樊佩瑤 王福川 高銀杰 徐志強(qiáng) 董漪 閆建國(guó) 曹麗麗 馮丹妮 鐘彥偉 張敏
摘要:目的探討血清前S1抗原(PreS1)水平作為預(yù)測(cè)干擾素α(IFN-α)治療48周的HBeAg陽(yáng)性慢性乙型肝炎(CHB)兒童HBsAg轉(zhuǎn)陰指標(biāo)的價(jià)值。方法納入2016年6月—2020年1月接受IFN-α治療48周的88例1~16歲HBeAg陽(yáng)性CHB患兒,每3個(gè)月評(píng)估患兒的HBsAg定量(qHBsAg)、HBV DNA定量、ALT等,并采用磁微?;瘜W(xué)發(fā)光免疫分析法(雙抗體夾心法)檢測(cè)PreS1水平。根據(jù)IFN-α治療48周終點(diǎn)時(shí)HBsAg是否轉(zhuǎn)陰分為轉(zhuǎn)陰組(n=17)和未轉(zhuǎn)陰組(n=71)。計(jì)量資料的兩組間比較采用Mann-Whitney U檢驗(yàn),計(jì)數(shù)資料的兩組間比較采用χ2檢驗(yàn)或Fisher精確檢驗(yàn)。用Spearman秩相關(guān)檢驗(yàn)評(píng)估PreS1水平和其他生物標(biāo)志物之間的關(guān)系。用受試者工作特征曲線下面積(AUC)評(píng)估不同標(biāo)志物對(duì)IFN-α治療48周終點(diǎn)HBsAg轉(zhuǎn)陰的預(yù)測(cè)價(jià)值。結(jié)果PreS1水平與血清qHBsAg、HBV DNA水平呈正相關(guān)(r值分別為0.912、0.535,P值均<0.05)?;€時(shí),PreS1/qHBsAg比值(AUC=0.694)較PreS1水平(AUC=0.530)和qHBsAg水平(AUC=0.514)具有較好的48周HBsAg轉(zhuǎn)陰預(yù)測(cè)價(jià)值。治療12周的PreS1水平(AUC=0.867,P<0.001)和PreS1/qHBsAg比值下降量(AUC=0.800,P=0.002)均對(duì)48周終點(diǎn)時(shí)HBsAg轉(zhuǎn)陰有很好的預(yù)測(cè)作用。治療24周的PreS1水平、qHBsAg水平和HBV DNA均可有效預(yù)測(cè)第48周的HBsAg轉(zhuǎn)陰,AUC分別為0.917、0.949和0.762(P值均<0.001)。結(jié)論治療12周時(shí)血清PreS1水平和PreS1/qHBsAg比值下降量是預(yù)測(cè)IFN-α治療期間CHB患兒HBsAg轉(zhuǎn)陰的候選標(biāo)志物。
關(guān)鍵詞:PreS1; 生物標(biāo)記; 乙型肝炎,? 慢性; 兒童; 干擾素α
基金項(xiàng)目:國(guó)家科技重大專項(xiàng) (2018ZX10301404); 北京市科技計(jì)劃項(xiàng)目 (Z201100005520048); 首都臨床診療技術(shù)研究及轉(zhuǎn)化應(yīng)用項(xiàng)目 (Z201100005520048)
Value of serum PreS1 in early prediction of HBsAg clearance after IFN-α treatment in children with HBeAg-positive chronic hepatitis B
FAN Peiyao WANG Fuchuan GAO Yinjie XU Zhiqiang DONG Yi YAN Jianguo CAO Lili FENG Danni ZHONG YanweiZHANG Min(1. Peking University 302 Clinical Medical School, Beijing 100191, China; 2. Department of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China)
Corresponding author:ZHANG Min, gcmw2001@163.com (ORCID:0000-0003-2497-6748)
