中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 39 Issue 4
Apr.  2023
Turn off MathJax
Article Contents

Research advances in antiviral drugs for the treatment of hepatitis D

DOI: 10.3969/j.issn.1001-5256.2023.04.007
Research funding:

John C. Martin Foundation (2017-G14)

More Information
  • Corresponding author: ZHANG Fujie, treatment@chinaaids.cn (ORCID: 0000-0001-6386-9879)
  • Received Date: 2022-10-08
  • Accepted Date: 2022-11-08
  • Published Date: 2023-04-20
  • Hepatitis D virus (HDV) is a satellite virus of hepatitis B virus (HBV) and needs the help of HBV envelope protein to complete its own assembly and replication and then establish a new infection cycle. Chronic HDV infection is considered the most severe form of viral hepatitis, which can accelerate disease progression and increase the risk of liver cancer. Effective antiviral therapy is urgently needed to delay disease progression in patients with HDV infection, but Bulevirtide conditionally approved by European Medicines Agency in July 2020 and interferon previously recommended are the only drugs used for the treatment of HDV infection. At present, studies are being conducted for several antiviral drugs targeting viral replication cycle, and early clinical trials have obtained good results. This means that important breakthroughs have been made in the development of antiviral drugs, bringing hope for the treatment of hepatitis D. This article summarizes the current antiviral drugs for hepatitis D and discusses related treatment regimens, so as to provide a reference for the treatment of hepatitis D.

     

