This is an author version of the contribution published on:
Questa è la versione dell’autore dell’opera:
[Minerva Gastroenterologica e Dietologica, 62 (3), 2017, DOI:
10.23736/S1121-421X.17.02378-9I]
ovvero [Gian Paolo Caviglia, Antonina Smedile, 63, Edizioni Minerva Medica, 2017,
pagg.169-171]
The definitive version is available at:
La versione definitiva è disponibile alla URL:
Hepatitis B core-related antigen: a novel biomarker for chronic hepatitis
B treatment
Gian Paolo CAVIGLIA1,*, Antonina SMEDILE1,2
1Department of Medical Sciences, University of Turin, Turin, Italy
2Department of Gastroenterology and Hepatology, Città della Salute e della Scienza – Molinette
Hospital, Turin, Italy
*Corresponding author: Gian Paolo Caviglia, Department of Medical Sciences, University of Turin, Turin 10100, Italy. E-mail: caviglia.giampi@libero.it
Conflict of interest: None
The introduction of novel potent nucleos(t)ide analogues (NAs) with high genetic barrier to resistance and the implementation of several reliable serological and molecular biomarkers allowed remarkable advances in the management of chronic hepatitis B virus (HBV) infected patients.1
Principal biomarkers for treatment monitoring include hepatitis B e antigen (HBeAg) for
seroconversion of HBeAg-positive patients, alanine-aminotransferase (ALT) for biochemical response and serum HBV DNA for virological response (Table I). Hepatitis B surface antigen (HBsAg)
quantitation became another meaningful marker to predict HBsAg loss and seroconversion to anti-HBs.2 Novel biomarkers such as microRNA and other epigenetic factors have been investigated in
order to provide clinicians novel tools for optimal chronic hepatitis B (CHB) patients management.3
However, results are conflicting and far from a potential use in clinical practice.
HBcrAg assay. Beside conventional serological markers for hepatitis B, a novel 22 kDa
precore/core protein (p22cr) that sharesan identical 149 long amino-acid sequence with HBeAg and hepatitis B core antigen (HBcAg), has been described as the main capsid protein in viral DNA-negative Dane particles.4 Recently, a fully automated chemiluminescence enzyme immunoassay (CLEIA) has
been developed for the simultaneous quantitation of HBeAg, HBcAg and p22cr, namely hepatitis B core-related antigen (HBcrAg) assay.5
HBcrAg and CHB infection phases. The different phases of CHB infection can be distinguished
according to HBcrAg serum levels.6 In a large European cohort predominantly infected with HBV
genotypes A and D, higher HBcrAg levels were found in immune tolerance and immune clearance phases (8.41 [7.42-9.61] vs. 8.11 [4.57-10.34] Log U/mL; p=0.002), whereas significantly lower levels were observed in HBeAg-negative CHB (4.82 [2.00-7.73] Log U/mL) and in inactive HBV carriers (2.00 [2.00-5.35] Log U/mL).7 Moreover, several studies pointed out a moderate correlation between
HBcrAg and HBsAg (from r=0.199 to r=0.765) and a good correlation between HBcrAg and HBV DNA (from r=0.498 to r=0.854), both in HBeAg-positive (r=0.765) and -negative patients (r=0.635).5-8
HBcrAg and HBV covalently closed circular DNA. Measurement of HBV covalently closed
circular DNA (cccDNA) holds important clinical implications but it is mainly limited by liver biopsy availability and the lack of sensitive standardized PCR methods. Recently, a significant correlation between HBcrAg and intrahepatic cccDNA was observed (from r=0.62 to r=0.70).9-11 HBcrAg and
cccDNA levels showed similar dynamics during pre- and post-transplantation in patients that underwent liver transplant for HBV-related liver disease.10 In addition, a large scale study including
305 liver biopsies and corresponding serum samples collected from 138 NAs-treated patients showed a median HBcrAg reduction at ≥6 years of therapy comparable to the magnitude of cccDNA decay.11
Indeed, due to its correlation with cccDNA levels, HBcrAg quantitation has been proposed as a useful tool for monitoring intrahepatic HBV status.
HBcrAg and NAs therapy. Finally, evidence from studies involving Asian population mainly infected with HBV genotypes B and C, suggests that HBcrAg could be a potential marker for NAs therapy cessation.12,13 Low HBcrAg levels were associated with favorable entecavir treatment outcome,
response to NAs/interferon-α sequential therapy and with lower risk of hepatitis reactivation following discontinuation of lamivudine in CHB patients or immunosuppressive therapy in occult HBV
carriers.14-16 Guidelines for avoiding risks resulting from discontinuation of NAs have been proposed
and incorporated in the official Japan Society of Hepatology (JSH) guidelines for the management of HBV infection.17 Such recommendations are based on a score that includes HBsAg and HBcrAg levels
for NAs therapy cessation in CHB patients with at least two years of NAs administration, undetectable serum HBV DNA and negative serum HBeAg.17 Accordingly, patients with HBsAg load <1.9 Log
IU/mL and HBcrAg <3.0 Log U/mL have a low risk of relapse (predicted success rate 80-90%) whereas patients with HBsAg >2.9 Log IU/mL and HBcrAg >4.0 Log U/mL must continue treatment (predicted success rate 10-20%).17Previously, studying a longitudinal cohort of NAs treated CHB
reaching undetectable values between months 6 and 12 (<2 Log U/mL) whereas another group
maintained sustained HBcrAg values at last follow up (4.4±0.6 Log U/mL at month 36) irrespectively from HBV DNA and HBsAg kinetics.5 According to JSH guidelines for NAs therapy cessation, all
HBcrAg rapid decliner patients were classified into the moderate risk group (relapse risk ≈50%), while patients of month-36 HBcrAg-positive group were classified into the high risk of relapse group
(p=0.0005),5 suggesting a potential clinical role for HBcrAg kinetic also in CHB genotype D patients
undergoing NAs treatment.