Abstract:ObjectiveTo investigate the value of PreS1 level in predicting HBsAg clearance in children with HBeAg-positive chronic hepatitis B (CHB) after 48 weeks of IFN-α treatment. MethodsA total of 88 children with HBeAg-positive CHB, aged 1-16 years, who received 48 weeks of IFN-α treatment from June 2016 to January 2020 were enrolled. HBsAg quantification (qHBsAg), HBV DNA quantification, and alanine aminotransferase were measured every three months, and magnetic particle chemiluminescence immunoassay (double-antibody sandwich) was used to measure the level of PreS1. According to whether HBsAg clearance was achieved at the end of IFN-α treatment for 48 weeks, the 88 children were divided into HBsAg clearance group with 17 children and non-HBsAg clearance group with 71 children. The Mann-Whitney U test was used for comparison of quantitative data between the two groups, and the chi-square test or the Fishers exact test was used for comparison of qualitative data between the two groups. The Spearman rank correlation test was used to evaluate the correlation of PreS1 level with other biomarkers, and the area under the ROC curve (AUC) was used to investigate the value of different markers in predicting HBsAg clearance at the end of 48-week IFN-α treatment. ResultsPreS1 level was positively correlated with the serum levels of qHBsAg and HBV DNA (r=0.912 and 0.535, both P<0.05), and baseline PreS1/qHBsAg ratio (AUC=0.694) had a better value than PreS1 level (AUC=0.530) and qHBsAg level (AUC=0.514) in predicting HBsAg clearance at week 48. PreS1 level (AUC=0.867, P<0.001) and the reduction in PreS1/qHBsAg ratio (AUC=0.800, P=0.002) at week 12 of treatment had a good value in predicting HBsAg clearance at week 48. PreS1 level, qHBsAg level, and HBV DNA at week 24 of treatment could effectively predict HBsAg clearance at week 48, with AUCs of 0.917, 0.949, and 0.762, respectively (all P<0.001). ConclusionSerum PreS1 level and the reduction in PreS1/qHBsAg ratio at week 12 of treatment can be used as candidate markers for predicting HBsAg clearance in children with CHB during IFN-α treatment.
Key words:PreS1; Biomarkers; Hepatitis B, Chronic; Child; Interferon-alpha
