Hepatitis delta: Epidemiology to recent advances in therapeutic agents.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
01 10 2023
01 10 2023
Historique:
received:
02
11
2022
accepted:
19
12
2022
medline:
27
9
2023
pubmed:
5
2
2023
entrez:
4
2
2023
Statut:
ppublish
Résumé
Hepatitis D virus (HDV) was first described in 1977 and is dependent on the presence of hepatitis B surface antigen (HBsAg) for its entry into cells and on the human host for replication. Due to the envelopment with the hepatitis B virus (HBV) envelope, early phases of HDV entry resemble HBV infection. Unlike HBV, HDV activates innate immune responses. The global prevalence of HDV is estimated to be about 5% of HBsAg positive individuals. However, recent studies have described a wide range of prevalence between 12 to 72 million individuals. Infection can occur as super-infection or co-infection. The diagnosis of active HDV infection involves screening with anti HDV antibodies followed by quantitative PCR testing for HDV RNA in those who are HBsAg positive. The diagnostic studies have evolved over the years improving the validity and reliability of the tests performed. HDV infection is considered the most severe form of viral hepatitis and the HDV genotype may influence the disease course. There are eight major HDV genotypes with prevalence varying by geographic region. HDV treatment has been challenging as HDV strongly depends on the host cell for replication and provides few, if any viral targets. Better understanding of HDV virology has led to the development of several therapeutic agents currently being studied in different phase II and III clinical trials. There is increasing promise of effective therapies that will ameliorate the course of this devastating disease.
Identifiants
pubmed: 36738087
doi: 10.1097/HEP.0000000000000331
pii: 01515467-990000000-00296
doi:
Substances chimiques
Hepatitis B Surface Antigens
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1306-1321Informations de copyright
Copyright © 2023 American Association for the Study of Liver Diseases.
Références
Rizzetto M, Canese MG, Arico S, Crivelli O, Trepo C, Bonino F, 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. Gut. 1977;18:997–1003.
Rizzetto M. Hepatitis D: thirty years after. J Hepatol. 2009;50:1043–50.
Smedile A, Rizzetto M, Gerin JL. Advances in hepatitis D virus biology and disease. Prog Liver Dis. 1994;12:157–75.
Rizzetto M, Hamid S, Negro F. The changing context of hepatitis D. J Hepatol. 2021;74:1200–1211.
Kos A, Dijkema R, Arnberg AC, van der Meide PH, Schellekens H. The hepatitis delta (delta) virus possesses a circular RNA. Nature. 1986;323:558–60.
Wang KS, Choo QL, Weiner AJ, Ou JH, Najarian RC, Thayer RM, et al. Structure, sequence and expression of the hepatitis delta (delta) viral genome. Nature. 1986;323:508–14.
Kuo MY, Goldberg J, Coates L, Mason W, Gerin J, Taylor J. Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J Virol. 1988;62:1855–61.
Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol. 2016;13:580–9.
Gudima S, Chang J, Moraleda G, Azvolinsky A, Taylor J. Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral proteins and RNA. J Virol. 2002;76:3709–19.
Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology. 2007;46:1759–68.
Lamas Longarela O, Schmidt TT, Schöneweis K, Romeo R, Wedemeyer H, Urban S, et al. Proteoglycans act as cellular hepatitis delta virus attachment receptors. PLoS One. 2013;8:e58340.
Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife. 2012;1:e00049.
Königer C, Wingert I, Marsmann M, Rösler C, Beck J, Nassal M. Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. Proc Natl Acad Sci USA. 2014;111:E4244–53.
Chou HC, Hsieh TY, Sheu GT, Lai MMC. Hepatitis delta antigen mediates the nuclear import of hepatitis delta virus RNA. J Virol. 1998;72:3684–90.
Macnaughton TB, Shi ST, Modahl LE, Lai MMC. Rolling circle replication of hepatitis delta virus RNA is carried out by two different cellular RNA polymerases. J Virol. 2002;76:3920–7.
Chang J, Nie X, Chang HE, Han Z, Taylor J. Transcription of hepatitis delta virus RNA by RNA polymerase II. J Virol. 2008;82:1118–27.
Greco-Stewart VS, Miron P, Abrahem A, Pelchat M. The human RNA polymerase II interacts with the terminal stem-loop regions of the hepatitis delta virus RNA genome. Virology. 2007;357:68–78.
Chen PJ, Kalpana G, Goldberg J, Mason W, Werner B, Gerin J, et al. Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci USA. 1986;83:8774–88.
Kuo MY, Sharmeen L, Dinter-Gottlieb G, Taylor J. Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J Virol. 1988;62:4439–4444.
Hsieh SY, Chao M, Coates L, Taylor J. Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen. J Virol. 1990;64:3192–8.
Kuo MY, Chao M, Taylor J. Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J Virol. 1989;63:1945–50.
