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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

27卷

期数:

2021年05期

页码:

520-523

栏目:

临床医学

出版日期:

2021-09-10

文章信息/Info

Title:

Dynamic changes and clinical significance of serum HBV RNA in patients with chronic hepatitis B during antiviral therapy

文章编号:

1006-8147(2021)05-0520-04

作者:

张荣芳¹; 钱磊¹; 常明杰¹; 付兵利²; 郭利敏3

（1.中国人民解放军陆军第八十三集团军医院检验科，新乡⁴⁵³000；2.北京市朝阳区桓兴肿瘤医院检验科，北京 100020；³.新乡市中心医院检验科，新乡⁴⁵³000）

Author(s):

ZHANG Rong-fang¹; QIAN Lei¹; CHANG Ming-jie¹; FU Bing-li²; GUO Li-min³

（1.Department of Clinical Laboratory，83rd Army Group Military Hospital，The People′s Liberation Army of China，Xinxiang 453000，China； 2. Department of Clinical Laboratory，Huanxing Cancer Hospital，Chaoyang District of Beijing，Beijing 100020，China; 3.Departme

关键词:

乙型肝炎病毒; 抗病毒治疗; HBV RNA; 共价闭合环状DNA

Keywords:

HBV; antiviral therapy; HBV RNA; covalently closed circular DNA

分类号:

R512.6+2

DOI:

-

文献标志码:

A

摘要:

目的：探讨血清HBV RNA在慢性乙型肝炎（CHB）抗病毒治疗过程中的动态变化及其临床意义。方法：慢性乙型肝炎患者62例采用恩替卡韦抗病毒治疗，分别在第0、7、14、30天以及第2、3、6、9、12个月来本院进行随访，TaqMan探针法定量检测HBV RNA水平，采用实时荧光定量PCR法进行HBV DNA水平检测，采用化学发光法进行HBsAg和HBeAg检测，采用酶法进行ALT及AST检测。结果：血清HBV RNA水平随着治疗时间的延长呈下降趋势，治疗3个月后下降速度趋缓，从9个月后变化不大。血清HBV RNA水平从0 d到6个月间，各个相邻监测点间变化均有统计学意义（均P<0.05），在治疗6～12个月两个时间点间差异无统计学意义（P>0.05）。HBeAg（+）患者基线血清HBV RNA与HBV DNA（rs =0.68，P<0.05）、HbsAg（rs =0.64，P<0.05）、HBeAg（rs=0.77，P<0.05）均强相关。在治疗前6个月各时间点，HBV RNA与HBV DNA呈强相关（rs＞0.5，P<0.05）。HBV RNA与HBsAg在治疗前3个月呈强相关（rs＞0.5，P<0.05），治疗6～9个月时为弱相关（rs=0.23，P=0.31；rs=0.28，P=0.23）。HBV RNA与HBeAg水平在各治疗时间点均为强相关（rs＞0.5，P<0.05）。HBeAg（-）患者在治疗30 d时血清HBV RNA与HBV DNA 呈正相关（rs=0.62，P<0.05），在治疗14 d时HBV RNA与HBsAg水平呈正相关（rs=0.60，P<0.05）。结论：抗病毒治疗时，慢性乙型肝炎患者血清HBV RNA水平随着治疗时间的延长呈下降趋势。患者血清HBV RNA水平与血清HBV DNA、HBsAg、HBeAg在治疗前和治疗初期有明显相关性，随着治疗时间延长，其相关性逐渐减弱。

Abstract:

