Hepatitis B

Hepatitis B is a viral infection caused by the hepatitis B virus (HBV). It occurs worldwide and is transmitted sexually, parenterally, or vertically. After an incubation period of 1–6 months, most patients develop asymptomatic or mild inflammation of the liver, which usually resolves spontaneously within a few weeks or months. However, 5% of adult patients and 90% of infants infected perinatally develop chronic hepatitis B (CHB). Individuals with CHB may be asymptomatic carriers or develop ongoing hepatic inflammation with an increased risk of cirrhosis and hepatocellular carcinoma. Serologic testing initially includes measurement of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). A detectable serum anti‑HBs (indicating seroconversion) is a sign of recovery or successful immunization. CHB with persistent liver inflammation is characterized by detectable HBsAg and elevated HBV DNA and ALT. Treatment of acute hepatitis B consists of supportive measures. In patients with fulminant hepatitis, liver transplantation may be necessary. For chronic active hepatitis B, nucleoside or nucleotide analogs (e.g., tenofovir) are the preferred agents for reducing viral replication and infectivity. Prophylactic immunization with a recombinant vaccine is recommended for all age groups. Other preventive measures include postexposure prophylaxis for infants born to individuals with HBsAg positive or unknown status and for unvaccinated individuals with recent exposure to HBV.

See also “Acute liver failure.”

• Prevalence: Following the introduction of the hepatitis B vaccine in 1991, rates of acute hepatitis B in the US have declined by approx. 82%. ^[1]
  • In 2016 there were an estimated 862,000 cases (∼ 0.3% of US population) in the US. ^[2][3]
  • In 2015, there were > 257 million cases worldwide (3.5% of the global population). ^[4]
  • The Western Pacific is the most affected region worldwide (6.2% of its population). ^[4]

Epidemiological data refers to the US, unless otherwise specified.

Virus

• Hepatitis B virus (HBV)
  • Member of the Hepadnavirus family
  • Circular, partially double-stranded DNA virus
• See “General virology” for more information on viral structure.

Transmission ^[4]

Frequency and patterns of transmission vary worldwide.

• Sexual: transmitted when bodily fluids come in contact with broken skin or mucous membranes (mouth, genitals, or rectum)
• Parenteral
  • Contaminated needles or instruments (including those for procedures like body piercings, tattoos, and acupuncture) that come into contact with the patient's blood
  • Blood transfusions or organ transplants
• Vertical transmission (mother-to-child transmission) ^[4]
• Common associations
  • Hepatitis C virus (HCV) and HIV-positive individuals
  • Travelers to regions where HBV is endemic ^[5]

Risk factors for HBV infection and groups at risk ^[6][7]

• Vertical transmission
  • Individuals born in countries with medium-to-high HBV prevalence (≥ 2%)
  • Unvaccinated children born to parents from countries with high HBV prevalence (≥ 8%)
  • Infants born to HBsAg-positive individuals
• Parenteral or sexual transmission
  • Injection drug use (current or previous)
  • History of sexually transmitted infections or multiple sexual partners
  • Sex workers
  • Men who have sex with men
  • Household, sexual, or needle-sharing contacts of individuals with HBV
  • Current or previously incarcerated individuals
  • Health care personnel (e.g., needlestick injury)
  • HIV infection
  • HCV infection (current or past)
  • Chronic liver disease
  • End-stage renal disease
  • Dialysis

Replication cycle of HBV ^[8][9][10]

HBV carries a DNA polymerase with both DNA and RNA-dependent functions, also known as reverse transcriptase (RT).

1. After entering the host cell's nucleus, reverse transcriptase completes the positive strand of the virus's partially double-stranded relaxed circular DNA (rcDNA).
2. The rcDNA is converted to covalently closed circular DNA (cccDNA) primarily by host enzymes in a process that is not entirely understood.
3. The cccDNA is then transcribed into viral mRNA by host RNA polymerase.
4. The viral mRNA leaves the nucleus and is translated into HBV core proteins and new reverse transcriptase in the cytoplasm.
5. Viral mRNA and reverse transcriptase are packaged into a capsid, where viral mRNA is then reverse-transcribed into viral rcDNA.
6. New viral DNA genomes are enveloped and leave the cell as progeny virions.

