Hepatitis B

Clinical Description

Identification

A small proportion of acute hepatitis B virus (HBV) infections may be clinically recognized; less than 10% of children and 30%–50% of adults with acute hepatitis B virus (HBV) infection show icteric disease. In those with clinical illness, the onset is usually insidious, with anorexia, vague abdominal discomfort, nausea and vomiting, sometimes arthralgias and rash, often progressing to jaundice. Fever may be absent or mild. Severity ranges from unapparent cases detectable only by liver function tests to fulminating, fatal cases of acute hepatic necrosis. The case-fatality rate is about 1%; higher in those over 40. Fulminant HBV infection also occurs in pregnancy and among newborns of infected mothers.

Chronic HBV infection is found in 0.5% of adults in North America and in 0.1%–20% in other parts of the world. After acute HBV infection, the risk of developing chronic infection varies inversely with age; chronic HBV infection occurs among about 90% of infants infected at birth, 20%–50% of children infected from 1 to 5 years, and 1%–10% of persons infected as older children and adults. Chronic HBV infection is common in persons with immunodeficiency. Persons with chronic infection may or may not have a history of clinical hepatitis. About one-third have elevated aminotransferases; biopsy findings range from normal to severe necro-inflammatory hepatitis, with or without cirrhosis. An estimated 15%–25% of persons with chronic HBV infection will die prematurely of either cirrhosis or hepatocellular carcinoma. HBV is the cause of up to 80% of all cases of hepatocellular carcinoma worldwide.

Infectious Agent

Hepatitis B virus (HBV), a hepadnavirus, is a 42-nanometer partially double-stranded DNA virus composed of a 27-nanometer nucleocapsid core (HBcAg), surrounded by an outer lipoprotein coat containing the surface antigen (HBsAg). HBsAg is antigenically heterogeneous, with a common antigen (designated a) and 2 pairs of mutually exclusive antigens (d, y, w (including several subdeterminants) and r), resulting in 4 major subtypes: adw, ayw, adr and ayr. The distribution of subtypes varies geographically; because of the common “a” determinant, protection against one subtype appears to confer protection against the other subtypes, and no differences in clinical features have been related to subtype. Genotype classification based on sequencing of genetic material has been introduced and is becoming the standard: HBV is currently classified into 8 main genotypes (A–H). There is growing evidence of differences in severity of liver disease between some HBV genotypes.


Diagnosis

Demonstration in sera of specific antigens and/or antibodies confirms diagnosis. Three clinically useful antigen-antibody systems are identified for hepatitis B:

  • Hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs)
  • Hepatitis B core antigen (HBcAg) and antibody to HBcAg (anti-HBc)
  • Hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe).

Commercial kits are available for all markers except HBcAg. HBsAg can be detected in serum from several weeks before onset of symptoms to days, weeks or months after onset; it is present in serum during acute infections and persists in chronic infections. The presence of HBsAg indicates that the person is infectious. Anti-HBc appears at the onset of illness and persists indefinitely. Demonstration of anti-HBc in serum indicates HBV infection, current or past; high titers of IgM anti-HBc occur during acute infection—IgM anti-HBc usually disappears within 6 months but can persist in some cases of chronic hepatitis; this test may reliably diagnose acute HBV infection. The presence of HBeAg is associated with relatively high infectivity.


Epidemiology

Mode of Transmission

Body substances capable of transmitting HBV include: blood and blood products; saliva (although no outbreaks of HBV infection due to saliva alone have been documented); cerebrospinal fluid; peritoneal, pleural, pericardial and synovial fluid; amniotic fluid; semen and vaginal secretions; any other body fluid containing blood; and unfixed tissues and organs. The presence of antigen or viral DNA (HBV-DNA above 105 copies/mL) indicates high virus titer and higher infectivity of these fluids.

Transmission occurs by percutaneous (IV, IM, SC, intradermal) and mucosal exposure to infective body fluids. Since HBV is stable on environmental surfaces for at least 7 days, indirect inoculation of HBV can occur via inanimate objects. Fecal-oral or vector-borne transmission has not been demonstrated.

