Hepatitis B Virus (HBV)
HBV was originally called “serum hepatitis,” or “long-incubation hepatitis,” and has an incubation period of 60-90 days (range, 29-180 days). HBV is found in blood and body secretions. Infection was originally thought to be limited to parenteral inoculation (blood transfusion or injection with a contaminated needle). Although this is still the major source of infection, the virus may be contracted by inoculation of infected blood, saliva, or semen through a small break in the skin or a mucous membrane (e.g., the rectum) or by sexual intercourse. The virus seems less infectious through nonparenteral transmission than is HAV. At least 30% of persons with serologic evidence of HBV infection (past or present) do not have a currently identified risk factor.
Interpretation of Hepatitis B Serologic Tests
I HBSAg positive, HBCAb negative*
About 5% (range, 0%-17%) of patients with early stage HBV acute infection (HBCAb rises later)
II HBSAg positive, HBCAb positive, HBSAb negative
a. Most of the clinical symptom stage
b. Chronic HBV carriers without evidence of liver disease (“asymptomatic carriers”)
c. Chronic HBV hepatitis (chronic persistent type or chronic active type)
III HbSAg negative, HBCAb positive,* HBSAb negative
a. Late clinical symptom stage or early convalescence stage (core window)
b. Chronic HBV infection with HBSAg below detection levels with current tests
c. Old previous HBV infection
IV HBSAg negative, HBCAb positive, HBSAb positive
a. Late convalescence to complete recovery
b. Old infection
*HBCAb=combined IgM+IgG. In some cases (e.g., category III), selective HbCAb-IgM assay is useful to differentiate recent and old infection.
There is a considerably increased incidence of HBV infection in male homosexuals (about 10% of yearly reported cases and 40%-80% with serologic evidence of infection), in intravenous drug abusers (about 25%-30% of yearly reported cases and 60%-90% with serologic evidence) of infection; and in renal dialysis patients or dialysis unit personnel. Although serologic evidence of infection in heterosexual males is low (about 5%-6%; range, 4%-18%), heterosexual HBV transmission is now about 20%-25% of yearly reported cases. Thirty percent or more of regular sex partners of actively infected persons become infected. There is an increased risk in renal transplant patients, and in persons with leukemia or lymphoma. Hospital personnel are also at risk for HBV infection, comprising about 5% (range, 2%-6%) of yearly reported cases, most often due to accidental needle stick after drawing blood from an infected patient. Thirteen percent to 24% of dentists and dental workers have serologic evidence of infection. It is reported that the risk of contracting HBV infection from a contaminated needle stick is 6%-30%. There is disagreement regarding risk of HBV spread in day-care centers. It has also been reported that 26%-77% of institutionalized mentally handicapped patients have antibodies against HBV and about 20% (range, 3%-53%) had detectable HBV antigen.
HBV infection is especially prevalent in Taiwan, various other areas of Southeast Asia, and parts of Africa. About 10%-15% of these populations are said to be HBV carriers. For comparison, U.S. male homosexuals have a carrier rate of about 4%-8% and intravenous (IV) drug abusers have a rate of about 7%.
Hepatitis B virus infection has a wide range of severity and is fatal in about 1% (range, 1%-3%) of patients. In general, only about 30%-40% (range, 10%-50%) of patients with acute HBV develop clinically apparent acute hepatitis. Neonates almost always are asymptomatic and most children do not develop jaundice.
Some 5%-15% of HBV infections become chronic, either as the carrier state or as chronic hepatitis. Although various definitions of these terms can be found in the literature, the carrier state is usually defined as persistence of HBV surface antigen for more than 6 months but with normal liver function tests and normal microscopic findings on liver biopsy. Chronic hepatitis can be divided into chronic persistent hepatitis (abnormal liver function tests plus relatively normal liver biopsy findings) and chronic active hepatitis (abnormal liver function tests plus abnormal findings on liver biopsy). The abnormalities on liver biopsy may exist in a spectrum of severity and may progress to cirrhosis. About 2% of HBV infections (15%-20% of chronic HBV) exist in the asymptomatic carrier state, about 6% are chronic persistent hepatitis, and about 3% are chronic active hepatitis. About 15%-30% of patients with chronic HBV infection (roughly 3% of all HBV patients; range, 0.75%-4.5%) develop cirrhosis. There is also a considerably increased risk for hepatocellular carcinoma (hepatoma); the relative risk for HBV carriers is quoted as 30-106 times noncarriers, while the relative risk for a carrier who has cirrhosis rises to nearly 500.
Mothers who acquire HBV infection during the third trimester or early postpartum, or who are HBV carriers, frequently transmit HBV infection to their infants during or after birth. Incidence varies from 12.5%-40% and may be as high as 70%-90% of cases when the mother is positive for HBV antigen by nucleic acid probe as well as positive by both HBV surface antigen by immunoassay plus the HBV e antigen. A lesser number (5%-10% in one study) become infected if the mother is negative by nucleic acid probe even though HBV surface antigen by immunoassay and HBV e antigen are both positive.