Objective： To investigate the dynamic changes and clinical significance of serum HBV RNA in patients with chronic hepatitis B（CHB） during antiviral therapy. Methods: A total of 62 patients with chronic hepatitis B were treated with Entecavir，the patients were followed up at 0，7，14，30 days and 2，3，6，9，12 months. Quantitative detection of HBV RNA was conducted by TaqMan probe，HBV DNA level was detected by real-time fluorescent quantitative PCR，HBsAg and HBeAg were detected by chemiluminescence，ALT and AST were detected by enzymatic. Results: The serum HBV RNA level showed a downward trend with the extension of treatment time，and the decline rate slowed down after 3 months of treatment，and there was little change after 9 months. The changes of serum HBV RNA between the adjacent monitoring points were all statistically significant（all P<0.05） from 0 day to 6 months. There was no significant difference between the two time points of 6-12 months（P>0.05）.Serum HBV RNA in patients with HBeAg（+） was strongly correlated with HBV DNA（rs =0.68，P<0.05），HbsAg（rs =0.64，P<0.05），HbeAg（rs =0.77，P<0.05） in the cardinal line. There was a strong correlation between HBV RNA and HBV DNA during 6 months of treatment（rs > 0.50，P<0.05）. The correlation between HBV RNA and HBsAg was strong during 3 months treatment（rs >0.50，P<0.05），and it was weak from 6 to 9 months during treatment（rs =0.23，P=0.31；rs =0.28，P=0.23）. The correlation between HBV RNA and HBeAg level was strong at each treatment time point（rs > 0.50，P<0.05）. The correlation between serum HBV RNA and HBV DNA in HbeAg（-） patients at 30 days of treatment was positive（rs =0.62，P<0.05），and the correlation between HBV RNA and HBsAg level at 14 days of treatment was positive（rs =0.60，P<0.05）. Conclusion: During antiviral treatment，the serum HBV RNA level of patients with chronic hepatitis B decreases with the extension of treatment time. There is a significant correlation between serum HBV RNA level and serum HBV DNA，HBsAg，HBeAg before and at the beginning of treatment. With the extension of treatment time，the correlation is gradually weakened.

参考文献/References:

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[28] PATEL H K，TAO N，LEE K M，et al. Elacestrant（RAD1901） exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors[J]. Breast Cancer Res，2019，21（1）：146
[29] DENG J，WANG E S，JENKINS R W，et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation[J]. Cancer Discov，2018，8（2）：216 [1] KIM E S，SCOTT L J. Palbociclib：a review in HR-positive，HER2-negative， advanced or metastatic breast cancer[J]. Target Oncol，2017，12（3）：373
[2] FINN R S，MARTIN M，RUGO H S，et al. Palbociclib and Letrozole in advanced breast cancer[J]. N Engl J Med，2016，375（20）：1925
[3] CRISTOFANILLI M，TURNER N C，Bondarenko I，et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive，HER2-negative metastatic breast cancer that progressed on previous endocrine therapy（PALOMA-3）：final analysis of the multicentre，double-blind，phase 3 randomised controlled trial[J]. Lancet Oncol，2016，17（4）：425
[4] SPRING L M，WANDER S A，ANDRE F，et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer：past，present，and future[J]. Lancet，2020，395（10226）：817
[5] GELBERT L M，CAI S，LIN X，et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219：in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine[J]. Invest New Drugs，2014，32（5）：825
[6] CALDON C E，SERGIO C M，SCH?譈TTE J，et al. Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc[J]. Mol Cell Biol，2009， 29（17）：4623
[7] PANDEY K，AN H J，KIM S K，et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer：a review[J]. Int J Cancer，2019，145（5）：1179
[8] BUTT A J，MCNEIL C M，MUSGROVE E A，et al. Downstream targets of growth factor and oestrogen signalling and endocrine resistance：the potential roles of c-Myc， cyclin D1 and cyclin E[J]. Endocr Relat Cancer，2005，12（1 Suppl）：S47
[9] VIJAYARAGHAVAN S，DOOSTAN I，CAREY JPW，et al. Abstract 2060：Characterizing acquired resistance to palbociclib in breast cancer[J]. Cancer Res，2017，77（13 Suppl）：DIO：10.1158/1538-7445.AM2017-2060
[10] MAO P，KUSIEL J，COHEN O， et al. Abstract PD4-01：The role of FGF/FGFR axis in resistance to SERDs and CDK4/6 inhibitors in ER+ breast cancer[J]. Cancer Res，2018，78（4 Suppl）：DOI：10.1158/1538-7445.SABCS17-PD4-01
[11] HERRERA-ABREU M T，PALAFOX M，ASGHAR U，et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer[J]. Cancer Res，2016，76（8）：2301
[12] MICHALOGLOU C，CRAFTER C，SIERSBAEK R，et al. Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer[J]. Mol Cancer Ther，2018，17（5）：908
[13] JANSEN V M，BHOLA N E，BAUER J A，et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer[J]. Cancer Res，2017，77（9）：2488
[14] MERENBAKH-LAMIN K，BEN-BARUCH N，YEHESKEL A，et al. D538G mutation in estrogen receptor-α：a novel mechanism for acquired endocrine resistance in breast cancer[J]. Cancer Res，2013， 73（23）：6856
[15] BARDIA A，HURVITZ S. Targeted therapy for premenopausal women with HR（+），HER2（-）advanced breast cancer：focus on special considerations and latest advances[J]. Clin Cancer Res，2018，24（21）：5206
[16] GYANCHANDANI R，KOTA K J，JONNALAGADDA A R，et al. Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole[J]. Oncotarget，2017，8（40）：66901
[17] SCHAER D A，BECKMANN R P，DEMPSEY J A，et al. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade[J]. Cell Rep，2018，22（11）：2978
[18] O′LEARY B，CUTTS R J，LIU Y，et al. The genetic landscape and clonal evolution of breast cancer resistance to Palbociclib plus Fulvestrant in the PALOMA-3 trial[J]. Cancer Discov，2018，8（11）：1390
[19] HAFNER M，MILLS C E，SUBRAMANIAN K，et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity[J]. Cell Chem Biol，2019，26（8）：1067
[20] WANDER S A，ZANGARDI M，NIEMIERKO A，et al. A multicenter analysis of abemaciclib after progression on palbociclib in patients（pts） with hormone receptor-positive（HR+）/HER2- metastatic breast cancer （MBC）[J]. J Clin Oncol，2019，37（15 suppl）：1057
[21] FORMISANO L，LU Y，SERVETTO A，et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer[J]. Nat Commun，2019，10（1）：1373
[22] MILLER T W，HENNESSY B T，González-Angulo A M，et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer[J]. J Clin Invest，2010，120（7）：2406
[23] ANDR?魪 F，CIRUELOS E，RUBOVSZKY G，et al. Alpelisib for PIK3CA-mutated，hormone receptor-positive advanced breast cancer[J]. N Engl J Med，2019，380（20）：1929
[24] COSTA C，WANG Y，LY A，et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer[J]. Cancer Discov，2020，10（1）：72
[25] 黄元夕. 2020年美国临床肿瘤学会年会乳腺癌内分泌治疗重要内容解读[J]. 医学研究杂志，2020，49（10）：7
[26] JURIC D，ISMAIL-KHAN R，CAMPONE M，et al. Abstract P3-14-01：Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+，HER2-breast cancer：safety，preliminary efficacy and molecular analysis[J]. Cancer Res，2016，76（4 Suppl）：DOI：10.1158/1538-7445.SABCS15-P3-14-01
[27] JONES R H，CASBARD A，CARUCCI M，et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic，oestrogen receptor-positive breast cancer （FAKTION）：a multicentre，randomised，controlled，phase 2 trial[J]. Lancet Oncol，2020，21（3）：345