Major modes of HBV transmission include sexual or close household contact with an infected person, perinatal mother-to-infant transmission, injecting drug use and nosocomial exposure. Sexual transmission from infected men to women is about 3 times more efficient than that from infected women to men. Anal intercourse, insertive or receptive, is associated with an increased risk of infection. Transmission of HBV in households primarily occurs from child to child. Communally used razors and toothbrushes have been implicated as occasional vehicles of HBV transmission in this setting. Perinatal transmission is common, especially when HBV-infected mothers are also HBeAg-positive or if they are highly viremic. The rate of transmission from HBsAg-positive, HBeAg-positive mothers is more than 70%; from HBsAg-positive, HBeAg-negative mothers it is less than 10%. Anti-HBe antibody-positive chronic hepatitis B was first described in patients of the Mediterranean Basin, where about 20% of HBsAg carriers were positive for anti-HBe antibodies and showed detectable serum levels of HBV DNA with liver necro-inflammation. The infecting HBV variants show mutations in the precore region that hamper HBeAg production. The HBeAg-negative form of chronic hepatitis B is present worldwide, and has been associated with transmission. Transmission through injecting drug use occurs though transfer of HBV-infected blood by sharing syringes and needles either directly or through contamination of drug preparation equipment. Nosocomial exposures such as transfusion of blood or blood products, hemodialysis, acupuncture and needle-stick or other “sharps” injuries sustained by hospital personnel have all resulted in HBV transmission. IG, heat-treated plasma protein fraction, albumin and fibrinolysin are considered safe.

Incubation Period

Usually 45–180 days, average 60–90 days. As short as 2 weeks to the appearance of HBsAg, and rarely as long as 6–9 months; variation is related in part to amount of virus in the inoculum, mode of transmission, and host factors.

Period of Communicability

All persons who are HBsAg-positive are potentially infectious. Blood from experimentally inoculated volunteers has been shown to be infective weeks before the onset of first symptoms and to remain infective through the acute clinical course of the disease. The infectivity of chronically infected individuals varies from high (HBeAg-positive, HBV-DNA above 105 copies/mL) to modest (anti-HBe-positive).

Reservoir

Humans. Chimpanzees are susceptible, but an animal reservoir in nature has not been recognized. Closely-related hepadnaviruses are found in woodchucks, ducks, ground squirrels and other animals, such as snow leopards and German herons; none cause disease in humans.

Susceptibility

Susceptibility is general. Disease is often milder and anicteric in children; in infants it is usually asymptomatic. Protective immunity follows infection if antibodies to HBsAg (anti-HBs) develop and HBsAg is negative. Persons with Down's syndrome, lymphoproliferative disease, HIV infection, immunosuppression and those on hemodialysis appear more likely to develop chronic infection.


Prevention and Control

1)    Preventive measures:

a)    Effective hepatitis B vaccines have been available since 1982. Two types of hepatitis B vaccines have been licensed and have been shown to be safe and highly protective against all subtypes of HBV. The first was prepared from plasma from HBsAg-positive persons, and was widely used in the past. The second, from recombinant DNA (rDNA), is produced by using HBsAg synthesized by yeast or cell-lines, into which a plasmid containing the gene for HBsAg has been inserted; this has now replaced the earlier vaccine. Combined passive-active immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and vaccine has been shown comparable to vaccine alone in stimulating anti-HBs titers, but is expensive and not available in all countries. Several combined vaccines (e.g. hepatitis A & B and tetra- and pentavalent vaccines) have been licensed and show comparable efficacy.

i)    In all countries, routine infant immunization should be the primary strategy to prevent HBV infection. Immunization of successive infant cohorts produces a highly immune population and suffices to interrupt transmission. In countries with high endemicity for HBV, routine infant immunization rapidly eliminates transmission because virtually all chronic infections are acquired among young children. Where HBV endemicity is low or intermediate, immunizing infants alone will not substantially lower disease incidence for about 15 years, because most infections occur among adolescents and young adults; vaccine strategies for older children, adolescents and adults may be desirable. Strategies to ensure high vaccine coverage of successive age group cohorts are likely to be most effective in eliminating HBV transmission. In addition, immunization strategies can be targeted to high-risk groups, which account for most cases among adolescents and adults.

ii)    Testing to exclude adolescent or adult people with pre-existing anti-HBs or anti-HBc is not required prior to immunization, but may be considered as a cost-saving method in countries where the level of preexisting infection is high.

iii)    Immunity against HBV persists for at least 15 years after successful immunization, and booster injections are not recommended.

