Management of chronic hepatitis B e antigen-negative disease: another step forward.

Chronic hepatitis B (CHB) infection is a global health problem affecting more than 2 billion people worldwide. Among them, more than 75% reside in AsiaPacific countries. Although only a minority (15%–40%) of infected individuals go on to develop cirrhosis, liver failure, and hepatocellular carcinoma (HCC), which account for an estimated 0.5–1.2 million deaths per year, CHB is ranked as the 10th leading cause of death worldwide [ 1 ]. In Asia, most patients acquire hepatitis B virus (HBV) infection either during the perinatal period or in early childhood. In general, the natural course of chronic HBV infection consists of 4 phases, although not all patients go through all phases [ 2 ]. The initial immune-tolerant phase is characterized by the presence of hepatitis B e antigen (HBeAg), high serum HBV DNA levels, and persistently normal levels of alanine aminotransferase (ALT). Most patients in the immune tolerant phase have minimal liver injury, and prognosis is favorable during follow-up of up to 10 years. There is usually no, or only minimal, disease progression while serum ALT concentrations remain normal [ 3 , 4 ]. This is followed by an immune clearance phase when the HBeAg-positive patients have raised ALT levels. During this phase, spontaneous HBeAg seroconversion occurs at a rate of 10%–20% per year. HBeAg seroconversion is frequently, but not always, accompanied by a sudden increase in ALT levels [ 5 ]. Patients who undergo spontaneous HBeAg seroconversion before the age of 40 have a good prognosis [ 6 ]. They then enter an inactive (carrier) phase, which is characterized by the absence of HBeAg, the presence of HBe antibody (anti-HBe), persistently normal ALT levels, and low or undetectable levels of serum HBV DNA. Patients in this phase have a favorable prognosis [ 7 ]. Recently, because of aging populations and increased availability of molecular technology, more patients in Asia are being noted to enter the 4th reactivation phase. This phase, also termed HBeAg-negative CHB, is characterized by the absence of HBeAg, the presence of anti-HBe, intermittently or persistently elevated serum HBV DNA and ALT levels, and active inflammation in the liver. The annual rates of reactivation of hepatitis B are 1.5%–3.3%, and these individuals usually have more advanced liver disease than patients in the other phases of the disease. Indeed, it is estimated that subjects with HBeAg-negative hepatitis developed cirrhosis, with or without HCC, at a rate of 3%–4% per year. Currently, 7 treatments are approved for CHB e antigen–negative patients, including 2 formulations of interferon (IFN; conventional IFN and PEG-IFN) and 5 nucleoside/nucleotide analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil). The use of these therapeutic agents results in varying success. Viral relapse occurs in almost all patients when nucleoside/nucleotide analogs are discontinued, and a 1-year course of PEGIFN resulted in undetectable serum HBV DNA and normalization of ALT levels in fewer than one-third of patients. Learning from chronic hepatitis C virus infection,