  • loading
  • [1]
    RIZZETTO M, CANESE MG, ARICÒ S, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers[J]. Gut, 1977, 18(12): 997-1003. DOI: 10.1136/gut.18.12.997.
    [2]
    GILMAN C, HELLER T, KOH C. Chronic hepatitis delta: A state-of-the-art review and new therapies[J]. World J Gastroenterol, 2019, 25(32): 4580-4597. DOI: 10.3748/wjg.v25.i32.4580.
    [3]
    LUCIFORA J, DELPHIN M. Current knowledge on Hepatitis Delta Virus replication[J]. Antiviral Res, 2020, 179: 104812. DOI: 10.1016/j.antiviral.2020.104812.
    [4]
    TAYLOR JM. Infection by hepatitis delta virus[J]. Viruses, 2020, 12(6): 648. DOI: 10.3390/v12060648.
    [5]
    ALFAIATE D, CLÉMENT S, GOMES D, et al. Chronic hepatitis D and hepatocellular carcinoma: A systematic review and meta-analysis of observational studies[J]. J Hepatol, 2020, 73(3): 533-539. DOI: 10.1016/j.jhep.2020.02.030.
    [6]
    KOH C, HELLER T, GLENN JS. Pathogenesis of and new therapies for hepatitis D[J]. Gastroenterology, 2019, 156(2): 461-476. DOI: 10.1053/j.gastro.2018.09.058.
    [7]
    WRANKE A, SERRANO BC, HEIDRICH B, et al. Antiviral treatment and liver-related complications in hepatitis delta[J]. Hepatology, 2017, 65(2): 414-425. DOI: 10.1002/hep.28876.
    [8]
    NEGRO F. Hepatitis D virus coinfection and superinfection[J]. Cold Spring Harb Perspect Med, 2014, 4(11): a021550. DOI: 10.1101/cshperspect.a021550.
    [9]
    CAREDDA F, ROSSI E, D'ARMINIO MONFORTE A, et al. Hepatitis B virus-associated coinfection and superinfection with delta agent: indistinguishable disease with different outcome[J]. J Infect Dis, 1985, 151(5): 925-928. DOI: 10.1093/infdis/151.5.925.
    [10]
    KIESSLICH D, CRISPIM MA, SANTOS C, et al. Influence of hepatitis B virus (HBV) genotype on the clinical course of disease in patients coinfected with HBV and hepatitis delta virus[J]. J Infect Dis, 2009, 199(11): 1608-1611. DOI: 10.1086/598955.
    [11]
    SMEDILE A, FARCI P, VERME G, et al. Influence of delta infection on severity of hepatitis B[J]. Lancet, 1982, 2(8305): 945-947. DOI: 10.1016/s0140-6736(82)90156-8.
    [12]
    TAYLOR JM. Virology of hepatitis D virus[J]. Semin Liver Dis, 2012, 32(3): 195-200. DOI: 10.1055/s-0032-1323623.
    [13]
    GIERSCH K, HELBIG M, VOLZ T, et al. Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection[J]. J Hepatol, 2014, 60(3): 538-544. DOI: 10.1016/j.jhep.2013.11.010.
    [14]
    CHEMIN I, PUJOL FH, SCHOLTÈS C, et al. Preliminary evidence for hepatitis delta virus exposure in patients who are apparently not infected with hepatitis B virus[J]. Hepatology, 2021, 73(2): 861-864. DOI: 10.1002/hep.31453.
    [15]
    GIERSCH K, ALLWEISS L, VOLZ T, et al. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection[J]. J Hepatol, 2015, 63(2): 346-353. DOI: 10.1016/j.jhep.2015.03.011.
    [16]
    SANDMANN L, CORNBERG M. Experimental drugs for the treatment of hepatitis D[J]. J Exp Pharmacol, 2021, 13: 461-468. DOI: 10.2147/JEP.S235550.
    [17]
    CASEY JL. Control of ADAR1 editing of hepatitis delta virus RNAs[J]. Curr Top Microbiol Immunol, 2012, 353: 123-143. DOI: 10.1007/82_2011_146.
    [18]
    CHEN R, LINNSTAEDT SD, CASEY JL. RNA editing and its control in hepatitis delta virus replication[J]. Viruses, 2010, 2(1): 131-146. DOI: 10.3390/v2010131.
    [19]
    YURDAYDIN C, KESKIN O, KALKAN Ç, et al. Interferon treatment duration in patients with chronic delta hepatitis and its effect on the natural course of the disease[J]. J Infect Dis, 2018, 217(8): 1184-1192. DOI: 10.1093/infdis/jix656.
    [20]
    SAGNELLI C, SAGNELLI E, RUSSO A, et al. HBV/HDV co-infection: epidemiological and clinical changes, recent knowledge and future challenges[J]. Life (Basel), 2021, 11(2): 169. DOI: 10.3390/life11020169.
    [21]
    KANG C, SYED YY. Bulevirtide: first approval[J]. Drugs, 2020, 80(15): 1601-1605. DOI: 10.1007/s40265-020-01400-1.
    [22]
    WEDEMEYER H, YURDAYDIN C, HARDTKE S, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-Ⅱ): a randomised, placebo controlled, phase 2 trial[J]. Lancet Infect Dis, 2019, 19(3): 275-286. DOI: 10.1016/S1473-3099(18)30663-7.
    [23]
    WEDEMEYER H, YURDAYDÌN C, DALEKOS GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta[J]. N Engl J Med, 2011, 364(4): 322-331. DOI: 10.1056/NEJMoa0912696.
    [24]
    HEIDRICH B, YURDAYD1N C, KABAÇAM G, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta[J]. Hepatology, 2014, 60(1): 87-97. DOI: 10.1002/hep.27102.
    [25]
    LAZEAR HM, SCHOGGINS JW, DIAMOND MS. Shared and distinct functions of type Ⅰ and type Ⅲ interferons[J]. Immunity, 2019, 50(4): 907-923. DOI: 10.1016/j.immuni.2019.03.025.
    [26]
    CHAN H, AHN SH, CHANG TT, et al. Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B)[J]. J Hepatol, 2016, 64(5): 1011-1019. DOI: 10.1016/j.jhep.2015.12.018.
    [27]
    ETZION O, HAMID S, LURIE Y, et al. End of study results from LIMT HDV study: 36% durable virologic response at 24 weeks post-treatment with pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection[J]. J Hepatol, 2019, 70(Suppl 1): e32.
    [28]
    KOH C, HERCUN J, RAHMAN F, et al. A phase 2 study of peginterferon lambda, lonafarnib and ritonavir for 24 weeks: end-of-treatment results from the LIFT HDV study[J]. J Hepatol, 2020, 73(Suppl 1): S130.
    [29]
    NKONGOLO S, NI Y, LEMPP FA, et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor[J]. J Hepatol, 2014, 60(4): 723-731. DOI: 10.1016/j.jhep.2013.11.022.
    [30]
    BLANCHET M, SUREAU C, LABONTÉ P. Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle[J]. Antiviral Res, 2014, 106: 111-115. DOI: 10.1016/j.antiviral.2014.03.017.
    [31]
    ABBAS Z, SAAD M, ASIM M, et al. The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D[J]. Turk J Gastroenterol, 2020, 31(2): 136-141. DOI: 10.5152/tjg.2020.18846.
    [32]
    BOGOMOLOV P, ALEXANDROV A, VORONKOVA N, et al. Treatment of chronic hepatitis D with the entry inhibitor Myrcludex B: First results of a phase Ⅰb/Ⅱa study[J]. J Hepatol, 2016, 65(3): 490-498. DOI: 10.1016/j.jhep.2016.04.016.
    [33]
    WEDEMEYER H, BOGOMOLOV P, BLANK A, et al. Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection[J]. J Hepatol, 2018, 68(Suppl 1): S3.
    [34]
    WEDEMEYER H, SCHÖNEWEIS K, BOGOMOLOV PO, et al. 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection[J]. J Hepatol, 2020, 73(Suppl 1): S52-S53.
    [35]
    WEDEMEYER H, SCHÖNEWEIS K, BOGOMOLOV PO, et al. GS-13-Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in cwith PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection[J]. J Hepatol, 2019, 70(Suppl 1): e81.
    [36]
    GLENN JS, WATSON JA, HAVEL CM, et al. Identification of a prenylation site in delta virus large antigen[J]. Science, 1992, 256(5061): 1331-1333. DOI: 10.1126/science.1598578.
    [37]
    KOH C, CANINI L, DAHARI H, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial[J]. Lancet Infect Dis, 2015, 15(10): 1167-1174. DOI: 10.1016/S1473-3099(15)00074-2.
    [38]
    YURDAYDIN C, KESKIN O, KALKAN Ç, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV-1 study[J]. Hepatology, 2018, 67(4): 1224-1236. DOI: 10.1002/hep.29658.
    [39]
    WEDEMEYER H, PORT K, DETERDING K, et al. PS-039 - A phase 2 dose-escalation study of lonafarnib plus ritonavir in patients with chronic hepatitis D: final results from the Lonafarnib with ritonavir in HDV-4 (LOWR HDV-4) study[J]. J Hepatol, 2017, 66(Suppl 1): S24.
    [40]
    SHEKHTMAN L, COTLER SJ, HERSHKOVICH L, et al. Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg[J]. Sci Rep, 2020, 10(1): 7837. DOI: 10.1038/s41598-020-64122-0.
    [41]
    BAZINET M, PÂNTEA 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[J]. Lancet Gastroenterol Hepatol, 2017, 2(12): 877-889. DOI: 10.1016/S2468-1253(17)30288-1.
    [42]
    BAZINET M, PÂNTEA V, CEBOTARESCU V, et al. Persistent control of hepatitis B virus and hepatitis delta virus infection following REP 2139-Ca and pegylated interferon therapy in chronic hepatitis B virus/hepatitis delta virus coinfection[J]. Hepatol Commun, 2021, 5(2): 189-202. DOI: 10.1002/hep4.1633.
    [43]
    YUEN MF, SCHIEFKE I, YOON JH, et al. RNA interference therapy with ARC-520 results in prolonged hepatitis B surface antigen response in patients with chronic hepatitis B infection[J]. Hepatology, 2020, 72(1): 19-31. DOI: 10.1002/hep.31008.
    [44]
    GANE E, LOCARNINI S, LIM T, et al. Short-term treatment with RNA interference therapy, JNJ-3989, results in sustained hepatitis B surface antigen supression in patients with chronic hepatitis B receiving nucleos(t)ide analogue treatment[J]. J Hepatol, 2020, 73(Suppl 1): S20.
    [45]
    JIAO WJ, ZHANG F, AI QG, et al. Study on the treatment of human interferon-α combined with traditional Chinese medicine on HBV/HDV co-infection[J]. Heilongjiang Med Pharm, 1993(4): 11-12. https://www.cnki.com.cn/Article/CJFDTOTAL-HJYY199304010.htm