Abeywickrama-Samarakoon N, Cortay JC, Sureau C, Müller S, Alfaiate D, Guerrieri F, et al. Hepatitis Delta Virus histone mimicry drives the recruitment of chromatin remodelers for viral RNA replication. Nat Commun. 2020;11:419.
Poison AG, Bass BL, Casey JL. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature. 1996;380:454–6.
Wong SK, Lazinski DW. Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc Natl Acad Sci USA. 2002;99:15118–23.
Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science. 1992;256:1331–3.
Otto JC, Casey PJ. The hepatitis delta virus large antigen is farnesylated both in vitro and in animal cells. J Biol Chem. 1996;271:4569–72.
Chao M, Hsieh SY, Taylor J. Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J Virol. 1990;64:5066–9.
Hwang SB, Lai MM. Isoprenylation masks a conformational epitope and enhances trans-dominant inhibitory function of the large hepatitis delta antigen. J Virol. 1994;68:2958–64.
Chang FL, Chen PJ, Tu SJ, Wang CJ, Chen DS. The large form of hepatitis delta antigen is crucial for assembly of hepatitis delta virus. Proc Natl Acad Sci USA. 1991;88:8490–4.
Hwang SB, Lai MM. Isoprenylation mediates direct protein-protein interactions between hepatitis large delta antigen and hepatitis B virus surface antigen. J Virol. 1993;67:7659–62.
Cornillez-Ty CT, Lazinski DW. Determination of the multimerization state of the hepatitis delta virus antigens in vivo. J Virol. 2003;77:10314–26.
Freitas N, Cunha C, Menne S, Gudima SO. Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles. J Virol. 2014;88:5742–54.
Lempp FA, Schlund F, Rieble L, Nussbaum L, Link C, Zhang Z, et al. Recapitulation of HDV infection in a fully permissive hepatoma cell line allows efficient drug evaluation. Nat Commun. 2019;10:2265.
Ni Y, Zhang Z, Engelskircher L, Verch G, Tu T, Lempp FA, et al. Generation and characterization of a stable cell line persistently replicating and secreting the human hepatitis delta virus. Sci Rep. 2019;9:10021.
Sopena S, Godoy C, Tabernero D, Homs M, Gregori J, Riveiro-Barciela M, et al. Quantitative characterization of hepatitis delta virus genome edition by next-generation sequencing. Virus Res. 2018;243:52–59.
Dziri S, Rodriguez C, Gerber A, Brichler S, Alloui C, Roulot D, et al. Variable in vivo hepatitis d virus (HDV) RNA editing rates according to the HDV genotype. Viruses. 2021;13:1572.
Verrier ER, Salvetti A, Pons C, Michelet M, Rivoire M, Baumert TF, et al. Loss of hepatitis D virus infectivity upon farnesyl transferase inhibitor treatment associates with increasing RNA editing rates revealed by a new RT-ddPCR method. Antiviral Res. 2022;198:105250.
Yan H, Peng B, He W, Zhong G, Qi Y, Ren B, et al. Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. J Virol. 2013;87:7977–91.
Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. J Hepatol. 2016;64:556–64.
Perez-Vargas J, Amirache F, Boson B, Mialon C, Freitas N, Sureau C, et al. Enveloped viruses distinct from HBV induce dissemination of hepatitis D virus in vivo. Nat Commun. 2019;10:2098.
Chemin I, Pujol FH, Scholtès C, Loureiro CL, Amirache F, Levrero M, et al. Preliminary evidence for hepatitis delta virus exposure in patients who are apparently not infected with hepatitis b virus. Hepatology. 2021;73:861–864.
Pflüger LS, Schulze zur Wiesch J, Polywka S, Lütgehetmann M. Hepatitis delta virus propagation enabled by hepatitis C virus-Scientifically intriguing, but is it relevant to clinical practice? J Viral Hepat. 2021;28:213–6.
Cappy P, Lucas Q, Kankarafou N, Sureau C, Laperche S. No Evidence of hepatitis c virus (HCV)-assisted hepatitis D Virus propagation in a large cohort of HCV-positive blood donors. J Infect Dis. 2021;223:1376–80.
Roggenbach I, Chi X, Lempp FA, Qu B, Walter L, Wu R, et al. HDV Seroprevalence in HBsAg-Positive Patients in China Occurs in Hotspots and Is Not Associated with HCV Mono-Infection. Viruses. 2021;13:1799.
Giersch K, Bhadra OD, Volz T, Allweiss L, Riecken K, Fehse B, et al. Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo. Gut. 2019;68:150–7.
Zhang Z, et al. Hepatitis D virus-induced interferon response and administered interferons control cell division-mediated virus spread. J Hepatol. 2022;77:957–66.
Tu T, Zehnder B, Wettengel JM, Zhang H, Coulter S, Ho V, et al. Mitosis of hepatitis B virus-infected cells in vitro results in uninfected daughter cells. JHEP Rep. 2022;4:100514.
