慢性乙型肝炎治愈新药研究进展
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摘要
<正>据2016年世界卫生组织报道,全球约有2.4亿慢性HBV感染者,每年约有65万人死于慢性HBV感染导致的肝硬化或肝癌[1]。2017年欧洲肝病研究学会对乙型肝炎治愈作出定义:(1)完全治愈(complete sterilizing cure),即血清HBsAg完全检测不到,HBV DNA彻底清除,包括共价闭合环状DNA(cccDNA)和整合的HBV DNA;(2)功能性治愈
引文
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[25]Bazinet M,Pantea V,Cebotarescu V,et al.Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection(REP 301 and REP 301-LTF):a non-randomised,open-label,phase 2 trial.Lancet Gastroenterol Hepatol,2017,2(12):877-889.
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[29]Wang XY,Yao X,Wan YM,et al.Responses to multiple injections with alum alone compared to injections with alum adsorbed to proteins in mice.Immunol Lett,2013,149(1-2):88-92.
[30]Lok AS,Pan CQ,Han SHB,et al.Randomized phase II study of GS-47 74 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B.J Hepatol,2016,65(3):509-516.
[31]Emery JS,Feld JJ.Treatment of hepatitis B virus with combination therapy now and in the future.Best Pract Res Cl Ga,2017,31(3):347-355.
[32]Lobaina Y,Michel ML.Chronic hepatitis B:Immunological profile and current therapeutic vaccines in clinical trials.Vaccine,2017,35(18):2308-2314.
[33]Agarwal K,Ahn SH,Elkhashab M,et al.Safety and efficacy of vesatolimod(GS-9620)in patients with chronic hepatitis Bwho are not currently on antiviral treatment.J Viral Hepat,2018,25(11):1331-1340.
[34]Man-Fung Yuen ME,Chen CY,Chen YF,et al.Inarigivir demonstrates potent dose dependent anti-viral activity in HBV treatment-naive patients:Role of HBe Ag status and baseline HBs Ag in anti-viral response.Hepatology,2018,68:48A.
[35]Janssen HLA,Brunetto MR,Kim YJ,et al.Safety,efficacy and pharmacodynamics of vesatolimod(GS-9620)in virally suppressed patients with chronic hepatitis B.J Hepatol,2018,68(3):431-440.
[36]Gane E,Gaggar A,Nguyen AH,et al.A phase1 study evaluating anti-PD-1 treatment with or without GS-4774 in HBe Ag negative chronic hepatitis B patients.J Hepatol,2017,66(1):S26-S27.
[37]Mak LY,Seto WK,Fung J,et al.Novel developments of hepatitis B:treatment goals,agents and monitoring tools.Expert Rev Clin Phar,2019,12(2):109-120.
[2]Lu FM,Zhuang H.Management of hepatitis B in China.Chin Med J,2009,122(1):3-4.
[3]Lok AS,Zoulim F,Dusheiko G,et al.Hepatitis B cure:From discovery to regulatory approval.Hepatology,2017,66(4):1296-1313.
[4]BJ.The natural history of chronic hepatitis B virus infection.Hepatology,2009,49(5):S45-S55.
[5]Trepo C,Chan HLY,Lok A.Hepatitis B virus infection.Lancet,2014,384(9959):2053-2063.
[6]Yapali S,Talaat N,Lok AS.Management of hepatitis B:Our practice and how it relates to the guidelines.Clin Gastroenterol H,2014,12(1):16-26.
[7]Hu P,Dou XG,Jiang JN,et al.Increased and sustained HBs Ag loss in HBe Ag positive CHB patients switched from NUC to Peg-IFN alfa-2a:A randomised open label trial(NEW SWITCHstudy).Hepatology,2016,64:36a-37a.
[8]Qiu K,Liu B,Li SY,et al.Systematic review with meta-analysis:combination treatment of regimens based on pegylated interferon for chronic hepatitis B focusing on hepatitis B surface antigen clearance.Aliment Pharm Ther,2018,47(10):1340-1348.
[9]Heiner Wedemeyer KS,Bogomolov PO,Voronkova NV,et al.Interim results of a multicentre,open label phase 2 clinical trial(MYR203)to assess safety and effcacy of myrcludex B in combination with peg-interferon alpha 2a in patients with chronic HBV/HDV co-infection.Hepatology,2018,68:11A.
[10]Lucifora J,Xia YC,Reisinger F,et al.Specific and nonhepatotoxic degradation of nuclear hepatitis B virus ccc DNA.Science,2014,343(6176):1221-1228.
[11]Xia YC,Stadler D,Lucifora J,et al.Interferon-gamma and tumor necrosis factor-alpha produced by T cells reduce the HBVpersistence form,ccc DNA,without cytolysis.Gastroenterology,2016,150(1):194-205.
[12]Xia YC,Lucifora J,Reisinger F,et al.VIROLOGY response to comment on“specific and nonhepatotoxic degradation of nuclear hepatitis B virus ccc DNA”.Science,2014,344(6189):142-144.
[13]Ramanan V,Shlomai A,Cox DBT,et al.CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus.Sci Rep-Uk,2015,5:132-136.
