The advent of new treatments of hepatitis C virus (HCV) infection—direct-acting antivirals—is a therapeutic revolution that enables eradication of the virus in over 90% of patients. However, despite this viral control, HCV infection induces various hepatic alterations favorable to its infectious cycle. HCV is an exemplary model of manipulation of cellular metabolism, and elucidation of the mechanisms involved would clarify disease progression.
Viral control in patients infected by HBV is another research priority. In its HBV Cure program, the ANRS is seeking to identify new therapeutic targets, notably to block HBV cccDNA, which is responsible for viral persistence.
Hepatitis C virus hijacks some lipid metabolism pathways to ensure its own replication. The metabolic alterations induced by chronic HCV infection can lead to a metabolic syndrome specific to hepatitis C which, in the long term, is associated with perturbations of hepatic functions.
HCV seems to have evolved this strategy to optimize its infectious cycle, but these metabolic alterations induce hepatic inflammation and oxidative stress and so can lead to hepatic fibrosis and hepatocellular carcinoma.
The research supported by the ANRS is intended to analyze the mechanisms underlying HCV-induced alteration of lipid metabolism so as to clarify disease progression.
Hepatocellular carcinoma is the most frequent (90%) of primary liver cancers. It usually occurs in a setting of chronic liver disease at the stage of cirrhosis, has a high 5-year mortality, and is the main life-threatening complication associated with cirrhosis in HCV-infected patients. Direct-acting antivirals can eliminate HCV in infected patients, but the risk of cancers such as hepatocellular carcinoma remains.
If we are to prevent hepatocellular carcinoma, it is essential to understand how it develops and is induced by HCV.
Direct-acting antivirals eradicate the hepatitis C virus in 90% of cases. However, they are expensive and access to them is difficult among the most vulnerable populations. In addition, reinfection remains possible. Also, many people infected by the hepatitis C virus are unaware of this, as the infection can persist without symptoms. This silent epidemic increases the risk of transmission of the virus.
A vaccine is therefore an essential and complementary tool in protecting against and preventing HCV infection.
The aim of ANRS research is to identify new therapeutic targets and new antiviral drugs so as to obtain a functional cure of hepatitis B. Research efforts are focused on viral persistence.
1) Define the molecular mechanisms responsible for the formation of cccDNA, the viral mini-chromosome, its homeostasis, and its half-life. Determine whether or not genetic or epigenetic approaches can eliminate part of the pool of cccDNA or render it transcriptionally silent.
2) Develop immunological approaches to eliminate HBV-infected cells selectively, through stimulation of B and T cells specific to HBV infection, inhibition of negative control mechanisms of T cell function, redirection of T cells to infected hepatocytes, and restoration of innate immunity.
It is important to complement these basic research efforts with translational and clinical research in hepatitis B, notably to:
1) Standardize methods for analysis of cccDNA (quantification, epigenetic and transcriptional status).
2) Develop and validate clinical immunology tools and monitor restoration of immunity in patients treated for chronic hepatitis B.
3) Identify and validate new biomarkers that predict, more reliably than HBs antigen, the control of hepatitis B (virological, serological, or molecular markers, cellular or genetic markers of the host).
4) Understand the consequences of the integration of the viral genome in the process of pathogenesis and liver carcinogenesis better.
HBV-HDV co-infection is associated with increased hepatic pathogenesis. Most patients fail to respond to interferon-based treatments. It is therefore important to identify and validate therapeutic targets of either the viral replication cycle or the immune response. Researchers are striving to shed light on the mechanisms of replication of the hepatitis D virus and its pathogenesis in experimental models and in a clinical setting.