Research funding:the National Science and Technology Major Project of the Infectious Diseases (2018ZX10301404) ;Beijing Science and Technology Program (Z201100005520048); the Capital Clinical Diagnosis and Treatment Technology Research and Translational Application Program (Z201100005520048)
以HBsAg轉(zhuǎn)陰為標(biāo)志的臨床治愈是慢性乙型肝炎(CHB)患者追求的理想終點(diǎn)。相比于成人[1],兒童CHB患者干擾素(IFN)抗病毒治療1年后的HBsAg陰轉(zhuǎn)率可達(dá)到20%以上[2],更可獲得臨床治愈。目前,預(yù)測(cè)CHB患兒抗病毒治療后HBsAg轉(zhuǎn)陰的因素并不十分明確。低齡[3-6]、低水平的HBsAg定量(qHBsAg)[4,7-8]、女孩[5]可能是HBsAg轉(zhuǎn)陰的優(yōu)勢(shì)應(yīng)答因素,近年來(lái)一些新型HBV標(biāo)志物如抗-HBc定量[4,9]、HBV RNA[10]和HBV核心相關(guān)抗原[1]等對(duì)CHB患者臨床結(jié)局的預(yù)測(cè)價(jià)值也有相關(guān)報(bào)道。血清前S1抗原(PreS1)作為一種經(jīng)典HBV生物標(biāo)志物,在預(yù)測(cè)CHB成人患者的臨床結(jié)局中起著重要作用[11-14],但是過(guò)去由于檢測(cè)方法的缺陷(多為ELISA的半定量檢測(cè)),PreS1的應(yīng)用受到了限制。近年來(lái)隨著檢測(cè)技術(shù)的進(jìn)步與提高[15-16],PreS1定量檢測(cè)方法也得到了發(fā)展,所以重新評(píng)估PreS1的臨床應(yīng)用價(jià)值很有必要。最近一項(xiàng)關(guān)于CHB兒童患者PreS1的探索性研究[4]表明, PreS1可能是CHB兒童接受抗病毒治療后HBsAg轉(zhuǎn)陰的良好預(yù)測(cè)指標(biāo),然而PreS1定量在預(yù)測(cè)CHB患兒HBsAg轉(zhuǎn)陰中的具體作用仍不明確。本研究評(píng)估了血清PreS1定量在HBeAg陽(yáng)性CHB患兒IFN-α治療期間HBsAg轉(zhuǎn)陰的預(yù)測(cè)價(jià)值,以期為CHB患兒的臨床治療決策提供依據(jù)。
1資料與方法
1.1研究對(duì)象收集2016年6月—2020年1月就診于解放軍總醫(yī)院第五醫(yī)學(xué)中心的88例CHB患兒的基本信息和臨床資料。CHB患兒的診斷標(biāo)準(zhǔn)主要參照《慢性乙型肝炎防治指南(2019年版)》[17],納入標(biāo)準(zhǔn):(1)1~16歲;(2)血清HBsAg陽(yáng)性持續(xù)6個(gè)月以上;(3)血清HBeAg陽(yáng)性,抗-HBe陰性;(4)血清HBV DNA>20 000 IU/mL;(5)ALT>60 U/L;(6)肝組織活檢或無(wú)創(chuàng)性檢查結(jié)果顯示有中度或重度炎癥壞死,伴或不伴纖維化。排除標(biāo)準(zhǔn):(1)曾因CHB感染接受過(guò)抗病毒治療;(2)失代償期肝硬化;(3)合并感染HAV、HCV、HDV或HEV、EB病毒、巨細(xì)胞病毒或人類免疫缺陷病毒等;(4)合并其他肝臟疾病,如自身免疫性肝炎、藥物性肝損傷或Wilson病等;(5)有精神疾病史;(6)其他嚴(yán)重的疾病。
1.2研究方法收集患者入院時(shí)的基線資料,包括年齡、性別、清晨空腹實(shí)驗(yàn)室指標(biāo)(ALT、HBsAg定量、HBV DNA定量、HBV基因型等)以及85例患兒入院時(shí)的肝組織活檢病理報(bào)告(炎癥活動(dòng)度和纖維化程度分期主要參照Scheuer標(biāo)準(zhǔn)[18])。88例患兒均接受了48周的IFN-α治療[19-20](肌肉或皮下注射,300~500萬(wàn)單位/m2體表面積,隔天1次),并完成了每3個(gè)月1次的規(guī)律隨訪,每次隨訪時(shí)收集患兒的實(shí)驗(yàn)室指標(biāo)以及不良反應(yīng)情況等,留取血清采用磁微粒化學(xué)發(fā)光免疫分析法(雙抗體夾心法)進(jìn)行PreS1蛋白的定量檢測(cè),檢測(cè)試劑盒由山東威高生物科技有限公司(山東省威海市)提供,檢測(cè)下限為0.01 ng/mL。
