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

被引:16
作者
Bazinet, Michel [1 ]
Anderson, Mark [2 ]
Pintea, Victor [3 ]
Placinta, Gheorghe [3 ]
Moscalu, Iurie [4 ]
Cebotarescu, Valentin [3 ]
Cojuhari, Lilia [3 ]
Jimbei, Pavlina [5 ]
Iarovoi, Liviu [3 ]
Smesnoi, Valentina [5 ]
Musteata, Tatina [5 ]
Jucov, Alina [3 ,4 ]
Dittmer, Ulf [6 ]
Gersch, Jeff [2 ]
Holzmayer, Vera [2 ]
Kuhns, Mary [2 ]
Cloherty, Gavin [2 ]
Valliant, Andrew [1 ]
机构
[1] Replicor Inc, 6100 Royalmt Ave, Montreal, PQ H4P 2R2, Canada
[2] Abbott Diagnost, Abbott Pk, IL USA
[3] Nicolae Testemicanu State Univ Med & Pharm, Dept Infect Dis, Kishinev, Moldova
[4] Republican Clin Hosp, ARENSIA Exploratory Med, Kishinev, Moldova
[5] Toma Ciorba Infect Clin Hosp, Kishinev, Moldova
[6] Univ Duisburg Essen, Inst Virol, Essen, Germany
关键词
HEPATITIS-B-VIRUS; PEGYLATED INTERFERON ALPHA-2A; CLOSED CIRCULAR DNA; SURFACE-ANTIGEN; REP; 2139; EFFICACY; ANALOGS; SAFETY; NAIVE;
D O I
10.1002/hep4.1767
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:1873 / 1887
页数:15
相关论文
共 50 条
[1]   Safety and Efficacy of Nucleic Acid Polymers in Monotherapy and Combined with Immunotherapy in Treatment-Naive Bangladeshi Patients with HBeAg plus Chronic Hepatitis B Infection [J].
Al-Mahtab, Mamun ;
Bazinet, Michel ;
Vaillant, Andrew .
PLOS ONE, 2016, 11 (06)
[2]  
Anderson Ryan T, 2021, Clin Gastroenterol Hepatol, V19, P463, DOI 10.1016/j.cgh.2020.05.041
[3]   Multiple Hepatitis B Virus (HBV) Quasispecies and Immune-Escape Mutations Are Present in HBV Surface Antigen and Reverse Transcriptase of Patients With Acute Hepatitis B [J].
Aragri, Marianna ;
Alteri, Claudia ;
Battisti, Arianna ;
Di Carlo, Domenico ;
Minichini, Carmine ;
Sagnelli, Caterina ;
Bellocchi, Maria Concetta ;
Pisaturo, Maria Antonietta ;
Starace, Mario ;
Armenia, Daniele ;
Carioti, Luca ;
Pollicita, Michela ;
Salpini, Romina ;
Sagnelli, Evangelista ;
Perno, Carlo Federico ;
Coppola, Nicola ;
Svicher, Valentina .
JOURNAL OF INFECTIOUS DISEASES, 2016, 213 (12) :1897-1905
[4]   Benefit of transaminase elevations in establishing functional cure of HBV infection during nap-based combination therapy [J].
Bazinet, Michel ;
Pantea, Victor ;
Placinta, Gheorghe ;
Moscalu, Iurie ;
Cebotarescu, Valentin ;
Cojuhari, Lilia ;
Jimbei, Pavlina ;
Iarovoi, Liviu ;
Smesnoi, Valentina ;
Musteata, Tatiana ;
Jucov, Alina ;
Dittmer, Ulf ;
Krawczyk, Adalbert ;
Vaillant, Andrew .
JOURNAL OF VIRAL HEPATITIS, 2021, 28 (05) :817-825
[5]   Persistent Control of Hepatitis B Virus and Hepatitis Delta Virus Infection Following REP 2139-Ca and Pegylated Interferon Therapy in Chronic Hepatitis B Virus/Hepatitis Delta Virus Coinfection [J].
Bazinet, Michel ;
Pantea, Victor ;
Cebotarescu, Valentin ;
Cojuhari, Lilia ;
Jimbei, Pavlina ;
Anderson, Mark ;
Gersch, Jeff ;
Holzmayer, Vera ;
Elsner, Carina ;
Krawczyk, Adalbert ;
Kuhns, Mary C. ;
Cloherty, Gavin ;
Dittmer, Ulf ;
Vaillant, Andrew .
HEPATOLOGY COMMUNICATIONS, 2021, 5 (02) :189-202
[6]   Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy [J].
Bazinet, Michel ;
Pantea, Victor ;
Placinta, Gheorghe ;
Moscalu, Iurie ;
Cebotarescu, Valentin ;
Cojuhari, Lilia ;
Jimbei, Pavlina ;
Iarovoi, Liviu ;
Smesnoi, Valentina ;
Musteata, Tatiana ;
Jucov, Alina ;
Dittmer, Ulf ;
Krawczyk, Adalbert ;
Vaillant, Andrew .
GASTROENTEROLOGY, 2020, 158 (08) :2180-2194
[7]   Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial [J].
Bazinet, Michel ;
Pantea, Victor ;
Cebotarescu, Valentin ;
Cojuhari, Lilia ;
Jimbei, Pavlina ;
Albrecht, Jeffrey ;
Schmid, Peter ;
Le Gal, Frederic ;
Gordien, Emmanuel ;
Krawczyk, Adalbert ;
Mijocevic, Hrvoje ;
Karimzadeh, Hadi ;
Roggendorf, Michael ;
Vaillant, Andrew .
LANCET GASTROENTEROLOGY & HEPATOLOGY, 2017, 2 (12) :877-889
[8]   Review of Hepatitis B Therapeutics [J].
Bhattacharya, Debika ;
Thio, Chloe L. .
CLINICAL INFECTIOUS DISEASES, 2010, 51 (10) :1201-1208
[9]   Inhibition of HBsAg secretion by nucleic acid polymers in HepG2.2.15 cells [J].
Blanchet, Matthieu ;
Sinnathamby, Vigigah ;
Vaillant, Andrew ;
Labonte, Patrick .
ANTIVIRAL RESEARCH, 2019, 164 :97-105
[10]   Characterization of the antiviral effects of REP 2139 on the HBV lifecycle in vitro [J].
Boulon, Richard ;
Blanchet, Matthieu ;
Lemasson, Matthieu ;
Vaillant, Andrew ;
Labonte, Patrick .
ANTIVIRAL RESEARCH, 2020, 183