The discovery of the Australia Antigen (Au) with its subsequent link to the hepatitis B virus (HBV) was an important landmark in medicine that precipitated a rapid expansion in research and many clinical advances in hepatitis B. The original description of the Australia antigen was made in 1965 by Baruch Blumberg, an NIH investigator, in a JAMA article titled “A ‘new’ antigen in leukemia sera” (1965;191:541-546). Eleven years later (Au + 11) Blumberg received the Nobel Prize for the discovery.
The Australia Antigen was originally thought to be an inherited serum lipoprotein that predisposed to leukemia and hepatitis. Within a few years, however, it was shown to be a component of HBV and was renamed the hepatitis B surface antigen (HBsAg). By 1972 (Au + 7), sensitive and specific assays to screen blood donations for HBsAg were introduced, leading to a marked decrease in posttransfusion hepatitis B. Development and commercial availability of other serological and virological tests followed (for anti-HBs, anti-HBc, HBeAg, anti-HBe, and HBV DNA). The first experimental HBV vaccines were evaluated in the early 1970s; later in the same decade, randomized controlled trials of commercial HBV vaccines demonstrated their safety and efficacy in several high-risk populations, leading to the licensure of the first HBV vaccine in 1982 (Au + 17). Initially recommended only for adults at high risk for acquiring hepatitis B, the vaccine later became part of routine immunizations for newborns and, as catch-up, for preteens. As a result of these recommendations, the incidence of new cases of acute hepatitis B has decreased markedly in the United States, and current rates are the lowest since the disease became reportable.
Advances in therapy for hepatitis B have lagged behind those in prevention. Interferon alfa was reported to have activity against HBV in 1976 (Au + 11), but not until recombinant interferons were available could suitably powered, controlled trials be performed to demonstrate efficacy. Interferon alfa was licensed as a treatment for chronic hepatitis B in 1992 (Au + 27). Small molecule therapy of hepatitis B began in the late 1970s, but the initial agents (adenine arabinoside, didanosine, fialuridine) were minimally effective and sometimes toxic. With the introduction of cell culture systems and small animal models to study HBV in the 1980s, agents could be screened rapidly and safely for antiviral activity. Lamivudine was initially evaluated in the early 1990s and was approved as therapy for hepatitis B in 1998 (Au + 33); adefovir dipivoxil followed in 2002 (Au + 37). In 2005, two new agents were approved for use in hepatitis B: the oral nucleoside entecavir and a long-acting formulation of interferon, peginterferon alfa-2a. Several other agents are currently in the “pipeline.”
Thus, 40 years after the description of the Australia Antigen (Au + 40) there are highly effective vaccines for its prevention and at least five licensed therapies for its treatment. Clearly, hepatitis B is a disease “on the run.”
Yet, prevention and control of hepatitis B are far from complete. Despite availability of a vaccine, cases of acute hepatitis B and even acute liver failure from HBV infection still occur. A sizeable number of Americans have chronic hepatitis B, but most are unaware of the infection. Furthermore, treatment of chronic hepatitis B is problematic. The disease can be controlled by antiviral therapy in most patients, and a long-term remission can be induced in a small proportion. However, the disease is usually not cured—only rare patients become HBsAg negative and develop anti-HBs. Furthermore, control of the disease often requires long-term, perhaps lifelong therapy, which is expensive and can be limited by antiviral resistance. Five effective agents are available, but there are no clear guidelines on how they should be used: who should be treated, at what stage of disease, with which agent or agents, whether in combination or alone, using what endpoints to measure success or failure. There are few diseases for which there are so many effective therapeutic agents but so little information on how they should be used. Hepatitis B may be on the run, but it has yet to be caught.
These considerations have led the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to sponsor a two-and-a-half-day workshop on “Management of Hepatitis B: 2006,” scheduled for April 6-8, 2006, on the NIH Campus in Bethesda, Maryland. The organizers are Drs. Anna Lok, John Vierling, Russell Fleisher, Jake Liang, Edward Doo, and Jay Hoofnagle. The meeting is co-sponsored by the AASLD, the Food and Drug Administration, and the Hepatitis B Foundation. Topics to be discussed include HBV virology, disease pathogenesis, diagnostic assays, role of liver biopsy, animal models, cell culture systems, mechanisms of action of antiviral agents, current status as well as benefits and risks of mono- versus combination therapy, viral resistance and its clinical significance, treatment of acute hepatitis B, safety of long-term therapy, and, finally, cost of treatment. The meeting will conclude with discussion of needs for future research and means of developing rational guidelines for therapy. A summary of the meeting will be prepared for publication. Further information on the workshop is available at: http://www.niddk.nih.gov/fund/other/conferences.htm.