1.3統(tǒng)計(jì)學(xué)方法使用R軟件(4.2.0版)和MedCalc軟件(20.110版)進(jìn)行數(shù)據(jù)分析。呈偏態(tài)分布的計(jì)量資料以M(P25~P75)表示,兩組間比較采用Mann-Whitney U檢驗(yàn),計(jì)數(shù)資料兩組間比較采用χ2檢驗(yàn)或Fisher精確檢驗(yàn)。生物標(biāo)志物數(shù)值進(jìn)行了對(duì)數(shù)轉(zhuǎn)換,并使用Spearman秩相關(guān)檢驗(yàn)來(lái)評(píng)估PreS1蛋白定量和其他生物標(biāo)志物之間的關(guān)系。計(jì)算受試者工作特征曲線下面積(AUC)來(lái)分析預(yù)測(cè)HBsAg轉(zhuǎn)陰的準(zhǔn)確性。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
2結(jié)果
2.1一般資料在IFN-α治療48周后,19.3%(17/88)的患者實(shí)現(xiàn)了HBsAg轉(zhuǎn)陰(<0.05 IU/mL),38.6%(34/88)的患者實(shí)現(xiàn)了HBeAg轉(zhuǎn)陰(<1 COI),63.6%(56/88)的患者實(shí)現(xiàn)了HBV DNA轉(zhuǎn)陰(<40 IU/mL)。根據(jù)48周IFN-α治療后患兒是否HBsAg轉(zhuǎn)陰將88例患兒分為轉(zhuǎn)陰組(n=17)和未轉(zhuǎn)陰組(n=71),轉(zhuǎn)陰組的年齡低于未轉(zhuǎn)陰組(P=0.006),除年齡外,兩組患兒在基線特征上差異均無(wú)統(tǒng)計(jì)學(xué)意義(表1)。
2.2PreS1與其他HBV指標(biāo)的相關(guān)性分析基線時(shí),血清PreS1水平與qHBsAg水平(r=0.912,P<0.001)強(qiáng)相關(guān),與HBV DNA水平(r=0.535,P<0.001)中等程度相關(guān),與年齡、ALT水平弱相關(guān)(r值分別為-0.280、-0.223,P值均<0.05)(圖1)。在85例接受肝組織活檢的患兒中,基線PreS1水平、qHBsAg水平、PreS1/qHBsAg比值與炎癥活動(dòng)度、纖維化程度無(wú)明顯相關(guān)(P值均>0.05)。
2.3基線各指標(biāo)對(duì)CHB患兒HBsAg轉(zhuǎn)陰的預(yù)測(cè)價(jià)值基線時(shí),PreS1/qHBsAg比值(AUC=0.694)較PreS1水平(AUC=0.530)和qHBsAg水平(AUC=0.514)具有較好的48周HBsAg轉(zhuǎn)陰預(yù)測(cè)價(jià)值。cut-off 值>0.073 8時(shí),陽(yáng)性預(yù)測(cè)值和陰性預(yù)測(cè)值分別為30.95% 和91.30%,敏感度和特異度分別為76.47%和59.15%(圖2)。
2.4治療12周各指標(biāo)對(duì)CHB患兒HBsAg轉(zhuǎn)陰的預(yù)測(cè)價(jià)值IFN-α治療第12周的PreS1水平以及PreS1/qHBsAg比值下降量(從基線到第12周的下降量)均可有效預(yù)測(cè)第48周的HBsAg轉(zhuǎn)陰,AUC分別為0.867和0.800(圖3),以第12周的PreS1水平≤1.91 log10 ng/mL為cut-off值,陽(yáng)性預(yù)測(cè)值和陰性預(yù)測(cè)值分別為72.73%和94.44%,敏感度和特異度分別為88.89% 和85.0%。以PreS1/qHBsAg比值下降量>0.045 5為cut-off值,陽(yáng)性預(yù)測(cè)值和陰性預(yù)測(cè)值分別為66.68%和85.01%,敏感度和特異度分別為66.67%和85.0%。
2.5治療24周各指標(biāo)對(duì)CHB患兒HBsAg轉(zhuǎn)陰的預(yù)測(cè)價(jià)值在IFN-α治療的第24周,PreS1水平、qHBsAg水平和HBV DNA均可有效預(yù)測(cè)第48周的HBsAg轉(zhuǎn)陰,AUC分別為0.917、0.949和0.762(P值均<0.001)。
2.6IFN-α治療的不良反應(yīng)在2年的隨訪期間,88例CHB患兒均未出現(xiàn)嚴(yán)重的不良反應(yīng)。59例患兒出現(xiàn)發(fā)熱,5例患兒出現(xiàn)惡心、納差,均能自行緩解;57例患兒出現(xiàn)中性粒細(xì)胞數(shù)減少(<2.0×109/L),給予對(duì)癥處理后不影響治療,IFN-α停藥后自行緩解。
