New Biomarkers of Chronic Hepatitis B
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Chronic hepatitis B (CHB) infection leads to clinically heterogeneous disease outcomes. Different viral markers are utilized to monitor treatment effects and predict risk of complications in patients with CHB. Hepatitis B core-related antigen (HBcrAg) is a novel serum composite viral protein whose performance has been proven to be superior to that of existing viral markers. It showed good correlation with intrahepatic covalently closed-circular DNA. Its profile differs drastically in patients in different disease phases, and the level declines with antiviral therapies. HBcrAg may be helpful for predicting hepatocellular carcinoma development and hepatitis B virus (HBV) reactivation in immunosuppressed patients. Another emerging measurable serum marker, HBV RNA, exists in the form of pregenomic RNA-containing virions. Its profile differs between patients in different disease phases in a similar manner to that of HBcrAg. HBV RNA is present in serum at lower levels than HBV DNA in treatment-naïve patients by 1–2 logs. In contrast, its level is higher than HBV DNA in patients receiving nucleos(t)ide analogues (NAs). A significant decline in serum RNA was observed in patients receiving novel antiviral therapies, including core protein allosteric modulators and RIG-1/NOD2 agonists. Both HBcrAg and HBV RNA may be helpful for predicting off-therapy sustained virological control in patients who stop long-term NA treatment.
Abstract
Chronic hepatitis B (CHB) infection leads to clinically heterogeneous disease outcomes. Different viral markers are utilized to monitor treatment effects and predict risk of complications in patients with CHB. Hepatitis B core-related antigen (HBcrAg) is a novel serum composite viral protein whose performance has been proven to be superior to that of existing viral markers. It showed good correlation with intrahepatic covalently closed-circular DNA. Its profile differs drastically in patients in different disease phases, and the level declines with antiviral therapies. HBcrAg may be helpful for predicting hepatocellular carcinoma development and hepatitis B virus (HBV) reactivation in immunosuppressed patients. Another emerging measurable serum marker, HBV RNA, exists in the form of pregenomic RNA-containing virions. Its profile differs between patients in different disease phases in a similar manner to that of HBcrAg. HBV RNA is present in serum at lower levels than HBV DNA in treatment-naïve patients by 1–2 logs. In contrast, its level is higher than HBV DNA in patients receiving nucleos(t)ide analogues (NAs). A significant decline in serum RNA was observed in patients receiving novel antiviral therapies, including core protein allosteric modulators and RIG-1/NOD2 agonists. Both HBcrAg and HBV RNA may be helpful for predicting off-therapy sustained virological control in patients who stop long-term NA treatment.
참고문헌 (48)
- Yuen MF, "Hepatitis B virus infection", Nat Rev Dis Primers, 4, pp.18035~ (2018)
- Lai CL, "The natural history and treatment of chronic hepatitis B : a critical evaluation of standard treatment criteria and end points", Ann Intern Med, 147, pp.58~61 (2007)
- European Association for the Study of the Liver, "EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection", J Hepatol, 67, pp.370~398 (2017)
- Zoulim F, "New insight on hepatitis B virus persistence from the study of intrahepatic viral cccDNA", J Hepatol, 42, pp.302~308 (2005)
- Mason AL, "Molecular basis for persistent hepatitis B virus infection in the liver after clearance of serum hepatitis B surface antigen", Hepatology, 27, pp.1736~1742 (1998)
- Yuen MF, "HBsAg seroclearance in chronic hepatitis B in Asian patients : replicative level and risk of hepatocellular carcinoma", Gastroenterology, 135, pp.1192~1199 (2008)
- Fung J, "Long-term outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance", Hepatology, 68, pp.462~472 (2018)
- Kim GA, "HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B : clinical outcomes and durability", Gut, 63, pp.1325~1332 (2014)
- Liu J, "Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance : a community-based follow-up study", Gastroenterology, 139, pp.474~482 (2010)
- Durantel D, "New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus", J Hepatol, 64, pp.S117~S131 (2016)
- Kimura T, "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, 280, pp.21713~21719 (2005)
- Kimura T, "Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load", J Clin Microbiol, 40, pp.439~445 (2002)
- Maasoumy B, "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, 21, pp.606~ (2015)
- Seto WK, "Linearized hepatitis B surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B", Clin Microbiol Infect, 20, pp.1173~1180 (2014)
- Seto WK, "Evidence of serologic activity in chronic hepatitis B after surface antigen (HBsAg) seroclearance documented by conventional HBsAg assay", Hepatol Int, 7, pp.98~105 (2012)
- Rokuhara A, "Hepatitis B virus core and core-related antigen quantitation in Chinese patients with chronic genotype B and C hepatitis B virus infection", J Gastroenterol Hepatol, 20, pp.1726~1730 (2005)