Acute infection ^[11]

• In acute infection, the cellular immune response causes damage to hepatocytes.
• Hepatitis B-infected hepatocytes express viral peptides ; on their surfaces → detection of the HBV-derived peptides by lymphocytes and the subsequent activation of CD8+ T cells that attack the infected hepatocytes → hepatic inflammation with destruction of hepatocytes ^[12]

Chronic infection ^[13]

Caused by viral persistence due to failing immune clearance, which promotes:

• Persistent hepatic inflammation → necrosis, mitosis, and regeneration processes → cirrhosis and cellular dysplasia → hepatocellular carcinoma (HCC)
• Integration of HBV DNA into the host genome → altered expression of endogenous genes, chromosomal instability → HCC
• HBV proteins fulfill numerous immune-modulating functions that allow them to elude detection by the immune system and avoid clearance. ^[12]

Acute hepatitis B virus infection

Acute HBV infection is defined as infection acquired in the past 6 months.

• Incubation period: 1–6 months ^[4]
• Clinical course: varies significantly ^[14][15]
  • Serum sickness-like syndrome can develop during the prodromal (preicteric) period 1–2 weeks after infection: rash, arthralgias, myalgias, fever ^[16]
  • Subclinical hepatitis (∼ 70% of cases) ^[2]
  • Symptomatic hepatitis (∼ 30% of cases; see also acute viral hepatitis)
    • Fever, skin rash, arthralgias, myalgias, fatigue
    • Nausea, anorexia
    • Jaundice
    • Right upper quadrant pain
  • Symptoms usually resolve after a few weeks, but can last up to 6 months. ^[2]
  • May develop into fulminant hepatitis (∼ 0.5% of cases)

Chronic hepatitis B virus infection ^[15]

Chronic HBV infection is defined as infection persisting for more than 6 months with detection of HBsAg and, possibly, signs and symptoms of liver damage.

• Most patients are inactive, noncontagious carriers. ^[17]
• Potential reactivation of chronic inactive hepatitis can manifest variably in the following ways:
  • Asymptomatic
  • Unspecific symptoms
    • Fatigue, malaise
    • Nausea, poor appetite
    • Unspecific abdominal pain
  • Similar to acute hepatitis
  • Hepatic failure
• The younger when infected, the more likely a patient develops chronic HBV ^[18]
  • 90% of infants
  • ∼ 50% of children between 1 and 5 years
  • Only 5% of adults

Indications for HBV screening ^[7][21][22]

Obtain initial HBV serology for the following individuals (see “Diagnostics” for interpretation of results):

• All individuals aged ≥ 18 years: at least once per lifetime
• Pregnant individuals: once per pregnancy, preferably in the first trimester (see “Perinatal hepatitis B”) ^[23]
• Individuals with risk factors for HBV infection ^[7][24]
• Patients with elevated transaminases of unknown etiology
• Blood and tissue donors ^[22]
• Individuals who require immunosuppression ^[22]
• Any individual who requests screening

Approach ^[22][25][26]

Suspected acute HBV infection

• Obtain HBV serology to confirm the diagnosis.
• Consider routine laboratory studies to assess liver damage and function.

Chronic HBV infection

• Perform a clinical evaluation to assess for:
  • Risk factors for comorbid liver disease, e.g., high-risk alcohol use, metabolic syndrome
  • Family history of HCC
  • Symptoms of cirrhosis
• Assess for liver fibrosis using, e.g.: ^[27]
  • Liver elastography
  • Noninvasive liver fibrosis scoring systems, e.g., APRI score or fibrosis-4 score
• Screen for other infections, including HCV, HDV, and HIV.
• Consider abdominal ultrasound and/or liver biopsy in certain patients.

Patients with chronic hepatitis B infection require further evaluation to identify and manage risk factors for liver-related morbidity and to identify patients eligible for antiviral therapy.

HBV serology ^[7][22][26]

• Indications
  • Screening for HBV infection
  • Patients with symptoms of acute HBV infection or chronic HBV infection
• Initial tests ; ^[7][22][25]
  • HBsAg
  • Anti-HBc
  • Anti-HBs
• Interpretation
  • HBsAg or anti-HBc IgM is detected: positive for HBV
  • Chronic HBV infection is confirmed if positive results persist for ≥ 6 months.
• Further disease markers: indicated to assess disease activity if initial tests are positive
  • HBeAg: marker of high HBV replication and transmissibility
  • Anti-HBe: An undetectable HBeAg with development of anti-HBe indicates immune clearance or an inactive carrier state.
  • HBV DNA: quantification of viral load

Interpretation of hepatitis B serology

HBeAg: BEware! Extremely infEctious.

