Benefit of transaminase elevations in establishing functional cure of HBV infection during nap‐based combination therapy

Bazinet, Michel; Pântea, Victor; Plăcintă, Gheorghe; Moscalu, Iurie; Cebotarescu, Valentin; Cojuhari, Lilia; Jimbei, Pavlina; Iarovoi, Liviu; Smeşnoi, Valentina; Musteata, Tatiana; Jucov, Alina; Dittmer, Ulf; Krawczyk, Adalbert; Vaillant, Andrew

doi:10.1111/jvh.13483

Cited by 14 publications

(15 citation statements)

References 33 publications

(99 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[ 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.…”

Section: Introductionmentioning

confidence: 99%

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

Bazinet¹,

Anderson²,

Pântea³

et al. 2022

Hepatol Commun

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Bazinet¹,

Anderson²,

Pântea³

et al. 2022

Hepatol Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Notwithstanding the limitations in the sensitivity of the HBV‐RNA and HBcrAg assays, the excellent suppression of HBV DNA and HBsAg in the absence of evidence of active HBsAg clearance by anti‐HBs strongly argues that not only is cccDNA suppressed (not eliminated) but the removal of hepatocytes with integrated HBV DNA (also a source of HBsAg) must also have occurred. This control of liver infection may also be due in part to the high incidence of strong host‐derived transaminase flares ( 21 ) and appears to persist in all participants achieving functional cure.…”

Section: Discussionmentioning

confidence: 99%

“…(18)(19)(20) These clinical benefits were recently shown to be linked to the high prevalence of therapeutic transaminase flares in the REP 401 study. (21) DOI 10.1002/hep4.1767 Potential conflict of interest: Dr. Anderson owns stock in and is employed by Abbott Laboratories. Dr. Bazinet is an employee and shareholder in Replicor Inc. Dr. Cloherty owns stock in and is employed by Abbott Laboratories.…”

Section: Hronic Hepatitis B Virus (Hbv) Infection Affectsmentioning

confidence: 99%

See 1 more Smart Citation

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

Bazinet¹,

Anderson

Pântea

et al. 2021

Hepatol Commun

Self Cite

View full text Add to dashboard Cite

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).

show abstract

“…In the latest study of TDF, pegIFN and REP 2139 or REP 2165, 95% of participants experienced transaminase flares (ALT and AST) as well as GGT flares, all of which were host-mediated [ 153 ]. Recent analysis of the effects of these high rates of flares on therapeutic outcomes in this latest study indicated that transaminase flares occurring during HBsAg clearance were associated with partial or functional cure, while transaminase flares occurring in the presence of HBsAg were associated with viral rebound after removal of therapy [ 154 ]. In cases of transaminase flares with HBsAg loss, HBsAg-specific exhaustion is absent, suggesting that these transaminase flares are associated with removal of all HBsAg reactive hepatocytes, those with active cccDNA or with integrated HBV DNA ( Figure 4 D).…”

Section: Transaminase Flares During Therapymentioning

confidence: 99%

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure

Vaillant¹

2021

Viruses

Self Cite

View full text Add to dashboard Cite

While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.

show abstract

Benefit of transaminase elevations in establishing functional cure of HBV infection during nap‐based combination therapy

Abstract: Treatment of HBV infection with nucleic acid polymers and pegIFN is accompanied by transaminase elevations in 95% of participants. HBV viral rebound, partial cure (HBV DNA < 2000 IU/mL, normal ALT) or functional cure (HBV DNA target not detected, HBsAg Show more

Cited by 14 publications

References 33 publications

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

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

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

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure

Contact Info

Product

Resources

About