Allweiss L, Volz T, Giersch K, Kah J, Raffa G, Petersen J, et al. Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo. Gut. 2018;67:542–52.
Giersch K, Helbig M, Volz T, Allweiss L, Mancke LV, Lohse AW, et al. Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. J Hepatol. 2014;60:538–44.
Samuel D, Zignego AL, Reynes M, Feray C, Arulnaden JL, David MF, et al. Long-term clinical and virological outcome after liver transplantation for cirrhosis caused by chronic delta hepatitis. Hepatology. 1995;21:333–9.
Mederacke I, Filmann N, Yurdaydin C, Bremer B, Puls F, Zacher BJ, et al. Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation. J Hepatol. 2012;56:115–22.
Hetzel U, Szirovicza L, Smura T, Prähauser B, Vapalahti O, Kipar A, et al. Identification of a novel deltavirus in boa constrictors. mBio. 2019;10:2.
Wille M, Netter H, Littlejohn M, Yuen L, Shi M, Eden JS, et al. A divergent hepatitis D-like agent in birds. Viruses. 2018;10:720.
Paraskevopoulou S, Pirzer F, Goldmann N, Schmid J, Corman VM, Gottula LT, et al. Mammalian deltavirus without hepadnavirus coinfection in the neotropical rodent Proechimys semispinosus. Proc Natl Acad Sci USA. 2020;117:17977–83.
Bergner LM, Orton RJ, Broos A, Tello C, Becker DJ, Carrera JE, et al. Diversification of mammalian deltaviruses by host shifting. Proc Natl Acad Sci USA. 2021;118:e2019907118.
Chang WS, Pettersson JHO, Le Lay C, Shi M, Lo N, Wille M, et al. Novel hepatitis D-like agents in vertebrates and invertebrates. Virus Evol. 2019;5:vez021.
Szirovicza L, Hetzel U, Kipar A, Martinez-Sobrido L, Vapalahti O, Hepojoki J. Snake deltavirus utilizes envelope proteins of different viruses to generate infectious particles. mBio. 2020;11. doi:10.1128/mBio.03250-19.
doi: 10.1128/mBio.03250-19
Mutz P, Metz P, Lempp FA, Bender S, Qu B, Schöneweis K, et al. HBV Bypasses the Innate immune response and does not protect HCV from antiviral activity of interferon. Gastroenterology. 2018;154:1791–804 e22.
Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA. 2004;101:6669–74.
Suslov A, Boldanova T, Wang X, Wieland S, Heim MH. Hepatitis B Virus does not interfere with innate immune responses in the human liver. Gastroenterology. 2018;154:1778–90.
Alfaiate D, Lucifora J, Abeywickrama-Samarakoon N, Michelet M, Testoni B, Cortay JC, et al. HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes. Antiviral Res. 2016;136:19–31.
Giersch K, Allweiss L, Volz T, Helbig M, Bierwolf J, Lohse AW, et al. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J Hepatol. 2015;63:346–53.
Zhang Z, Filzmayer C, Ni Y, Sültmann H, Mutz P, Hiet MS, et al. Hepatitis D virus replication is sensed by MDA5 and induces IFN-beta/lambda responses in hepatocytes. J Hepatol. 2018;69:25–35.
Gillich N, et al. Effect of variants in LGP2 on MDA5-mediated activation of interferon response and suppression of hepatitis D virus replication. J Hepatol. 2022;78:78–89.
Zhang Z, Urban S. Interplay between hepatitis D virus and the interferon response. Viruses. 2020;12:1334.
Zhang Z, Urban S. New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies. J Hepatol. 2021;74:686–99.
Borrmann A, Milles S, Plass T, Dommerholt J, Verkade JMM, Wießler M, et al. Genetic encoding of a bicyclo[6.1.0]nonyne-charged amino acid enables fast cellular protein imaging by metal-free ligation. Chembiochem. 2012;13:2094–9.
Hercun J, Koh C, Heller T. Hepatitis delta: prevalence, natural history, and treatment options. Gastroenterol Clin North Am. 2020;49:239–52.
Chen HY, Shen DT, Ji DZ, Han PC, Zhang WM, Ma JF, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2019;68:512–21.
Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, et al. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis. 2020;221:1677–87.
Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C, et al. The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol. 2020;73:523–32.
Safaie P, Razeghi S, Rouster SD, Privitera I, Sherman KE. Hepatitis D diagnostics:utilization and testing in the United States. Virus Res. 2018;250:114–7.
Palom A, Rando-Segura A, Vico J, Pacín B, Vargas E, Barreira-Díaz A, et al. Implementation of anti-HDV reflex testing among HBsAg-positive individuals increases testing for hepatitis D. JHEP Rep. 2022;4:100547.