Without therapy, 80%-90% of infected infants become chronic carriers of HBV surface antigen. These infants are said to have a 25% risk of fatal cirrhosis or hepatoma. A combination of HBV vaccine and HBV immune globulin administered to the newborn can reduce risk of the chronic carrier stateby 85%-95%.
Tests for Hepatitis B virus infection
Studies have shown that the intact HBV molecule (Dane particle) has a double shell structure that contains several different antigens or antigenic material. There is an outer envelope that incorporates the hepatitis B surface antigen (HBsAg, formerly known as the Australia antigen, or HAA antigen). There is an inner core that contains an HBV core antigen HBcAg). Also within the core is a structure consisting of double-stranded viral deoxyribonucleic acid (DNA), as well as the material called HBV e antigen (ABeAg) and an enzyme known as DNA polymerase.
Currently, there are three separate HBV antigen-antibody systems: surface antigen, core antigen, and e antigen.
HBV surface antigen
HBV surface antigen (HBsAg) can be detected by nucleic acid probe or by immunoassay.
About 20%-60% of chronic persistent HBV hepatitis and 9%-60% of HBV chronic active hepatitis have detectable HBsAg by immunoassay. It has been reported that the new recombinant hepatitis B vaccines produce a transient (detectable) passive transfer antigenemia in infants (but not adults), lasting about a week but occasionally as long as 2-3 weeks.
Antigenic subgroups of HBsAg exist; the most important to date are adw, ayw, adr, and ayr, but others have been discovered. These are thought to indicate possible subgroups (strains) of HBV.
HBs Ag by Immunoassay
Appearance
2-6 weeks after exposure (range, 6 days-6 months). 5%-15% of patients are negative at onset of jaundice
Peak
1-2 weeks before to 1-2 weeks after onset of symptoms
Becomes nondetectable
1-3 months after peak (range, 1 week-5 months)
HBsAg by nucleic acid probe (DNA probe)
HBsAg-DNA is somewhat more sensitive than HBsAg by immunoassay in the very early stage of acute HBV infection. In one study, HBV-DNA was positive in 53% of patients seen before the peak of ALT elevation. It is also somewhat more sensitive than HBsAg by immunoassay in chronic HBV infection, both in serum and when applied to liver biopsy specimens. HBsAg-DNA using the polymerase chain reaction (PCR) amplification method is said to increase HBsAg detection rates by up to 66% over nonamplified HBsAg-DNA probe.
HBsAg-DNA is most often used as an index of HBV activity or infectivity. Detection of HBV-DNA in serum more than 4 weeks after the alanine aminotransferase (ALT) peak (over 8 weeks after onset of symptoms) is said to be a reliable predictor of progression to chronic HBV infection. Loss of serum HBV-DNA with HBeAg still positive in acute HBV infection commonly precedes loss of HBeAg and seroconversion to HBeAb (total).
HBsAb-Total behaves like a typical IgG antibody, rising (most often) after HBsAg is no longer detectable and remaining elevated for years. Presence of HBsAb-Total therefore usually means the end of acute HBV infection and predicts immunity to reinfection. However, there are reports that HBsAg and HBsAb-Total may coexist at some point in time in about 5% of patients (range, 2%-25% of cases); this most often happens in association with decreased immunologic mechanisms; such as occurs with acquired immunodeficiency syndrome (AIDS). However, it possibly could also result from subsequent infection by a different subgroup (strain) of HBV. Also, about 15% of patients have been reported to lose HBsAb-Total in less than 6 years.
Hepatitis B virus core antigen and antibodies HBV Core Antigen (HBc Ag)
Currently, there is no commercially available test to detect HBcAg.
HBV core antibodies (HBc Ab)
Tests are commercially available for IgM and for total antibody (IgM + IgG)
In chronic HBV infection, there is disagreement in the literature whether HBcAb-IgM is detectable, with some investigators stating it is usually absent and others finding it elevated in varying numbers of patients. This disagreement partially is due to a tendency of the HBcAb-IgM antibody to increase titer in relation to the degree of HBV activity. The ongoing quantity of liver cells being injured is less in most cases of chronic HBV than in acute HBV. In addition, sensitivity of the HBcAb-IgM test is not the same for all manufacturer’s kits. For example, one manufacturer (Abbott) dilutes the patient’s serum specimen to a degree that only a considerably elevated HBcAb-IgM titer will be detected. This is done so that HBcAb-IgM will only be detected in patients with active acute or recent acute HBV infection. Other manufacturer’s kits who use lesser patient serum dilution may detect lower HBcAb-IgM titers, such as may be present in some cases of chronic HBV infection.
Fig. 17-3 surface antigen and antibody (HbsAg and HBsAb-Total).