3討論
CHB患兒抗病毒治療后HBsAg轉(zhuǎn)陰的有效預(yù)測(cè)指標(biāo)對(duì)于治療決策有著重要指導(dǎo)意義。而PreS1作為HBV感染性顆粒的特征性指標(biāo),其意義依舊引人關(guān)注。近年來(lái)隨著PreS1蛋白定量檢測(cè)技術(shù)的進(jìn)步,重新評(píng)估PreS1蛋白的臨床應(yīng)用價(jià)值受到了很大的關(guān)注。已有德國(guó)學(xué)者[15]證實(shí)在成人CHB患者中,抗病毒治療3個(gè)月的PreS1水平(AUC=0.839)是治療終點(diǎn)HBsAg轉(zhuǎn)陰的有力預(yù)測(cè)指標(biāo)。然而,目前PreS1水平在CHB兒童抗病毒治療中的預(yù)測(cè)作用尚無(wú)數(shù)據(jù)。本研究首次評(píng)估了PreS1水平在預(yù)測(cè)CHB患兒48周IFN-α治療后HBsAg轉(zhuǎn)陰中的作用,結(jié)果顯示:在IFN-α治療的第12周,PreS1水平和PreS1/qHBsAg比值的下降量對(duì)治療終點(diǎn)(48周)的HBsAg轉(zhuǎn)陰具有良好的預(yù)測(cè)作用。
HBsAg由三種表面蛋白組成,即?。⊿HB)、中(MHB)和大(LHB)表面蛋白。LHB包含S、PreS2和PreS1結(jié)構(gòu)域,PreS1結(jié)構(gòu)域僅存在于LHB中,HBV通過(guò)LHB的PreS1結(jié)構(gòu)域與牛磺膽酸鈉共轉(zhuǎn)運(yùn)多肽結(jié)合感染肝細(xì)胞[21],PreS1誘導(dǎo)免疫反應(yīng)作用較強(qiáng)[22]。在基線時(shí),血清PreS1水平與qHBsAg、HBV DNA水平呈正相關(guān),這與既往文獻(xiàn)[11-13]報(bào)道基本一致,研究結(jié)果略有差異表明了建立PreS1(LHB)和HBsAg水平檢測(cè)國(guó)際化標(biāo)準(zhǔn)的必要性。血清PreS1水平與qHBsAg水平呈正相關(guān),因?yàn)镻reS1蛋白只存在于LHB中[23],是HBsAg的重要成分之一;PreS1和HBV DNA存在相關(guān)性也有理論依據(jù),因?yàn)镻reS1主要存在于Dane顆粒中,并包含病毒入侵肝細(xì)胞所必需的受體結(jié)合域[21]。PreS1和其他HBV標(biāo)志物之間的良好相關(guān)性進(jìn)一步表明PreS1可能成為評(píng)估HBV感染的潛在生物標(biāo)志物。
本研究顯示,基線PreS1/qHBsAg比值高的患者容易實(shí)現(xiàn)HBsAg轉(zhuǎn)陰,推測(cè)是由于PreS1對(duì)B淋巴細(xì)胞和T淋巴細(xì)胞都有很強(qiáng)的免疫原性,基線PreS1/qHBsAg比值較高的宿主對(duì)HBV的PreS1域產(chǎn)生了更強(qiáng)的病毒特異性免疫反應(yīng),更有利于清除HBV并防止HBV感染/再感染肝細(xì)胞[22]。這進(jìn)一步支持了筆者關(guān)于PreS1/qHBsAg比值從基線到第12周的下降量對(duì)第48周HBsAg轉(zhuǎn)陰有預(yù)測(cè)作用的發(fā)現(xiàn)。PreS1/qHBsAg比值從基線到第12周的下降量越大,病毒特異性免疫反應(yīng)越強(qiáng),越容易實(shí)現(xiàn)HBsAg轉(zhuǎn)陰。既往也有文獻(xiàn)[24]報(bào)道血清PreS1/qHBsAg比值反映了肝纖維化的程度,但是本研究未得出此結(jié)論,可能與研究對(duì)象為兒童有關(guān)。此外,第12周的低PreS1水平對(duì)HBeAg陽(yáng)性CHB患兒的HBsAg轉(zhuǎn)陰也有很高的預(yù)測(cè)價(jià)值,推測(cè)是PreS1誘導(dǎo)了CD4+T淋巴細(xì)胞反應(yīng),在外周循環(huán)中產(chǎn)生了抗-PreS1以清除病毒,導(dǎo)致血清PreS1下降[22]。值得注意的是,第12周的PreS1水平比qHBsAg水平具有更高的預(yù)測(cè)價(jià)值,支持其作為HBsAg轉(zhuǎn)陰的一個(gè)早期預(yù)測(cè)因素。