Stockdale AJ, Chaponda M, Beloukas A, Phillips RO, Matthews PC, Papadimitropoulos A, et al. Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis. Lancet. Glob Health. 2017;5:e992–e1003.
Lin HH, Lee SSJ, Yu ML, Chang TT, Su CW, Hu BS, et al. Changing hepatitis D virus epidemiology in a hepatitis B virus endemic area with a national vaccination program. Hepatology. 2015;61:1870–9.
Kucirka LM, Farzadegan H, Feld JJ, Mehta SH, Winters M, Glenn JS, et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J Infect Dis. 2010;202:845–52.
Zhang JY, Jin ZH, Wang CJ. [A seroepidemiological study on hepatitis D virus (HDV) infection in Henan Province, China]. Zhonghua Liu Xing Bing Xue Za Zhi. 1995;16:365–8.
Chen X, Xuan M, Yin Y. [Study of HDV infection in Shandong province]. Zhonghua Liu Xing Bing Xue Za Zhi. 1998;19:138–40.
Liao B, Zhang F, Lin S, He H, Liu Y, Zhang J, et al. Epidemiological, clinical and histological characteristics of HBV/HDV co-infection: a retrospective cross-sectional study in Guangdong, China. PLoS ONE. 2014;9:e115888.
Saravanan S, Madhavan V, Velu V, Murugavel KG, Waldrop G, Solomon SS, et al. High prevalence of hepatitis delta virus among patients with chronic hepatitis B virus infection and HIV-1 in an intermediate hepatitis B virus endemic region. J Int Assoc Provid AIDS Care. 2014;13:85–90.
Chakraborty P, Kailash U, Jain A, Goyal R, Gupta RK, Das BC, et al. Seroprevalence of hepatitis D virus in patients with hepatitis B virus-related liver diseases. Indian J Med Res. 2005;122:254–7.
Mumtaz K, Hamid SS, Adil S, Afaq A, Islam M, Abid S, et al. Epidemiology and clinical pattern of hepatitis delta virus infection in Pakistan. J Gastroenterol Hepatol. 2005;20:1503–7.
Abbasi A, Bhutto AR, Butt N, Mahmood K. HDV seroprevalence in HBsAg positive patients. J Coll Physicians Surg Pak. 2014;24:624–7.
Louisirirotchanakul S, Wasi C, Uneklabh C, Phutiprawan T, Suwanagool S, Chainuvati T, et al. High prevalence of delta virus infection in Thai intravenous drug abusers. Southeast Asian J Trop Med Public Health. 1988;19:191–5.
Pouri AA, Ghojazadeh M, Baiaz B, Hamzavi FS, Pourasghari B, Somi MH. Prevalence of hepatitis D virus among HBsAg-positive individuals, 2015-2016: Azar cohort study. Health Promot Perspect. 2020;10:38–42.
Sayad B, Naderi Y, Alavian SM, Najafi F, Janbakhsh A, Mansouri F, et al. Hepatitis D virus infection in Kermanshah, west of Iran: seroprevalence and viremic infections. Gastroenterol Hepatol Bed Bench. 2018;11:145–52.
Chen X, Oidovsambuu O, Liu P, Grosely R, Elazar M, Winn VD, et al. A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus-infected mongolians. Hepatology. 2017;66:1739–49.
Al-Traif I, Ali A, Dafalla M, Al Tamimi W, Qassem L. Prevalence of hepatitis delta antibody among HBsAG carriers in Saudi Arabia. Ann Saudi Med. 2004;24:343–4.
Tozun N, Ozdogan O, Cakaloglu Y, Idilman R, Karasu Z, Akarca U, et al. Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study. Clin Microbiol Infect. 2015;21:1020–6.
Mese S, Nergiz S, Tekes S, Gul K. Seroprevalence of serum HBsAg positivity and hepatitis delta virus infection among blood donors in Southeastern Turkey. Clin Ter. 2014;165:95–8.
Değertekin H, Yalçιn K, Yakut M, Yurdaydin C. Seropositivity for delta hepatitis in patients with chronic hepatitis B and liver cirrhosis in Turkey: a meta-analysis. Liver Int. 2008;28:494–8.
Tamura I, Kurimura O, Koda T, Ichimura H, Katayama S, Kurimura T, et al. Risk of liver cirrhosis and hepatocellular carcinoma in subjects with hepatitis B and delta virus infection: a study from Kure, Japan. J Gastroenterol Hepatol. 1993;8:433–6.
Toukan AU, Abu-El-Rub OA, Abu-Laban SA, Tarawneh MS, Kamal MF, Hadler SC, et al. The epidemiology and clinical outcome of hepatitis D virus (delta) infection in Jordan. Hepatology. 1987;7:1340–5.
Ilyassova B, Yenin Y, Baymakhanov B, Doskhanov M. Clinical and morphologic diagnostic assessments of liver diseases after liver transplant. Exp Clin Transplant. 2018;16 Suppl 1(suppl 1):89–94.
