Towards a Functional Cure for Hepatitis B Virus: A 2022 Update on New Antiviral Strategies
Elisabetta Degasperi 1 , Maria Paola Anolli 1 , Pietro Lampertico 1 2
Affiliations
Affiliations
1
Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
2
CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.
PMID: 36366502 DOI: 10.3390/v14112404
Abstract
Chronic infection with hepatitis B virus (HBV) represents one of the main causes of the development of cirrhosis and its complications. Treatment with potent third-generation nucleos(t)ide analogues (NUCs) results in >99% HBV DNA undetectability, and prevents fibrosis progression and liver-related complications. However, NUCs are not able to induce the so-called functional cure, which is hepatitis B surface antigen (HBsAg) loss and anti-HBs seroconversion. Consequently, NUC treatment is currently intended as being long-term or lifelong, resulting in the need for clinical monitoring and potentially suffering from compliance issues. Consequently, drug development in HBV has the goal of developing new agents in order to achieve a functional cure for HBV. Currently, the three main strategies include the following: inhibition of viral replication, inhibition of viral antigens, and immune modulation. This review summarizes the most recent updates concerning HBV compounds among these three main classes.
Currently, the most common strategy adopted by ongoing investigational studies
is based on the combination of HBsAg lowering agents (siRNA or ASO) with different
types of immune modulators (TLR-agonists, therapeutic vaccines, or immune checkpoint
inhibitors). The supposed rationale is that lowering the HBsAg burden would facilitate
or restore the capability of the immune system to respond to immune stimulation. For
these reasons, the study designs of many Phase 1 or 2 ongoing trials adopt a sequential
instead of de novo combination, where the immune stimulation is administered some
weeks/months after the siRNA/ASO treatment (always with a backbone NUC). This is
the case of ongoing OSPREY Phase 1 trial (siRNA JNJ-3989 followed by addition of JNJ-
0535 therapeutic vaccine), ASO-001 Phase 2 trial (Bepirovirsen 12 or 24 weeks followed
by chimpanzee adenoviral vector (ChAdOx1-HBV), and a heterologous modified Ankara
boost (MVA-HBV)), and OCTOPUS-1 Phase 2 trial (siRNA JNJ-3989 for 16 weeks followed
by addition of Nivolumab).
[Figure 2 and 3 in the paper are very interesting]