中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Issue 5
May  2018
Turn off MathJax
Article Contents

New strategies for clinical cure and Institute of hepatitis B:viral suppression combined with immune modulation and its road map

DOI: 10.3969/j.issn.1001-5256.2018.05.002
Research funding:

 

  • Received Date: 2018-02-07
  • Published Date: 2018-05-20
  • Chronic hepatitis B virus ( HBV) infection remains a major global health issue. At present, nucleos ( t) ide analogues ( NAs) and interferon ( IFN) or pegylated interferon ( PEG-IFN) are used as the antiviral therapy. NA therapy is generally safe and well tolerated, but it has a high virological recurrence rate after drug withdrawal and a long course of treatment which may require lifelong medication. PEG-IFN therapy has the advantages of relatively shorter course of treatment, longer response, and lower rate of resistance; however, only some patients can achieve sustained response to IFN, and IFN has a high rate of adverse events, which limits the wide application of IFN in clinical practice. Since HBV covalently closed circular DNA and the integrated HBV genome stably exist in the nuclei of infected hepatocytes, it is difficult to achieve the elimination ( complete cure) of HBV. The ideal endpoint of antiviral therapy for chronic hepatitis B recommended by most guidelines is the sustained disappearance of HBs Ag, with or without HBs Ab seroconversion ( functional cure) . Theoretically, a combination of antiviral agents with different anti-HBV mechanisms, including the drugs for viral suppression and immune modulation, is a promising strategy for the treatment of chronic hepatitis B. Latest studies have demonstrated that compared with NA alone, NA given concurrently or sequentially with PEG-IFN has certain advantages in virologic and serological response. Our articles published in Journal of Hepatology in 2015 and Journal of Infectious Diseases in December 2017 introduce the research advances in treatment strategies for chronic hepatitis B and put forward our thoughts on clinical cure of chronic hepatitis B and related clinical routes, with reference to research findings in China and foreign countries. This article provides some updated information.

     

  • loading
  • [1]OTT JJ, STEVENS GA, GROEGER J, et al.Global epidemiology of hepatitis B virus infection:new estimates of age-specific HBs Ag seroprevalence and endemicity[J].Vaccine, 2012, 30 (12) :2212
    [2]WHO.Hepatitis B factsheet[EB/OL].http://www.who.int/mediacentre/factsheets/fs204/en/.
    [3]LEVRERO M, POLLICINO T, PETERSEN J, et al.Control of ccc DNA function in hepatitis B virus infection[J].J Hepatol, 2009, 51 (3) :581-592.
    [4]OP den BROUW ML, BINDA RS, van ROOSMALEN MH, et al.Hepatitis B virus surface antigen impairs myeloid dendritic cell function:a possible immune escape mechanism of hepatitis B virus[J].Immunology, 2009, 126 (2) :280-289.
    [5]LANG T, LO C, SKINNER N, et al.The hepatitis B e antigen (HBe Ag) targets and suppresses activation of the toll-like receptor signaling pathway[J].J Hepatol, 2011, 55 (4) :762-769.
    [6]DAS A, HOARE M, DAVIES N, et al.Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection[J].J Exp Med, 2008, 205 (9) :2111-2124.
    [7]BONI C, FISICARO P, VALDATTA C, et al.Characterization of hepatitis B virus (HBV) -specific T-cell dysfunction in chronic HBV infection[J].J Virol, 2007, 81 (8) :4215-4225.
    [8] European Association for the Study of the Liver.EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection[J].J Hepatol, 2017, 67 (2) :370-398.
    [9]LAMPERTICO P, LIAW YF.New perspectives in the therapy of chronic hepatitis B[J].Gut, 2012, 61 (Suppl 1) :i18-i24.
    [10]SCAGLIONE SJ, LOK AS.Effectiveness of hepatitis B treatment in clinical practice[J].Gastroenterology, 2012, 142 (6) :1360-1368.e1.
    [11]CHAN HL, WONG VW, TSE AM, et al.Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response[J].Clin Gastroenterol Hepatol, 2007, 5 (12) :1462-1468.
    [12]MOUCARI R, MACKIEWICZ V, LADA O, et al.Early serum HBs Ag drop:a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBe Ag-negative patients[J].Hepatology, 2009, 49 (4) :1151-1157.
    [13]MARTINOT-PEIGNOUX M, LAPALUS M, ASSELAH T, et al.HBs Ag quantification:useful for monitoring natural history and treatment outcome[J].Liver Int, 2014, 34 (Suppl 1) :97-107.
