Chronic Hepatitis B Virus (HBV) Infection

Background

• Hepatitis B virus (HBV) is an enveloped, partially double-stranded circular DNA virus of the Hepadnaviridae family that may cause an acute self-limited infection, fulminant hepatic failure, or may develop into a chronic disease.
• Globally, approximately 240 million patients are infected with hepatitis B, with prevalence ranging from < 2% in the United States and other western countries to over 5% in some parts of East Asia, Southeast Asia, and sub-Saharan Africa.
• In the United States, the overall incidence is lower due to preventive strategies such as vaccination, about 800,000 to 1.4 million people have chronic HBV infection.
• HBV is transmitted via infected body fluids, as with sexual contact, needle sharing, needlestick injury, or perinatally.
• The risk of progression from acute to chronic infection is inversely related to the patient age at the time of the initial infection; about 90% of infant infections, 25%-50% of infections in children aged 1-5 years, and < 5% of infections in older children and adults result in chronic disease.
• Chronic HBV infection can be divided into different phases depending on the level of immune activity.
  • 4 successive phases:
    • immune-tolerant phase - little hepatic inflammation with normal liver tests despite elevated HBV DNA and positive HBV e antigen
    • immune-active phase - hepatic inflammation with elevated liver tests, decreased HBV DNA levels compared to immune-tolerant phase, and ultimately loss of HBV e antigen and the appearance of HBV e antibody
    • inactive carrier phase - normal liver tests, low HBV DNA levels, and HBV e antigen negative
    • reactivation phase - normal or high liver tests, high HBV DNA levels, remain HBV e antigen negative or revert to HBV e antigen positive
  • Not all patients go through the 4 phases, and immune clearance and reactivation phases can sometimes be prolonged.
• Extrahepatic manifestations may include polyarteritis nodosa, cryoglobulinemia, and renal disease.
• All-cause mortality associated with HBV infection is about 6%-8% and 15%-40% of untreated patients with chronic hepatitis B develop serious sequelae such as cirrhosis, and hepatocellular carcinoma.

Evaluation

• Patients with chronic HBV infection may have no evidence of liver disease, or may have spectrum of disease ranging from chronic hepatitis to cirrhosis or liver cancer.
• Confirm the diagnosis using serologic testing and HBV viral load testing. The hepatitis B viral serologic panel includes the following:
  • hepatitis B surface antigen (HBsAg)
  • hepatitis B surface antibody (HBsAb)
  • hepatitis B core antibody
  • hepatitis B "e" antigen (HBeAg)
  • hepatitis B envelope antibody (HBeAb)
• Chronic infection is characterized by a positive HBsAg test that is persistently positive for > 6 months. HBeAg is variably positive with chronic infection.
• Additional testing that may help determine the disease severity, the disease stage, and the need for treatment includes:
  • hepatitis B viral load
  • liver function tests
  • liver imaging such as ultrasound elastography (may be considered for noninvasive assessment of fibrosis)
  • liver biopsy
• Screen patients diagnosed with hepatitis B infection for coinfections including hepatitis C virus, hepatitis D virus, and HIV.
• Vaccinate all non-immune patients against hepatitis A virus (HAV) (i.e. anti-HAV immunoglobulin G negative).
• Recommend minimization of alcohol use to prevent disease progression.

Management

• As chronic HBV infection cannot be cured, the goals of treatment are to suppress viral replication, to halt progression of liver disease, and to prevent hepatocellular carcinoma.
• The recommended treatment timing and duration vary by the status of chronic HBV.
  • immune-tolerant chronic hepatitis B:
    • No antiviral therapy is indicated for most patients.
    • Consider antiviral therapy in patients > 40 years old with a normal alanine aminotransferase (ALT) level and elevated HBV DNA (≥ 1,000,000 units/mL) and a liver biopsy indicating moderate-to-severe necroinflammation or fibrosis.
  • Immune-active chronic hepatitis B (HBeAg-negative or HBeAg-positive):
    • Antiviral therapy is recommended to reduce the risk of liver-associated complications.
    • Preferred drug options for initial therapy include peginterferon and nucleoside/nucleotide analogs (NAs) entecavir and tenofovir.
  • HBeAg-positive, immune-active chronic hepatitis B with seroconversion to anti-HBe on nucleoside analog (NA) therapy:
    • If no cirrhosis, consider discontinuing NA therapy after a period of treatment consolidation.
    • If cirrhosis present, consider indefinite antiviral therapy to reduce the risk of potential clinical decompensation and death, unless strong indication for treatment discontinuation.
  • Chronic hepatitis B with persistent low-level viremia on NA monotherapy:
    • If HBV DNA level is persistently < 2,000 units/mL, consider continuation of NA monotherapy regardless of the ALT level.
    • If there is detection of virologic breakthrough, consider:
      • the potential for medication non-compliance and reinforce taking medications as prescribed with laboratory monitoring
      • a switch to another antiviral monotherapy with a high barrier to resistance if compliance confirmed OR
      • the addition of a second antiviral drug that does not have cross-resistance
  • Chronic hepatitis B with cirrhosis and low-level viremia (< 2,000 units/mL):
    • If compensated cirrhosis, consider antiviral therapy regardless of the ALT level to reduce the risk of decompensation.
    • If decompensated cirrhosis, give indefinite antiviral therapy regardless of the HBV DNA level, HBeAg status, or ALT level to reduce the risk for worsening liver-associated complications.
• Treatment failure:
  • May be associated with primary nonresponse, poor medication adherence, or the development of resistance.
  • Resistance testing can be used to distinguish primary nonresponse from a drug-resistant strain, and to guide the selection of a rescue regimen along with the patient drug history.

Prevention

• Vaccination is recommended for all children, and in the United States vaccination should be offered to all unvaccinated adults, particularly those at high risk for infection.
• Recommendations for postexposure prophylaxis vary with the host immune status and the type of exposure and may include the use of hepatitis B immunoglobulin, vaccination, or both.
• Prophylactic oral antiviral therapy recommended in immunocompromised patients
  • with detectable HBsAg at high risk for HBV reactivation due to certain chemotherapy or immunosuppressive therapy.
  • without detectable HBsAg, but with antibodies against hepatitis B core antigen (anti-HBc positive) receiving B cell depleting agents (such as rituximab) or undergoing stem cell transplantation.