Khodjaeva M, Ibadullaeva N, Khikmatullaeva A, Joldasova E, Ismoilov U, Colombo M, et al. The medical impact of hepatitis D virus infection in Uzbekistan. Liver Int. 2019;39:2077–81.
Khan A, Kurbanov F, Tanaka Y, Elkady A, Sugiyama M, Dustov A, et al. Epidemiological and clinical evaluation of hepatitis B, hepatitis C, and delta hepatitis viruses in Tajikistan. J Med Virol. 2008;80:268–76.
Husseini AA, Saeed KMI, Yurdcu E, Sertoz R, Bozdayi AM. Epidemiology of blood-borne viral infections in Afghanistan. Arch Virol. 2019;164:2083–90.
Triki H, Said N, Ben Salah A, Arrouji A, Ben Ahmed F, Bouguerra A, et al. Seroepidemiology of hepatitis B, C and delta viruses in Tunisia. Trans R Soc Trop Med Hyg. 1997;91:11–4.
Makuwa M, Caron M, Souquière S, Malonga-Mouelet G, Mahé A, Kazanji M. Prevalence and genetic diversity of hepatitis B and delta viruses in pregnant women in Gabon: molecular evidence that hepatitis delta virus clade 8 originates from and is endemic in central Africa. J Clin Microbiol. 2008;46:754–6.
Mahale P, Aka P, Chen X, Pfeiffer RM, Liu P, Groover S, et al. Hepatitis D virus infection, cirrhosis and hepatocellular carcinoma in The Gambia. J Viral Hepat. 2019;26:738–49.
Lunel-Fabiani F, Mansour W, Amar AO, Aye M, Le Gal F, Malick FZF, et al. Impact of hepatitis B and delta virus co-infection on liver disease in Mauritania: a cross sectional study. J Infect. 2013;67:448–57.
Besombes C, Njouom R, Paireau J, Lachenal G, Texier G, Tejiokem M, et al. The epidemiology of hepatitis delta virus infection in Cameroon. Gut. 2020;69:1294–1300.
Butler EK, Rodgers MA, Coller KE, Barnaby D, Krilich E, Olivo A, et al. High prevalence of hepatitis delta virus in Cameroon. Sci Rep. 2018;8:11617.
Makiala-Mandanda S, Le Gal F, Ngwaka-Matsung N, Ahuka-Mundeke S, Onanga R, Bivigou-Mboumba B, et al. High prevalence and diversity of hepatitis viruses in suspected cases of yellow fever in the Democratic Republic of Congo. J Clin Microbiol. 2017;55:1299–312.
Daw MA, Daw AM, Sifennasr NEM, Draha AM, Daw AM, Daw AM, et al. The epidemiology of hepatitis D Virus in North Africa: A systematic review and meta-analysis. ScientificWorldJournal. 2018;2018:9312650.
Sagnelli E, Sagnelli C, Pisaturo M, Macera M, Coppola N. Epidemiology of acute and chronic hepatitis B and delta over the last 5 decades in Italy. World J Gastroenterol. 2014;20:7635–43.
Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, Wedemeyer H. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat. 2009;16:883–94.
Manesis EK, Vourli G, Dalekos G, Vasiliadis T, Manolaki N, Hounta A, et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J Hepatol. 2013;59:949–56.
Servant-Delmas A, Le Gal F, Gallian P, Gordien E, Laperche S. Increasing prevalence of HDV/HBV infection over 15 years in France. J Clin Virol. 2014;59:126–8.
Shadur B, MacLachlan J, Cowie B. Hepatitis D virus in Victoria 2000-2009. Intern Med J. 2013;43:1081–7.
Coghill S, McNamara J, Woods M, Hajkowicz K. Epidemiology and clinical outcomes of hepatitis delta (D) virus infection in Queensland, Australia. Int J Infect Dis. 2018;74:123–7.
Braga WSM, Castilho MC, Borges FG, Leão JRDT, Martinho ACS, Rodrigues IS, et al. Hepatitis D virus infection in the Western Brazilian Amazon - far from a vanishing disease. Rev Soc Bras Med Trop. 2012;45:691–5.
Jat SL, Gupta N, Kumar T, Mishra S, S A, Yadav V, et al. Prevalence of hepatitis D virus infection among hepatitis B virus-infected individuals in India. Indian J Gastroenterol. 2015;34:164–8.
Gish R, e.a., Prevalence and characteristics of hepatitis delta in the United States: an analysis of all-payer claims database. AASLD 2021 Poster698.
Osiowy C, Swidinsky K, Haylock-Jacobs S, Sadler MD, Fung S, Wong D, et al. Molecular epidemiology and clinical characteristics of hepatitis D virus infection in Canada. JHEP Rep. 2022;4:100461.
Liu H Sr, ea, Prevalence and clinical characteristics of hepatitis D in southwest of China. AASLD 2021, P699.