During the window period, anti-HBc IgM and anti-HBe may be the only markers available to diagnose an acute HBV infection.

Seroconversion of HBsAg to anti‑HBs indicates resolution of acute hepatitis.

Additional laboratory studies ^[26][27]

• Liver chemistries: elevated in acute infection, normal or elevated in chronic infection
  • Mixed hyperbilirubinemia
  • Ferritin
  • ALP
  • GGT
  • ALT and AST
    • AST:ALT ratio < 1 in acute infection
    • AST:ALT ratio > 1 in chronic hepatitis may be a sign of cirrhosis.
• Laboratory diagnostics for cirrhosis
  • ↓ Albumin, ↑ INR
  • ↑ Bilirubin
  • ↓ Platelets
• Evaluation of coinfection
  • Hepatitis C serology (anti-HCV antibodies)
  • Hepatitis D (anti-HDV antibodies)
  • HIV testing
  • Hepatitis A serology (anti-HAV IgG antibodies)

Laboratory findings in chronic HBV infection are highly variable; liver function tests may be normal or only mildly abnormal.

Abdominal ultrasound ^[26][27][29]

• Indication: to evaluate liver parenchyma and biliary tract and screen for fibrosis and/or HCC
• Findings in acute hepatitis
  • ↓ Liver echogenicity
  • ↑ Echogenicity of portal vein radicle walls
• Findings in chronic hepatitis
  • ↑ Liver echogenicity
  • ↓ Echogenicity, and number, of portal vein radicle walls

Liver biopsy ^[27]

• Indications
  • Diagnostic uncertainty when results will be used to guide treatment decisions
  • Exclusion of other possible causes of liver damage in chronic disease or severely affected individuals
  • Assessment of the severity of liver disease
• Findings: See “Pathology of viral hepatitis.”

Active viral hepatitis ^[30][31]

• Eosinophilic single-cell necrosis (Councilman bodies)
• Bridging necrosis
• Kupffer cell proliferation

Chronic viral hepatitis ^[30][31]

• Formation of lymphoid follicles and mononuclear infiltrates
• Interface hepatitis (piecemeal necrosis)
  • Periportal liver cell necrosis with lymphocytic infiltration
  • The cause of interface hepatitis is a CD8 T-cell‑induced hepatocyte apoptosis.
  • Indicates chronic active hepatitis and poor prognosis
• Fibrous septa ^[32]
• Ground glass hepatocytes ; ^[33]
  • Hepatocytes with swollen transparent cytoplasm due to hyperplasia of the endoplasmic reticulum resulting in a ground glass appearance
  • Pathognomonic for hepatitis B
  • Result from increased production of viral membrane particles (HBsAg)

Ground glass hepatocytes are pathognomonic for HBV, whereas interface hepatitis, fibrous septa, and periportal infiltrates also occur in other types of chronic hepatitis.

For an overview comparing the different types of viral hepatitis see “Overview of viral hepatitides.”

The differential diagnoses listed here are not exhaustive.

Approach ^{[22][26][27][28]}

• All patients
  • Provide supportive care; and patient education as needed.
  • Consider referral for liver transplantation in patients with:
    • End-stage liver disease due to HBV
    • Fulminant hepatic failure (emergency transplantation)
• Acute hepatitis B
  • Antiviral therapy is generally not indicated.
  • In rare cases, patients may require management of acute liver failure.
• Chronic hepatitis B
  • Assess the need for antiviral therapy; refer to hepatology if indicated or uncertainty remains.
  • Patients not on antiviral therapy should be monitored at fixed intervals based on disease activity.
  • Consider indications for HCC screening.

Most acute hepatitis B infections in adults are self-limited. Antiviral therapy is not routinely indicated.

Antiviral therapy for chronic hepatitis B ^[22][26][27]

Treatment decisions should be made by a specialist and based on the risk of liver-related morbidity and mortality. The following information applies to nonpregnant individuals; for pregnant individuals, see “Management of hepatitis B in pregnancy.”

