Analysis of HBsAg Immunocomplexes and cccDNA Activity During and Persisting After NAP‐Based Therapy

Abstract

Therapy with nucleic acid polymers (NAPs), tenofovir disoproxil fumarate (TDF), and pegylated interferon (pegIFN) achieve high rates of HBsAg loss/seroconversion and functional cure in chronic hepatitis B virus (HBV) infection. The role of hepatitis B surface antigen (HBsAg) seroconversion and inactivation of covalently closed circular DNA (cccDNA) in establishing functional cure were examined. Archived serum from the REP 401 study was analyzed using the Abbott ARCHITECT HBsAg NEXT assay (Chicago, IL), Abbott research use-only assays for HBsAg immune complexes (HBsAg ICs), circulating HBV RNA, and the Fujirebio assay for hepatitis B core-related antigen (HBcrAg; Malvern, PA). HBsAg became < 0.005 IU/mL in 23 participants during NAP exposure, which persisted in all participants with functional cure. HBsAg IC declined during lead-in TDF monotherapy and correlated with minor declines in HBsAg. Following the addition of NAPs and pegIFN, minor HBsAg IC increases (n = 13) or flares (n = 2) during therapy were not correlated with HBsAg decline, hepatitis B surface antibody (anti-HBs) titers, or alanine aminotransferase. HBsAg IC universally declined during follow-up in participants with virologic control or functional cure. Universal declines in HBV RNA and HBcrAg during TDF monotherapy continued with NAP + pegIFN regardless of therapeutic outcome. At the end of therapy, HBV RNA was undetectable in only 5 of 14 participants with functional cure but became undetectable after removal of therapy in all participants with functional cure. Undetectable HBV RNA at the end of therapy in 5 participants was followed by relapse to virologic control or viral rebound. Conclusion: Anti-HBs-independent mechanisms contribute to HBsAg clearance during NAP therapy. Inactivation of cccDNA does not predict functional cure following NAP-based therapy; however, functional cure is accompanied by persistent inactivation of cccDNA. Persistent HBsAg loss with functional cure may also reflect reduction/clearance of integrated HBV DNA. Clinicaltrials.org number NCT02565719. (Hepatology Communications 2021;0:1-15).

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

“…[ 36 , 37 ] In HBeAg‐positive chronic infection, rapid clearance and seroconversion of HBeAg are also observed, [ 36 ] and in HBV/HDV co‐infection, additional rapid clearance of HDV RNA occurs. [ 33 ] When combined with pegylated interferon (pegIFN) or tenofovir disoproxil fumarate (TDF) and pegIFN, NAP‐based combination therapy leads to high rates of HBsAg loss (<0.005 IU/ml) and seroconversion, host‐mediated transaminase flares, high rates of cccDNA silencing, and high rates of functional cure of HBV with persistent HBsAg seroconversion [ 38 , 39 , 40 ] and persistent undetectable HDV RNA (in co‐infected individuals). [ 41 ] A retrospective analysis of changes in HBsAg isoform composition during therapy and follow‐up from NAP‐based combination therapy was performed to establish the pattern of response in each HBsAg isoform during therapy and treatment‐free follow‐up.…”

Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment

“…Nevertheless, previous studies revealed that low baseline HBsAg was more reliable than serum HBV DNA levels for predicting good response to antiviral treatment in HBeAg-positive patients ( 30 – 34 ). Actually, the decrease of HBsAg indicates the decrease of cccDNA ( 35 , 36 ), which is important for predicting the outcome of PEG-IFN α treatment in CHB patients. Theoretically, low baseline HBsAg is more likely to achieve HBsAg loss, but our data suggested that there was no significant difference in baseline HBsAg levels between the two groups, which may be due to the small sample size of our study.…”

An Ideal Hallmark Closest to Complete Cure of Chronic Hepatitis B Patients: High-sensitivity Quantitative HBsAg Loss

“…Second, more and more new drugs that inhibit HBV and improve host immune response are in the process of clinical trials. 99,102 The effectiveness and safety of these novel drugs, as well as the best treatment strategy in complete cure, still need a lot of exploration. HBsAg cannot reflect the efficacy of some new drugs that inhibit or scavenge cccDNA because the integrated HBV DNA can still express HBsAg.…”

“…Persistent HBsAg loss can also reflect marked reduction or clearance of integrated HBV DNA. 99 Characteristics of conventional and high-sensitive HBsAg quantitative assays are summarized in Table 2. 95,97,100 Journal of Clinical and Translational Hepatology 2022 In addition, HBsAg loss can likely stimulate and restore HBVspecific immune responses that promote complete resolution of HBV infection.…”