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In spite of the fact that safe and effective vaccines have been available for over 40 years, hepatitis B virus (HBV) remains a major public health problem, as there are 296 million chronically HBV-infected individuals worldwide and 820 000 HBV-related deaths taking place every year. Achieving the goal of HBV cure remains a challenge due to the particularities of the HBV cycle underlying viral persistence. The new understanding of HBV biology and antiviral immune responses has allowed to identify novel drug targets. This has led to a renewed interest in developing new curative strategies and combinations for HBV. In the present review, we aim to summarise the biological and clinical challenges associated with chronic HBV infection. Moreover, we consider the lessons that have been learnt in the past years regarding the preclinical and clinical evaluation of compounds against HBV and how this is driving the field to explore new directions.
In spite of the fact that safe and effective vaccines have been available for over 40 years, hepatitis B virus (HBV) remains a major public health problem, as there are 296 million chronically HBV-infected individuals worldwide and 820 000 HBV-related deaths taking place every year. Achieving the goal of HBV cure remains a challenge due to the particularities of the HBV cycle underlying viral persistence. The new understanding of HBV biology and antiviral immune responses has allowed to identify novel drug targets. This has led to a renewed interest in developing new curative strategies and combinations for HBV. In the present review, we aim to summarise the biological and clinical challenges associated with chronic HBV infection. Moreover, we consider the lessons that have been learnt in the past years regarding the preclinical and clinical evaluation of compounds against HBV and how this is driving the field to explore new directions.
ObjectiveA convenient, reproducible biomarker of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) transcriptional activity is lacking. We measured circulating HBV RNA (cirB-RNA) in untreated and nucleos(t)ide analogues (NUC) treated chronic hepatitis B (CHB) patients to define its correlation with intrahepatic viral markers and HBV core-related antigen (HBcrAg).DesignPaired liver biopsy and serum samples were collected from 122 untreated and 30 NUC-treated CHB patients. We measured cirB-RNA, HBV DNA, hepatitis B surface antigen (HBsAg), HBcrAg and alanine aminotransferase levels. cirB-RNA was quantified using an investigational HBV RNA assay for use on the cobas 6800 system. The test detects a region spanning the HBV canonical polyadenylation site. cccDNA and 3.5 kb RNA in liver tissue were assessed by quantitative PCR and droplet digital PCR.ResultscirB-RNA was detectable in 100% of HBeAg(+) chronic hepatitis (CH), 57% and 14% of HBeAg(−) CH and chronic infection untreated patients and 47% of NUC-treated patients. cirB-RNA undetectability was associated with lower intrahepatic cccDNA transcriptional activity, as well as serum HBcrAg, but no significant differences in HBsAg, in both untreated and treated patients. In untreated HBeAg(−) patients, cirB-RNA correlated with intrahepatic 3.5 kb RNA and cccDNA transcriptional activity, serum HBV DNA and HBcrAg, but not with HBsAg or total cccDNA levels. Combined undetectability of both cirB-RNA and HBcrAg detection in untreated HBeAg(−) patients identified a subgroup with the lowest levels of intrahepatic transcriptionally active cccDNA.ConclusionOur results support the usefulness of quantification of circulating HBV RNA expressed from cccDNA as an indicator of intrahepatic active viral reservoir in both untreated and NUC-treated CHB patients.Trial registration numberNCT02602847.
ObjectiveAchieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment.DesignWe identifiedTLR8-expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN’s indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN’s effect were validated using transcriptomic data from HBV-infected patients.ResultsHepaticTLR8expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg,S100A12) and downregulated genes associated with the KC identity (eg,SPIC). Treatment of hepatocytes with SLGN-CM downregulatedNTCPand impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition.ConclusionOur transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection.
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