[28] PATEL H K，TAO N，LEE K M，et al. Elacestrant（RAD1901） exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors[J]. Breast Cancer Res，2019，21（1）：146
[29] DENG J，WANG E S，JENKINS R W，et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation[J]. Cancer Discov，2018，8（2）：216 [1] KIM E S，SCOTT L J. Palbociclib：a review in HR-positive，HER2-negative， advanced or metastatic breast cancer[J]. Target Oncol，2017，12（3）：373
[2] FINN R S，MARTIN M，RUGO H S，et al. Palbociclib and Letrozole in advanced breast cancer[J]. N Engl J Med，2016，375（20）：1925
[3] CRISTOFANILLI M，TURNER N C，Bondarenko I，et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive，HER2-negative metastatic breast cancer that progressed on previous endocrine therapy（PALOMA-3）：final analysis of the multicentre，double-blind，phase 3 randomised controlled trial[J]. Lancet Oncol，2016，17（4）：425
[4] SPRING L M，WANDER S A，ANDRE F，et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer：past，present，and future[J]. Lancet，2020，395（10226）：817
[5] GELBERT L M，CAI S，LIN X，et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219：in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine[J]. Invest New Drugs，2014，32（5）：825
[6] CALDON C E，SERGIO C M，SCH?譈TTE J，et al. Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc[J]. Mol Cell Biol，2009， 29（17）：4623
[7] PANDEY K，AN H J，KIM S K，et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer：a review[J]. Int J Cancer，2019，145（5）：1179
[8] BUTT A J，MCNEIL C M，MUSGROVE E A，et al. Downstream targets of growth factor and oestrogen signalling and endocrine resistance：the potential roles of c-Myc， cyclin D1 and cyclin E[J]. Endocr Relat Cancer，2005，12（1 Suppl）：S47
[9] VIJAYARAGHAVAN S，DOOSTAN I，CAREY JPW，et al. Abstract 2060：Characterizing acquired resistance to palbociclib in breast cancer[J]. Cancer Res，2017，77（13 Suppl）：DIO：10.1158/1538-7445.AM2017-2060
[10] MAO P，KUSIEL J，COHEN O， et al. Abstract PD4-01：The role of FGF/FGFR axis in resistance to SERDs and CDK4/6 inhibitors in ER+ breast cancer[J]. Cancer Res，2018，78（4 Suppl）：DOI：10.1158/1538-7445.SABCS17-PD4-01
[11] HERRERA-ABREU M T，PALAFOX M，ASGHAR U，et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer[J]. Cancer Res，2016，76（8）：2301
[12] MICHALOGLOU C，CRAFTER C，SIERSBAEK R，et al. Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer[J]. Mol Cancer Ther，2018，17（5）：908
[13] JANSEN V M，BHOLA N E，BAUER J A，et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer[J]. Cancer Res，2017，77（9）：2488
[14] MERENBAKH-LAMIN K，BEN-BARUCH N，YEHESKEL A，et al. D538G mutation in estrogen receptor-α：a novel mechanism for acquired endocrine resistance in breast cancer[J]. Cancer Res，2013， 73（23）：6856
[15] BARDIA A，HURVITZ S. Targeted therapy for premenopausal women with HR（+），HER2（-）advanced breast cancer：focus on special considerations and latest advances[J]. Clin Cancer Res，2018，24（21）：5206
[16] GYANCHANDANI R，KOTA K J，JONNALAGADDA A R，et al. Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole[J]. Oncotarget，2017，8（40）：66901
[17] SCHAER D A，BECKMANN R P，DEMPSEY J A，et al. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade[J]. Cell Rep，2018，22（11）：2978
[18] O′LEARY B，CUTTS R J，LIU Y，et al. The genetic landscape and clonal evolution of breast cancer resistance to Palbociclib plus Fulvestrant in the PALOMA-3 trial[J]. Cancer Discov，2018，8（11）：1390
[19] HAFNER M，MILLS C E，SUBRAMANIAN K，et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity[J]. Cell Chem Biol，2019，26（8）：1067
[20] WANDER S A，ZANGARDI M，NIEMIERKO A，et al. A multicenter analysis of abemaciclib after progression on palbociclib in patients（pts） with hormone receptor-positive（HR+）/HER2- metastatic breast cancer （MBC）[J]. J Clin Oncol，2019，37（15 suppl）：1057
[21] FORMISANO L，LU Y，SERVETTO A，et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer[J]. Nat Commun，2019，10（1）：1373
[22] MILLER T W，HENNESSY B T，González-Angulo A M，et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer[J]. J Clin Invest，2010，120（7）：2406
[23] ANDR?魪 F，CIRUELOS E，RUBOVSZKY G，et al. Alpelisib for PIK3CA-mutated，hormone receptor-positive advanced breast cancer[J]. N Engl J Med，2019，380（20）：1929
[24] COSTA C，WANG Y，LY A，et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer[J]. Cancer Discov，2020，10（1）：72
[25] 黄元夕. 2020年美国临床肿瘤学会年会乳腺癌内分泌治疗重要内容解读[J]. 医学研究杂志，2020，49（10）：7
[26] JURIC D，ISMAIL-KHAN R，CAMPONE M，et al. Abstract P3-14-01：Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+，HER2-breast cancer：safety，preliminary efficacy and molecular analysis[J]. Cancer Res，2016，76（4 Suppl）：DOI：10.1158/1538-7445.SABCS15-P3-14-01
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备注/Memo

备注/Memo:

作者简介 张荣芳(1982-)，女，主管技师，硕士，研究方向：病原生物学；通信作者：钱磊，E-mail：112690653@qq.com。

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更新日期/Last Update: 2021-09-01