慢性乙型肝炎抗病毒治疗新进展

doi:10.3969/j.issn.1672-5069.2017.01.035

摘要/Abstract

摘要： 慢性乙型肝炎是由乙型肝炎病毒感染引起的、以肝脏炎症和坏死病变为主的一种全身性感染病。目前,治疗乙型肝炎的抗病毒药物主要包括干扰素和核苷酸类似物两类。现在正在探索开发新药及优化联合、免疫疗法或凋亡疗法（促进感染细胞凋亡）来彻底根除慢性HBV 感染。

关键词: 慢性乙型肝炎, 抗病毒治疗, 进展

Abstract: Chronic hepatitis B is caused by hepatitis B viral infection. It is a systemic infections mainly including inflammation and necrosis lesions of liver. At present,antiviral drugs to treat hepatitis B mainly include two categories,e.g. interferon and nucleotide analogues. Now,scholars are exploiting new agents,the optimization of combination therapy,immune or apoptosis therapy to eradicate chronic HBV infection.

Key words: Chronic hepatitis B, Antiviral therapy, Progress

侯春艳综述, 杨永峰审校. 慢性乙型肝炎抗病毒治疗新进展[J]. 实用肝脏病杂志, 2017, 20(1): 124-128.

Hou Chunyan, Yang Yongfeng.. Antiviral therapy for chronic hepatitis B[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2017, 20(1): 124-128.