    [14]ARENDS P, SONNEVELD MJ, ZOUTENDIJK R, et al.Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B:limited role for risk scores in Caucasians[J].Gut, 2015, 64 (8) :1289-1295.
    [15]DARGAN A, WONG SY, COBEN R, et al.Persistent risk for hepatocellular carcinoma after more than a decade of successful hepatitis B virus suppression[J].Minerva Gastroenterol Dietol, 2017, 63 (1) :74-76.
    [16] SARIN SK, KUMAR M, LAU GK, et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B:a 2015 update[J].Hepatol Int, 2016, 10 (1) :1-98.
    [17]TERRAULT NA, BZOWEJ NH, CHANG KM, et al.AASLD guidelines for treatment of chronic hepatitis B[J].Hepatology, 2016, 63 (1) :261-283.
    [18]SADLER AJ, WILLIAMS BR.Interferon-inducible antiviral effectors[J].Nat Rev Immunol, 2008, 8 (7) :559-568.
    [19]SAMUEL CE.Antiviral actions of interferons[J].Clin Microbiol Rev, 2001, 14 (4) :778-809.
    [20]BONI C, LACCABUE D, LAMPERTICO P, et al.Restored function of HBV-specific T cells after long-term effective therapy with nucleos (t) ide analogues[J].Gastroenterology, 2012, 143 (4) :963-973.e9.
    [21]DANDRI M, LOCARNINI S.New insight in the pathobiology of hepatitis B virus infection[J].Gut, 2012, 61 (Suppl 1) :16-17.
    [22]WIELAND SF, EUSTAQUIO A, WHITTEN-BAUER C, et al.Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids[J].Proc Natl Acad Sci U S A, 2005, 102 (28) :9913-9917.
    [23]XU C, GUO H, PAN XB, et al.Interferons accelerate decay of replication-competent nucleocapsids of hepatitis B virus[J].J Virol, 2010, 84 (18) :9332-9340.
    [24]BELLONI L, ALLWEISS L, GUERRIERI F, et al.IFN-αinhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear ccc DNA minichromosome[J].J Clin Invest, 2012, 122 (2) :529-537.
    [25]BRUNETTO MR, BONINO F.Interferon therapy of chronic hepatitis B[J].Intervirology, 2014, 57 (3-4) :163-170.
    [26]KIM SR, YANG J, KUDO M, et al.Recent advances in the management of chronic hepatitis B[J].Hepat Mon, 2011, 11 (8) :601-611.
    [27]LAU GK, PIRATVISUTH T, LUO KX, et al.Peginterferon alfa-2a HBe Ag-positive chronic hepatitis B study group.Peginterferon alfa-2a, lamivudine, and the combination for HBe Ag-positive chronic hepatitis B[J].N Engl J Med, 2005, 352 (26) :2682-2695.
    [28]JANSSEN HL, van ZONNEVELD M, SENTURK H, et al.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBe Ag-positive chronic hepatitis B:a randomised trial[J].Lancet, 2005, 365 (9454) :123-129.
    [29]CHANG TT, GISH RG, de MAN R, et al.A comparison of entecavir and lamivudine for HBe Ag-positive chronic hepatitis B[J].N Engl J Med, 2006, 354 (10) :1001-1010.
    [30]LAI CL, CHIEN RN, LEUNG NW, et al.A one-year trial of lamivudine for chronic hepatitis B[J].N Engl J Med, 1998, 339 (12) :61-68.
    [31]LAI CL, GANE E, LIAW YF, et al.Telbivudine versus lamivudine in patients with chronic hepatitis B[J].N Engl J Med, 2007, 357 (25) :2576-2588.
    [32]MARCELLIN P, CHANG TT, LIM SG, et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B[J].N Engl J Med, 2003, 348 (9) :808-816.
    [33]MARCELLIN P, HEATHCOTE EJ, BUTI M, et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B[J].N Engl J Med, 2008, 359 (23) :2442-2455.
    [34]LIAW YF, GANE E, LEUNG N, et al.2-Year GLOBE trial results:telbivudine is superior to lamivudine in patients with chronic hepatitis B[J].Gastroenterology, 2009, 136 (2) :486-495.
    [35]CHANG TT, LAI CL, KEW YOON S, et al.Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B[J].Hepatology, 2010, 51 (2) :422-430.
    [36]GISH RG, LOK AS, CHANG TT, et al.Entecavir therapy for up to96 weeks in patients with HBe Ag-positive chronic hepatitis B[J].Gastroenterology, 2007, 133 (5) :1437-1444.
    [37]MARCELLIN PGE, FLISIAK R, TRINH H, et al.Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance:8 year results from two phase 3 trials[J].Hepatology, 2014, 60 (10) :313-314.