PreS1和qHBsAg在第24周的預(yù)測(cè)作用都強(qiáng)于第12周,且24周時(shí)qHBsAg預(yù)測(cè)作用略強(qiáng)于PreS1,然而第12周的檢驗(yàn)指標(biāo)預(yù)測(cè)HBsAg轉(zhuǎn)陰能夠早期指導(dǎo)CHB治療。值得一提的是,本研究發(fā)現(xiàn)基線PreS1和qHBsAg水平對(duì)HBsAg轉(zhuǎn)陰沒(méi)有預(yù)測(cè)作用,這與基線qHBsAg水平可以預(yù)測(cè)HBsAg轉(zhuǎn)陰的文獻(xiàn)報(bào)道相悖[8]。但是兩項(xiàng)研究均存在樣本量較小、回顧性研究等局限,未來(lái)還需進(jìn)行大樣本前瞻性研究,以得出確切的結(jié)論。綜上所述,早期(12周)血清PreS1水平和PreS1/qHBsAg比值下降量是HBeAg陽(yáng)性CHB兒童在IFN-α治療期間HBsAg轉(zhuǎn)陰的良好預(yù)測(cè)指標(biāo),可為CHB患兒的臨床治療決策提供參考,及時(shí)調(diào)整治療方案以規(guī)避不良事件的發(fā)生。
此外,在納入的研究對(duì)象中,轉(zhuǎn)陰組的患兒較未轉(zhuǎn)陰組的患兒年齡更小,這與以往的文獻(xiàn)[3-4]報(bào)道一致??赡艿脑蛴械妄g患兒的HBV感染持續(xù)時(shí)間尚短、低齡患兒(1~3歲)的免疫系統(tǒng)具有特殊性、外周血淋巴細(xì)胞比例更高、肝細(xì)胞處于生長(zhǎng)分裂期可能會(huì)有cccDNA的丟失以及生長(zhǎng)激素對(duì)HBV的拮抗作用等[25]。
本研究結(jié)果表明血清PreS1水平在預(yù)測(cè)CHB患兒抗病毒治療期間HBsAg轉(zhuǎn)陰方面具有臨床價(jià)值,可為兒童肝病醫(yī)生提供臨床管理的啟示。然而本研究尚存在一定的局限性,如采用回顧性觀察研究方法、納入的樣本例數(shù)較少、研究對(duì)象單一,且為單中心研究。簡(jiǎn)而言之,本研究結(jié)論需要進(jìn)行國(guó)際多中心的前瞻性大隊(duì)列研究來(lái)進(jìn)一步驗(yàn)證,進(jìn)一步闡明早期(12周)血清PreS1水平和PreS1/qHBsAg比值下降量對(duì)IFN-α治療期間CHB患兒的HBsAg轉(zhuǎn)陰有較強(qiáng)的預(yù)測(cè)作用的潛在機(jī)制,為CHB患兒的臨床抗病毒治療決策提供理論依據(jù)。
綜上所述,早期(12周)血清PreS1水平和PreS1/qHBsAg比值下降量對(duì)IFN-α治療期間CHB患兒的HBsAg轉(zhuǎn)陰有較強(qiáng)的預(yù)測(cè)作用,對(duì)CHB患兒的臨床決策具有重要的指導(dǎo)意義。
倫理學(xué)聲明:本研究方案于2020年4月經(jīng)由解放軍總醫(yī)院第五醫(yī)學(xué)中心倫理委員會(huì)審批,批號(hào):2020048D,患者監(jiān)護(hù)人均簽署知情同意書。 利益沖突聲明:本文不存在任何利益沖突。 作者貢獻(xiàn)聲明:王福川、高銀杰、徐志強(qiáng)、董漪、閆建國(guó)、曹麗麗和馮丹妮負(fù)責(zé)收集數(shù)據(jù)和初步統(tǒng)計(jì)分析;樊佩瑤負(fù)責(zé)數(shù)據(jù)統(tǒng)計(jì)分析和撰寫初稿;張敏、鐘彥偉負(fù)責(zé)課題設(shè)計(jì),擬定寫作思路,指導(dǎo)撰寫文章并最后定稿。
參考文獻(xiàn):
[1]BRAKENHOFF SM, de KNEGT RJ, OLIVEIRA J, et al. Levels of antibodies to hepatitis B core antigen are associated with liver inflammation and response to peginterferon in patients with chronic hepatitis B[J]. J Infect Dis, 2022, 227(1): 113-122. DOI: 10.1093/infdis/jiac210.
[2]LIU YH, LI H, YAN XH, et al. Long-term efficacy and safety of peginterferon in the treatment of children with HBeAg-positive chronic hepatitis B[J]. J Viral Hepat, 2019, 26(Suppl 1): 69-76. DOI: 10.1111/jvh.13154.
