Abstract Body

Hepatitis B remains a significant cause of liver disease and remains the leading cause of hepatocellular carcinoma worldwide.  Effective therapy for hepatitis B is available, and nucleos(t)ide analogs (NAs) suppress hepatitis B DNA levels and normalize ALT levels. Long-term treatment can lead to reduction in necroinflammatory activity, with potential improvement in fibrosis or reduction in fibrosis progression, as well as a reduction in the risk of hepatocellular carcinoma.  Treatment recommendations are guided by the degree of inflammation as reflected by ALT levels, HBV DNA levels and the degree of fibrosis.  Current societal guidelines have recommended treatment during certain phases of hepatitis B infection in those who are HBeAg+ or HBeAg- with elevated HBV DNA levels and intermittently or persistently elevated ALT levels.  However, approximately 30% of individuals with chronic hepatitis B remain in the gray zone including both HBeAg+ and HBeAg – infected individuals where HBV DNA and ALT levels do not fit into these well-described phases.   Recent cohort studies have suggested that patients within the gray zone remain at risk for significant fibrosis and development of hepatocellular carcinoma.  One limitation of gray zone patients has been the lack of histologic assessment of inflammation and fibrosis, rather relying on ALT and non-invasive measures of fibrosis. One recent study identified 242 individuals with chronic HBV infection in the gray zone, of whom 73% had significant histological disease.  More recent treatment recommendations have suggested lower thresholds for treatment.  Given the effectiveness of NA therapy and the recent data demonstrating improved functional cure rates with emerging therapies, patients in the gray zone should be assessed for treatment to reduce the incidence of advanced fibrosis, disease progression, and hepatocellular carcinoma in this highly prevalent disease. New biomarkers and risk models are needed to more accurately identify patients with significant inflammation and fibrosis who reside in the gray zones and would benefit from antiviral treatment and surveillance for hepatocellular cancer. Regardless, close follow-up of hepatitis B patients is required, given the highly dynamic interplay between the virus and the host.