iv)    Vaccines licensed in different parts of the world may have varying dosages and schedules; in the USA they are most commonly administered in 3 IM doses: for infants, the first dose is given at birth or at 1–2 months of age with subsequent doses 1 to 2 and 6 to 18 months later. For infants born to HBsAg positive women, the schedule should be birth, 1–2 and 6 months of age. These infants should also receive 0.5 ml of HBIG. The dose of vaccine varies by manufacturer. In mid-1999, it was hypothesized that very small infants who receive multiple doses of vaccines containing thiomersal/thimerosal would be at risk of receiving more than the recommended limits for mercury exposure as set out by regulatory guidelines. On the basis of this hypothetical risk of mercury exposure, elimination of thiomersal/thimerosal in vaccines was implemented, although pharmacological and epidemiological data render it highly unlikely that such vaccines give rise to neurological adverse effects. A significant number of hepatitis B vaccines available today are antigen preservative-free.

v)    Pregnancy is not a contraindication for receiving hepatitis B vaccine.

b)    The current WHO hepatitis B prevention strategy is based on routine universal newborn or infant immunization. The greatest fall in incidence and prevalence of hepatitis B is in countries with high vaccine coverage at birth or in infancy. Vaccination of adolescents is also valuable, as it protects against transmission through sexual contact or injecting drug use. The current hepatitis B prevention strategy in the USA includes the following aspects:

i)    Screening of all pregnant women for the presence of HBsAg, providing HBIG and hepatitis B vaccine to infants of HBsAg positive mothers, and providing hepatitis B vaccine to susceptible household contacts

ii)    Pregnant women who are identified as being at risk for HBV infection during pregnancy (e.g., more than one sex partner during the previous 6 months, previous evaluation or treatment for an STD, recent or current injecting-drug use, or having had an HBsAg-positive sex partner) should be vaccinated

iii)    Providing routine hepatitis B immunization for all infants

iv)    Providing catch-up immunization to previously unimmunized children, with highest priority for children aged 11–12 years, in groups with high rates of chronic HBV infection (Alaskan natives, Pacific Islanders, first generation immigrants from countries with high prevalence of chronic HBV infection)

v)    Intensified efforts to immunize adolescents and adults in defined risk groups.

c)    Persons at high risk who should routinely receive pre-exposure hepatitis B immunization include:

i)    Those who are diagnosed as having recently acquired other STDs and people who have a history of sexual activity with more than one partner in the previous 6 months

ii)    Men who have sex with men

iii)    Sexual partners and household contacts of HBsAg positive persons

iv)    Inmates of juvenile detention facilities, prisons and jails

v)    Health care and public safety workers who perform tasks involving contact with blood or blood-contaminated body fluids

vi)    Clients and staff of institutions for the developmentally disabled

vii)     Hemodialysis patients

viii)    Patients with bleeding disorders who receive blood products

ix)    International travelers who plan to spend more than 6 months in areas with intermediate to high rates of chronic HBV infection (2% or greater), and who will have close contact with the local population.

d)    Adequately sterilize all syringes and needles (including acupuncture needles) and lancets for finger puncture; use disposable, mono-use equipment whenever possible. A sterile syringe and needle are essential for each individual receiving skin tests, parenteral inoculations or venepuncture. Enforce aseptic sanitary practices in tattoo parlors, including proper disposal of sharp or cutting tools, and discourage traditional tattooing and scarring practices.

e)    In blood banks, all donated blood should be tested for HBsAg by sensitive tests; reject as donors all persons with a history of viral hepatitis, those who have a history of injecting drug use or show evidence of drug addiction, or those who have received a blood transfusion or tattoo within the preceding 6 months. Avoid using paid donors.

f)    Limit administration of unscreened whole blood or potentially hazardous blood products to those in life-threatening need of such therapeutic measures.

g)    Maintain surveillance for all cases of post-transfusion hepatitis; keep a register of all people who donated blood for each case. Notify blood banks of potential carriers so that future donations may be identified promptly.

h)    Although few public health authorities have established recommendations for HBV-positive health care workers, there is general consensus that HBeAg-positive HBV carriers should not perform exposure-prone surgery or similar treatment of patients. In several countries (including the USA), medical and dental personnel infected with HBV and who are HBeAg-positive and/or have significant levels of viremia, should not perform invasive procedures unless they have sought counsel from an expert review panel and have been advised under what circumstances—if any—they may continue to perform these procedures.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Official report obligatory in some countries; Class 2

b)    Isolation: Universal precautions to prevent exposures to blood and body fluids.

c)    Concurrent disinfection: Of equipment contaminated with blood or infectious body fluids.

d)    Quarantine: Not applicable.

e)    Immunization of contacts: Products available for post-exposure prophylaxis include hepatitis B vaccine and HBIG. Administer hepatitis B vaccine and, when indicated, HBIG as soon as possible after exposure.

