Hepatitis B core-related antigen dynamics and risk of subsequent clinical relapses after nucleos(t)ide analog cessation
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Background/Aims: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). Methods: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. Results: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5–40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7–67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1–62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12–2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21–0.81). Conclusions: Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.
Abstract
Background/Aims: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). Methods: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. Results: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5–40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7–67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1–62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12–2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21–0.81). Conclusions: Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.
참고문헌 (30)
- Chang TT, "Longterm entecavir therapy results in the reversal of fibrosis", cirrhosis and continued histological improvement in patients with chronic hepatitis B, 2010, pp.52, 886~893
- Chiang CJ, "Significant reduction in end-stage liver diseases burden through the national viral hepatitis therapy program in Taiwan", Hepatology, 61, pp.1154~1162 (2015)
- Wu CY, "Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B : a nationwide cohort study", Gastroenterology, 147, pp.143~151 (2014)
- Werle-Lapostolle B, "Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy", Gastroenterology, 126, pp.1750~1758 (2004)
- Chevaliez S, "Longterm hepatitis B surface antigen(HBsAg)kinetics during nucleoside", nucleotide analogue therapy : finite treatment duration unlikely, 2013, pp.58, 676~683
- Seto WK, "Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B : a multicentre prospective study", Gut, 64, pp.667~672 (2015)
- Hsu YC, "Severe acute exacerbation after cessation of nucleos(t)ide analog for chronic hepatitis B : A real-world study of routine practice", Clin Gastroenterol Hepatol, 20, pp.1413~1415 (2022)
- Berg T, "Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients-FINITE study", J Hepatol, 67, pp.918~924 (2017)
- Jeng WJ, "Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B", Hepatology, 68, pp.425~434 (2018)
- Rinker F, "Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B", J Hepatol, 69, pp.584~593 (2018)
- Rivino L, "Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation", J Clin Invest, 128, pp.668~681 (2018)
- 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)
- Wong DK, "Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA", Liver Int, 37, pp.995~1001 (2017)
- Chen EQ, "Serum hepatitis B core-related antigen is a satisfactory surrogate marker of intrahepatic covalently closed circular DNA in chronic hepatitis B", Sci Rep, 7, pp.173~ (2017)
- 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)
- Inoue T, "The role of hepatitis B core-related antigen", Genes(Basel), 10, pp.357~ (2019)
- Shinkai N, "Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection", Hepatol Res, 36, pp.272~276 (2006)
- Matsumoto A, "Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B", Hepatol Res, 42, pp.139~149 (2012)
- Hsu YC, "Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk", Aliment Pharmacol Ther, 49, pp.107~115 (2019)
- Hsu YC, "Association between serum level of hepatitis B surface antigen at end of entecavir therapy and risk of relapse in E antigen-negative patients", Clin Gastroenterol Hepatol, 14, pp.1490~1498 (2016)
- Sarin SK, "Asian-Pacific clinical practice guidelines on the management of hepatitis B : a 2015 update", Hepatol Int, 10, pp.1~98 (2016)
- Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology, "JSH Guidelines for the management of hepatitis B virus infection", Hepatol Res, 44(Suppl S1), pp.1~58 (2014)
- Sonneveld MJ, "Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels : A multicenter study(CREATE)", Clin Gastroenterol Hepatol, 20, pp.e784~e793 (2022)
- Fan R, "Combining hepatitis B virus RNA and hepatitis B core-related antigen : Guidance for safely stopping nucleos(t)ide analogues in hepatitis B e antigen-positive patients with chronic hepatitis B", J Infect Dis, 222, pp.611~618 (2020)
- Kuo YH, "Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation", Hepatol Int, 15, pp.301~309 (2021)
- Chien NH, "Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy", BMC Gastroenterol, 17, pp.154~ (2017)
- Kao JH, "APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients", Hepatol Int, 15, pp.833~851 (2021)
- Su TH, "Distinct relapse rates and risk predictors after discontinuing tenofovir and entecavir therapy", J Infect Dis, 217, pp.1193~1201 (2018)
- Jaroenlapnopparat A, "Novel viral markers and the prediction of off-treatment relapse in chronic hepatitis B patients : A systematic review", J Gastroenterol Hepatol, 36, pp.2349~2362 (2021)
- Kao JH, "Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B", Gastroenterology, 118, pp.554~559 (2000)