[3]FAN HM, LIN LP, JIA SJ, et al. Interferon alpha treatment leads to a high rate of hepatitis B surface antigen seroconversion in Chinese children with chronic hepatitis B[J]. J Viral Hepat, 2019, 26(Suppl 1): 77-84. DOI: 10.1111/jvh.13165.
[4]PAN J, WANG HY, YAO TT, et al. Clinical predictors of functional cure in children 1-6 years-old with chronic hepatitis B[J]. J Clin Transl Hepatol, 2022, 10(3): 405-411. DOI: 10.14218/JCTH.2021.00142.
[5]ZHU SS, DONG Y, XU ZQ, et al. A retrospective study on HBsAg clearance rate after antiviral therapy in children with HBeAg-positive chronic hepatitis B aged 1-7 years[J]. Chin J Hepatol, 2016, 24(10): 738-743. DOI: 10.3760/cma.j.issn.1007-3418.2016.10.005.朱世殊, 董漪, 徐志強(qiáng), 等. 1~7歲慢性乙型肝炎HBeAg陽(yáng)性兒童經(jīng)抗病毒治療HBsAg清除率的回顧性研究[J]. 中華肝臟病雜志, 2016, 24(10): 738-743. DOI: 10.3760/cma.j.issn.1007-3418.2016.10.005.
[6]WANG LM, ZHAO JF, LIU JY, et al. Long-term benefits of interferon-α therapy in children with HBeAg-positive immune-active chronic hepatitis B[J]. J Viral Hepat, 2021, 28(11): 1554-1562. DOI: 10.1111/jvh.13598.
[7]REN Y, BIAN DD, LIANG C, et al. Predictive value of serum sphingolipids combined with HBsAg quantification in HBsAg clearance of chronic hepatitis B patients treated with nucleos(t)ide analog add-on pegylated interferon α[J]. Translat Med J, 2023, 12(1): 15-21. DOI: 10.3969/j.issn.2095-3097.2023.01.004.任艷, 卞丹丹, 梁晨, 等. 血清鞘脂聯(lián)合定量HBsAg對(duì)核苷(酸)類似物經(jīng)治慢性乙型肝炎患者加用聚乙二醇干擾素α后HBsAg陰轉(zhuǎn)的預(yù)測(cè)價(jià)值[J]. 轉(zhuǎn)化醫(yī)學(xué)雜志, 2023, 12(1): 15-21. DOI: 10.3969/j.issn.2095-3097.2023.01.004.
[8]ZHONG YW, SHI YM, CHU F, et al. Prediction for HBsAg seroconversion in children with chronic hepatitis B[J]. BMC Infect Dis, 2021, 21(1): 1211. DOI: 10.1186/s12879-021-06883-1.
[9]WANG WX, JIA R, GAO YY, et al. Quantitative anti-HBc combined with quantitative HBsAg can predict HBsAg clearance in sequential combination therapy with PEG-IFN-α in NA-suppressed chronic hepatitis B patients[J]. Front Immunol, 2022, 13: 894410. DOI: 10.3389/fimmu.2022.894410.
[10]WU WK, YUAN XJ, ZHANG WL, et al. Clinical significance of novel biomarkers to predict the natural course of hepatitis B infection[J]. Front Public Health, 2022, 10: 1037508. DOI: 10.3389/fpubh.2022.1037508.
[11]RINKER F, BREMER CM, SCHRDER K, et al. Quantitation of large, middle and small hepatitis B surface proteins in HBeAg-positive patients treated with peginterferon Alfa-2a[J]. Liver Int, 2020, 40(2): 324-332. DOI: 10.1111/liv.14298.
[12]ZHU XJ, GONG QM, YU DM, et al. Early serum hepatitis B virus large surface protein level: A stronger predictor of virological response to peginterferon Alfa-2a than that to entecavir in HBeAg-positive patients with chronic hepatitis B[J]. J Clin Virol, 2013, 57(4): 318-322. DOI: 10.1016/j.jcv.2013.04.003.
[13]WANG NY, ZHANG D, ZHAO W, et al. Hepatitis B virus large surface protein in serum as a candidate biomarker for evaluating hepatitis B virus infection[J]. Clin Biochem, 2011, 44(14-15): 1199-1204. DOI: 10.1016/j.clinbiochem.2011.07.002.
