399
Views
5
CrossRef citations to date
0
Altmetric
Review

Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials

& ORCID Icon
Pages 905-920 | Received 14 May 2021, Accepted 03 Sep 2021, Published online: 01 Oct 2021

References

  • Rizzetto M, Canese MG, Arico S, et al. Immunofluorescence detection of new antigen-antibody system (S/anti-5) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut [Internet]. 1977;18:2021. Available from: http://gut.bmj.com/.
  • Rizzetto M, Canese MG, Gerin JL, et al. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees [internet]. J. Infect. Dis. 1980. [ cited 2021 Mar 27]. Available from: https://academic.oup.com/jid/article/141/5/590/886813.
  • Rizzetto M, Gocke D, Verme G, et al. Incidence and significance of antibodies to delta antigen in hepatitis B virus infection. Lancet. 1979;314(8150):986–990.
  • Miao Z, Zhang S, Ou X, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis [Internet]. 2020. cited 2021 Mar 22];221(10):1677–1687. Available from: https://academic.oup.com/jid/article/221/10/1677/5645271.
  • 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. Gut [Internet]. 2019. [ cited. 2021 Mar 27;68:512–521. Available from:
  • Fattovich G, Boscaro S, Noventa F, et al. Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis. 1987;155(5):931–935.
  • Puigvehí M, Moctezuma-Velázquez C, Villanueva A, et al. The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP Reports [Internet]. 2019. [ cited. 2021 Mar 27;1(2):120–130. Available from:
  • Wang K-S, Choo Q-L, Weiner AJ, et al. Structure, sequence and expression of the hepatitis delta (δ) viral genome. Nature. 1986;323(6088):508–514.
  • Yurdaydin, Cihan. “Treatment of chronic delta hepatitis.„ Seminars in liver disease. Vol. 32. No. 03. Thieme Medical Publishers, 2012.
  • Sleijfer, Stefan, et al. Side effects of interferon-α therapy. Pharm World Sci. 2005;27(6):423.
  • Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology [Internet]. 2018. [ cited 2021 Mar 27];67:1560–1599. Available from: /pmc/articles/PMC5975958/.
  • Lampertico P, Agarwal K, Berg T, et al. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–398.
  • Brook G, Brockmeyer N, van de Laar T, et al. 2017 European guideline for the screening, prevention and initial management of hepatitis B and C infections in sexual health settings. Int J STD AIDS [Internet]. 2018. [ cited 2021 Jul 26];29:949–967. Available from: http://www.iusti.org/regions/europe/pdf/2017/ProtocolForProduction2017.pdf.
  • Chen X, Oidovsambuu O, Liu P, et al. A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus–infected mongolians. Hepatology [Internet]. 2017. [ cited 2021 Jul 26];66:1739–1749. Available from: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.28957.
  • Gomes-Gouvêa MS, Soares MCP, Bensabath G, et al. Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (labrea black fever) in the western Brazilian Amazon region. J Gen Virol [Internet]. 2009. [ cited 2021 Apr 3];90:2638–2643. Available from: https://pubmed.ncbi.nlm.nih.gov/19605587/.
  • Le Gal F, Brichler S, Drugan T, et al. Genetic diversity and worldwide distribution of the deltavirus genus: a study of 2,152 clinical strains. Hepatology [Internet]. 2017. [ cited 2021 Apr 3];66(6):1826–1841. Available from: https://pubmed.ncbi.nlm.nih.gov/28992360/.
  • Dény P. Hepatitis delta virus genetic variability: from genotypes I, II, III to eight major clades? [internet]. Curr. Top. Microbiol. Immunol. Springer Verlag. 2006. [ cited 2021 Apr 3]; 151–171. Available from: https://link.springer.com/chapter/10.1007/3-540-29802-9_8.
  • Brichler S, Le Gal F, Butt A, et al. Commercial real-time reverse transcriptase PCR assays can underestimate or fail to quantify hepatitis delta virus viremia. Clin Gastroenterol Hepatol [Internet]. 2013. [ cited 2021 Apr 3];11:734–740. Available from: https://pubmed.ncbi.nlm.nih.gov/23376798/.
