Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2018; 24(17): 1825-1838
Published online May 7, 2018. doi: 10.3748/wjg.v24.i17.1825
Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?
Elia Moreno-Cubero, Robert T Sánchez del Arco, Julia Peña-Asensio, Eduardo Sanz de Villalobos, Joaquín Míquel, Juan Ramón Larrubia
Robert T Sánchez del Arco, Internal Medicine Service, Guadalajara University Hospital, University of Alcalá, Guadalajara 19002, Spain
Julia Peña-Asensio, Department of Biology of Systems, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
Juan Ramón Larrubia, Department of Medicine and Medical Specialties, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
Author contributions: Moreno-Cubero E and Sánchez del Arco RT wrote the manuscript; Peña-Asensio J, Sanz de Villalobos E and Míquel J revised the manuscript for important intellectual content; Larrubia JR designed the manuscript and revised the final version for important intellectual content.
Supported by grants from the “Instituto de Salud Carlos III”, Spain and the “European Regional Development Fund (ERDF), a way of making Europe”, No. PI12/00130 and No. PI15/00074; and from the “Gilead Spain & Instituto de Salud Carlos III”, No. GLD14_00217 and No. GLD16_00014.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Juan Ramón Larrubia, MD, MSc, PhD, Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Guadalajara 19002, Spain.
Telephone: +34-949-209200 Fax: +34-949-909256
Received: April 1, 2018
Peer-review started: April 2, 2018
First decision: April 19, 2018
Revised: April 21, 2018
Accepted: April 23, 2018
Article in press: April 23, 2018
Published online: May 7, 2018

Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host’s immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.

Keywords: CD8, Lamivudine, Nucleos(t)ide analogues, Tenofovir, Chronic hepatitis B, Entecavir, Hepatitis B virus, Treatment cessation

Core tip: Nucleos(t)ide analogue (NA) treatment efficiently suppress hepatitis B virus replication. However, hepatitis B surface antigen loss, the optimal endpoint of NA therapy, is rarely achieved. Thus, a major unmet need in the management of chronic hepatitis B is the definition of earlier and safe treatment stopping points. There is growing clinical evidence that the majority of patients can benefit from this strategy after long-term NA therapy; yet, no criteria that distinguish which cases can safely stop treatment is established. We review here different biomarkers that could serve as a prognostic tool to safely discontinue therapy, focusing on host antiviral immunity.