    焦文举, 张甫, 艾钦光, 等. 精制人白细胞α—干扰素配伍中药治疗乙、丁型肝炎病毒重叠感染的研究[J]. 黑龙江医药, 1993(4): 11-12. https://www.cnki.com.cn/Article/CJFDTOTAL-HJYY199304010.htm
    [46]
    CHEN NL, GU F, JIA KM, et al. Treatment on 26 cases with HBV/HDV co-infection with Xiao Chaihu decoction[J]. Chin J Intern Med, 1990, 29(3): 144-146.

    陈乃玲, 顾芳, 贾克明, 等. 小柴胡汤对26例乙型、丁型肝炎重叠感染治疗的探讨[J]. 中华内科杂志, 1990, 29(3): 144-146.
    [47]
    LIN HH, LEE SS, YU ML, et al. Changing hepatitis D virus epidemiology in a hepatitis B virus endemic area with a national vaccination program[J]. Hepatology, 2015, 61(6): 1870-1879. DOI: 10.1002/hep.27742.
    [48]
    SORIANO V, SHERMAN KE, BARREIRO P. Hepatitis delta and HIV infection[J]. AIDS, 2017, 31(7): 875-884. DOI: 10.1097/QAD.0000000000001424.
    [49]
    SERVANT-DELMAS A, LE GAL F, GALLIAN P, et al. Increasing prevalence of HDV/HBV infection over 15 years in France[J]. J Clin Virol, 2014, 59(2): 126-128. DOI: 10.1016/j.jcv.2013.11.016.
    [50]
    CHANG SY, YANG CL, KO WS, et al. Molecular epidemiology of hepatitis D virus infection among injecting drug users with and without human immunodeficiency virus infection in Taiwan[J]. J Clin Microbiol, 2011, 49(3): 1083-1089. DOI: 10.1128/JCM.01154-10.
    [51]
    SHEN DT, HAN PC, JI DZ, et al. Epidemiology estimates of hepatitis D in individuals co-infected with human immunodeficiency virus and hepatitis B virus, 2002-2018: A systematic review and meta-analysis[J]. J Viral Hepat, 2021, 28(7): 1057-1067. DOI: 10.1111/jvh.13512.
    [52]
    STOCKDALE AJ, KREUELS B, HENRION M, et al. The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis[J]. J Hepatol, 2020, 73(3): 523-532. DOI: 10.1016/j.jhep.2020.04.008.
    [53]
    WANG L, ZHUANG H. Advances in hepatitis D epidemiology[J]. Chin J Viral Dis, 2021, 11(6): 420-426. DOI: 10.16505/j.2095-0136.2021.0053.

    王麟, 庄辉. 丁型肝炎流行病学进展[J]. 中国病毒病杂志, 2021, 11(6): 420-426. DOI: 10.16505/j.2095-0136.2021.0053.
    [54]
    CHEN HY, SHEN DT, JI DZ, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis[J]. Gut, 2019, 68(3): 512-521. DOI: 10.1136/gutjnl-2018-316601.
    [55]
    FATTOVICH G, BOSCARO S, NOVENTA F, et al. Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B[J]. J Infect Dis, 1987, 155(5): 931-935. DOI: 10.1093/infdis/155.5.931.
  • 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

    Figures(1)  / Tables(1)

    Article Metrics

    Article views (580) PDF downloads(102) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return