  • Hetzel U, Szirovicza L, Smura T, et al. Identification of a novel deltavirus in boa constrictors. MBio [Internet]. 2019. [ cited 2021 Apr 3];10:1–8. Available from: /pmc/articles/PMC6445931/.
  • Wille M, Netter HJ, Littlejohn M, et al. A divergent hepatitis D-like agent in birds. Viruses [Internet]. 2018. [ cited 2021 Apr 3];10. Available from: https://pubmed.ncbi.nlm.nih.gov/30562970/.
  • Iwamoto M, Shibata Y, Kawasaki J, et al. Identification of novel avian and mammalian deltaviruses provides new insights into deltavirus evolution. Virus Evol [Internet]. 2021. [ cited 2021 Apr 3];7. Available from: https://pubmed.ncbi.nlm.nih.gov/33614159/.
  • Flores R, Owens RA, Taylor J, et al. Pathogenesis by subviral agents: viroids and hepatitis delta virus [internet]. Curr Opin Virol. 2016. Elsevier B.V. [ cited 2021 Mar 27]; 87–94. Available from: https://pubmed.ncbi.nlm.nih.gov/26897654/. DOI:10.1016/j.coviro.2016.01.022.
  • Magnius, Lars, et al. ICTV virus taxonomy profile: deltavirus. J Gen Virol. 2018;99(12):1565-1566.
  • Taylor JM. Host RNA circles and the origin of hepatitis delta virus [internet]. World J Gastroenterol. 2014. WJG Press. [ cited 2021 Mar 27]; 2971–2978. Available from: /pmc/articles/PMC3961984/. DOI:10.3748/wjg.v20.i11.2971.
  • Rizzetto M, Hoyer B, Canese MG, et al. Delta agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of B-infected chimpanzees (liver disease/infectious agent). 1980
  • Gudima S, Chang J, Moraleda G, et al. Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral Proteins and RNA. J Virol [Internet]. 2002. [ cited 2021 Mar 28];76:3709–3719. Available from: http://jvi.asm.org/.
  • Lee CH, Chang SC, Wu CHH, et al. A novel chromosome Region maintenance 1-independent nuclear export signal of the large form of hepatitis delta antigen that is required for the viral assembly. J Biol Chem. 2001;276:8142–8148.
  • Weiner AJ, Choo Q, Wang K, et al. A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p248 and p278 downloaded from [internet]. J Virol. 1988. cited 2021 Apr 3]. Available from: http://jvi.asm.org/. DOI:10.1128/jvi.62.2.594-599.1988.
  • Urban S, Bartenschlager R, Kubitz R, et al. Strategies to inhibit entry of HBV and HDV into hepatocytes [internet]. Gastroenterology. 2014. W.B. Saunders. [ cited 2021 Mar 28]; 48–64. Available from: https://pubmed.ncbi.nlm.nih.gov/24768844/. DOI:10.1053/j.gastro.2014.04.030.
  • Sureau C, Negro F. The hepatitis delta virus: replication and pathogenesis [internet]. J Hepatol. 2016. Elsevier B.V. [ cited 2021 Mar 28]; S102–S116. Available from: https://pubmed.ncbi.nlm.nih.gov/27084031/. DOI:10.1016/j.jhep.2016.02.013.
  • Lamas Longarela O, Schmidt TT, Schöneweis K, et al. Proteoglycans act as cellular hepatitis delta virus attachment receptors. PLoS One. 2013. cited 2021 Mar 28];8. Available from: https://pubmed.ncbi.nlm.nih.gov/23505490/.
  • Leistner CM, Gruen-Bernhard S, Glebe D, et al. Role of glycosaminoglycans for binding and infection of hepatitis B virus. Cell Microbiol [Internet]. 2008. [ cited 2021 Mar 28];10:122–133. Available from: https://pubmed.ncbi.nlm.nih.gov/18086046/.
  • Schulze A, Gripon P, Urban S, et al. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology [Internet]. 2007. [ cited 2021 Mar 28];46(6):1759–1768. Available from: https://pubmed.ncbi.nlm.nih.gov/18046710/.
  • Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife [Internet]. 2012. cited 2021 Mar 28];2012. Available from: https://pubmed.ncbi.nlm.nih.gov/25409679/.
  • Hughes SA, Wedemeyer H, Harrison PM, et al. Hepatitis delta virus. Lancet. Elsevier 2011;73–85. DOI:10.1016/S0140-6736(10)61931-9.
  • Xia Y, Yeh C, C Lai MM, et al. Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a Protein complex downloaded from [internet]. J Virol. 1992. cited 2021 Mar 28]. Available from: http://jvi.asm.org/. DOI:10.1128/jvi.66.2.914-921.1992.
  • Wi MMC. THE MOLECULAR BIOLOGY OF HEPATITIS DELTA VIRUS [internet]. Ann u. Rev. Biochem. 1995. [ cited 2021 Mar 28]. Available from: www.annualreviews.org.
  • Chang J, Nie X, Chang HE, et al. Transcription of hepatitis delta virus RNA by RNA polymerase II. J Virol [Internet]. 2008. [ cited 2021 Mar 28];82:1118–1127. Available from: /pmc/articles/PMC2224410/.
  • Macnaughton TB, Shi ST, Modahl LE, et al. Rolling circle replication of hepatitis delta virus RNA is carried out by two different cellular RNA polymerases. J Virol [Internet]. 2002. [ cited 2021 Apr 3];76:3920–3927. Available from: https://pubmed.ncbi.nlm.nih.gov/11907231/.
  • Casey JL. Control of ADAR1 editing of hepatitis delta virus RNAs. Curr Top Microbiol Immunol [Internet]. 2012. [ cited 2021 Mar 28];353:123–143. Available from: /pmc/articles/PMC3572862/.
  • Reid CE, Lazinski DW. A host-specific function is required for ligation of a wide variety of ribozyme-processed RNAs. Proc Natl Acad Sci USA [Internet]. 2000. cited 2021 Mar 28];97:424–429. Available from: https://pubmed.ncbi.nlm.nih.gov/10618434/.
  • Greco-Stewart VS, Miron P, Abrahem A, et al. The human RNA polymerase II interacts with the terminal stem–loop regions of the hepatitis delta virus RNA genome. Virology [Internet]. 2007. [ cited 2021 Mar 28];357(1):68–78. Available from: https://pubmed.ncbi.nlm.nih.gov/16959288/.
  • Alfaiate D, Dény P, Durantel D, et al. Hepatitis delta virus: from biological and medical aspects to current and investigational therapeutic options [internet]. Antiviral Res. 2015. Elsevier B.V. [ cited 2021 Mar 27]; 112–129. Available from:. DOI:10.1016/j.antiviral.2015.08.009 .
  • Chen Y-S, Huang W-H, Hong S-Y, et al. ERK1/2-mediated phosphorylation of small hepatitis delta antigen at serine 177 enhances hepatitis delta virus antigenomic RNA replication. J Virol [Internet]. 2008. [ cited 2021 Apr 3];82:9345–9358. Available from: /pmc/articles/PMC2546944/.
  • Hong S-Y, Chen P-J. Phosphorylation of serine 177 of the small hepatitis delta antigen regulates viral antigenomic RNA replication by interacting with the processive RNA polymerase II. J Virol [Internet]. 2010. [ cited 2021 Apr 3];84:1430–1438. Available from: /pmc/articles/PMC2812350/.
  • Li Y-J, Stallcup MR, Lai MMC, et al. Hepatitis delta virus antigen is methylated at arginine residues, and methylation regulates subcellular localization and RNA replication downloaded from. J Virol [Internet]. 2004. [ cited 2021 Apr 3];78:13325–13334. Available from: http://jvi.asm.org/.
  • Otto JC, Casey PJ. The hepatitis delta virus large antigen is farnesylated both in vitro and in animal cells. J Biol Chem. 1996;271(9):4569–4572.
  • Glenn JS, Watson JA, Havel CM, et al. Identification of a prenylation site in delta virus large antigen. Science (80-) [Internet]. 1992. cited 2021 Apr 3];256(5061):1331–1333. Available from: http://science.sciencemag.org/.