i)    Infants born to HBsAg positive mothers should receive a single dose of vaccine within 12 hours of birth and, where available, HBIG (0.5 ml IM), the first dose of vaccine to be given concurrently with HBIG but at a separate site; second and third doses of vaccine (without HBIG) 1–2 and 6 months later. It is recommended to test the infant for HBsAg and anti-HBs at 9–15 months of age to monitor the success or failure of prophylaxis. Infants who are anti-HBs positive and HBsAg negative are protected and do not need further vaccine doses. Infants found to be anti-HBs negative and HBsAg negative should be re-immunized.

ii)    After percutaneous (e.g. needle-stick) or mucous membrane exposures to blood that might contain HBsAg, a decision to provide post-exposure prophylaxis must include consideration of: (i) whether the source of the blood is available; (ii) the HBsAg status of the source; and (iii) the hepatitis B immunization status of the exposed person. For previously unimmunized persons exposed to blood from an HBsAg positive source, a single dose of HBIG (0.06 ml/kg, or 5 ml for adults) should be given as soon as possible, but at least within 24 hours of high-risk needle-stick exposure, and the hepatitis B vaccine series should be started. If active immunization cannot be given, another dose of HBIG should be given 1 month after the first. HBIG is not usually given for needle-stick exposure to blood that is not known or highly suspected to be positive for HBsAg, since the risk of infection in these instances is small; however, initiation of hepatitis B immunization is recommended if the person has not previously been immunized. For previously immunized persons exposed to an HBsAg positive source, post-exposure prophylaxis is not needed in cases with a protective antibody response to immunization (anti-HBs titer of 10 milli-IUs/mL or greater). For persons whose response to immunization is unknown, hepatitis B vaccine and/or HBIG should be administered.

iii)    After sexual exposure to a person with acute HBV infection, application of hepatitis B vaccine together with a single dose of HBIG (0.06 ml/kg) is recommended if it can be given within 14 days of the last sexual contact. For all exposed sexual contacts of persons with acute and chronic HBV infection, vaccine should be administered.

f)    Investigation of contacts and source of infection.

g)    Specific treatment: No specific treatment is available for acute hepatitis B. In fulminant hepatitis B, uncontrolled reports suggest some efficacy of lamivudine; therefore, it may be tried (as may any other rapidly acting antiviral drug) if there is evidence of ongoing HBV replication. Two major groups of antiviral treatment have been licensed for the treatment of chronic hepatitis B in the USA and many other countries. These include interferon alpha (IFNa, or PEG-IFNa) and nucleoside or nucleotide analogues such as lamivudine, adefovir, entecavir and telbivudine. Many other drugs are being evaluated (e.g. tenofovir, emtricitabine, clevudine, elvucitabine, valtorcitabine, and amdoxovir). Patients who are candidates for therapy should have evidence of severe necro-inflammatory disease; treatment is most effective in individuals in the high-replicative phase (HBeAg positive) of infection, because these are the most likely to be symptomatic, infectious, and at risk of long-term sequelae. Although decision to treat and the choice of the appropriate therapy remain challenging, considerable progress has been made in the treatment of chronic hepatitis B. Studies show that alpha interferon is successful in arresting viral replication in about 25%–40% of treated patients. Approximately 10% of patients who respond lose HBsAg 6 months after therapy. Clinical trials of long-term treatment with nucleoside or nucleotide analogues have demonstrated sustained clearance of HBV DNA from serum, followed by improvements in serum aminotransferase levels and histological improvement. The majority of the patients will require prolonged treatment in order to maintain suppression of viral replication. Consequently, treatment costs in both developing and developed countries are currently prohibitively high. The efficacy of combination therapy will have to be studied further, but it is likely to diminish the occurrence of virus mutants resistant to treatment. These medications have significant side-effects that require careful monitoring.

3)    Epidemic measures:

When 2 or more cases occur in association with some common exposure, search for additional cases. Institute strict aseptic techniques. If a plasma derivative such as antihemophilic factor, fibrinogen, pooled plasma or thrombin is implicated, withdraw the lot from use and trace all recipients of the same lot in a search for additional cases.

4)    Disaster implications:

Relaxation of sterilization precautions and emergency use of unscreened blood for transfusions may result in an increased number of cases.

5)    International measures:

None.

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.


Available Vaccines

WHO-Prequalified hepatitis B vaccines
 

Common Disease Taxonomy: