Lower pretreatment HBV DNA levels are associated with better off-treatment outcomes after nucleo(s)tide analogue withdrawal in patients with HBeAg-negative chronic hepatitis B: A multicentre cohort study

Milan J Sonneveld; Shao-Ming Chiu; Jun Yong Park; Sylvia M Brakenhoff; Apichat Kaewdech; Wai-Kay Seto; Yasuhito Tanaka; Ivana Carey; Margarita Papatheodoridi; Piero Colombatto; Florian van Bömmel; Thomas Berg; Fabien Zoulim; Sang Hoon Ahn; George N Dalekos; Nicole S Erler; Maurizia Brunetto; Heiner Wedemeyer; Markus Cornberg; Man-Fung Yuen; Kosh Agarwal; Andre Boonstra; Maria Buti; Teerha Piratvisuth; George Papatheodoridis; Chien-Hung Chen; Benjamin Maasoumy; CREATE study group

doi:10.1016/j.jhepr.2023.100790

Lower pretreatment HBV DNA levels are associated with better off-treatment outcomes after nucleo(s)tide analogue withdrawal in patients with HBeAg-negative chronic hepatitis B: A multicentre cohort study

JHEP Rep. 2023 May 12;5(8):100790. doi: 10.1016/j.jhepr.2023.100790. eCollection 2023 Aug.

Authors

Milan J Sonneveld¹, Shao-Ming Chiu², Jun Yong Park³, Sylvia M Brakenhoff¹, Apichat Kaewdech⁴, Wai-Kay Seto⁵, Yasuhito Tanaka⁶, Ivana Carey⁷, Margarita Papatheodoridi⁸, Piero Colombatto⁹, Florian van Bömmel¹⁰, Thomas Berg¹⁰, Fabien Zoulim¹¹, Sang Hoon Ahn³, George N Dalekos¹², Nicole S Erler^{13

14}, Maurizia Brunetto⁹, Heiner Wedemeyer¹⁵, Markus Cornberg¹⁵, Man-Fung Yuen⁵, Kosh Agarwal⁷, Andre Boonstra¹, Maria Buti¹⁶, Teerha Piratvisuth⁴, George Papatheodoridis⁸, Chien-Hung Chen², Benjamin Maasoumy¹⁵; CREATE study group

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
² Department of Internal Medicine, Koahsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
³ Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
⁴ Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand.
⁵ Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
⁶ Department of Gastroenterology and Hepatology, Kumamoto University, Kumamoto, Japan.
⁷ Institute of Liver Studies, King's College Hospital, London, UK.
⁸ Department of Gastroenterology, 'Laiko' General Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece.
⁹ Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
¹⁰ Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
¹¹ INSERM Unit 1052, Lyon, France.
¹² Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
¹³ Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
¹⁴ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
¹⁵ Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.
¹⁶ Liver Unit, Hospital Universitari Vall d'Hebron and Ciberehd del Intituto Carlos III de Barcelona, Spain.

Abstract

Background & aims: Pretreatment predictors of finite nucleo(s)tide analogue (NUC) therapy remain elusive. We studied the association between pretreatment HBV DNA levels and outcomes after therapy cessation.

Methods: Patients with chronic hepatitis B who were HBeAg negative at the start of NUC treatment were enrolled from sites in Asia and Europe. We studied the association between pretreatment HBV DNA levels and (1) clinical relapse (defined as HBV DNA >2,000 IU/ml + alanine aminotransferase >2 × the upper limit of normal or retreatment) and (2) HBsAg loss after NUC withdrawal.

Results: We enrolled 757 patients, 88% Asian, 57% treated with entecavir, with a median duration of treatment of 159 (IQR 156-262) weeks. Mean pretreatment HBV DNA levels were 5.70 (SD 1.5) log IU/ml and were low (<20,000 IU/ml) in 150 (20%) and high (>20,000 IU/ml) in 607 (80%). The cumulative risk of clinical relapse at 144 weeks after therapy cessation was 22% among patients with pretreatment HBV DNA levels <20,000 IU/ml vs. 60% among patients with pretreatment HBV DNA levels >20,000 IU/ml, whereas the cumulative probabilities of HBsAg loss were 17.5% vs. 5% (p <0.001). In multivariable analysis, pretreatment HBV DNA levels <20,000 IU/ml were independently associated with a reduced likelihood of clinical relapse (adjusted hazard ratio 0.379, p <0.001) and with an increased chance of HBsAg loss (adjusted hazard ratio 2.872, p <0.001).

Conclusions: Lower pretreatment HBV DNA levels are associated with a lower risk of clinical relapse and a higher chance of HBsAg loss after cessation of NUC therapy, independent of end-of-treatment viral antigen levels. Further studies are needed to confirm these findings in non-Asian populations.

Impact and implications: A subgroup of patients with chronic hepatitis B may not require retreatment after stopping antiviral therapy. In this study, comprising 757 patients with chronic hepatitis B from Europe and Asia, we found that higher viral load before initiation of treatment was a risk factor for relapse after stopping treatment. Patients with a low HBV DNA level before starting antiviral therapy had the lowest risk of relapse, and a high chance of HBsAg loss, after stopping treatment. These findings can help select patients for treatment withdrawal and guide intensity of off-treatment monitoring.

Keywords: Entecavir; HBV DNA; HBcrAg; HBsAg; HBsAg loss; Tenofovir.