• Indications for antiviral therapy for HBV infection include:
  • Cirrhosis or advanced fibrosis
  • Acute liver failure
  • Immune active phase: ALT ≥ 2× ULN plus significantly elevated HBV DNA levels with or without HBeAg ^[22]
  • HBV reactivation: an increase in HBV DNA or change from HBsAg negative to HBsAg positive in anti-HBc-positive patients
  • Immunosuppression in HBV-positive patients
  • Coinfection with HCV or HIV
  • Family history of HCC
• Agents: For details on mechanisms of action and adverse effects, see “Overview of antivirals against hepatitis B” and “Overview of antivirals against both hepatitis B and C.”
  • Nucleotide reverse transcriptase inhibitors (NtRTIs), e.g., tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)
  • Nucleoside reverse transcriptase inhibitors (NRTIs), e.g., entecavir (ETV)
  • Pegylated interferon alfa (PEG-IFN-α)
• Treatment regimens
  • NtRTIs or NRTIs; are usually the preferred option; treatment duration varies but can be indefinite.
  • PEG-IFN (e.g., for 48 weeks) is a treatment option for certain patient groups (e.g., younger patients with compensated liver disease, patients with HDV coinfection).

Treatment goals include immunologic cure (i.e., clearance of HBsAg and sustained HBV DNA suppression) and reduction of liver-related morbidity and mortality.

Pegylated interferon is a pregnancy category C drug, and is contraindicated in patients who have decompensated cirrhosis or uncontrolled psychiatric conditions.

Supportive care and patient education

• Avoid hepatotoxic medications.
• Advise alcohol cessation.
• Provide treatment of alcohol use disorder and/or management of substance use disorder as indicated.
• Provide counseling on weight and diet changes to encourage weight loss as indicated. ^[34]
• Educate patients on measures to prevent HBV transmission, including: ^[22]
  • Vaccinating household and sexual contacts
  • Abstaining from blood and tissue donation
  • Practicing safer sex (e.g., using condoms)
  • Covering open wounds
  • Cleaning up blood spills with diluted bleach
  • Avoiding IV drug use or practicing harm reduction strategies if injecting drugs
  • Avoiding sharing of personal care items, such as razors, toothbrushes, glucometers, and injection equipment

HBV can survive outside the body (e.g., in dried blood on a surface) for at least 7 days, and remains infectious during that time. ^[5]

Acute liver failure

• Epidemiology: Affects ∼ 1% of acute HBV infections ^[35]
• Diagnosis: evidence of hepatic injury (e.g., ↑ transaminases, ↑ bilirubin), hepatic encephalopathy, and coagulopathy (INR > 1.5).
• Management: See “Acute liver failure.”

Long-term complications of hepatitis B ^[15]

• Liver cirrhosis
• Hepatocellular carcinoma (HCC) ^[36]
• Extrahepatic manifestations (10–20% of cases) ^[37]
  • Polyarteritis nodosa (strong correlation: in 36% of cases, hepatitis B virus is the causative agent) ^[38]
  • Glomerulonephritis
    • Membranous glomerulonephritis (more common)
    • Membranoproliferative glomerulonephritis type 1 (less common)
  • Aplastic anemia
• Reactivation of previous HBV infection due to immunosuppression
• Post‑hepatitis syndrome
  • Chronic fatigue, weakness
  • Nausea, loss of appetite
  • Possible upper quadrant pain

We list the most important complications. The selection is not exhaustive.

Vaccination ^[5][39]

• The hepatitis B vaccine (HBV vaccine) is an inactivated recombinant vaccine that contains a subunit of the hepatitis B virus. ^[40]
  • Single-antigen HBV vaccine
  • Three-antigen HBV vaccine
  • Combination HBV vaccines:
    • DTaP-HepB-IPV vaccine
    • DTaP-IPV-Hib-HepB vaccine
    • HepA-HepB vaccine
• The first dose of a 3-dose HBV vaccine series should be administered to all infants at birth
  • Birth weight ≥ 2 kg: within 24 hours after birth
  • Birth weight < 2 kg: at 1 month of age or hospital discharge (whichever occurs first)
• Catch-up vaccination
  • Unvaccinated children and adults aged < 59 years: Recommend for all.
  • Unvaccinated adults aged ≥ 60 years
    • With risk factors for HBV infection: Recommend vaccination.
    • Without risk factors for HBV infection: Offer vaccination.
• See “ACIP immunization schedule” for details.