    [38]MARCELLIN P, LAU GK, BONINO F, et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBe Ag-negative chronic hepatitis B[J].N Engl J Med, 2004, 351 (12) :1206-1217.
    [39]TASSOPOULOS NC, VOLPES R, PASTORE G, et al.Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B[J].Hepatology, 1999, 29 (3) :889-896.
    [40]LAI CL, SHOUVAL D, LOK AS, et al.Entecavir versus lamivudine for patients with HBe Ag-negative chronic hepatitis B[J].N Engl J Med, 2006, 354 (10) :1011-1020.
    [41]HADZIYANNIS SJ, TASSOPOULOS NC, HEATHCOTE EJ, et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B[J].N Engl J Med, 2003, 348 (12) :800-807.
    [42]HADZIYANNIS SJ, TASSOPOULOS NC, HEATHCOTE EJ, et al.Long-term therapy with adefovir dipivoxil for HBe Ag-negative chronic hepatitis B for up to 5 years[J].Gastroenterology, 2006, 131 (6) :1743-1751.
    [43] Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B:a 2015 update[J].J Clin Hepatol, 2015, 31 (12) :1941-1960. (in Chinese) 中华医学会肝病学分会, 中华医学会感染病学分会.慢性乙型肝炎防治指南 (2015年更新版) [J].临床肝胆病杂志, 2015, 31 (12) :1941-1960.
    [44]THIMME R, DANDRI M.Dissecting the divergent effects of interferon-alpha on immune cells:time to rethink combination therapy in chronic hepatitis B?[J].J Hepatol, 2013, 58 (2) :205-209.
    [45]WU D, HAN M, NING Q.An integration of deep viral suppression with sequential immune modulation (cocktail therapy) to restore antiviral capacity:the future of chronic hepatitis B?[J].J Hepatol, 2015, 62 (2) :240-241.
    [46]PICCOLO P, LENCI I, DEMELIA L, et al.A randomized controlled trial of pegylated interferon-alpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B[J].Antivir Ther, 2009, 14 (8) :1165-1174.
    [47]WURSTHORN K, LUTGEHETMANN M, DANDRI M, et al.Peginterferon alpha-2b plus adefovir induce strong ccc DNA decline and HBs Ag reduction in patients with chronic hepatitis B[J].Hepatology, 2006, 44 (3) :675-684.
    [48]MARCELLIN P, WURSTHORN K, WEDEMEYER H, et al.Telbivudine plus pegylated interferon alfa-2a in a randomized study in chronic hepatitis B is associated with an unexpected high rate of peripheral neuropathy[J].J Hepatol, 2015, 62 (1) :41-47.
    [49]MARCELLIN P, AHN SH, MA X, et al.Combination of tenofovir disoproxil fumarate and peginterferonα-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B[J].Gastroenterology, 2016, 150 (1) :134-144.e10.
    [50]JANSEN L, de NIET A, STELMA F, et al.HBs Ag loss in patients treated with peginterferon alfa-2a and adefovir is associated with SLC16A9 gene variation and lower plasma carnitine levels[J].J Hepatol, 2014, 61 (4) :730-737.
    [51]STELMA F, JANSEN L, SINNIGE MJ, et al.HLA-C and KIR combined genotype as new response marker for HBe Ag-positive chronic hepatitis B patients treated with interferon-based combination therapy[J].J Viral Hepat, 2016, 23 (8) :652-659.
    [52]TANGKIJVANICH P, CHITTMITTRAPRAP S, POOVORAWAN K, et al.A randomized clinical trial of peginterferon alpha-2b with or without entecavir in patients with HBe Ag-negative chronic hepatitis B:role of host and viral factors associated with treatment response[J].J Viral Hepat, 2016, 23 (6) :427-438.
    [53]NING Q, HAN M, SUN Y, et al.Switching from entecavir to Peg IFN alfa-2a in patients with HBe Ag-positive chronic hepatitis B:a randomised open-label trial (OSST trial) [J].J Hepatol, 2014, 61 (4) :777-784.
    [54]HAN M, JIANG J, HOU J, et al.Sustained immune control in HBe Ag-positive patients who switched from entecavir therapy to pegylated interferon-α2a:1 year follow-up of the OSST study[J].Antivir Ther, 2016, 21 (4) :337-344.
    [55]BOGLIONE L, D'AVOLIO A, CARITI G, et al.Sequential therapy with entecavir and PEGINF in patients affected by chronic hepatitis B and high levels of HBV-DNA with non-D genotypes[J].J Viral Hepat, 2013, 20 (4) :e11-e19.
