Author information

¹Toronto Centre for Liver Disease, University Health Network, Canada.

²The Toronto Viral Hepatitis Care Network (VIRCAN), Canada.

³Institute of Medical Science, University of Toronto, Canada.

⁴Department of Epidemiology, Biostatistics, Erasmus Medical Center, Rotterdam, Netherlands.

⁵Institute of Health Policy, Management and Evaluation, University of Toronto, Canada.

⁶Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

⁷Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

⁸Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong SAR, China.

⁹Department of Medicine and State Key Laboratory of Liver Research, School of Clinical Medicine, The University of Hong Kong, Hong Kong, SAR, China.

¹⁰Viral Hepatitis Research Group, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.

¹¹Medical School of National and Kapodistrian University of Athens, Greece.

¹²Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, Netherlands.

¹³Hospital Clinic Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Spain.

¹⁴Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Linkou, Taiwan.

¹⁵Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.

¹⁶Center for Liver Diseases, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.

¹⁷Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; Centre for Individualized Infection Medicine (CiiM), Hannover, Germany.

Abstract

Background: Complete viral suppression with nucleos(t)ide analogues (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among chronic hepatitis B (CHB) patients. Finite therapy yields higher rates of functional cure however, initial HBV DNA and ALT elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation.

Methods: Well-suppressed CHB patients who were HBeAg negative at NA cessation and remained off-treatment without HBsAg loss at 12 months were included (n=945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2x ULN, and an ALT flare as ALT ≥5x ULN.

Results: Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0±1.5 log10 IU/mL, an ALT flare was 15.6% with a median peak ALT x ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months.

Conclusion: Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.