Chudy M, et al., Collaborative study to establish a World Health Organization international standard for hepatitis D virus RNA for nucleic acid amplification technique (NAT)-based assays. 2013. 29.
Lin GY, Wu YL, Wang CS, Ko CY, Chen CH, Chen PJ, et al. Performance of commercially available anti-HDV enzyme-linked immunosorbent assays in Taiwan. Virol J. 2020;17:76.
Rocco C, Bonavolta R, Vallefuoco L, Braschi U, Sorrentino R, Terracciano D, et al. Comparison of anti-hepatitis D virus (HDV) ETI-AB-DELTAK-2 assay and the novel LIAISON(R) XL MUREX anti-HDV assay in the diagnosis of HDV infection. Diagn Microbiol Infect Dis. 2019;95:114873.
Chow SK, Atienza EE, Cook L, Prince H, Slev P, Lapé-Nixon M, et al. Comparison of enzyme immunoassays for detection of antibodies to hepatitis D virus in serum. Clin Vaccine Immunol. 2016;23:732–4.
Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet. 2011;378:73–85.
Le Gal F, Brichler S, Sahli R, Chevret S, Gordien E. First international external quality assessment for hepatitis delta virus RNA quantification in plasma. Hepatology. 2016;64:1483–94.
Le Gal F, Dziri S, Gerber A, Alloui C, Ben Abdesselam Z, Roulot D, et al. Performance characteristics of a new consensus commercial kit for hepatitis D Virus RNA viral load quantification. J Clin Microbiol. 2017;55:431–41.
Lempp FA, Roggenbach I, Nkongolo S, Sakin V, Schlund F, Schnitzler P, et al. A rapid point-of-care test for the serodiagnosis of hepatitis delta virus infection. Viruses. 2021;13:2371.
Saracco G, Rosina F, Brunetto MR, Amoroso P, Caredda F, Farci P, et al. Rapidly progressive HBsAg-positive hepatitis in Italy. The role of hepatitis delta virus infection. J Hepatol. 1987;5:274–81.
Fattovich G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut. 2000;46:420–6.
Farci P, Niro G. Clinical features of hepatitis D. Semin Liver Dis. 2012;32:228–36.
Wu JC. Functional and clinical significance of hepatitis D virus genotype II infection. Curr Top Microbiol Immunol. 2006;307:173–86.
Su CW, Huang YH, Huo TI, Shih HH, Sheen IJ, Chen SW, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology. 2006;130:1625–35.
Smedile A, Verme G, Cargnel A, Dentico P, Opolon P, Vergani D, et al. Influence of delta infection on severity of hepatitis B. Lancet. 1982;320:945–7.
Alves C, Branco C, Cunha C. Hepatitis delta virus: a peculiar virus. Adv Virol. 2013;2013:560105.
Sedhom D, D’Souza M, John E, Rustgi V. Viral Hepatitis and Acute Liver Failure: Still a Problem. Clin Liver Dis. 2018;22:289–300.
Romeo R, Foglieni B, Casazza G, Spreafico M, Colombo M, Prati D. High serum levels of HDV RNA are predictors of cirrhosis and liver cancer in patients with chronic hepatitis delta. PLoS One. 2014;9:e92062.
Da BL, Surana P, Takyar V, Kleiner DE, Heller T, Koh C. Vibration-controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection. J Viral Hepat. 2020;27:428–36.
Da BL, Surana P, Kleiner DE, Heller T, Koh C. The Delta-4 fibrosis score (D4FS): a novel fibrosis score in chronic hepatitis D. Antiviral Res. 2020;174:104691.
Surana P, Hercun J, Takyar V, Kleiner DE, Heller T, Koh C. Platelet count as a screening tool for compensated cirrhosis in chronic viral hepatitis. World J Gastrointest Pathophysiol. 2021;12:40–50.
Takyar V, Surana P, Kleiner DE, Wilkins K, Hoofnagle JH, Liang TJ, et al. Noninvasive markers for staging fibrosis in chronic delta hepatitis. Aliment Pharmacol Ther. 2017;45:127–38.
Etzion O, et al. Limited utility of noninvasivetests for prediction of biopsy-proven cirrhosis in chronic hepatitis D infected patients: insights from the D-LIVR trial. AASLD. 2021;74S1:157–1288.
Niro GA, Smedile A, Ippolito AM, Ciancio A, Fontana R, Olivero A, et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol. 2010;53:834–40.
Abbas Z, Hamid S, Qureshi M, Jafri W. Hepatocellular carcinoma in hepatitis D: does it differ from hepatitis B monoinfection? Saudi J Gastroenterol. 2012;18:18–22.
Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009;136:1629–38.
Kushner T, Serper M, Kaplan DE. Delta hepatitis within the Veterans Affairs medical system in the United States: prevalence, risk factors, and outcomes. J Hepatol. 2015;63:586–92.