参考文献

[1] Asselah T,Marcellin P. Long-term results of treatment with nucleoside and nucleotide analogues （entecavir and tenofovir） for chronic hepatitis B. Clin Liver Dis,2013,17:445-450.
[2] Perrill R. Benefits and risks of interferon therapy for hepatitis B.Hepatology,2009,49（5）:103-111.
[3] Lai CL,Ahn SH,Lee KS,et al. Phase Ⅱb multicentred randomised trial of besifovir（LB80380） versus entecavir in Asian patients with chronic hepatitis B. Gut,2014,63（6）:996-1004.
[4] Painter GR,Almond MR,Trost LC,et al. Evaluation of hexa-decyloxypropyl-9-R-[2-（phosphonomethoxy）propyl]-adenine,CMX157,as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections. Antimicrob Agents Chronicle,2007,51（10）:3505-3509.
[5] Murakami E,Wang T,Park Y,et al. Implications of efficient hepatic delivery by tenofovir alafenamide（GS-7340） for hepati tis B virus therapy. Antimicrob Agents Chronicle,2015,59（6）:3563-3569.
[6] Agarwal K,Fung SK,Nguyen TT,et al. Twenty-eight day safety,antiviral activity,and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection.J Hepatol,2015,62（3）:533-540.
[7] Yan H,Zhong G,Xu G,et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. ELife,2012,1:e00049
[8] Barrera A,Guerra B,Notvall L,et al. Mapping of the hepatitis B virus pre-S1 domain involved in receptor recognition. J Virol,79:9786-9798.
[9] Blank A,Markert C,Hohmann N,et al. Myrcludex B: successful first-in-human administration of a first in class hepatitis B and hepatitis D virus entry inhibitor. J Hepatol,2016,S0168-8278（16）:30145-30153.
[10] Belloni L,Pollicino T,Cimino L,et al. Nuclear HBx binds in vivo on the HBV minichromosome,modifies the epigenetic regulation of ccc-DNA function and potentiates HBV eplication.Proc Natl Acad Sci USA,2009,106（47）:19975-19979.
[11] Pollicino T,Belloni L,Raffa G,et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 istones.Gastroenterology,2006,1 30（3）:823-837.
[12] Baltayiannis G,Karayiannis P. Treatment options beyond IFNa and NUCs for chronic HBV infection：expectations for tomorrow.J Viral Hepat,2014,21（11）:753-761.
[13] Lucifora J,Xia Y,Reisinger F,et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science,2014,343（6176）:1221-1228.
[14] Fire A,Xu S,Montgomery MK,et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.Nature,1998,391:806-811.
[15] Keck K,Volper EM,Spengler RM,et al. Rational designleadsto more potent RNA interference against hepatitis B virus：factors efecting silencing eficiency.Mol Ther,2009,17（3）:538-547.
[16] Deng Y,Wang CC,Choy KW,et al. Therapeutic potentials of gene silencing by RNA interference：Principles,challenges,and new strategies.Gene,2013,538（2014）:217-227.
[17] Wang Y,Sheng G,Juranek S,et al. Structure of the guide-strand-containing argonaute silencing complex.Nature,2008,456:209-213.
[18] Li G,Fu L,Jiang J, et al. siRNA combinations mediate greater suppression of hepatitis B virus replication in mice.Cell Biochem Biophys,2014,69（3）:641-647.
[19] Robbins M,Judge A,Ambegia E,et al. Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation.Hum Gene Ther,2008,19（10）:991-999.
[20] Deres K,Schroder CH,Paessens A,et al. Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids.Science,2003,299（5608）:893-896.
[21] King RW,Ladner SK,Miller TJ,et al. Inhibition of human hepatitis B virus replication by AT-61,a phenylpropenamide derivative,alone and in combination with（-）beta-L-2',3 '-dideoxy-3'-thiacytidine.Antimicrob Agents Chemother,1998,42（12）:3179-3186.
[22] Locarnini SA,Feld JJ,Colledge D,et al. The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antiviral Res,2007,76（2）:168.
[23] Billiouda G,Pichouda C,Puerstinger G,et al. The main hepatitis B virus（HBV） mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication.Antiviral Res,2011,92（2）:271-276.
[24] Delaney WE,Ros Edwards,Danni Colledge,et al. Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine resistant strains of hepatitis B virus in vitro. Antimicrob Agents Chemother,2002,46（9）:3057-3060.
[25] Zhang EJ,Kosinska A,Li MJ,et al. Current status of immunomodulatory therapy in chronic hepatitis B,fifty years after discovery of the virus:search for the “magic bullet” to kill cccDNA. Antiviral Res,2015,123:193-203.
[26] Xu DZ,Zhao K,Guo H,et al. A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients. PLoS One,2008,3（7）:2565.
[27] Xu DZ,Wang X,Shen XL,et al. Results of a phase III clinical trial with all HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients：experiences and findings. J Hepatol,2013,59（3）:450-456.
[28] Flingai S,Czerwonko M,Goodman J,et al. Synthetic DNA vaccines:improved vaccine potency by electroporation and codelivered genetic adjuvants.Front Immunol,2013,4:354-363.
[29] Michel ML,Bourgine M,Fontaine H,et al. Therapeutic vaccines in treating chronic hepatitis B：the end of the beginning or the beginning of the end Med Microbiol Immunol,2015,204（1）:121-129.
[30] Gaggar A,Coeshott C,Apelian D,et al. Safety,tolerability and immunogenicity of GS-4774,a hepatitis B virus-specific therapeutic vaccine,in healthy subjects:a randomized study. Vaccine,2014,32（39）:4925-4931.
[31] Ma Z,Zhang E,Yang D,et al. Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses.Cell Mol Immunol,2015,12（3）:273-282.
[32] Lanford RE,Guerra B,Chavez D,et al. GS-9620,an oral agonist of Toll-like receptor-7,induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology,2013,144:508-517.
[33] Topalian SL,Hodi FS,Brahmer JR,et al. Safety,activity,and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med,2012,366:2443-2454.
[34] Liu J,Zhang E,Ma Z,et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog,2014,10:e1003856.
[35] Bohne F,Chmielewski M,Ebert G,et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes.Gastroenterology,2008,134:239-247.
[36] Krebs1 K,Bottinger1 N,Chmielewski M,et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology,2013,145:456-465.
[37] Ebert G,Preston S,Allison C,et al. Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus. Proc Natl Acad Sci USA,2015,112:5797-5802
[38] Vince1 JE,Khan N,Feltham R,et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell,2007,131（4）:682-93.
[39] Ebert G,Allison C,Preston S,et al. Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis. PNAS,2015,112 （18）:5803.