  • Lee CZ, Chen PJ, Lai MMC, et al. Isoprenylation of large hepatitis delta antigan is necessary but not sufficient for hepatitis delta virus assembly. Virology. 1994;199:169–175.
  • O’Malley B, Lazinski DW. Roles of Carboxyl-terminal and farnesylated residues in the functions of the large hepatitis delta antigen. J Virol. 2005;79(2):1142–1153.
  • Bordier BB, Ohkanda J, Liu P, et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest [Internet]. 2003. [ cited 2021 Apr 3];112:407–414. Available from: https://pubmed.ncbi.nlm.nih.gov/12897208/.
  • Bordier BB, Marion PL, Ohashi K, et al. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J Virol [Internet]. 2002. [ cited 2021 Apr 3];76:10465–10472. Available from: https://pubmed.ncbi.nlm.nih.gov/12239323/.
  • Huang C, Chang SC, Yu I-C, et al. Large hepatitis delta antigen is a novel clathrin adaptor-like protein. J Virol [Internet]. 2007. [ cited 2021 Apr 3];81:5985–5994. Available from: http://jvi.asm.org/.
  • Wang YC, Huang CR, Chao M, et al. The C-terminal sequence of the large hepatitis delta antigen is variable but retains the ability to bind clathrin. Virol J [Internet]. 2009. [ cited 2021 Apr 3];6:1–11. Available from: https://link.springer.com/articles/10.1186/1743-422X-6-31.
  • Peters M. Mechanisms of action of interferons TYPES OF INTERFERON. Semin Liver Dis. 1989. DOI:10.1055/s-2008-1040516.
  • Guedj J, Rotman Y, Cotler SJ, et al. Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling. Hepatology [Internet]. 2014. [ cited 2021 Mar 20];60:1902–1910. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/hep.27357.
  • Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science (80-) [Internet]. 1998. cited 2021 Mar 20];282:103–107. Available from: http://science.sciencemag.org/.
  • Ribeiro RM, Germanidis G, Powers KA, et al. Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections. J Infect Dis [Internet]. 2010. cited 2021 Mar 20];202(9):1309–1318. Available from: https://academic.oup.com/jid/article-lookup/doi/10.1086/656528.
  • Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med [Internet]. 1994. cited 2021 Apr 4];330(2):88–94. Available from: http://www.nejm.org/doi/abs/10.1056/NEJM199401133300202.
  • Farci P, Roskams T, Chessa L, et al. Long-term benefit of interferon α therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126(7):1740–1749.
  • Heidrich B, Yurdaydin C, Kabaçam G, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87–97.
  • Castelnau C, Le Gal F, Ripault M-P, et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology [Internet]. 2006. [ cited 2021 Apr 4];44:728–735. Available from.
  • Niro GA, Ciancio A, Gaeta GB, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology [Internet]. 2006. [ cited 2021 Apr 4];44:713–720. Available from.
  • Hercun J, Kim GE, Da BL, et al. Durable virological response and functional cure of chronic hepatitis D after long-term peginterferon therapy. Aliment Pharmacol Ther. 2021. DOI:10.1111/apt.16408.
  • Lim YS. Management of antiviral resistance in chronic hepatitis B [internet]. Gut Liver. 2017. Joe Bok Chung. [ cited 2021 Apr 4]; 189–195. Available from: /pmc/articles/PMC5347642/. DOI:10.5009/gnl15562.
  • Prifti G-M, Moianos D, Giannakopoulou E, et al. Recent advances in hepatitis B treatment. Pharmaceuticals [Internet]. 2021. [ cited 2021 Jul 26];14. Available from: /pmc/articles/PMC8147224/.
  • Niro GA, Ciancio A, Tillman HL, et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther [Internet]. 2005. cited 2021 Apr 4];22:227–232. Available from.
  • Kabacam G, Onder FO, Yakut M, et al. Entecavir treatment of chronic hepatitis D. Clin Infect Dis [Internet]. 2012. cited 2021 Apr 4];55:645–650. Available from:.