Béguelin C, Moradpour D, Sahli R, Suter-Riniker F, Lüthi A, Cavassini M, et al. Hepatitis delta-associated mortality in HIV/HBV-coinfected patients. J Hepatol. 2017;66:297–303.
Huo TI, Wu JC, Lai CR, Lu CL, Sheng WY, Lee SD. Comparison of clinico-pathological features in hepatitis B virus-associated hepatocellular carcinoma with or without hepatitis D virus superinfection. J Hepatol. 1996;25:439–44.
Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O, et al. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy. J Hepatol. 2019;70:1008–15.
Lampertico P, Agarwal K, Berg T, Buti M, Janssen H, Papatheodoridis G, et al. European Association for the Study of the Liver. Electronic address, e.e.e. and L. European Association for the Study of the. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.
Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 Hepatitis B Guidance. Clin Liver Dis (Hoboken). 2018;12:33–34.
Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126:1740–9.
Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N, et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-u. Hepatology. 2006;44:728–35.
Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology. 2006;44:713–20.
Farci P, Mandas A, Coiana A, Lai ME, Desmet V, Van Eyken P, et al. Treatment of chronic hepatitis D with interferon alfa-2a. N Engl J Med. 1994;330:88–94.
Yurdaydin C, Bozkaya H, Karaaslan H, Önder FO, Erkan ÖE, Yalçin K, et al. A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis. J Viral Hepat. 2007;14:812–6.
Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364:322–31.
Heidrich B, Yurdaydin C, Kabaçam G, Ratsch BA, Zachou K, Bremer B, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60:87–97.
Heller T, Rotman Y, Koh C, Clark S, Haynes-Williams V, Chang R, et al. Long-term therapy of chronic delta hepatitis with peginterferon alfa. Aliment Pharmacol Ther. 2014;40:93–104.
Lutterkort GL, Wranke A, Hengst J, Yurdaydin C, Stift J, Bremer B, et al. Viral dominance patterns in chronic hepatitis delta determine early response to interferon alpha therapy. J Viral Hepat. 2018;25:1384–94.
Gunsar F, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G, et al. Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther. 2005;10:721–6.
Yurdaydin C, Keskin O, Kalkan Ç, Karakaya F, Çalişkan A, Kabaçam G, et al. Interferon treatment duration in patients with chronic delta hepatitis and its effect on the natural course of the disease. J Infect Dis. 2018;217:1184–92.
Spaan M, Carey I, Bruce M, Shang D, Horner M, Dusheiko G, et al. Hepatitis delta genotype 5 is associated with favourable disease outcome and better response to treatment compared to genotype 1. J Hepatol. 2020;72:1097–104.
Lau DTY, Kleiner DE, Park Y, di Bisceglie AM, Hoofnagle JH. Resolution of chronic delta hepatitis after 12 years of interferon alfa therapy. Gastroenterology. 1999;117:1229–33.
Hercun J, Kim GE, Da BL, Rotman Y, Kleiner DE, Chang R, et al. Durable virological response and functional cure of chronic hepatitis D after long-term peginterferon therapy. Aliment Pharmacol Ther. 2021;54:176–82.
Giersch K, Homs M, Volz T, Helbig M, Allweiss L, Lohse AW, et al. Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice. Sci Rep. 2017;7:3757.
Urban S, Neumann-Haefelin C, Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut. 2021;70:1782–94.
Etzion O, Hamid SS, Lurie Y, Gane E, Bader N, Yardeni D, et al. PS-052-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(Supplement):e32.
Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol. 2005;79:1613–22.
Glebe D, Urban S, Knoop EV, Çağ N, Krass P, Grün S, et al. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology. 2005;129:234–45.
Schulze A, Schieck A, Ni Y, Mier W, Urban S. Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J Virol. 2010;84:1989–2000.
Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, von Weizsäcker F, et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol. 2008;26:335–41.
Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T, et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65:483–9.
Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65:490–8.
Wedemeyer H, Bogomolov P, Blank A, Allweiss L, Dandri-Petersen M, Bremer B, 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. 2018;68:S3.
Wedemeyer H, et al. Safety and efficacy of bulevirtide in combination with tenofovir disoproxil fumarate in patients with hepatitis B virus and hepatitis D virus coinfection (MYR202): a multicentre, randomised, parallel-group, open-label, phase 2 trial. Lancet Infect Dis. 2022:117–29.
Schwarz C, Chromy D, Bangert C, Schwarz M, Jachs M, Reiberger T, et al. Immediate-type hypersensitivity reaction to bulevirtide and successful desensitization in a patient with HBV/HDV-associated compensated cirrhosis. J Hepatol. 2022;77:254–5.
