提出了HBeAg陽(yáng)性CHB的理想終點(diǎn)為持續(xù)HBsAg轉(zhuǎn)陰或血清轉(zhuǎn)換，滿意終點(diǎn)為持續(xù)HBeAg血清轉(zhuǎn)換，考慮到持續(xù)HBsAg轉(zhuǎn)陰較為困難，研究以HBeAg血清轉(zhuǎn)換作為治療終點(diǎn)的衡量標(biāo)準(zhǔn)。研究結(jié)果顯示治療60周，A、B組的HBeAg消失和血清轉(zhuǎn)換率高于C組；A、C組的HBV-DNA轉(zhuǎn)陰率高于B組。主要原因存在于ADV通過(guò)競(jìng)爭(zhēng)性抑制HBV DNA多聚酶活性直接抑制HBV-DNA復(fù)制而發(fā)揮抗病毒作用。既往也有學(xué)者[15]對(duì)PEG-IFNα-2a和ADV單獨(dú)治療CHB的用藥效果進(jìn)行觀察，指出ADV對(duì)HBV DNA的作用優(yōu)勢(shì)明顯。隨訪至24周時(shí)，A、B組患者的HBeAg消失和血清轉(zhuǎn)換率高于C組，各組HBV DNA轉(zhuǎn)陰率差異均無(wú)統(tǒng)計(jì)學(xué)意義。這表明A、B組可取得相當(dāng)?shù)闹委熜Чc安紅杰等[13]報(bào)道結(jié)果(先經(jīng) ADV 治療降低 HBV DNA后再聯(lián)合PEG-IFN α-2a治療更為經(jīng)濟(jì)、有效)稍有差異。本研究未發(fā)現(xiàn)B組可獲得更高的療效，但在獲得相當(dāng)療效時(shí)的用藥時(shí)間和用藥量相對(duì)較少，可能對(duì)降低整體用藥費(fèi)用、減輕患者經(jīng)濟(jì)負(fù)擔(dān)有積極意義。由于本研究未做長(zhǎng)期觀察，尚無(wú)法得出確切結(jié)論，尚需進(jìn)一步研究對(duì)此加以證實(shí)。此外，3組患者的不良反應(yīng)以低熱、頭痛、肌肉酸痛等流感樣癥狀和骨髓抑制為主，主要由PEG-IFNα-2a所致，但其組間發(fā)生率差異無(wú)統(tǒng)計(jì)學(xué)意義，表明3種方案的安全性相當(dāng)。

綜上所述，PEG-IFNα-2a和ADV用藥時(shí)間對(duì)HBeAg陽(yáng)性CHB患者的臨床療效有影響，先經(jīng)ADV 治療降低HBV DNA水平再予以PEG-IFNα-2a，可取得與二者聯(lián)用相當(dāng)?shù)男Ч?，可能?duì)減小PEG-IFN α-2a用藥時(shí)間和降低用藥量有一定的指導(dǎo)意義。

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InfluenceofcombinationmodeofPEG-IFNα-2aandadefovirdipivoxilonoutcomeofpatientswithHBeAg-positivechronichepatitisB

WUXioali.

(DepartmentofInfectiousDiseases,YuchengPeople′sHospital,Yucheng,Shandong251200,China)

ObjectiveTo investigate the influence of the sequence of PEG-IFNα-2a and adefovir dipivoxil (ADV) on the clinical outcome of patients with HBeAg-positive chronic hepatitis B (CHB).MethodsA total of 86 patients with HBeAg-positive CHB who were treated in Yucheng People’s Hospital from September 1, 2011 to November 1, 2013 were enrolled and randomly divided into groups A (28 patients, among whom one dropped out in the late stage), B (29 patients, among whom two dropped out in the late stage), and C (29 patients, among whom three dropped out in the late stage). All patients were treated with PEG-IFNα-2a combined with ADV; the patients in group A were given PEG-IFNα-2a and ADV concurrently, those in group B were given PEG-IFNα-2a for 24 weeks, followed by PEG-IFNα-2a combined with ADV, and those in group C were given ADV for 24 weeks, followed by PEG-IFNα-2a combined with ADV. The course of treatment was 60 weeks for all groups. The patients were followed up for 24 weeks after drug withdrawal. The three groups were compared in terms of clinical outcome [HBeAg disappearance rate and seroconversion rate, HBsAg clearance rate, HBV DNA clearance rate, and alanine aminotransferase (ALT) normalization rate]. An analysis of variance orttest was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups.ResultsAfter 60 weeks of treatment, there were significant differences in HBeAg disappearance rate and seroconversion rate between the three groups (85.2% vs 81.5% vs 69.2%,χ2=6.253,P<0.05), and groups A and B had significantly higher rates than group C (allP<0.012 5); there was a significant difference in HBV DNA clearance rate between the three groups (81.5% vs 55.6% vs 80.8%,χ2=7.409,P<0.05), and groups A and C had a significantly higher rate than group B (bothP<0.012 5); there was a significant difference in ALT normalization rate between the three groups (81.5% vs 80.8% vs 57.7%,χ2=7.425,P<0.05), and group A had a significantly higher rate than group C (P<0.012 5). After 24 weeks of drug withdrawal, there were significant differences in HBeAg disappearance rate and seroconversion rate between the three groups (81.5% vs 81.5% vs 65.4%,χ2=6.723,P<0.05), and groups A and B had significantly higher rates than group C (allP<0.012 5); there was a significant difference in ALT normalization rate between the three groups (81.5% vs 74.1% vs 53.8%,χ2=9.690,P<0.05), and group A had a significantly higher rate than group C (P<0.012 5). Most adverse reactions occurred within 24 weeks of treatment and mainly manifested as influenza-like symptoms such as low-grade fever, headache, and sore muscle, and most of the patients were relieved spontaneously without intervention. Some patients experienced bone marrow suppression manifesting as reductions in leukocytes, neutrophils, and platelets and were relieved after the treatment with granulocyte colony-stimulating factor.ConclusionADV given at first to reduce HBV DNA and followed by the addition of PEG-IFNα-2a can achieve a similar effect as ADV given concurrently with PEG-IFNα-2a and has certain significance in shortening the duration of PEG-IFNα-2a treatment and reducing the dose of PEG-IFNα-2a.

hepatitis B, chronic; interferon alfa-2a; adefovir dipivoxil

R512.62; R452

A

1001-5256(2017)12-2311-05

10.3969/j.issn.1001-5256.2017.12.011

2017-07-14；修回日期：2017-09-18。 作者簡(jiǎn)介：武曉麗(1970-)，女，副主任醫(yī)師，主要從事肝炎、肝硬化診治方面的研究。

引證本文：WU XL. Influence of combination mode of PEG-IFNα-2a and adefovir dipivoxil on outcome of patients with HBeAg-positive chronic hepatitis[J]. J Clin Hepatol, 2017, 33(12): 2311-2315. (in Chinese)

武曉麗. PEG-IFNα-2a與阿德福韋酯的聯(lián)用方式對(duì)HBeAg陽(yáng)性慢性乙型肝炎療效的影響[J]. 臨床肝膽病雜志, 2017, 33(12): 2311-2315.

(本文編輯：林 姣)