Document text
Principal Investigator: Marc Ghany
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2024
Award: $614,571
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Summary:
Globally there are an estimated 254 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 results in >1 million deaths annually worldwide from complications of cirrhosis and hepatocellular carcinoma (HCC).
As the population with chronic hepatitis B (CHB) ages, the prevalence of HBeAg negative CHB is increasing. This has led to 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 HBV DNA and ALT levels and whether such individuals would benefit from treatment 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.
The desired surrogate outcome of CHB is loss of hepatitis B surface antigen (HBsAg) as this is associated with reduced progression to cirrhosis and development of HCC. However, the rate of spontaneous HBsAg loss is low, ~1%. Although there have been studies to investigate factors associated with HBsAg loss, the question of whether race affects HBsAg loss is unclear because of the tight correlation between HBV genotype and race and prior studies have been restricted to homogenous racial cohorts. To investigate the influence of race on rates of HBsAg loss we assessed the incidence and factors associated with HBsAg loss in a multiracial cohort of CHB patients that included patients followed at the Alaska Native Tribal Health Consortium (HEP-B-AK cohort) patients from The Hepatitis B Research Network (HBRN cohort) and patients followed in the Liver Diseases Branch, NIDDK, NIH (NIH cohort). The cumulative incidence of any HBsAg loss was 1.45 per 100 PYs; being 1.35, 1.54 and 1.96 per 100 PYs among the HEP-B-AK, HBRN and NIH cohorts, respectively. A multivariate analysis for sustained HBsAg loss identified age, gender, race, HBV DNA and HBV genotype as significant predictors of HBsAg loss. Indeed, genotype and race had the strongest association with any and sustained HBsAg loss, respectively.
Similarly, there is limited data on outcome of CHB infection by race. We sought to investigate the influence of rate on outcome and whether disparities in treatment initiation exist and may affect outcomes of CHB. The incidence of major adverse liver outcomes was 0.1 per 100 person-years and did not differ by race. The cumulative probabilities of treatment initiation after meeting the criteria for treatment were not significantly different among racial groups (African American or Black, 0.45; Asian, 0.51; White, 0.51 at 72 weeks; P = .68). African American or Black participants were less likely than individuals of other races to meet treatment criteria, but among those who did, receipt of HBV treatment did not differ significantly by race or socioeconomic factors. Taken together, the two studies suggest that racial disparities do not exist regarding initiation of antiviral treatment or clinical outcome but functional cure (HBsAg loss) is affected by race potentially implicating a genetic element in clearance of HBV.
2) Develop and evaluate novel, safer and more effective therapies for chronic viral hepatitis.
Current therapy for CHB remains sub-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 a novel approach to this problem, 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 IRB and FDA approved and is expected to start enrollment in the fall of 2024.
3) Elucidate the mechanism of action of peginterferon in chronic HBV infection and determine if Covid-19 infection influences reactivation of CHB.
Peginterferon (pegIFN) results in functional cure (HBsAg loss) in only 1-3% of patients with CHB. Reasons for this low response rate remain unexplained. It has been suggested that HBV itself may inhibit pegIFN’s action. We sought to determine if presence of HBsAg alters intrahepatic gene expression to pegIFN. We utilized paired liver biopsies from a study of add-on pegIFN therapy to ongoing nucleoside analogue treatment. Digital spatial profiling was used to select HBsAg positive and negative hepatocyte regions of interest (ROI) followed by transcriptomic analysis. Differential gene expression (DEG) and gene set enrichment analyses utilizing Hallmark gene set were performed comparing HBsAg+ to - hepatocytes in pre-pegIFN and in 6 hours after pegIFN ROIs, and between pre- and 6 hours post-pegIFN based on HBsAg staining. Comparing post- to pre-pegIFN biopsies, there were 100 upregulated and 10 downregulated DEGs. The majority of upregulated genes were interferon stimulated genes (ISGs) with 42 upregulated genes common to both HBsAg+ and – hepatocytes, 32 genes unique to HBsAg+ hepatocytes and 17 to HBsAg- hepatocytes. A proportion of CHB patients appear to be resistant to pegIFN but this does not fully explain the poor overall response to pegIFN. Notably, HBsAg does not influence intrahepatic response to pegIFN.
Response rates to vaccinations have been reported to be lower among patients with CLD, especially those with cirrhosis. Whether this is true for newer mRNA vaccines is uncertain and whether SARS-COV-2 infection may lead to reactivation of HBV is unknown. We aimed to compare the SARS-CoV-2 spike protein anti-IgG antibody (anti-Spike-Ab) response 1- year after initial vaccination between patients with CLD and healthy persons and to determine if SARS-COV-2 infection may lead to reactivation of HBV. At 1-year post-initial SARS-CoV-2 vaccine, mean concentration of anti-Spike-Ab was similar in CLD patients and healthy persons (7.93±8.32 vs 7.29±7.27 g/mL, p-value=0.67) and among patients with and without cirrhosis (8.3±8.26 vs 6.61±8.54, p-value=0.32). Among persons who were HBsAg negative and SARS-CoV-2 spike protein anti-IgG antibody positive and anti-nucleocapsid-Ab positive (indicating prior Covid-19 infection), no HBsAg sero-reversion or increase in HBV DNA levels were observed. Patients with CLD have similar response to vaccination against SARS-CoV-2 as healthy persons. Moreover, among patients with CLD, those with cirrhosis have similar immune responses as those without cirrhosis, likely due to greater immunogenicity of mRNA vaccines. SARS-COV-2 infection does not appear to result in HBV reactivation.
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