Infants and children who did not receive a dose of vaccine at birth should receive the first dose as soon as possible.

Hepatitis B postvaccination serology ^[5][24]

Indications

• Individuals at risk of occupational exposure (e.g., health care workers)
• Immunocompromised individuals
• Patients receiving hemodialysis
• Sexual partners of HBsAg-positive persons
• Infants born to individuals with HBsAg positive or unknown status

Method

• Adults
  • Test: anti-HBs titers
  • Timing: 1–2 months after completion of vaccination
• Infants ^[41]
  • Tests: anti-HBs titers and HBsAg
  • Timing: at ≤ 9 months of age and ≥ 1 month after the last dose of HBV vaccine

In infants, do not check postvaccination serology until they are least 9 months of age and their last HBV vaccine dose was at least 1 month ago. ^[42]

Follow up

• Anti-HBS ≥ 10 IU/mL: immune, and no further management is required
• Anti-HBS < 10 IU/mL: non-immune
  • Additional dose(s) and repeat postvaccination serology are required. Choose one of the following options:
    • Administer 1 dose of HBV vaccine and repeat serology after 1–2 months. ^[5][24]
    • Administer a second 3-dose HBV vaccine series and repeat serology after 1–2 months. ^[5][24]
  • If repeat anti-HBs titers remain < 10 IU/mL after two complete series of HBV vaccine, the individual is considered an HBV vaccine nonresponder.
    • Check HBsAg and anti-HBc levels to assess for HBV infection. ^[43]
    • If HBsAg negative, counsel on measures to prevent HBV transmission.
    • If exposed to HBV, see “Hepatitis B postexposure prophylaxis.”
• HBsAg positive (in infants): Provide treatment for hepatitis B infection.

Hepatitis B postexposure prophylaxis ^[5]

For perinatal postexposure prophylaxis recommendations, see “Infants born to individuals with HBsAg positive or unknown status.”

• Exposure is defined as percutaneous or mucosal contact with blood or body fluids.
• Irrigate exposed tissue. ^[5]
  • Mucous membranes: water
  • Wounds and skin: soap and water
• HBV PEP recommendations differ for exposures in occupational and nonoccupational settings.
• Depending on immunization status, affected individuals will receive one of the following:
  • Active immunization (i.e., hepatitis B vaccination)
  • Passive immunization (i.e., hepatitis B immune globulin)
  • Combined active and passive immunization
  • No intervention

Occupational exposure (i.e., health care providers)

• Verify vaccination status and immune response in the exposed health care provider (HCP).
  • If series is complete and anti-HBs ≥ 10 mIU/mL is already documented, source patient HBsAg is not required.
  • If series is complete and immune response is unknown, measure exposed HCP anti-HBs and source patient HBsAg.
  • If unvaccinated or series is incomplete, measure source patient HBsAg only.
• See “Health care personnel exposures” for additional information, e.g., on needlestick injuries.

Modification of work duties and sexual practices of HCPs following exposure to a patient with a positive or unknown HBsAg status is unnecessary during the 6-month follow-up period. Pregnancy and breastfeeding are safe during this time. ^[5]

HCPs exposed to a patient with a positive or unknown HBsAg status should not donate blood products, organs, tissue, and/or semen during the 6-month follow-up period. ^[5]

Nonoccupational exposure

• Exposure types include needle sharing and high-risk sexual contact.
• Obtain vaccination history and measure HBsAg, anti-HBs, and anti-HBc in unvaccinated exposed patients.
• Do not withhold or delay vaccination for prevaccination testing.

Approach ^[5][7][45]

• Perform universal screening for HBV in pregnancy, preferably in first trimester.
• If anti-HBs < 10 mIU/mL in a pregnant individual, initiate a 3-dose HBV vaccine series.
• If HBV serology indicates infection, manage HBV infection in pregnancy, including:
  • Specialist referral
  • Case reporting to relevant public health agencies
  • Monitoring of HBV DNA and ALT
  • Initiation of antiviral therapy in third trimester if HBV DNA > 200,000 IU/mL
• Provide appropriate immunoprophylaxis to infants born to individuals with HBsAg positive or unknown status.
  • Administer first dose of HBV vaccine within 12 hours of birth.
  • Infants born to HBsAg positive individuals: Additionally, administer 1 dose of HBIG within 12 hours of birth.