  • Brancaccio G, Fasano M, Grossi A, et al. Clinical outcomes in patients with hepatitis D, cirrhosis and persistent hepatitis B virus replication, and receiving long-term tenofovir or entecavir. Aliment Pharmacol Ther [Internet]. 2019. cited 2021 Apr 4];49:1071–1076. Available from.
  • Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med [Internet]. 2011. cited 2021 Apr 4];364:322–331. Available from: http://www.nejm.org/doi/abs/10.1056/NEJMoa0912696.
  • Wedemeyer, Heiner, et al. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial. The Lancet Infect Dis. 2019;19(3):275-286.
  • Gripon P, Cannie I, Urban S, et al. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol [Internet]. 2005. [ cited 2021 Apr 5];79:1613–1622. Available from: https://pubmed.ncbi.nlm.nih.gov/15650187/.
  • Lütgehetmann M, Mancke LV, Volz T, et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology [Internet]. 2012. [ cited 2021 Apr 5];55(3):685–694. Available from: https://pubmed.ncbi.nlm.nih.gov/22031488/.
  • 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 Hepatol. 2016;65(3):490–498.
  • 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 Hepatol [Internet]. 2018. cited 2021 Apr 5];68:S3. Available from: https://www.researchgate.net/publication/324698205.
  • Wedemeyer H, Schoneweis K, Bogomolov P, et al. Final results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in combination with PEG-interferon alpha 2a in patients with chronic HBV/HDV co-infection. Progr Abstr Int Liver Congr. 2019
  • Wedemeyer H, Schoneweis K, Gmbh M, et al. Safety and efficacy of 10mg (high‐dose) bulevirtide (myrcludex B) in combination with PEG‐interferon alpha 2A or tenofovir in patients with chronic HBV/HDV co‐infection: week 24 interim results of the MYR203 extension study. Hepatology. 2019;70:58A–59A.
  • Loglio A, Ferenci P, Uceda Renteria SC, et al. Excellent safety and effectiveness of high-dose myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis: a case report of 3 patients. J Hepatol. 2019;71:834–839.
  • Dong Z, Ekins S, Polli JE, et al. Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP). Mol Pharm [Internet]. 2013. [ cited 2021 Apr 5];10:1008–1019. Available from: www.collaborativedrug.com.
  • Blanchet M, Sureau C, Labonté P, et al. Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle. Antiviral Res. 2014;106:111–115.
  • Sainz, Bruno, et al. Identification of the Niemann-Pick C1–like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med; 2012;18(2):281-285.
  • Lucifora J, Esser K, Protzer U, et al. Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antiviral Res. 2013;97(2):195–197.
  • Abbas, Zaigham, et al. The effect of twelve weeks of treatment with ezetimibe on HDV RNA level in patients with chronic hepatitis D. Turk J Gastroenterol. 2020;31(2):136.
  • Kieran MW, Packer RJ, Onar A, et al. Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a pediatric brain tumor consortium study. J Clin Oncol [Internet]. 2007. cited 2021 Apr 4];25:3137–3143. Available from: http://ascopubs.org/doi/10.1200/JCO.2006.09.4243.
  • Castaneda C, Meadows KL, Truax R, et al. Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;67(2):455–463.
  • Capell BC, Erdos MR, Madigan JP, et al. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of hutchinson-gilford progeria syndrome [internet]. 2005. [ cited 2021 Apr 4]. Available from: www.pnas.orgcgidoi10.1073pnas.0506001102.
  • U.S. Food and Drug, Administration. FDA approves first treatment for hutchinson-gilford progeria syndrome and some progeroid laminopathies. US Food Drug Adm [Internet]. 2020. [ cited 2021 May 2];2–3. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-hutchinson-gilford-progeria-syndrome-and-some-progeroid-laminopathies.
  • Einav S, Glenn JS. Prenylation inhibitors: a novel class of antiviral agents [internet]. J Antimicrob Chemother. 2003. J Antimicrob Chemother. [ cited 2021 Apr 4]; 883–886. Available from: https://pubmed.ncbi.nlm.nih.gov/14613953/. DOI:10.1093/jac/dkg490.
  • Ghosal A, Chowdhury SK, Tong W, et al. Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (sarasar). Drug Metab Dispos [Internet]. 2006. [ cited 2021 Mar 20];34:628–635. Available from: http://dmd.aspetjournals.org.
  • Koh, Christopher, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 2015;15(10):1167-1174.
  • Ravoet C, Mineur P, Robin V, et al. Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study the experiments comply with laws of Belgium including ethics approval. Ann Hematol. 2008;87(11):881–885.
  • Feldman EJ, Cortes J, Deangelo DJ, et al. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Leukemia. 2008. cited 2021 Mar 20];22(9):1707–1711. Available from: www.nature.com/leu.
  • Yurdaydin C, Keskin O, Ç K, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: the LOWR HDV-1 study. Hepatology. 2018;67:1224–1236.
  • Yurdaydin C, Kalkan C, Karakaya F, et al. Subanalysis of the LOWR HDV-2 study reveals high response rates to lonafarnib in patients with low viral loads. J Hepatol. 2018;68:S89.
  • Koh C, Surana P, Han T, et al. A phase 2 study exploring once daily dosing of ritonavir boosted lonafarnib for the treatment of chronic delta hepatitis – end of study results from the LOWR HDV-3 study. J Hepatol. 2017;66(1):S101–S102.
  • Wedemeyer H, Port K, Deterding K, et al. 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 Hepatol. 2017;66(1):S24.
  • Kotenko SV, Gallagher G, Baurin VV, et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex [internet]. Nat Immunol. 2003. Nature Publishing Group. [ cited 2021 Apr 5];69–77. Available from: http://www.nature.com/natureimmunology. DOI:10.1038/ni875.
  • Hong SH, Cho O, Kim K, et al. Effect of interferon-lambda on replication of hepatitis B virus in human hepatoma cells. Virus Res [Internet]. 2007. [ cited 2021 Apr 5];126:245–249. Available from: https://pubmed.ncbi.nlm.nih.gov/17451832/.
  • Lázaro CA, Chang M, Tang W, et al. Hepatitis C virus replication in transfected and serum-infected cultured human fetal hepatocytes. Am J Pathol [Internet]. 2007. [ cited 2021 Apr 5];170:478–489. Available from: /pmc/articles/PMC1851861/.
  • Marcello T, Grakoui A, Barba-Spaeth G, et al. Interferons α and λ inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology [Internet]. 2006. [ cited 2021 Apr 5];131:1887–1898. Available from: https://pubmed.ncbi.nlm.nih.gov/17087946/.
  • Sommereyns C, Paul S, Staeheli P, et al. IFN-lambda (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog [Internet]. 2008. [ cited 2021 Apr 5];4:1000017. Available from: /pmc/articles/PMC2265414/.
  • Muir AJ, Shiffman ML, Zaman A, et al. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology [Internet]. 2010. [ cited 2021 Apr 5];52:822–832. Available from.
  • Chan HLY, 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 Hepatol [Internet]. 2016. cited 2021 Apr 5];64:1011–1019. Available from: https://pubmed.ncbi.nlm.nih.gov/26739688/.
  • Giersch, Katja, et al. “Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice. Sci Rep. 2017;7(1):1-11.
  • Etzion, Ohad, 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 Hepatol. 2019;70(1):e32.
  • Hamid, Saeed S., et al. A phase 2 randomized clinical trial to evaluate the safety and efficacy of pegylated interferon lambda monotherapy in patients with chronic hepatitis delta virus infection: interim results from the LIMT HDV Study. Hepatology. 2017;66:496A.
  • Etzion, Ohad, et al. Characterization of HDV, HBsAg and ALT kinetics under peginterferon-lambda monotherapy: the phase 2 LIMT study. AASLD (2019): LP12. https://www.aasld.org/sites/default/files/2019-10/2019-TLM-LateBreakingAbstracts-v2.pdf
  • 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 Hepatol. 2020;73:S130.
  • Eckstein F. Phosphorothioates, essential components of therapeutic oligonucleotides. Nucleic Acid Ther. 2014;374–387. Mary Ann Liebert Inc. DOI:10.1089/nat.2014.0506.
  • Guzman EM, Cheshenko N, Shende V, et al. Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression. Antivir Ther [Internet]. 2007;12:1147–1156. Available from: http://survey.hshsl.umaryland.edu/?url=http://search.ebscohost.com/login.aspx?direct=true&db=cmedm&AN=18240855&site=eds-live.
  • Matsumura T, Hu Z, Kato T, et al. Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry. YGAST. 2009;137:673–681.
  • Vaillant A, Juteau J-M, Lu H, et al. Phosphorothioate oligonucleotides inhibit human immunodeficiency virus type 1 fusion by blocking gp41 core formation downloaded from. Antimicrob Agents Chemother [Internet]. 2006. [ cited 2020 May 2];50:1393–1401. Available from: http://aac.asm.org/.
  • Kocisko DA, Vaillant A, Lee KS, et al. Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides. Antimicrob Agents Chemother. 2006;50(3):1034–1044.
  • Guillot C, Martel N, Berby F, et al. Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes. PLoS One. 2017;12(6):1–15.
  • Koller E, Vincent TM, Chappell A, et al. Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes. [ cited 2020 May 4]. Available from: https://academic.oup.com/nar/article-abstract/39/11/4795/1150354.
  • Yang, B., et al. High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides. Nucleic Acids Res. 2015;43(4):1987-1996.
  • Blanchet M, Sinnathamby V, Vaillant A, et al. Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells. 2019. cited 2020 Apr 7]. Available from: . doi:10.1016/j.antiviral.2019.02.009
  • Bazinet M, Pântea V, Placinta G, et al. Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naïve to nucleos(t)ide therapy. Gastroenterology [Internet]. 2020. [ cited 2020 Apr 6]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0016508520303206.
  • 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. Lancet Gastroenterol Hepatol [Internet]. 2017. [ cited 2021 Feb 26];2:877–889. Available from: www.thelancet.com/gastrohep.
  • Streinu-cercel A, Bazinet M, Elsner C, et al. Interferon free clearance of HDV RNA and HBsAg seroconversion in a cirrhotic subject with chronic HBV/HDV co-infection with TDF and REP 2165-Mg Poster 0827 INTRODUCTION.: 2165.
  • Yuen M-F, Locarnini S, Given B, et al. First clinical experience with RNA interference-based triple combination therapy in chronic hepatitis B: JNJ-3989, JNJ-6379 and a Nucleos(t)ide analogue. Hepatology. 2019;70:1489A.
  • Huang Y-W, Hsu C-W, Lu S-N, et al. Ropeginterferon alfa-2b every 2 weeks as a novel pegylated interferon for patients with chronic hepatitis B. Hepatol Int [Internet]. 2020. [ cited 2021 Apr 5];14:997–1008. Available from: http://link.springer.com/10.1007/s12072-020-10098-y.
  • Zhang E, Zhang X, Liu J, et al. The expression of PD-1 ligands and their involvement in regulation of T cell functions in acute and chronic woodchuck hepatitis virus infection. PLoS One. 2011. Wang F-S, editor. [ cited 2021 Apr 5];6(10):e26196. Available from: https://dx.plos.org/10.1371/journal.pone.0026196.
  • Chisari FV, Maier H, Isogawa M, et al. T lymphocytes in the liver + CD8 functional suppression of virus-specific PD-1: PD-L1Interactions contribute to the. 2007. [ cited 2021 Apr 5]. Available from: http://www.jimmunol.org/content/178/5/2714.
  • Gane E, Verdon DJ, Brooks AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J Hepatol [Internet]. 2019. cited 2021 Apr 5];71(5):900–907. Available from:.
  • Ponzetto A, Hoyer BH, Popper H, et al. Titration of the infectivity of hepatitis D virus in chimpanzees. J Infect Dis [Internet]. 1987. cited 2021 Apr 6];155(1):72–78. Available from: https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/155.1.72.
  • Yurdaydin C, Abbas Z, Buti M, et al. Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy. J Hepatol. Elsevier B.V 2019;1008–1015. DOI:10.1016/j.jhep.2018.12.022.
  • 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. Sci Rep [Internet]. 2020. cited 2021 Apr 3];10. Available from: /pmc/articles/PMC7217939/.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.