HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
19
07
2021
received:
14
11
2020
accepted:
01
08
2021
pubmed:
26
9
2021
medline:
3
5
2022
entrez:
25
9
2021
Statut:
ppublish
Résumé
Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility.
Identifiants
pubmed: 34561972
doi: 10.1002/hep4.1821
pmc: PMC8870014
pii: 02009842-202203000-00007
doi:
Substances chimiques
Antiviral Agents
0
DNA, Viral
0
Hepatitis B Core Antigens
0
Interferon-alpha
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
480-495Informations de copyright
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
Références
Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet 2011;378:73‐85.
Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 2016;13:580‐589.
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;364:322‐331.
Wedemeyer H, Yurdaydin C, Hardtke S, Caruntu FA, Curescu MG, Yalcin K, et al. Peginterferon alfa‐2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT‐II): a randomised, placebo controlled, phase 2 trial. Lancet Infect Dis 2019;19:275‐286.
Heidrich B, Yurdaydın 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.
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;65:490‐498.
Loglio A, Ferenci P, Uceda Renteria SC, Tham CYL, van Bömmel F, Borghi M, 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.
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;15:1167‐1174.
Wedemeyer H, Schöneweis K, Bogomolov PO, Voronkova N, Chulanov V, Stepanova T, 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 Hepatol 2019;70:e81.
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;70:1008‐1015.
Kimura T, Ohno N, Terada N, Rokuhara A, Matsumoto A, Yagi S, et al. Hepatitis B virus DNA‐negative dane particles lack core protein but contain a 22‐kDa precore protein without C‐terminal arginine‐rich domain. J Biol Chem 2005;280:21713‐21719.
Suzuki F, Miyakoshi H, Kobayashi M, Kumada H. Correlation between serum hepatitis B virus core‐related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol 2009;81:27‐33.
Seto W‐K, Wong D K‐H, Fung J, Huang F‐Y, Liu K S‐H, Lai C‐L, et al. Linearized hepatitis B surface antigen and hepatitis B core‐related antigen in the natural history of chronic hepatitis B. Clin Microbiol Infect 2014;20:1173‐1180.
Maasoumy B, Wiegand SB, Jaroszewicz J, Bremer B, Lehmann P, Deterding K, et al. Hepatitis B core‐related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. Clin Microbiol Infect 2015;21:606.e1‐606.e10.
van Campenhout MJH, Brouwer WP, van Oord GW, Xie Q, Zhang Q, Zhang N, et al. Hepatitis B core‐related antigen levels are associated with response to entecavir and peginterferon add‐on therapy in hepatitis B e antigen‐positive chronic hepatitis B patients. Clin Microbiol Infect 2016;22:571.e5‐e9.
Cornberg M, Lok A‐F, Terrault NA, Zoulim F, Berg T, Brunetto MR, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B—report from the 2019 EASL‐AASLD HBV Treatment Endpoints Conference. J Hepatol 2020;72:539‐557.
Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, Bock T, et al. Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. J Clin Microbiol 2010;48:2022‐2029.
Harrell FEJ, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996;15:361‐387.
Cornberg M, Wong VW‐S, Locarnini S, Brunetto M, Janssen HLA, Chan HL‐Y. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017;66:398‐411.
Ricco G, Popa DC, Cavallone D, Iacob S, Salvati A, Tabacelia D, et al. Quantification of serum markers of hepatitis B (HBV) and delta virus (HDV) infections in patients with chronic HDV infection. J Viral Hepat 2018;25:911‐919.
Wranke A, Heidrich B, Ernst S, Calle Serrano B, Caruntu FA, Curescu MG, et al. Anti‐HDV IgM as a marker of disease activity in hepatitis delta. PLoS ONE 2014;9:e101002.
Lucifora J, Protzer U. Attacking hepatitis B virus cccDNA—the holy grail to hepatitis B cure. J Hepatol 2016;64(Suppl. 1):S41‐S48.
Pollicino T, Raffa G, Santantonio T, Gaeta GB, Iannello G, Alibrandi A, et al. Replicative and transcriptional activities of hepatitis B virus in patients coinfected with hepatitis B and hepatitis delta viruses. J Virol 2011;85:432‐439.
Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 2014;343:1221‐1228.
Wong D‐H, Seto W‐K, Cheung K‐S, Chong C‐K, Huang F‐Y, Fung J, et al. Hepatitis B virus core‐related antigen as a surrogate marker for covalently closed circular DNA. Liver Int 2017;37:995‐1001.
Testoni B, Lebossé F, Scholtes C, Berby F, Miaglia C, Subic M, et al. Serum hepatitis B core‐related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J Hepatol 2019;70:615‐625.
Farag MS, van Campenhout MJH, Pfefferkorn M, Fischer J, Deichsel D, Boonstra A, et al. Hepatitis B virus RNA as early predictor for response to pegylated interferon alpha in HBeAg‐negative chronic hepatitis B. Clin Infect Dis 2020;72:202‐211.
Jansen L, Kootstra NA, van Dort KA, Takkenberg RB, Reesink HW, Zaaijer HL. Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa‐2a and nucleos(t)ide analogues. J Infect Dis 2016;213:224‐232.
van Bömmel F, van Bömmel A, Krauel A, Wat C, Pavlovic V, Yang L, et al. Serum HBV RNA as a predictor of peginterferon alfa‐2a response in patients with HBeAg‐positive chronic hepatitis B. J Infect Dis 2018;218:1066‐1074.
Ma G, Lou B, Lv F, Zhao D, Zhang Z, Chen Y. HBcrAg and pg RNA and the therapeutic effect in HBeAg‐positive patients receiving anti‐viral therapy, baseline serum HBV‐RNA is a powerful predictor of response. J Viral Hepat 2020;27:837‐846.
Chuaypen N, Posuwan N, Payungporn S, Tanaka Y, Shinkai N, Poovorawan Y, et al. Serum hepatitis B core‐related antigen as a treatment predictor of pegylated interferon in patients with HBeAg‐positive chronic hepatitis B. Liver Int 2016;36:827‐836.
Zhang M, Li G, Shang J, Pan C, Zhang M, Yin Z, et al. Rapidly decreased HBV RNA predicts responses of pegylated interferons in HBeAg‐positive patients: a longitudinal cohort study. Hepatol Int 2020;14:212‐224.
Anastasiou OE, Yurdaydin C, Maasoumy B, Hardtke S, Caruntu FA, Curescu MG, et al. A transient early HBV‐DNA increase during PEG‐IFNα therapy of hepatitis D indicates loss of infected cells and is associated with HDV‐RNA and HBsAg reduction. J Viral Hepat 2021;28:410‐419.
Sonneveld MJ, van Oord GW, van Campenhout MJ, De Man RA, Janssen HLA, de Knegt RJ, et al. Relationship between hepatitis B core‐related antigen levels and sustained HBeAg seroconversion in patients treated with nucleo(s)tide analogues. J Viral Hepat 2019;26:828‐834.
Hsu Y‐C, Nguyen MH, Mo L‐R, Wu M‐S, Yang T‐H, Chen C‐C, et al. Combining hepatitis B core‐related and surface antigens at end of nucleos(t)ide analogue treatment to predict off‐therapy relapse risk. Aliment Pharmacol Ther 2019;49:107‐115.
Carey I, Gersch J, Wang B, Moigboi C, Kuhns M, Cloherty G, et al. Pre‐genomic HBV RNA and HBcrAg predict outcomes in HBeAg negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy. Hepatology 2020;72:42‐57.
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;67:1224‐1236.