Natural History, Therapy and Pathogenesis of Chronic Viral Hepatitis B

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Summary: Globally there are an estimated 257 million persons infected with hepatitis B virus (HBV). In the United States, there are 1.25 million affected individuals. Chronic HBV infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC) worldwide. The natural history of chronic hepatitis B (CHB) appears to be changing with an increasing prevalence of HBeAg negative CHB and recognition of a group of patients with moderate levels of HBV DNA and ALT levels with undetermined natural history. Knowledge of the rate of disease progression among individuals with moderate levels of HBV DNA and ALT levels is unknown. Despite the availability of safe and effective oral nucleoside analogues for treatment of CHB, therapy remains problematic due to the need for prolonged therapy and limited effectiveness and tolerability of the alternate treatment, interferon. Clearance of hepatitis B surface antigen (HBsAg) is the desired surrogate endpoint of therapy but is rarely achieved with current therapy. Identifying the optimal regimen, defining when to treat, for how long and when to stop therapy to achieve this endpoint are major unresolved issues. In addition, defining the best parameters to monitor patients both on and off therapy are not clear. Hypotheses/problems addressed: 1) Define the host, viral and environmental factors that determine the natural history and outcome of HBV infection. Two forms of CHB are recognized based on hepatitis B e antigen (HBeAg) status either HBeAg positive or negative. The IC phase of HBeAg negative CHB represents an important milestone indicating transition from a high to low replicative phase but requires monitoring for 1 year to confirm. The ability to determine phase of infection based on a single timepoint determination would be highly desirable to reduce the monitoring burden and to advise patients more accurately on prognosis. Whether incorporation of two novel virological biomarkers HBV RNA and hepatitis B core-related antigen (HBcrAg) into the phase assessment could identify sustained IC phase without need for long-term monitoring is unknown. Using Cox proportional hazard modeling we demonstrated that a low HBcrAg level was useful in identifying sustained IC phase and may allow for less frequent monitoring. HBV RNA was helpful in predicting an increase in viremia and patients who should be monitored more closely. Therefore, single point determination with these novel markers may lead to more personalized monitoring schedules. Clearance of HBsAg is associated with immunological control and represents an important landmark during CHB. Therefore, HBsAg loss is now the goal of novel therapies in development for CHB. Whether HBsAg loss is truly associated with improved clinical outcomes is uncertain. We conducted a systematic review and meta-analysis to assess the impact of HBsAg loss on clinical outcomes following spontaneous and treatment-related HBsAg loss. Based on analyzed studies, HBsAg loss was associated with a non-significant 32% reduction in risk of HCC as compared to those who remained HBsAg positive. In subgroup meta-analysis, treatment-induced HBsAg loss was associated with a non-significant increase in pooled proportion of HCC as compared to spontaneous HBsAg loss. HCC development after HBsAg loss was significantly higher in males, those with underlying cirrhosis and with family history of HCC. The analysis suggests that HBsAg loss is associated with a reduced risk of clinical outcomes. 2) Develop and evaluate novel, safer and more effective therapies for chronic viral hepatitis. Current therapy for CHB remains less than optimal. Only two classes of drugs are approved for use-nucleos(t)ide analogues and peginterferon. Relapse is common if nucleos(t)ides are discontinued after one year in the absence of HBsAg loss. Consequently, they must often be administered long-term or indefinitely. However, long-term use is associated with increased risk of side effects and higher costs. Therefore, the focus of current studies is to develop strategies to induce HBsAg loss (functional cure) to permit discontinuation of therapy and improve outcome of the infection. We are taking several approaches to this problem. The first approach is to combine the two available therapies, peginterferon alfa with tenofovir, compared to tenofovir alone. This is being conducted as part of the Hepatitis B Research Network- a multicenter trial that enrolled 200 subjects. After 192 weeks of therapy and 48 weeks of off-treatment observation, the rate of HBsAg loss was not significantly different in the group that received combination peginterferon alfa with tenofovir compared to the group that received tenofovir alone for 192 weeks. Clearance of HBsAg appeared to be influenced by viral genotype. These data underscore the need for better approaches to treat CHB. A second approach is to use relatively high doses of hepatitis B antibody in the form of hepatitis B immunoglobulin to remove HBsAg from serum. This study will address the fundamental question of the role of HBsAg in the host immune response. We postulate that high levels of circulating HBsAg may disrupt the innate immune response and its removal may lead to partial restoration of the host immune response, that is characteristic of patients with CHB. Start of the study was delayed due to COVID-19 and we anticipate enrollment to begin in the fall. A third approach is to employ siRNA technology to reduce HBsAg levels by decreasing HBsAg mRNA. This approach alone may be insufficient to clear HBsAg and therefore we plan to combine the siRNA with peginterferon as a therapeutic modality. The primary endpoint will be loss of HBsAg and secondary analyses will investigate the virological, histological, and immunological profiles following therapy with this regimen. The protocol is currently in scientific review. 3) Elucidate the viral pathogenesis of HBV infection and assess novel markers of HBV disease activity. Better markers are needed to monitor untreated and treated patients with CHB. Two novel markers, HBV RNA and hepatitis B core-related antigen (HBcrAg) are strongly correlated with activity of covalently closed circular DNA (cccDNA), the transcriptional template for all viral proteins. Therefore, we hypothesized that they might be more useful than existing markers (HBV DNA, ALT, HBsAg levels) in predicting loss of HBeAg and HBsAg which are important milestones in CHB. We developed a series of logistic regression models incorporating each of these variables to a base model consisting of other host and viral factors to predict HBeAg and HBsAg loss. Incorporation of either marker alone or in combination did not significantly improve the predictive ability of the model. HBeAg and HBsAg levels were the best predictors of HBeAg and HBsAg loss, respectively. Hepatitis B core (HBcAg) and surface (HBsAg) antigen expression have been shown to correlate with disease activity in CHB. However, the effect of inhibition of viral replication and transcription on the expression of these two markers is unknown. We assessed the effect of inhibition of viral replication and transcription on HBcAg and HBsAg expression and explored whether HBcAg and HBsAg staining could predict HBsAg loss. There was a significant decline in HBcAg but not HBsAg staining after 4 years of nucleos(t)ide analogue treatment but their respective staining patterns remain unchanged. This result suggests that HBcAg but not HBsAg staining was closely associated with viral replication. Persistence of HBsAg after inhibition of viral replication and transcription particularly among HBeAg negative patients suggest that HBsAg is derived from integrated HBV DNA. Low HBsAg staining is predictive of HBsAg loss in serum.