[14]Seeger C,Sohn JA.Complete sof CRISPR/Cas9-induced mutations on HBV ccc DNA.Mol Ther,2016,24(7):1258-1266.
[15]Tropberger P,Mercier A,Robinson M,et al.Mapping of histone modifications in episomal HBV ccc DNA uncovers an unusual chromatin organization amenable to epigenetic manipulation.Proc Natl Acad Sci USA,2015,112(42):E5715-E5724.
[16]Murphy CM,Xu YP,Li F,et al.Hepatitis B virus X protein promotes degradation of SMC5/6 to enhance HBV replication.Cell Rep,2016,16(11):2846-2854.
[17]Streinu-Cercel A,Gane E,Cheng W,et al.A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBe Ag positive and negative virally suppressed subjects with hepatitis B.J Hepatol,2017,66(1):S688-S689.
[18]Wooddell CI,Yuen MF,Chan HLY,et al.RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBs Ag.Sci Transl Med,2017,9(409):182-187.
[19]Ganeea EJ.First results with RNA interference(RNAi)in chronic hepatitis B(CHB)using ARO-HBV.Hepatology,2018,68:LB-25.
[20]Fabien Zoulim JY,Vandenbossche JJ,Moscalu I,et al.Safety,pharmacokinetics and antiviral activity of a novel hepatitis Bvirus(HBV)capsid assembly modulator,JNJ-56136379,in patients with chronic hepatitis B(CHB).Hepatology,2018,68:47A-48A.
[21]Man-Fung Yuen KA,Gane EJ,Schwabe C,et al.Final results of a phase 1b 28-day study of ABI-H0731,a novel core inhibitor,in noncirrhotic viremic subjects with chronic hepatitis B.Hepatology,2018,68:46A-47A.
[22]Yuen MF,Kim DJ,Weilert F,et al.Nvr 3-778,a first-in-class HBVcore inhibitor,alone and in combination with peg-interferon(Pegifn),in treatment-naive Hbeag-positive patients:Early reductions in HBV DNA and HbeAg.J Hepatol,2016,64:S210-S211.
[23]Schwabe C.A phase 1 single and multiple dose-escalating study to evaluate the safety,tolerability,pharmacokinetics and effect of ARO-AAT on serum alpha-1 antitrypsin levels in normal adult volunteers.J Hepatol,2016,62:195-198.
[24]Al-Mahtab M,Bazinet M,Vaillant A.Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naive Bangladeshi patients with HBe Ag+chronic hepatitis B infection.PLoS One,2016,11(6):e0156667.
[25]Bazinet M,Pantea V,Cebotarescu V,et al.Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection(REP 301 and REP 301-LTF):a non-randomised,open-label,phase 2 trial.Lancet Gastroenterol Hepatol,2017,2(12):877-889.
[26]Ko C,Michler T,Protzer U.Novel viral and host targets to cure hepatitis B.Curr Opin Virol,2017,24:38-45.
[27]Xu DZ,Zhao K,Guo LM,et al.A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients.PLo S One,2008,3(7):e2565.
[28]Xu DZ,Wang XY,Shen XL,et al.Results of a phase III clinical trial with an HBs Ag-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients:experiences and findings.J Hepatol,2013,59(3):450-456.
[29]Wang XY,Yao X,Wan YM,et al.Responses to multiple injections with alum alone compared to injections with alum adsorbed to proteins in mice.Immunol Lett,2013,149(1-2):88-92.
[30]Lok AS,Pan CQ,Han SHB,et al.Randomized phase II study of GS-47 74 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B.J Hepatol,2016,65(3):509-516.
[31]Emery JS,Feld JJ.Treatment of hepatitis B virus with combination therapy now and in the future.Best Pract Res Cl Ga,2017,31(3):347-355.
[32]Lobaina Y,Michel ML.Chronic hepatitis B:Immunological profile and current therapeutic vaccines in clinical trials.Vaccine,2017,35(18):2308-2314.
[33]Agarwal K,Ahn SH,Elkhashab M,et al.Safety and efficacy of vesatolimod(GS-9620)in patients with chronic hepatitis Bwho are not currently on antiviral treatment.J Viral Hepat,2018,25(11):1331-1340.
[34]Man-Fung Yuen ME,Chen CY,Chen YF,et al.Inarigivir demonstrates potent dose dependent anti-viral activity in HBV treatment-naive patients:Role of HBe Ag status and baseline HBs Ag in anti-viral response.Hepatology,2018,68:48A.
[35]Janssen HLA,Brunetto MR,Kim YJ,et al.Safety,efficacy and pharmacodynamics of vesatolimod(GS-9620)in virally suppressed patients with chronic hepatitis B.J Hepatol,2018,68(3):431-440.
[36]Gane E,Gaggar A,Nguyen AH,et al.A phase1 study evaluating anti-PD-1 treatment with or without GS-4774 in HBe Ag negative chronic hepatitis B patients.J Hepatol,2017,66(1):S26-S27.
[37]Mak LY,Seto WK,Fung J,et al.Novel developments of hepatitis B:treatment goals,agents and monitoring tools.Expert Rev Clin Phar,2019,12(2):109-120.