Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation

BMC Gastroenterology - Tập 23 - Trang 1-11 - 2023
Yandi Xie1, Minghui Li2, Xiaojuan Ou3, Sujun Zheng4, Yinjie Gao5, Xiaoyuan Xu6, Ying Yang7, Anlin Ma8, Jia Li9, Yuemin Nan10, Huanwei Zheng11, Juan Liu12, Lai Wei13, Bo Feng1
1Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Peking University Hepatology Institute, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
2Department of Hepatology Division, Beijing Ditan Hospital, Capital Medical University, Beijing, China
3Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
4Complicated Liver Diseases and Artificial Liver Treatment and Training Center, Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment and Research, Beijing Youan Hospital, Capital Medical University, Beijing, China
5Department of Infectious Diseases, The Fifth Medical Center, General Hospital of PLA, Beijing, China
6Department of Infectious Diseases, Peking University First Hospital, Beijing, China
7Department of Infectious Diseases, The Second Hospital of Xingtai, Xingtai, China
8Department of Infectious Disease, Friendship Hospital, Beijing, China
9Department of Liver Disease, Tianjin Second People’s Hospital, Tianjin, China
10Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
11Department of Liver Disease, Shijiazhuang Fifth Hospital, Shijiazhuang, China
12Research Center for Technologies in Nucleic Acid-Based Diagnostics, Changsha, China
13Department of Hepatopancreatobiliary Disease, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China

Tóm tắt

Since hepatitis B surface antigen (HBsAg) loss is rarely achieved with nucleos(t)ide analog (NA) treatment, most patients require life-long NA treatment. Previous studies have shown that some patients remain virologically responsive even after NA cessation. However, there is still controversy surrounding whether NA discontinuation increases the HBsAg loss rate. Therefore, this study aimed to assess the cumulative rate of HBsAg loss and identify the predictors of HBsAg loss after NA discontinuation. This multicenter prospective study included HBV e antigen (HBeAg)-positive patients without cirrhosis from 12 hospitals in China who met the inclusion criteria. The enrolled patients stopped NA and were followed up with clinical and laboratory assessments every 3 months for 24 months after NA cessation or until clinical relapse (CR) occurred. Overall, 158 patients were classified into two groups. Group A included patients with HBsAg positivity at NA cessation (n = 139), and Group B included patients with HBsAg negativity at NA cessation (n = 19). In Group A, the 12-month and 24-month cumulative rates of HBsAg loss were4.3%and 9.4%, respectively. End of treatment (EOT) HBsAg (hazard ratio (HR) = 0.152, P < 0.001) and EOT hepatitis B core-related antigen (HBcrAg) (HR = 0.257, P = 0.001) were associated with HBsAg loss. The areas under the receiver operating characteristic curves for EOT HBsAg and HBcrAg levels were 0.952 (P < 0.001) and 0.765 (P < 0.001), respectively. Patients with EOT HBsAg ≤ 135 IU/mL (59.2% vs. 1.3%, P < 0.001) or HBcrAg ≤ 3.6 logU/mL (17% vs. 5.4%, P = 0.027) had a higher 24-month cumulative HBsAg loss rate. In Group B, none of the patients experienced virological relapse after NA cessation. Only 1 (5.3%) patient had HBsAg reversion. EOT HBsAg ≤ 135 IU/mL or HBcrAg ≤ 3.6 logU/mL can be used to identify patients with a higher likelihood of HBsAg loss after NA cessation. Patients with HBsAg negativity after NA cessation have favorable clinical outcomes, and HBsAg loss was durable in most cases.

