1Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. firstname.lastname@example.org.
2Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, Laboratoire d'Excellence HepSYS, Service d'Hépato-gastroénterologie, Pôle Hépato-digestif, IHU Strasbourg, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France.
3Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
4New Zealand Liver Transplant Unit, Auckland City Hospital, University of Auckland, Auckland, New Zealand.
5Epigenetics, Microenvironment and Liver Cancer Laboratory of INSERM Unit 1052, Institute of Hepatology, Hepatology Department, Hospices Civils de Lyon, University of Lyon, Lyon, France.
6Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
7Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
8Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
9Viral Hepatitis Research Laboratory of INSERM Unit 1052, Institute of Hepatology, Hepatology Department, Hospices Civils de Lyon, University of Lyon, Lyon, France.
Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.