- Rokuhara A, "Clinical evaluation of a new enzyme immunoassay for hepatitis B virus core-related antigen; a marker distinct from viral DNA for monitoring lamivudine treatment", J Viral Hepat, 10, pp.324~330 (2003)
- Wong DK, "Hepatitis B virus core-related antigens as markers for monitoring chronic hepatitis B infection", J Clin Microbiol, 45, pp.3942~3947 (2007)
- Wong DK, "Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA", Liver Int, 37, pp.995~1001 (2017)
- Lam YF, "Seven-year treatment outcome of entecavir in a real-world cohort : effects on clinical parameters, HBsAg and HBcrAg levels", Clin Transl Gastroenterol, 8, pp.e125~ (2017)
- Suzuki F, "Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients", J Med Virol, 81, pp.27~33 (2009)
- Lai CL, "Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B", J Hepatol, 66, pp.275~281 (2017)
- Ma H, "HBcrAg identifies patients failing to achieve HBeAg seroconversion treated with pegylated interferon Alfa-2b", Chin Med J(Engl), 129, pp.2212~2219 (2016)
- Yuen MF, "Differential reductions in viral antigens expressed from CCCDNAVS integrated DNA in treatment naïve HBEAG positive and negative patients with chronic HBV after RNA interference therapy with ARC-520", J Hepatol, 64, pp.S390~S391 (2016)
- Tada T, "HBcrAg predicts hepatocellular carcinoma development : an analysis using time-dependent receiver operating characteristics", J Hepatol, 65, pp.48~56 (2016)
- Cheung KS, "Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy", J Viral Hepat, 24, pp.654~661 (2017)
- Seto WK, "Association of hepatitis B core-related antigen with hepatitis B virus reactivation in occult viral carriers undergoing high-risk immunosuppressive therapy", Am J Gastroenterol, 111, pp.1788~1795 (2016)
- 이한아, "Hepatitis B surface antigen titer is a good indicator of durable viral response after entecavir off-treatment for chronic hepatitis B", Clinical and Molecular Hepatology, 22(3), pp.382~389 (2016), 대한간학회
- Jung KS, "Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients", J Gastroenterol, 51, pp.830~839 (2016)
- Mak LY, "Review article : hepatitis B core-related antigen(HBcrAg) : an emerging marker for chronic hepatitis B virus infection", Aliment Pharmacol Ther, 47, pp.43~54 (2018)
- Gerelsaikhan T, "Hepatitis B virus nucleocapsid envelopment does not occur without genomic DNA synthesis", J Virol, 70, pp.4269~4274 (1996)
- Perlman D, "Duck hepatitis B virus virion secretion requires a double-stranded DNA genome", J Virol, 77, pp.2287~2294 (2003)
- Wang J, "Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound", J Hepatol, 65, pp.700~710 (2016)
- Rokuhara A, "Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy", J Gastroenterol, 41, pp.785~790 (2006)
- Jansen L, "Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa-2a and nucleos(t)ide analogues", J Infect Dis, 213, pp.224~232 (2016)
- Hatakeyama T, "Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine", Hepatology, 45, pp.1179~1186 (2007)
- Kurosaki M, "Serum HBV RNA as a possible marker of HBV replication in the liver during nucleot(s)ide analogue therapy", J Gastroenterol, 48, pp.777~778 (2013)
- Su Q, "Circulating hepatitis B virus nucleic acids in chronic infection : representation of differently polyadenylated viral transcripts during progression to nonreplicative stages", Clin Cancer Res, 7, pp.2005~2015 (2001)
- van Bömmel F, "Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors", Hepatology, 61, pp.66~76 (2015)
- Huang YW, "On-treatment low serum HBV RNA level predicts initial virological response in chronic hepatitis B patients receiving nucleoside analogue therapy", Antivir Ther, 20, pp.369~375 (2015)
- Tsuge M, "Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients", J Gastroenterol, 48, pp.1188~1204 (2013)
- Butler EK, "HBV serum DNA and RNA levels in nucleos(t)ide analogue-treated or untreated patients during chronic and acute infection", Hepatology, 68, pp.2016~2117 (2018)
- Wang J, "Natural history of serum HBV-RNA in chronic HBV infection", J Viral Hepat, 25, pp.1038~1047 (2018)
- Gao Y, "Serum hepatitis B virus DNA, RNA, and HBsAg : which correlated better with intrahepatic covalently closed circular DNA before and after nucleos(t)ide analogue treatment", J Clin Microbiol, 55, pp.2972~2982 (2017)
- Wang J, "Reply to : "Serum HBV pgRNA as a clinical marker for cccDNA activity" : consistent loss of serum HBV RNA might predict the"para-functional cure"of chronic hepatitis B", J Hepatol, 66, pp.462~463 (2017)
- Yuen MF, "NVR3-778, a first-in-class HBV core inhibitor, alone and in combination with Peg-interferon(PegIFN), in treatment-naive HBeAg-positive patients : early reductions in HBV DNA and HBeAg", J Hepatol, 64, pp.S210~ (2016)[DOI]
- Yuen MF, "SB 9200 an oral selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients : results from cohort 1 of the ACHIEVE trial", Hepatology, 66, pp.22~23A (2017)
- Sato S, "The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus", Immunity, 42, pp.123~132 (2015)