Tài liệu tham khảo

Jeng WJ, Chen YC, Chien RN, et al. 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. 2018;68:425–34. Marcellin P, Wong DK, Sievert W, et al. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int. 2019;39:1868–75. Van Hees S, Chi H, Hansen B, et al. Sustained off-treatment viral control is associated with high hepatitis B surface antigen seroclearance rates in caucasian patients with nucleos(t)ide analogue-induced HBeAg seroconversion. J Viral Hepatitis. 2019;26:766–9. Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, et al. DARING-B: discontinuation of effective entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B. Antivir Ther. 2018;23:677–85. Hadziyannis SJ, Sevastianos V, Rapti I, et al. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology. 2012;143:629–36. Papatheodoridi M, Hadziyannis E, Berby F, et al. Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg-negative chronic hepatitis B. J Viral Hepat. 2020;27:118–26. Ha M, Zhang G, Diao S, et al. A prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients with stringent cessation criteria for adefovir. Arch Virol. 2012;157:285–90. Chen CH, Hung CH, Hu TH, et al. Association between level of hepatitis B surface antigen and relapse after entecavir therapy for chronic hepatitis B virus infection. Clin Gastroenterol Hepatol. 2015;13:1984–92. Carey I, Gersch J, Wang B, et al. Pregenomic HBV RNA and hepatitis B core-related antigen predict outcomes in hepatitis B e antigen-negative chronic hepatitis B patients suppressed on nucleos(t)ide analogue therapy. Hepatology. 2020;72:42–57. Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014;63:1325–32. Yip TC, Wong GL, Wong VW, et al. Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients. J Hepatol. 2018;68:63–72. Chi H, Wong D, Peng J, et al. Durability of response after hepatitis B surface antigen seroclearance during nucleos(t)ide analogue treatment in a multiethnic cohort of chronic hepatitis B patients: results after treatment cessation. Clin Infect Dis. 2017;65:680–3. Xie YD, Li MH, Ou XJ, et al. HBeAg-positive patients with HBsAg < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation. J Gastroenterol. 2021;56:856–67. Hou JL, Lai W. [The guideline of prevention and treatment for chronic hepatitis B: a 2015 update]. Zhonghua Gan Zang Bing Za Zhi. 2015;23:888–905. van Bömmel F, Stein K, Heyne R, et al. A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B. J Hepatol. 2023;78:926–36. Chen CH, Lu SN, Hung CH, et al. The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment. J Hepatol. 2014;61:515–22. Chan HL, Wong GL, Chim AM, et al. Prediction of off-treatment response to lamivudine by serum hepatitis B surface antigen quantification in hepatitis B e antigen-negative patients. Antivir Ther. 2011;16:1249–57. Chen H, Ding X, Liao G, et al. Hepatitis B surface antigen kinetics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B. J Viral Hepat. 2021;28:1121–9. Sonneveld MJ, Chiu SM, Park JY, et al. Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels. J Hepatol. 2022;76:1042–50. Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143(4):963–73. Rinker F, Zimmer CL, Höner Zu Siederdissen C, Manns MP, Kraft ARM, Wedemeyer H, et al. Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Hepatol. 2018;69:584–93. Berg T, Lampertico P. The times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy. J Hepatol. 2021;75:474–80. Manolakopoulos S, Kranidioti H, Kourikou A, et al. Long-term clinical outcome of HBeAg-negative chronic hepatitis B patients who discontinued nucleos(t)ide analogues. Liver Int. 2021;41:48–57. Liu J, Li T, Zhang L, et al. The role of hepatitis B surface antigen in nucleos(t)ide analogues cessation among asian patients with chronic hepatitis B: a systematic review. Hepatology. 2019;70:1045–55. Chen CH, Hung CH, Wang JH, et al. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect. 2018;24:997–1003. Seto WK, Cheung KS, Wong DK, et al. Hepatitis B surface antigen seroclearance during nucleoside analogue therapy: surface antigen kinetics, outcomes, and durability. J Gastroenterol. 2016;51:487–95. Fan R, Peng J, Xie Q, Tan D, Xu M, Niu J, et al. 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. 2020;222:611–8. Seto WK, Wong DK, Fung J, 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. Tseng TN, Hu TH, Wang JH, et al. Incidence and factors associated with HBV relapse after cessation of entecavir or tenofovir in patients with HBsAg below 100 IU/mL. Clin Gastroenterol Hepatol. 2020;18:2803–12. Testoni B, Lebossé F, Scholtes C, et al. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J Hepatol. 2019;70:615–25. Hsu Y, Nguyen MH, Mo L, et al. Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk. Aliment Pharm Ther. 2019;49:107–15. Seto WK, Liu KS, Mak LY, et al. Role of serum HBV RNA and hepatitis B surface antigen levels in identifying asian patients with chronic hepatitis B suitable for entecavir cessation. Gut. 2021;70:775–83. Wang J, Shen T, Huang X, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol. 2016;65:700–10. Suárez E, Buti M, Rodríguez M, et al. Hepatitis B surface antigen loss after discontinuing nucleos(t)ide analogue for treatment of chronic hepatitis B patients is persistent in White patients. Eur J Gastroenterol Hepatol. 2019;31:267–71. Chu CM, Liaw YF. Prevalence of and risk factors for hepatitis B viremia after spontaneous hepatitis B surface antigen seroclearance in hepatitis B carriers. Clin Infect Dis. 2012;54:88–90. Wong RJ, Nguyen MT, Trinh HN, et al. Hepatitis B surface antigen loss and sustained viral suppression in asian chronic hepatitis B patients: a community-based real-world study. J Viral Hepat. 2017;24:1089–97. Pfefferkorn M, Schott T, Böhmet S, et al. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B. J Hepatol. 2021;74:283–92.
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