[14]LIU C, WU WN, SHANG HY, et al. Prediction value of serum HBV large surface protein in different phases of HBV infection and virological response of chronic hepatitis B patients[J]. Clin Chimica Acta, 2018, 481: 12-19. DOI: 10.1016/j.cca.2018.02.015.
[15]PFEFFERKORN M, SCHOTT T, BHM S, et al. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B[J]. J Hepatol, 2021, 74(2): 283-292. DOI: 10.1016/j.jhep.2020.08.039.
[16]PFEFFERKORN M, BHM S, SCHOTT T, et al. Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers[J]. Gut, 2018, 67(11): 2045-2053. DOI: 10.1136/gutjnl-2017-313811.
[17]Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association.Guidelines for the prevention and treatment of chronic hepatitis B (version 2019) [J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969 /j.issn.1001-5256.2019.12.007.中華醫(yī)學(xué)會(huì)感染病學(xué)分會(huì), 中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì). 慢性乙型肝炎防治指南(2019年版)[J]. 臨床肝膽病雜志, 2019, 35(12): 2648-2669. DOI: 10.3969 /j.issn.1001-5256.2019.12.007.
[18]SCHEUER PJ. Classification of chronic viral hepatitis: A need for reassessment[J]. J Hepatol, 1991, 13(3): 372-374. DOI: 10.1016/0168-8278(91)90084-0.
[19]CUI AX, DOU XG, DING Y. Antiviral therapy for pregnant women and children with chronic HBV infection[J]. J Clin Hepatol, 2022, 38(11): 2448-2451. DOI: 10.3969/j.issn.1001-5256.2022.11.003.崔傲雪, 竇曉光, 丁洋. 慢性HBV感染孕婦和兒童的抗病毒治療藥物選擇及療效評(píng)價(jià)[J]. 臨床肝膽病雜志, 2022, 38(11): 2448-2451. DOI: 10.3969/j.issn.1001-5256.2022.11.003.
[20]CLEMENTE MG, ANTONUCCI R, SOTGIU G, et al. Present and future management of viral hepatitis B and C in children[J]. Clin Res Hepatol Gastroenterol, 2020, 44(6): 801-809. DOI: 10.1016/j.clinre.2020.02.010.
[21]YAN H, ZHONG GC, XU GW, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. eLife, 2012, 1: e00049. DOI: 10.7554/eLife.00049.
[22]BIAN YJ, ZHANG Z, SUN ZC, et al. Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice[J]. Hepatology, 2017, 66(4): 1067-1082. DOI: 10.1002/hep.29239.
[23]ZHUANG H. Clinical significance of determining the serum levels of large, middle, and small hepatitis B virus surface proteins[J]. J Clin Hepatol, 2022, 38(3): 528-531. DOI: 10.3969/j.issn.1001-5256.2022.03.007.莊輝. 血清HBV大、中、小表面蛋白檢測(cè)的臨床意義[J]. 臨床肝膽病雜志, 2022, 38(3): 528-531. DOI: 10.3969/j.issn.1001-5256.2022.03.007.
[24]NISHIDA Y, IMAMURA M, TERAOKA Y, et al. Serum PreS1 and HBsAg ratio reflects liver fibrosis and predicts the development of hepatocellular carcinoma in chronic hepatitis B patients[J]. J Viral Hepat, 2021, 28(9): 1304-1311. DOI: 10.1111/jvh.13557.
[25]ZHANG M, LI J, WANG FS. Antiviral therapy and clinical cure for chronic hepatitis B in children: Progress and challenges[J]. Chin J Hepatol, 2021, 29(12): 1218-1223. DOI: 10.3760/cma.j.cn501113-20210628-00303.張敏, 李靜, 王福生. 兒童慢性乙型肝炎抗病毒治療與臨床治愈: 進(jìn)展與挑戰(zhàn)[J]. 中華肝臟病雜志, 2021, 29(12): 1218-1223. DOI: 10.3760/cma.j.cn501113-20210628-00303.
收稿日期:2022-12-07;錄用日期:2023-01-16
本文編輯:王瑩
引證本文:FAN PY, WANG FC, GAO YJ, et al. Value of serum PreS1 in early prediction of HBsAg clearance after IFN-α treatment in children with HBeAg-positive chronic hepatitis B[J]. J Clin Hepatol, 2023, 39(8):? 1825-1831.