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.
HBV
HDV
hepatitis B
hepatitis D
interferon
viral kinetics
Journal
Journal of viral hepatitis
ISSN: 1365-2893
Titre abrégé: J Viral Hepat
Pays: England
ID NLM: 9435672
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
30
04
2020
revised:
02
09
2020
accepted:
19
10
2020
pubmed:
14
11
2020
medline:
1
9
2021
entrez:
13
11
2020
Statut:
ppublish
Résumé
HBV-DNA levels are low or even undetectable in the majority HDV-infected patients. The impact of PEG-IFNα on HBV-DNA kinetics in HDV-infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV-RNA-positive patients were randomized to receive PEG-IFNα-2a plus tenofovir-disoproxil-fumarate (PEG-IFNα/TDF, n = 59) or placebo (PEG-IFNα/PBO; n = 61) for 96 weeks. At week 96, HBV-DNA was still quantifiable in 71% of PEG-IFNα/PBO-treated patients but also in 76% of PEG-IFNα/TDF-treated patients, despite low HBV-DNA baseline values. Surprisingly, a transient HBV-DNA increase between weeks 12 and 36 was observed in 12 in PEG-IFNα/TDF-treated and 12 PEG-IFNα/PBO-treated patients. This increase was positively associated with HBsAg loss [(P = 0.049, odds ratio (OR) 5.1] and HDV-RNA suppression (P = 0.007, OR 4.1) at week 96. Biochemical markers of cell death (M30 and ALT) were higher during the HBV-DNA peak but no distinct systemic immune pattern could be observed by screening 91 soluble inflammatory markers. In conclusion, an early increase in HBV-DNA during PEG-IFNα-2a therapy occurred in more than 20% of patients, even in TDF-treated patients. This transient HBV-DNA rise may indicate PEG-IFNα-induced cell death and lead to long-term HDV-RNA suppression and HBsAg loss.
Substances chimiques
Antiviral Agents
0
DNA, Viral
0
Hepatitis B Surface Antigens
0
Interferon-alpha
0
Polyethylene Glycols
3WJQ0SDW1A
RNA
63231-63-0
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
410-419Informations de copyright
© 2020 John Wiley & Sons Ltd.
Références
Chen H-Y, Shen D-T, Ji D-Z, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2019;68(3):512-521.
Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7(1):31-40.
Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364(4):322-331.
Niro GA, Ciancio A, Gaeta GB, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology. 2006;44(3):713-720.
Wranke A, Serrano BC, Heidrich B, et al. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology. 2017;65(2):414-425.
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. Lancet Infect Dis. 2019;19(3):275-286.
Heidrich B, Yurdaydin C, Kabacam G, et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87-97.
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 Hepatol. 2015;63(2):346-353.
Dahari H, Shudo E, Ribeiro RM, Perelson AS. Modeling complex decay profiles of hepatitis B virus during antiviral therapy. Hepatology (Baltimore, MD). 2009;49(1):32-38.
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 (Baltimore, MD). 2014;60(6):1902-1910.
Mederacke I, Bremer B, Heidrich B, 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(6):2022.
Proteomics O.Data normalization and standardization. https://wwwolinkcom/content/uploads/2018/05/Data-normalization-and-standardization_v10pdf. 2018.
Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359(23):2442-2455.
Marcellin P, Ahn SH, Ma X, et al. Combination of tenofovir disoproxil fumarate and peginterferon α-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology. 2016;150(1):134-144.e110.
Akarca U, Ersoz G, Gunsar F, et al. Interferon-lamivudine combination is no better than lamivudine alone in anti-HBe-positive chronic hepatitis B. Antivir Ther. 2004;9:325-334.
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. 2012;55(3):685-694.
Alfaiate D, Lucifora J, Abeywickrama-Samarakoon N, et al. HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes. Antivir Res. 2016;136:19-31.
Yurdaydin C, Borochov N, Kalkan C, et al. Hepatitis delta virus kinetics under the prenylation inhibitor lonafarnib suggest HDV-mediated suppression of HBV replication. J Hepatol. 2016;64(2):S587.
Testoni B, Lebossé F, Scholtes C, 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(4):615-625.
Yurdaydin C, Keskin O, Kalkan Ç, et al. Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The LOWR HDV-1 study. Hepatology. 2018;67(4):1224-1236.
Hengst J, Falk CS, Schlaphoff V, et al. Direct-acting antiviral-induced hepatitis C virus clearance does not completely restore the altered cytokine and chemokine milieu in patients with chronic hepatitis C. J Infect Dis. 2016;214(12):1965-1974.
Sawa Y, Arima Y, Ogura H, et al. Hepatic interleukin-7 expression regulates T cell responses. Immunity. 2009;30(3):447-457.
Oo YH, Shetty S, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver. Dig Dis. 2010;28(1):31-44.
Tan AT, Hoang LT, Chin D, et al. Reduction of HBV replication prolongs the early immunological response to IFNα therapy. J Hepatol. 2014;60(1):54-61.
Micco L, Peppa D, Loggi E, et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol. 2013;58(2):225-233.