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 291 million persons infected with hepatitis B virus (HBV). In the United States, there are 1.25 million individuals with chronic HBV infection. 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. Patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) with moderate levels of HBV DNA and ALT levels (indeterminate CHB) represent a conundrum for clinicians whether they should receive antiviral treatment or be observed. Understanding the natural history of this group of patients is crucial for management of these patients. Among 88/787 HBsAg+, HBeAg- patients followed by the LDB, 75% met criteria for indeterminate CHB. Clinical decompensation occurred at a rate of 0.83 per 100-person years and occurred primarily in patients with low HBV DNA but raised ALT levels, 14% ever required antiviral treatment and HBsAg loss occurred at a rate of 1.75 per 100-person years. These data suggest that indeterminate CHB is prevalent and associated with favorable short-term outcomes. As a follow-up to this study, we conducted a larger study utilizing data on indeterminate CHB from the hepatitis B research network, a multicenter, NIH funded study. Among adult and pediatric participants with indeterminate CHB, rates per 100 person-year phenotype changes, HBsAg loss, treatment initiation and clinical outcomes were determined. Patients with high (>2,000 IU/ml) levels compared to those with low HBV DNA (<2,000 IU/ml) levels had nearly double the rate for experiencing a phenotype transition and initiating treatment, respectively. HBsAg loss occurred only among participants with a low HBV DNA level. The rate of clinical outcomes was 0.44 100 person-years. After 5 years, the estimated percent of patients with high and low HBV DNA transitioning to active CHB were 14% and 12%, respectively. Over 5 years only a minority of indeterminate CHB participants progress to active CHB and require treatment. Taken together the results suggest that the short-term prognosis of indeterminate CHB is good, and most of these patients can be safely observed without the need for antiviral therapy. 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 more influenced by viral genotype. These data underscore the need for better approaches to treat CHB. A second 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 under IRB review. 3) Elucidate the viral pathogenesis of HBV infection and assess novel markers of HBV disease activity. We have previously reported that race may influence outcome of CHB. Functional cure or HBsAg loss and HBV DNA below level of quantification is the desired outcome of HBV infection. The role of race in clearance of HBsAg has been difficult to assess due to prior studies being performed in homogenous racial cohorts. To address this, we assembled a large multiracial cohort of CHB patients to assess incidence and factors including race associated with HBsAg loss (functional cure). Among 3608 patients, the cumulative incidence of HBsAg loss was 1.51 per 100 PYs. Factors associated with HBsAg loss were age 51 years, male sex, Caucasian race, genotype A, higher BMI, ALT, AST and alkaline phosphatase. In contrast, elevated HBV DNA and lower platelet were associated with lower odds of HBsAg loss. In this multiracial cohort of CHB patients, at initial presentation among multiple demographic, virologic and clinical factors, Caucasian race had the strongest association with HBsAg loss. High circulating levels of HBsAg may contribute to immune exhaustion characteristic of CHB and viral persistence. It may also affect response to treatment with pegylated interferon (Peg-IFN) as higher HBsAg levels have been shown to be associated with a lower response to Peg-IFN. Therefore, this study was conducted to evaluate whether HBsAg expression affects the hepatocyte response to Peg-IFN. We performed spatial transcriptomics on paired liver biopsies pre- and 6 hours post-Peg-IFN treatment of patients with CHB. In total, 17 HBsAg (+) and 19 HBsAg (-) hepatocyte regions of interest (ROIs) were analyzed. Minimal change in gene expression post-Peg-IFN was observed in one non-responder patient. Comparing HBsAg (+) to HBsAg () hepatocytes post- to pre-PEG-IFN, there were 42 upregulated genes common to both (majority of DEGs were ISGs), 32 genes unique to HBsAg (+) hepatocytes and 17 to HBsAg (-) hepatocytes. Finally, comparing HBsAg (+) and HBsAg () hepatocytes post- to pre-peg-IFN in the responder to the non-responder with no change in HBsAg level, there were 14 common DEGs (majority ISGs) and 59 genes unique to the responder (majority were upregulated ISGs) and 12 unique to the non-responder (majority non-ISGs). The data suggests, the presence of HBsAg does not substantially influence intrahepatic response to PEG-IFN. Rather, the intrahepatic response to Peg-IFN is highly variable among patients with responders displaying a greater breadth of DEGs (primarily ISGs) compared to non-responders.