Discussion

Viral Antigens and Host Antibody Responses

Serologic testing for the diagnosis of hepatitis B virus (HBV) infection involves measurement of a panel of distinct HBV-specific antigens and host antibodies that react to these antigens (Figure 1)[1,2,3]. The interpretation of these tests can be complicated, and multiple possibilities exist based on the overall panel of responses (Figure 2)[4]. In general, the panel of responses can determine whether a patient is susceptible to infection, immune as a result of resolved infection, immune as a result of vaccination, acutely infected, or chronically infected.

Serologic Response to Acute HBV Infection

The incubation period (time from the acquisition of HBV to the onset of clinical symptoms) typically consists of 8 to 12 weeks[1]. The diagnosis of acute HBV infection is established by a characteristic serologic profile. During acute infection, the appearance of virologic markers and host antibody responses develop in a typical pattern (Figure 3)[8]. The first serologic marker to appear is hepatitis B surface antigen (HBsAg), which can initially be detected in serum from 1 to 12 weeks (average, 30 to 60 days) after infection. Shortly thereafter, hepatitis B e antigen (HBeAg) generally becomes evident[5,6]. Although serum HBV DNA assays will show the presence of HBV DNA prior to the appearance of HBsAg or HBeAg, with HBV DNA levels often exceeding 10 to 100 million IU/ml, this test is not generally performed for the purpose of diagnosing acute HBV infection[7]. About the time that clinical symptoms develop, antibody to hepatitis B core antigen (anti-HBc) appears, primarily detectable as the IgM class (IgM anti-HBc)[1]. In addition, with the onset of clinical symptoms, patients will have increases in serum hepatic aminotransferase levels that reflect hepatic injury. The degree of hepatic injury generally correlates directly with the vigor of the immune response[3]. Although IgM anti-HBc antibodies typically decline to undetectable levels within 6 months, the IgG class (IgG anti-HBc) persists indefinitely as a marker of past HBV infection.

Serologic Response With Resolved HBV Infection

Following acute HBV infection, the evolution of the pattern of serologic markers depends on the outcome of the host immune response[8]. The likelihood of the patient resolving HBV infection correlates with their age and the strength of the initial immune response to HBV[2,3]. Following acute HBV infection, approximately 90% of adults will resolve the HBV infection, whereas 30 to 90% of young children will fail to resolve the infection and thus develop chronic HBV infection. The weak immune response generated by young children acutely infected with HBV generally corresponds with minimal killing of HBV-infected hepatocytes; for this reason, clinical symptoms suggestive of acute HBV infection are frequently absent in this patient population[7]. For those patients who resolve their infection, HBsAg disappears at about 3 to 6 months, often just prior to the detection of antibodies to hepatitis B surface antigen (anti-HBs). The presence of anti-HBs following acute infection generally indicates recovery and protective immunity against re-infection. In addition, patients with resolution of infection have disappearance of HBeAg and development of antibodies to hepatitis B e antigen (anti-HBe). Patients with resolved infection have persistence of anti-HBc for life, but about 4 to 6 months after the appearance of anti-HBc, the total anti-HBc predominantly consists of IgG. Some patients with self-limited infection, however, may still have low levels of HBV DNA in blood; whether the HBV DNA is part of intact virions remains unknown[7,9].

Serologic Result With Chronic HBV Infection

Patients who develop chronic (persistent) HBV infection have a serologic response in the acute phase of HBV infection that is similar to patients who subsequently resolve the HBV infection. With chronic (persistent) HBV infection, HBsAg and anti-HBc (IgG antibodies) generally persist for life and HBV DNA can usually be detected by nucleic acid amplification methods (Figure 4)[8]. The presence of HBsAg for longer than 6 months after acute infection indicates chronic infection. The detection of HBsAg and absence of IgM anti-HBc in a single serum specimen also generally indicates chronic HBV infection. Although most persons with chronic HBV infection are without symptoms, they are at risk for subsequently developing chronic hepatitis, cirrhosis, and liver cancer[2]. The continued presence of HBeAg generally reflects higher HBV DNA levels and greater infectiousness. Some patients with chronic HBV infection may have resolution of their HBeAg along with appearance of anti-HBe, and this usually correlates with low (or absent) HBV levels and relatively normal levels of hepatic aminotransferase levels (Figure 5)[8]. Previously, investigators believed that HBV DNA disappeared in all patients with the onset of anti-HBe, but older studies had used the less sensitive HBV DNA hybridization assays[7,10]. Newer, more sensitive PCR assays have shown that greater than 70% of persons who develop anti-HBe have persistent HBV DNA, typically in the range of 200 to 2,000 IU/ml [7,11]. In addition, some patients with chronic HBV infection have absent HBeAg, increased aminotransferase levels, and relatively high HBV DNA levels; these findings generally occur in association with precore or core promoter mutations. These mutations prevent (or diminish) HBeAg formation by an otherwise normally replicating HBV[7,12].

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    Figure 1 - Virologic and Host Markers with Hepatitis B Virus Infection Figure 1
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    Figure 2 Interpretation of Serologic Markers in HBV Infection

    This table is adapted and modified from Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33.

    Figure 2
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    Figure 3 is a FLASH animation - Virologic and Serologic Response to Acute HBV Infection with RecoveryFigure 3
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    Figure 4 - Virologic and Serologic Markers in Patients who Progress
to Chronic Hepatitis B Virus Infection with Persistent HBeAg Figure 4
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    Figure 5 - Virologic and Serologic Markers in Patients who Progress to Chronic Hepatitis B Virus Infection with Resolution of HBeAg Figure 5