Hepatitis B in pregnancy ^[22][27][45]

The prevalence of HBV infection in pregnant individuals in the US is 0.9%. ^[46]

Screening for HBV infection in pregnancy ^[7][23][45]

Method

• During each pregnancy, as part of initial prenatal screening for comorbidities during the first trimester
  • All pregnant individuals: Test for HBsAg.
  • Individuals with any of the following: Measure anti-HBs and anti-HBc titers.
    • No documented completion of HBV vaccine series
    • No documented initial HBV serology after 18 years of age
    • Risk factors for HBV infection developed after documentation of initial HBV serology and/or are ongoing
• When admitted for delivery, screen individuals if either:
  • Screening was not done in prenatal period
  • Or ongoing risk factors for HBV infection are present

Further management

• Anti-HBs < 10 mIU/mL: Administer a 3-dose hepatitis B vaccine series.
• HBV serology indicating infection: See “Management of hepatitis B in pregnancy.”

Management of HBV infection in pregnancy ^[47][48]

During pregnancy

• For patients with newly positive HBsAg on prenatal screening, obtain additional HBV serology, including:
  • Initial tests (i.e., anti-HBs, anti-HBc) if not already done
  • Tests for additional disease markers (e.g., HBV DNA level, HBeAg, anti-HBe, and ALT level)
• Refer to infectious disease and/or hepatology specialists.
• Report case to state and local perinatal hepatitis B prevention programs (see “Tips and Links”). ^[44]
• Monitor HBV DNA and ALT every 3 months.
• Evaluate the need for antiviral therapy with tenofovir disoproxil fumarate (preferred drug) ; ^[27][48]
  • Standard indications for antiviral therapy for HBV infection (e.g., cirrhosis): A hepatologist may recommend therapy throughout pregnancy to prevent complications. ^[27][48]
  • HBV DNA > 200,000 IU/mL: Initiate therapy during the third trimester to reduce the risk of vertical transmission.

Antiviral treatment is recommended in pregnant individuals with an HBV viral load > 200,000 IU/mL to reduce the risk of vertical transmission. ^[45]

Pegylated interferon alfa is a pregnancy category C drug and is therefore not recommended as first-line therapy for HBV infection in pregnant individuals. ^[48]

During delivery

• HBV infection is not an indication for cesarean delivery. ^[22][45]
• Follow standard precautions. ^[49]

After delivery

• Breastfeeding may be started immediately if there are no contraindications (e.g., cracked or bleeding nipples), regardless of whether individuals:
  • Have HBsAg positive or unknown status ^[5]
  • Are receiving antiviral therapy ^[22][45]
• Continue close monitoring (e.g., of HBV DNA and ALT levels) for at least 6 months postpartum. ^[47]

Hepatitis B in infants ^[5][24][45]

Management of infants born to individuals with HBsAg positive or unknown status

These infants are at risk of acquiring perinatal HBV infection and developing complications.

• Administer the birth dose of HBV vaccine to all infants within 12 hours of life.
• If the birthing parent's HBsAg status is unknown, obtain test immediately.
• Determine the need for HBIG.
  • This depends on the birthing parent's HBsAg status and infant's birth weight (see table).
  • If HBIG and HBV vaccine are administered concurrently, they should be given in different limbs.
• Report case to state and local perinatal hepatitis B prevention programs (see “Tips and Links”).

Infants born to HBsAg-positive individuals should receive 1 dose of HBIG and the first dose of HBV vaccine within 12 hours of birth. ^[5][24]

If birth weight is < 2000 g, the dose of HBV vaccine given at birth does not count towards the vaccine series. ^[5]

Infants with HBV infection

• Transaminases are usually normal or only mildly elevated.
• Acute hepatitis B may develop in rare cases.
• Chronic HBV infection ^[5]
  • Develops in 80–90% of infants infected at birth
  • 25% of those with chronic infection develop cirrhosis or liver cancer, leading to premature mortality.