. 2022 Apr 2.
doi: 10.1002/hep4.1951. Online ahead of print.
HBsAg isoform dynamics during NAP-based therapy of HBeAg-negative chronic HBV and HBV/HDV infection
Michel Bazinet 1 , Mark Anderson 2 , Victor Pântea 3 , Gheorghe Placinta 3 , Iurie Moscalu 4 , Valentin Cebotarescu 3 , Lilia Cojuhari 3 , Pavlina Jimbei 5 , Liviu Iarovoi 3 , Valentina Smesnoi 5 , Tatina Musteata 5 , Alina Jucov 3 4 , Ulf Dittmer 6 , Jeff Gersch 2 , Vera Holzmayer 2 , Mary Kuhns 2 , Gavin Cloherty 2 , Andrew Vaillant 1
Affiliations
Affiliations
1
Replicor Inc., Montreal, Quebec, Canada.
2
Abbott Diagnostics, Abbott Park, Illinois, USA.
3
Department of Infectious Diseases, Nicolae Testemiţanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova.
4
ARENSIA Exploratory Medicine, Republican Clinical Hospital, Chișinău, Republic of Moldova.
5
Toma Ciorbǎ Infectious Clinical Hospital, Chișinău, Republic of Moldova.
6
Institute for Virology, University of Duisburg-Essen, Essen, Germany.
PMID: 35368148 DOI: 10.1002/hep4.1951
Abstract
Nucleic acid polymers block the assembly of hepatitis B virus (HBV) subviral particles, effectively preventing hepatitis B surface antigen (HBsAg) replenishment in the circulation. Nucleic acid polymer (NAP)-based combination therapy of HBV infection or HBV/hepatitis D virus (HDV) co-infection is accompanied by HBsAg clearance and seroconversion, HDV-RNA clearance in co-infection, and persistent functional cure of HBV (HBsAg < 0.05 IU/ml, HBV-DNA target not dected, normal alanine aminotransferase) and persistent clearance of HDV RNA. An analysis of HBsAg isoform changes during quantitative HBsAg declines (qHBsAg), and subsequent treatment-free follow-up in the REP 301/REP 301-LTF (HBV/HDV) and REP 401 (HBV) studies was conducted. HBsAg isoforms were analyzed from frozen serum samples using Abbott Research Use Only assays for HBsAg isoforms (large [L], medium [M], and total [T]). The relative change over time in small HBsAg relative to the other isoforms was inferred by the change in the ratio over time of T-HBsAg to M-HBsAg. HBsAg isoform declines followed qHBsAg declines in all participants. No HBsAg isoforms were detectable in any participants with functional cure. HBsAg declines > 2 log10 IU/ml from baseline were correlated with selective clearance of S-HBsAg in 39 of 42 participants. Selective S-HBsAg decline was absent in 9 of 10 participants with HBsAg decline < 2 log10 IU/ml from baseline. Mild qHBsAg rebound during follow-up <10 IU/ml consisted mostly of S-HBsAg and M-HBsAg and not accompanied by significant covalently closed circular DNA activity. Conclusion: The faster observed declines in S-HBsAg indicate the selective clearance of subviral particles from the circulation, consistent with previous mechanistic studies on NAPs. Trace HBsAg rebound in the absence of HBV DNA may reflect HBsAg derived from integrated HBV DNA and not rebound of viral infection.