探讨长期核苷(酸)类药物治疗慢性乙型肝炎患者停药后复发的影响因素
|
摘要
核苷(酸)类药物[Nucleos(t)ide-analogues,NAs]在临床上广泛用于抗乙型肝炎病毒(hepatitis B virus,HBV)治疗,然而其疗程长,难以达到理想的治疗终点停药。近年来,NAs治疗何时能够停药以及何种指标能够较为准确预测停药后应答,备受临床关注。本文从病毒学和宿主免疫学两个方面,概述了关于影响停止NAs治疗后复发的主要因素:(1)血清表面抗原(HBsAg)、核心相关抗原(HBcrAg)和血清HBV RNA这三种病毒学因素在NAs抗病毒治疗终点的研究中具有重要价值;(2)宿主免疫学因素包括细胞因子水平、天然免疫应答以及适应性免疫应答,其中NK细胞和HBV特异性T细胞与NAs停药后细胞宿主免疫应答密切相关;(3)病毒因素以及宿主因素之间的相互作用决定了HBV感染的临床结局。
Nucleos(t)ide-analogues(NAs) is widely applied to the antiviral therapy of hepatitis B virus(HBV)clinically.However, few patients treated with NAs could reach HBsAg clearance, considering the ideal end-point of treatment. Over the past decades, researchers have increasingly focused on optimal stopping strategies, mainly in which indicators could effectively predict clinical outcomes and during which optimal time point to perform. The report summarizes the crucial factors causing the relapse after the NAs treatment is stopped based on virology and host immunology:(1)Serum HBsAg, HBcrAg, and HBV RNA play crucial roles in determining end-point of NAs' antiviral therapy.(2)Immunological factors including levels of cytokines, natural immune responses and adaptive immune responses. In addition, NK cell and HBV-specific T cell are closely associated with host immune response.(3)The interaction between virological and immunological factors induce the clinical outcomes.
Nucleos(t)ide-analogues(NAs) is widely applied to the antiviral therapy of hepatitis B virus(HBV)clinically.However, few patients treated with NAs could reach HBsAg clearance, considering the ideal end-point of treatment. Over the past decades, researchers have increasingly focused on optimal stopping strategies, mainly in which indicators could effectively predict clinical outcomes and during which optimal time point to perform. The report summarizes the crucial factors causing the relapse after the NAs treatment is stopped based on virology and host immunology:(1)Serum HBsAg, HBcrAg, and HBV RNA play crucial roles in determining end-point of NAs' antiviral therapy.(2)Immunological factors including levels of cytokines, natural immune responses and adaptive immune responses. In addition, NK cell and HBV-specific T cell are closely associated with host immune response.(3)The interaction between virological and immunological factors induce the clinical outcomes.
引文
[1]Stanaway JD,Flaxman AD,Naghavi M,et al.The global burden of viral hepatitis from 1990 to 2013:findings from the Global Burden of Disease Study 2013[J].Lancet,2016,388(10049):1081-1088.
[2]Lozano RP,Naghavi MP,Foreman KM,et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010:a systematic analysis for the Global Burden of Disease Study 2010[J].Lancet,2012,380(9859):2095-2128.
[3]Ruan P,Xu SY,Zhou BP,et al.Hepatitis B surface antigen seroclearance in patients with chronic hepatitis B infection:A clinical study[J].J Int Med Res,2013,41(5):1732-1739.
[4]Seto W,Hui A J,Wong V W,et al.Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B:a multicentre prospective study[J].Gut,2015,64(4):667-672.
[5]Chen C H,Hsu Y C,Lu S N,et al.The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients[J].J Viral Hepat,2018,25(5):590-597.
[6]Wang C,Tseng K,Hsieh T,et al.Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg[J].Am J Gastroenterol,2016,111(9):1286-1294.
[7]Wang J,Shen T,Huang X,et al.Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound[J].JJHepatol,2016,65(4):700-710.
[8]Wang J,Du M,Huang H,et al.Consistent loss of serum HBV RNA might predict the“para-functional cure”of chronic hepatitis B[J].J Hepatol,2016,66(2):462-463.
[9]Wang Jing,Yu Yiqi,Li Guojun,et al.Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients[J].J Hepatol,2017,8278(17):32261-32264.
[10]Akinori Rokuhara,Akihiro Matsumoto,Eiji Tanaka,et al.Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy[J].JGastroenterol,2006,41(8):785-790.
[11]Yoon S K,Jang J W,Kim C W,et al.Long-Term Results of Lamivudine Monotherapy in Korean Patients with HBeAgPositive Chronic Hepatitis B:Response and Relapse Rates,and Factors Related to Durability of HBeAg Seroconversion[J].Intervirology,2005,48(6):341-349.
[12]Ryu DK,Ahn Y,Ryu WS,et al.Development of a novel hepatitis B virus encapsidation detection assay by viral nucleocapsid-captured quantitative RT-PCR[J].Biotechniques,2015,59(5):287-293.
[13]Kimura T,Ohno N,Terada N,et al.Hepatitis B Virus DNA-negative Dane Particles Lack Core Protein but Contain a22-kDa Precore Protein without C-terminal Arginine-rich Domain[J].J Biol Chem,2005,280(23):21713-21719.
[14]Wang B,Carey I,Bruce M,et al.HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg-positive patients treated with nucleos(t)ide analogues[J].JViral Hepat,2018,25(8):886-893.