To date, the major goal in CHB treatment is to prevent disease progression suppressing viral replication and maintaining a virological remission. The final endpoint is HBsAg loss and eventually seroconversion to anti-HBs (“functional cure”). On the other hand, novel antiviral drugs for definitive cccDNA elimination are under development in order to obtain a “complete cure”, thus ensuring protection from the risk of relapse following therapy withdrawal or from viral reactivation in case of immunosuppression. In this scenario, HBcrAg may represent both a non-invasive approach to
investigate and monitor intrahepatic virological status and a useful biomarker for safe discontinuation of NAs therapy in non-cirrhotic patients chronically infected with HBV of different genotypes.
References
1. Caviglia GP, Abate ML, Pellicano R, Smedile A.Chronic hepatitis B therapy: available drugs and treatment guidelines. Minerva Gastroenterol Dietol 2015;61:61-70.
2. Burdino E, Ruggiero T, Proietti A, Milia MG, Olivero A, Caviglia GP, et al. Quantification of hepatitis B surface antigen with the novel DiaSorin LIAISON XL Murex HBsAg Quant: correlation with the ARCHITECT quantitative assays. J Clin Virol 2014;60:341-6.
3. Petrini E, Caviglia GP, Abate ML, Fagoonee S, Smedile A, Pellicano R. MicroRNAs in HBV-related hepatocellular carcinoma: functions and potential clinical applications. Panminerva Med 2015;57:201-9.
4. Kimura T, Ohno N, Terada N, Rokuhara A, Matsumoto A, Yagi S, et al.Hepatitis B virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domain.J Biol Chem 2005;280:21713-9.
5. Caviglia GP, Abate ML, Noviello D,Olivero A, Rosso C, Troshina G, et al. Hepatitis B core-related antigen kinetics in chronic hepatitis B virus genotype D-infected patients treated with nucleos(t)ide analogues or pegylated-interferon-α. Hepatol Res 2016; in press.
6. Seto WK, Wong DK, Fung J, Huang FY, Liu KS, Lai CL, et al. Linearized hepatitis B surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B. Clin Microbiol Infect 2014;20:1173-80.
7. Maasoumy B, Wiegand SB, Jaroszewicz J, Bremer B, Lehmann P, Deterding K, et al. Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. Clin Microbiol Infect 2015;21:606.e1-10.
8. Zhang ZQ, Lu W, Wang YB, et al. Measurement of the hepatitis B core-related antigen is valuable for predicting the pathological status of liver tissues in chronic hepatitis B patients. J Virol Methods 2016; 235: 92-98.
9. Suzuki F, Miyakoshi H, Kobayashi M, Kumada H. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol 2009;81:27-33.
10. Matsuzaki T, Tatsuki I, Otani M, Akiyama M, Ozawa E, Miuma S, et al. Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation. J Gastroenterol Hepatol 2013;28:1217-22.
11. Wong DKH, Seto Wk, Cheung CK, Chong CK, Huang FY, et al. Hepatitis B virus core-related antigen as asurrogate marker for covalently closed circular DNA. Liver Int 2016; in press. 12. Matsumoto A, Yatsuhashi H, Nagaoka S,Suzuki Y, Hosaka T, Tsuge M, et al. Factors
associated with the effect of interferon-α sequential therapy in order to discontinue
nucleoside/nucleotide analog treatment in patients with chronic hepatitis B. Hepatol Res 2015; 45:1195-202.
13. Matsumoto A, Tanaka E, Minami M, Okanoue T, Yatsuhashi H, Nagaoka S, et al. Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy. Hepatol Res 2007;37:661-6.
14. Tanaka E, Matsumoto A, Yoshizawa K, Maki N. Hepatitis B core-related antigen assay is useful for monitoring the antiviral effects of nucleoside analogue therapy. Interviroloy 2008;54:S3-6.
15. Okuhara S, Umemura T, Joshita S, Shibata S, Kimura T, Morita S, et al. Serum levels of interleukin-22 and hepatitis B core-related antigen are associated with treatment response to entecavir therapy in chronic hepatitis B. Hepatol Res 2014;44:E172-80.
16. Seto WK, Wong DH, Chan TY, Hwang YY, Fung J, et al. Association of hepatitis B core-related antigen with hepatitis B virus reactivation in occult viral carriers undergoing high-risk immunosuppressive therapy. Am J Gastroenterol 2016;111:1788-95.
17. Drafting Committee for Hepatitis Management Guidelines and the Japan Society of
Hepatology.JSH Guidelines for the Management of Hepatitis B Virus Infection. Hepatol Res 2014;44:S1-58.
