Table of Contents
I. Introduction
A. World Hepatitis Day and its significance
B. Global concern for chronic hepatitis B virus infection
C. Importance of HBV cure research
II. Novel Therapeutic Strategies for HBV Cure
A. Combination of antiviral approaches targeting virus and human cells
B. Pre-clinical studies on mice and their promising results
C. Antiviral therapy goal and combination of peginterferon and nucleotide analog
III. Insights into the Immune System Responses for HBV Cure
IV. Viral Biomarkers for Monitoring Chronic Hepatitis B Virus Infection
A. Significance of viral biomarkers
B. Antibodies against viral epitopes, viral proteins and molecular surrogate markers
C. Importance of HBV DNA, HBsAg, and HBcrAg quantification
V. Conclusion
World Hepatitis Day, observed on July 28 every year, aims to raise global awareness of hepatitis and encourage prevention, diagnosis and treatment. Chronic hepatitis B virus infection is a global health concern as it affects over 240 million people worldwide. “Some 900 000 people dying unnecessarily of hepatitis B every year is simply unacceptable,” said Peter Revill, ICE-HBV Chair and Senior Medical Scientist in the Victorian Diseases Reference Laboratory at the Doherty Institute. “HBV cure research could make all the difference and prevent adverse outcomes in all people infected with HBV, allowing them to live treatment-free fully productive lives and reduce the stigma associated with this chronic infection.”
Several novel therapeutic strategies are being researched and studied. Pre-clinical studies in animals also presented at ILC 2018 revealed that the most promising strategies are based on a combination of antiviral approaches that target both the virus itself (direct acting) and the human cells that host the virus (indirect acting). Indeed, getting HBV to stop replicating seems necessary, but it isn’t enough to stop the virus returning after treatment is discontinued. In mice, effective new direct antivirals targeting the virus, combined with a therapeutic vaccination that aims to eliminate the virus, followed by immune boosting, gave promising results towards achieving a HBV “functional cure” – i.e. where HBV is reduced to permanently harmless levels after stopping treatment, but some residual virus may still be present in the body. Developing treatment strategies that can lead to a complete cure could eliminate potential adverse events associated with the long-term use of these nucleos(t)ide agents.
The ultimate goal of antiviral therapy would be to eliminate all forms of potentially replicating HBV and to accomplish it a combination of antiviral drugs that target different steps in the HBV life cycle or immunomodulatory therapies to restore host immune response to HBV will be needed. Conceptually, combination of peginterferon with a nucleotide analog would be more likely to result in synergy because the drugs have different mechanisms of action. The concept being that inhibition of viral replication with a nucleotide analog may augment the immune effects of peginterferon. Starting with nucleotide analog first and adding peginterferon later would seem to be the most logical approach to combination therapy. The idea being that the nucleotide analog would rapidly lower viral load and restore T-cell responsiveness and then adding peginterferon might hasten the decline of circulating and intrahepatic viral antigens leading to an improvement in the innate immune response.
Scientists from Karolinska Institute and Hannover Medical School have published two studies that provide insights into how the immune system responds and helps to clear a hepatitis B infection after treatment interruption. In one of the studies they characterised T cell responses during the early phase of virological relapse, following discontinuation of NA therapy in HBsAg negative patients. The T cell phenotype of patients with CHB on longterm NA therapy was markedly different compared to healthy individuals, but was only slightly altered after discontinuation of therapy. T cells from patients with HBsAg loss expressed low levels of KLRG1 and PD-1 at all time-points and high levels of Ki-67 and CD38 at week 12 after treatment cessation. In vitro peptide stimulated HBV-specific T cell responses were increased in several patients after NA cessation. Blocking of PD-L1 further enhanced HBV-specific T cell responses, especially after discontinuation of therapy. Their hypothesise is, relapse of HBV replication could change the cytokine milieu and lead to an increased responsiveness of HBV-specific T cells, which might be interesting for new therapeutic approaches to induce HBsAg decline or loss. Thus, discontinuation of therapy could be a favourable option for selected patients and may be combined with novel treatment options.
Another study published in J of infectious disease authors tried to elucidate cellular immune responses, including natural killer (NK) cell responses, explaining virological events following NA treatment cessation. Cessation of NA treatment resulted in minor phenotypic alterations, but it significantly augmented NK cell natural cytotoxicity responses in the chronic Hep b patients. This increased NK cell functionality correlated with alanine aminotransferase flares in the patients and was particularly enhanced in patients experiencing HBsAg seroclearance at long-term follow-up. With theses results they concluded that increased NK cell function is associated with active hepatitis and HBsAg seroclearance following structured NA cessation. Thus again it was an additional knowledge of the immunological events that develop following cessation of NA treatment in chronic Hep b patients.
Viral biomarkers are being considered as an important tools for monitoring chronic hepatitis B virus (HBV) hepatitis B early antigen (HBeAg) negative infection, both in its natural course as well as during and after treatment. The biomarkers consist of antibodies against viral epitopes, viral proteins, and molecular surrogate markers of the quantity and transcriptional activity of the stable episomal HBV covalently closed circular DNA (cccDNA) which is located in the nuclei of the infected hepatocytes. HBV deoxyribonucleic acid (DNA) or else viral load measurement in plasma or serum is a marker of HBV replication of major clinical importance. HBV DNA is used for staging and treatment monitoring as described in international scientific guidelines. Quantification of HBV antigens, mainly hepatitis B surface antigen (HBsAg) as well as Hepatitis B core related antigen (HBcrAg), play an important yet secondary role, especially in cases of low or undetectable HBV DNA and has been evaluated for the classification of the inactive carrier state, as a predictor of subsequent HBsAg clearance, treatment outcome, and development of hepatocellular carcinoma (HCC). The measurement of the replicative intermediate HBV RNA in serum is currently evaluated and may also prove to be a significant biomarker particularly in patients treated with nucleot(s)ide analogs.
Hep C recent research updates –
In chronic HCV infection, effective therapy now exists for all populations regardless of severity of liver disease, HIV co-infection or other co-morbidities such as CKD. However, despite these recent results, 8 weeks of therapy for HIV/HCV co-infected patients is not currently recommended. In selecting appropriate therapy, providers need to be aware of potential drug–drug interactions between anti-retrovirals and DAAs. It is not recommended that HIV therapy be interrupted to allow for treatment of hepatitis C. Patients with HCV infection are at increased risk for the development of CKD due to extra-hepatic manifestations including cryoglobulinemia, diabetes and membranoproliferative glomerulonephritis (MPGN). A meta-analysis of haemodialysis-dependent patients found that not only does HCV increase the incidence of liver-related deaths but patients with HCV also have increased risk of death from cardiovascular disease. Due to significantly adverse events and the toxicity of interferon therapy in this patient population, many patients with CKD previously went untreated. While all DAAs can be administered to patients with mild renal impairment. As research into HCV treatment continues, we can expect shorter treatment courses and cure rates approaching 100% for all populations.