HBV Surface Antibody (HBsAb-Total; Both IgM + IgG)
Appearance
2-6 weeks after disappearance of HBsAg (range, HBsAg still present to over a year after HBsAg is gone); about 10% of patients do not produce HBsAb
Peak
2-8 weeks after initial appearance
Becomes nondetectable
About 85% of patients have persistent HBsAb-Total for many years or life, although there is often a slow decline to lower titers. About 15% (range, 2%-33%) of patients lose HBsAb-Total in less than 6 years
Summary: HBV Surface Antigen and Antibody
HBsAg by Immunoassay
1. Means current active HBV infection.
2. Persistance over 6 months indicates carrier/chronic HBV infection.
HBsAg by Nucleic Acid Probe
1. Same significance as detection by immunoassay.
2. Present before and longer than HBsAg by immunoassay.
3. More reliable marker for increased infectivity than HBsAg by immunoassay and/or HBeAg.
HBcAb-IgM
Appearance
About 2 weeks (range, 0-6 weeks) after HBsAg appears
Peak
About 1 week after onset of symptoms
Becomes nondetectable
3-6 months after appearance (range, 2 weeks-2 years)
HBcAb-Total
Appearance
3-4 weeks (range, 2-10 weeks) after HBsAg appears
Peak
3-4 weeks after first detection
Becomes nondetectable
Elevated throughout life; may have slow decline to lower titers over many years
Therefore, the HBcAb-IgM level rises during active HBV infection, remains elevated during convalescence (during the time between loss of HBsAg and rise of HBsAb-Total, known as the “core window”), and becomes nondetectable in the early weeks or months of the recovery phase.
In the majority of patients, HBcAb-Total becomes detectable relatively early, before HBsAg has disappeared, and maintains elevation throughout the gap between disappearance of HBsAg and appearance of HBsAb-Total (the core window). It is elevated for many years. Thus, the HBcAb-Total level begins rising somewhat similar to an IgM antibody level and remains elevated like an IgG antibody. If it is the sole test used, HBcAb-Total could give positive results during late-stage active acute infection, convalescence, chronic infection, or recovery since, in its early stage, HBcAb-Total may coexist with HBsAg.
Fig. 17-4 HBV core antibodies (HBcAb = HBcAb-IgM + HBcAb-IgG combined).
Fig. 17-5 HBV surface antigen-antibody and core antibodies (note “core window”) *HBcAb = HBcAb-IgM + HBcAb-IgG (combined).
In many persons with HBV there is a time lag or gap in time of variable length between disappearance of the HBV surface antigen and appearance of the surface antibody. This has been called the “core window,” because the core total antibody is elevated during this time and represents the only HBV marker elevated in acute infection that is consistently detectable (the core IgM antibody is also present during part or all of the acute infection and also during part or all of the core window, but may become nondetectable during the window period, depending on when the patient specimen was obtained and the time span of the core window). The core window typically is 2-8 weeks in length but varies from 1 week (or less) to more than a year. Elevation of HBcAb-Total in itself does not mean that one has discovered the core window; a test for HBsAg (and, if nondetectable, a test for HBsAb-Total) must be performed because both HBsAg and HBsAb-Total must be absent. The core antibody nearly always is present in chronic hepatitis when surface antigen is detectable unless the patient is severely immunosuppressed.
HBcAb-Total (1) may be elevated in later stages of acute infection, in convalescence (core window), or in old infection; (2) is only useful to show old HBV infection if HBsAg and HBcAb-IgM are both negative.
Summary: Diagnosis of HBV Infection
Best all-purpose test(s) to diagnose acute or chronic HBV infection
—HBs Ag *(active infection, acute or chronic)
—HBc Ab-IgM (late acute and recent or convalescent stage)
*HBV-DNA probe may be necessary in some cases.
Hepatitis B virus e antigen and antibodies
The e antigen is usually not employed for diagnostic purposes. Since the e antigen is considered a marker for continued replication of the HBV, the e antigen is often used as an index of HBV infectivity. It is generally accepted that the presence of the e antigen (without e antibody) means several times greater potential to infect others compared to infectivity when the e antigen is not detectable. The presence of HBsAg by DNA probe is an even stronger marker for infectivity than the e antigen (as mentioned previously).
HBeAb appears either at the time e antigen disappears or within 1-2 weeks later. Since the disappearance of the e antigen occurs shortly before disappearance of the surface antigen, detection of e antibody usually means that the acute stage of HBV infection is over or nearly over and that infectivity for others is much less. In a few cases there is a short period of e-antigen and e-antibody coexistence. Immunologic tests for the e antigen and the e antibody (total) are commercially available.
HBe Ag
Appearance
About 3-5 days after appearance of HBs Ag
Peak
About the same time as HBs Ag peak
Becomes nondetectable
About 2-4 weeks before HBs Ag disappears in about 70% of cases
About 1-7 days after HBs Ag disappears in about 20% of cases
Accompanies persistant HBs Ag in 30%-50% or more patients who become chronic HBV carriers or have chronic HBV infection; however, may eventually convert to antibody in up to 40% of these patients
HBe Ab-Total
Appearance
At the same time as or within 1-2 weeks (range, 0-4 weeks) after e antigen disappears (2-4 weeks before HBs Ag loss to 2 weeks after HBs Ag loss)
Peak
During HBV core window
Becomes nondetectable
Persists for several years (4-6 years)
Summary: HBV e Antigen and Antibody
HBeAg
When present, especially without HBe Ab, suggests increased patient infectivity
HBeAb-Total
When present, suggests less patient infectivity