Jachs M, Panzer Schwarz C, Schwarz C, Panzer M, Hartl L, Bota S, et al. Virologic response to bulevirtide is delayed in cirrhotic HDV patients with clinically significant portal hypertension. J Hepatol. 2022;77(S1):S665–S939.
Killer A, Ghavemi M, Smaranda G, Bode J, Jensen B, Köhler J, et al. Improvement of liver-stiffness after 6 months of therapy: real-life data for HBV/HDV co-infected patients treated with bulevirtide. J Hepatol. 2022;77(S1):S665–S939.
Manhas S, Han B, Xu S, May L, Han D, Yazdi T, et al. ea, Bulevirtide is broadly active against all HDV genotypes expressing envelopes from HBV genotypes A-H and a large panel of clinical isolates. Journal of Hepatology Supplement. 2022;77:S244.
Herta T, Hahn M, Maier M, Niemeyer J, Gerhardt F, Schumacher J, et al. Real-world data on treatment with bulevirtide in patients with chronic hepatitis B and D coinfection. J Hepatol. 2022;77(S1):S665–S939.
Dietz C, Tacke F, Zöllner C, Zöllner C, Demir M, Schmidt H, et al. Bulevirtide treatment of hepatitis D in Germany: multicentre realworld experience. J Hepatol. 2022;77(S1):S665–S939.
Loglio A, Ferenci P, Deterding K, Uceda Renteria SC, Sambarino D, Jachs M, et al. Bulevirtide 2 mg/day monotherapy in patients with chronic hepatitis delta with or without cirrhosis: a multicenter european cohort real-life study. J Hepatol. 2022;77(S1):S665–S939.
Fontaine H F-LC, Gordien E, et al. Real life study of bulevirtide in chronic hepatitis delta:preliminary results of the ANRS HD EP01 BuleDelta prospective cohort. J Hepatol. 2022;77(S1):S1–S118.
O'Malley B, Lazinski DW. Roles of carboxyl-terminal and farnesylated residues in the functions of the large hepatitis delta antigen. J Virol. 2005;79:1142–53.
Bordier BB, Ohkanda J, Liu P, Lee SY, Salazar FH, Marion PL, et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J Clin Invest. 2003;112:407–14.
Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, Haynes-Williams V, 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;15:1167–74.
Yurdaydin C, Keskin O, Kalkan Ç, Karakaya F, Çalişkan A, Karatayli E, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV-1 study. Hepatology. 2018;67:1224–36.
Yurdaydin C, Kalkan C, Karakaya F, Caliskan A, Karatayli S, Keskin O, 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 e.a. A Phase 2 Study of Peginterferon Lambda, Lonafarnib and Ritonavir for 24 weeks: End-ofStudy Results from the LIFT HDV Study. 2020; Available from: https://www.eigerbio.com/wp-content/uploads/2020/11/KohHDVLIFTAASLD2020Final-Read-Only.pdf
Boulon R, Blanchet M, Lemasson M, Vaillant A, Labonté P. Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro. Antiviral Res. 2020;183:104853.
Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, 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;2:877–889.
Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Anderson M, 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. Hepatol Commun. 2021;5:189–202.
Cao D, Haussecker D, Huang Y, Kay MA. Combined proteomic-RNAi screen for host factors involved in human hepatitis delta virus replication. RNA. 2009;15:1971–9.
van den Berg F, Limani SW, Mnyandu N, Maepa MB, Ely A, Arbuthnot P. Advances with RNAi-based therapy for hepatitis B virus infection. Viruses. 2020;12:851.
Duriez M, Mandouri Y, Lekbaby B, Wang H, Schnuriger A, Redelsperger F, et al. Alternative splicing of hepatitis B virus: a novel virus/host interaction altering liver immunity. J Hepatol. 2017;67:687–99.
Neumann AU, Phillips S, Levine I, Ijaz S, Dahari H, Eren R, et al. Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells. Hepatology. 2010;52:875–85.
Yuen MF, et al. Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB. J Hepatol. 2022;77:1287–98.
Yuen MF, et al. Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy. J Hepatol. 2022;77:967–7.
Lim Y-S, Yuen MF, Cloutier D, Thanawala V, Shen L, Gupta SV, et al. OS090 - Longer treatment duration of monthly VIR-2218 results in deeper and more sustained reductions in hepatitis B surface antigen in participants with chronic hepatitis B infection. J Hepatol. 2022;77:S69–S70.
Ottobrelli A, Marzano A, Smedile A, Recchia S, Salizzoni M, Cornu C, et al. Patterns of hepatitis delta virus reinfection and disease in liver transplantation. Gastroenterology. 1991;101:1649–55.
Cholongitas E, Goulis I, Antoniadis N, Fouzas I, Imvrios G, Giakoustidis D, et al. Nucleos(t)ide analog(s) prophylaxis after hepatitis B immunoglobulin withdrawal against hepatitis B and D recurrence after liver transplantation. Transpl Infect Dis. 2016;18:667–73.