[15]Shinkai N,Tanaka Y,Orito E,et al.Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection[J].Hepatol Res,2006,36(4):272-276.
[16]Matsumoto A,Tanaka E,Minami M,et al.Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy[J].Hepatol Res,2007,37(8):661-666.
[17]Boni CLDLP.Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues[J].Gastroenterology,2012,143(4):963-973.
[18]Papatheodoridis G,Vlachogiannakos I,Cholongitas E,et al.Discontinuation of oral antivirals in chronic hepatitis B:A systematic review[J].Hepatol Res,2016,63(5):1481-1492.
[19]Siederdissen C,Rinker F,Maasoumy B,et al.Viral and Host Responses After Stopping Long-term Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B[J].J Infect Dis,2016,214(10):1492-1497.
[20]Christine L.Zimmer FRCH.Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss[J].J Infect Dis,2018,217(10):1656-1666.
[21]Caligiuri M A.Human natural killer cells[J].Blood,2008,112(3):461-469.
[22]Vivier E,Tomasello E,Baratin M,et al.Functions of natural killer cells[J].Nature Immunology,2008,9(5):503-510.
[23]Rinker FZCHZ:Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg negative chronic hepatitis B[J].J Hepatol,2018,69(3):584-593.
[24]Rivino L LBNG:Hepatitis B virus-specific T cells 2018JCI[J].J Clin Invest,2018,128(2):668-681.
[2]Lozano RP,Naghavi MP,Foreman KM,et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010:a systematic analysis for the Global Burden of Disease Study 2010[J].Lancet,2012,380(9859):2095-2128.
[3]Ruan P,Xu SY,Zhou BP,et al.Hepatitis B surface antigen seroclearance in patients with chronic hepatitis B infection:A clinical study[J].J Int Med Res,2013,41(5):1732-1739.
[4]Seto W,Hui A J,Wong V W,et al.Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B:a multicentre prospective study[J].Gut,2015,64(4):667-672.
[5]Chen C H,Hsu Y C,Lu S N,et al.The incidence and predictors of HBV relapse after cessation of tenofovir therapy in chronic hepatitis B patients[J].J Viral Hepat,2018,25(5):590-597.
[6]Wang C,Tseng K,Hsieh T,et al.Assessing the Durability of Entecavir-Treated Hepatitis B Using Quantitative HBsAg[J].Am J Gastroenterol,2016,111(9):1286-1294.
[7]Wang J,Shen T,Huang X,et al.Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound[J].JJHepatol,2016,65(4):700-710.
[8]Wang J,Du M,Huang H,et al.Consistent loss of serum HBV RNA might predict the“para-functional cure”of chronic hepatitis B[J].J Hepatol,2016,66(2):462-463.
[9]Wang Jing,Yu Yiqi,Li Guojun,et al.Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients[J].J Hepatol,2017,8278(17):32261-32264.
[10]Akinori Rokuhara,Akihiro Matsumoto,Eiji Tanaka,et al.Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy[J].JGastroenterol,2006,41(8):785-790.
[11]Yoon S K,Jang J W,Kim C W,et al.Long-Term Results of Lamivudine Monotherapy in Korean Patients with HBeAgPositive Chronic Hepatitis B:Response and Relapse Rates,and Factors Related to Durability of HBeAg Seroconversion[J].Intervirology,2005,48(6):341-349.
[12]Ryu DK,Ahn Y,Ryu WS,et al.Development of a novel hepatitis B virus encapsidation detection assay by viral nucleocapsid-captured quantitative RT-PCR[J].Biotechniques,2015,59(5):287-293.
[13]Kimura T,Ohno N,Terada N,et al.Hepatitis B Virus DNA-negative Dane Particles Lack Core Protein but Contain a22-kDa Precore Protein without C-terminal Arginine-rich Domain[J].J Biol Chem,2005,280(23):21713-21719.
[14]Wang B,Carey I,Bruce M,et al.HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg-positive patients treated with nucleos(t)ide analogues[J].JViral Hepat,2018,25(8):886-893.
[15]Shinkai N,Tanaka Y,Orito E,et al.Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection[J].Hepatol Res,2006,36(4):272-276.
[16]Matsumoto A,Tanaka E,Minami M,et al.Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy[J].Hepatol Res,2007,37(8):661-666.
[17]Boni CLDLP.Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues[J].Gastroenterology,2012,143(4):963-973.
[18]Papatheodoridis G,Vlachogiannakos I,Cholongitas E,et al.Discontinuation of oral antivirals in chronic hepatitis B:A systematic review[J].Hepatol Res,2016,63(5):1481-1492.
[19]Siederdissen C,Rinker F,Maasoumy B,et al.Viral and Host Responses After Stopping Long-term Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B[J].J Infect Dis,2016,214(10):1492-1497.
[20]Christine L.Zimmer FRCH.Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss[J].J Infect Dis,2018,217(10):1656-1666.
[21]Caligiuri M A.Human natural killer cells[J].Blood,2008,112(3):461-469.
[22]Vivier E,Tomasello E,Baratin M,et al.Functions of natural killer cells[J].Nature Immunology,2008,9(5):503-510.
[23]Rinker FZCHZ:Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg negative chronic hepatitis B[J].J Hepatol,2018,69(3):584-593.
[24]Rivino L LBNG:Hepatitis B virus-specific T cells 2018JCI[J].J Clin Invest,2018,128(2):668-681.