Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (184 page)

   Anti-HBs is the only antibody produced in response to vaccine. Its presence indicates immunity. Antibody develops in approximately 95% of healthy adults after a three-dose immunization series. Seroreactivity may wane in vaccinated individuals, but immunity to infection is typically preserved. Escape mutants, which lack the “a” determinant of the vaccine, may cause infection in vaccinated patients who demonstrate anti-HBs.

   Antibodies to hepatitis B core antigens (anti-HBc) are the first antibodies to appear after HBV infection. Total and IgM antibodies typically appear 4–10 weeks after appearance of HBsAg.
Anti-HBc-total
remains detectable for years or for lifetime. In chronic HBV infection, total anti-HBc and HBsAg are always present, and anti-HBs is absent.

   
Anti-HBc-IgM
is the earliest specific antibody to develop in response to HBV infection. It is found in high titer for a short time during the acute disease stage and is the sole marker of HBV infection during the window between HBsAg and anti-HBs detection. Anti-HBc-IgM declines to low levels during recovery. Because this is the only test unique to recent infection, it may be used to differentiate acute from chronic HBV. However, because some patients with chronic Hepatitis B infection become positive for anti-HBc-IgM during flares, it is not an absolutely reliable marker of acute illness. Before anti-HBc-IgM disappears, anti-HBc-IgG appears and lasts indefinitely.

   Hepatitis B e-antigen (
HBeAg
) indicates virus replication and a highly infectious state. HBeAg appears within 1 week after HBsAg. HBeAg disappears prior to the disappearance of HBsAg during resolution of acute infection. HBeAg is detected only when HBsAg and HBV DNA are detectable in the circulation. HBeAg occurs early in disease, before biochemical changes, and disappears after the serum ALT peaks. Levels are usually detectable for 3–6 weeks in uncomplicated HBV infection. It is a marker of active HBV replication in the liver. HBeAg at the time of delivery is an accurate predictor of risk (approximately 90%) of vertical transmission to neonates.

   HBeAg may be used to determine resolution of HBV infection. Persistence >20 weeks suggests progression to chronic carrier state and possible chronic hepatitis. Antibody to HBe (
anti-HBe
) appears after HBeAg disappears and remains detectable for years. Detection of anti-HBe is associated with decreasing infectivity and suggests a good prognosis for resolution of acute infection. A positive reaction for anti-HBe and anti-HBc, in the absence of HBsAg and anti-HBs, confirms recent acute infection (2–16 weeks).

   Detection of
HBV DNA
by PCR indicates active infection. It is the most sensitive and specific assay for early diagnosis of HBV infection and may be detected when all other markers are negative (e.g., in immunocompromised patients). Detection of HBV DNA indicates active viral replication, even if HBeAg is not detectable. HBV DNA viral load may be used to assess disease status and prognosis or to monitor the response to therapy. A level of 100,000 copies per mL has been proposed for initiation of therapy in HBeAg-positive patients. DNA levels decrease in patients who respond to therapy. An increased risk for the development of HCC and cirrhosis is seen in chronically infected patients with persistently elevated HBV DNA levels (>10
⁵
copies/mL).

   HBV genotype analysis may be useful for management of patients with chronic HBV infection who are treated with antiviral agents. The replication of the HBV genome is prone to misreading, resulting in a pool of “quasispecies” in the patient’s circulating pool of HBV. A quasispecies resistant to the antiviral agent may become the predominant circulating form of virus in the presence of antiviral selection, resulting in failure of therapy. Genotype analysis may identify quasispecies with specific mutations of the HBV polymerase gene that confer resistance to the antiviral agents used to treat chronic HBV. If identified early, therapy may be changed before hepatitis reactivation occurs.

Correlation of HBV Serologic Test Results and Disease Status

Typical patterns of HBV serologic tests for different disease status are given below. Atypical patterns may be due to testing during transitions between disease phases but may also be caused by false-positive or false-negative test results. Unexpected test results should be confirmed and, if confirmed, repeated after several months to see if the pattern resolves. Additional testing, like genetic analysis, may be performed, if relevant, for resolution.

   
No HBV infection
: Negative reactions for HBsAg and anti-HBc IgM rule out acute HBV infection.

   
HBV immune status
: Anti-HBs may be added to assess a patient’s immune status. Patients with immunity due to natural infection show positive reactions for anti-HBs and anti-HBc and a negative reaction for HBsAg. Patients with immunity due to hepatitis B vaccination are positive for anti-HBs and negative for HBsAg and anti-HBc.