HBsAg isoform dynamics during NAP‐based therapy of HBeAg‐negative chronic HBV and HBV/HDV infection

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.

Hepatitis B Surface Antigen Isoforms: Their Clinical Implications, Utilisation in Diagnosis, Prevention and New Antiviral Strategies

“…The NAPs combination therapy was also shown to improve levels of HDV RNA in HBV/HDV co-infected patients [153]. HBsAg isoform changes during NAPs therapy in HBV/HDV co-infected patients displayed a more rapid clearance of SHB than other HBsAg isoforms in patients with strong total HBsAg level declines [154]. This selective clearance of subviral particles was consistent with previous NAP studies.…”

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

“…HBsAg loss during therapy was shown to be <0.005 IU/mL (up to 8 log 10 reduction from baseline) and accompanied by inactivation of cccDNA and clearance of integrated HBV DNA [103]. HBsAg isoform analysis showed selective clearance of the small isoform of HBsAg, confirming the selective targeting of SVP by NAPs in human infection [104]. A small proof of concept trial demonstrated that REP 2139 also had potent effects against HDV infection in co-infected patients, with simultaneous clearance of HDV RNA and HBsAg [105], which has persisted for 3.5 years in 7/11 and 4 of these 7 patients, respectively [106].…”

Hepatitis D virus infection: Pathophysiology, epidemiology and treatment. Report from the first international delta cure meeting 2022

“…REP-2139 is a nucleic acid polymer that inhibits HDV replication via direct interaction with HDAg and blocks HDV release by inhibiting viral envelopment using the HBV subviral particle assembly pathway. 63 , 64 Administration of REP-2139 250 mg subcutaneously in combination with PegIFN 90 μg/week and tenofovir disoproxil fumarate for 48 weeks was reported in four patients with compensated cirrhosis (and without PegIFN in a patient with decompensated cirrhosis). Two patients showed HBsAg loss, which was preceded by an ALT flare in one case.…”