    [56]HU P, GONG G, XIE Q, et al.High HBs Ag loss rate in HBe Ag loss CHB patients SWITCH from NUC to Peg-IFN alfa-2 a (NEW SWITCH study) [C].Asian Pacific Association for the Study of the Liver, 2017:s46.
    [57]WU D, HAN MF, CHEN YP, et al.THU-165-Sequential combination therapy with IFN, rh IL-2 and therapeutic vaccine enhanced HBs Ag loss in entecavir-suppressed CHB patients (the Endeavor study) :an interim analysis[J].J Hepatol, 2017, 66 (1) :s261.
    [58]BROUWER WP, XIE Q, SONNEVELD MJ, et al.Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B:a multicenter randomized trial (ARES study) [J].Hepatology, 2015, 61 (5) :1512-1522.
    [59]HNER ZU SIEDERDISSEN C, CORNBERG M.The role of HBs Ag levels in the current management of chronic HBV infection[J].Ann Gastroenterol, 2014, 27 (2) :105-112.
    [60]HAN MF, WU D, TAN DM, et al.Combination/sequential therapy with ETV, Peg-IFN alpha-2b and GMCSF enhanced HBs Ag loss and appearance of HBs Ab in NA suppressed CHB patients (the Anchor A study) :an interim analysis[C].American Association for the Study of Liver Diseases, 2017:o29.
    [61]MAINI MK, SCHURICH A.The molecular basis of the failed immune response in chronic HBV:therapeutic implications[J].J Hepatol, 2010, 52 (4) :616-619.
    [62]THIMME R, WIELAND S, STEIGER C, et al.CD8 (+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection[J].J Virol, 2003, 77 (1) :68-76.
    [63]BILLERBECK E, BOTTLER T, THIMME R.Regulatory T cells in viral hepatitis[J].World J Gastroenterol, 2007, 13 (36) :4858-4864.
    [64]MICCO L, PEPPA D, LOGGI E, et al.Differential boosting of innate and adaptive antiviral responses during pegylated-interferonalpha therapy of chronic hepatitis B[J].J Hepatol, 2013, 58 (2) :225-233.
    [65]PENNA A, LACCABUE D, LIBRI I, et al.Peginterferon-αdoes not improve early peripheral blood HBV-specific T-cell responses in HBe Ag-negative chronic hepatitis[J].J Hepatol, 2012, 56 (6) :1239-1246.
    [66]PEPPA D, MICCO L, JAVAID A, et al.Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection[J].PLo S Pathog, 2010, 6 (12) :e1001227.
    [67]ALLWEISS L, LTGEHETMANN M, VOLZ T, et al.Pegylatedinterferon-alpha alone or in combination with entecavir restores ISG responsiveness and reduces intrahepatic viral loads and antigenemia in hepatitis B virus infected humanized mice[J].J Hepatol, 2012, 56 (Suppl 2) :s18-s19.
    [68]de NIET A, STELMA F, JANSEN L, et al.Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy[J].J Hepatol, 2016, 64 (3) :539-546.
    [69]TAN AT, HOANG LT, CHIN D, et al.Reduction of HBV replication prolongs the early immunological response to IFNαtherapy[J].J Hepatol, 2014, 60 (1) :54-61.
    [70]YAN W, WU D, WANG X, et al.Upregulation of NKG2C+natural killer cells, TLR-2 expression on monocytes and downregulation of regulatory T-cells influence PEG-IFN treatment efficacy in entecavir-suppressed patients with CHB[J].Antivir Ther, 2015, 20 (6) :591-602.
    [71]HAN M, LI Y, WU W, et al.Altered expression of interferonstimulated genes is strongly associated with therapeutic outcomes in hepatitis B virus infection[J].Antiviral Res, 2017, 147:75-85.
    [72]LUCIFORA J, XIA Y, REISINGER F, et al.Specific and nonhepatotoxic degradation of nuclear hepatitis B virus ccc DNA[J].Science, 2014, 343 (6189) :1221-1228.
    [73]LI Y, XIA Y, HAN M, et al.IFN-α-mediated base excision repair pathway correlates with antiviral response against hepatitis B virus infection[J].Sci Rep, 2017, 7 (1) :12715.
    [74]LIN CL, KAO JH.Review article:novel therapies for hepatitis B virus cure-advances and perspectives[J].Aliment Pharmacol Ther, 2016, 44 (3) :213-222.
    [75]YANG HC, KAO JH.Viral hepatitis.HBV cure-can we pin our hopes on immunotherapy?[J].Nat Rev Gastroenterol Hepatol, 2015, 12 (3) :129-131.
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (3138) PDF downloads(632) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return