Course of HBV infection and reactivation HBV is transmitted by perinatal, percutaneous, or sexual exposure, and potentially other close person to person contact (1)
- exposure to HBV can result in acute infection
- from subclinical to icteric hepatitis, and even, in rare cases, fulminant hepatitis
- in adults, more than 95% of HBV infections are self-limited, with the disappearance of serum HBV DNA, appearance of hepatitis B core antibody (anti-HBc), HBeAg to anti-HBe seroconversion, and, finally, HBsAg to hepatitis B surface antibody (anti- HBs) seroconversion during recovery
- despite the serologic resolution, traces of HBV DNA may persist in the liver for years or decades
- in contrast, perinatal transmission leads to chronic infection in 90% of newborns in the absence of appropriate HBV immunoprophylaxis
A minority of individuals with chronic infection may eventually achieve HBsAg clearance with or without the appearance of anti-HBs
- occurs either spontaneously or rarely by antiviral therapy
- similar to individuals who naturally recover from acute infection, and has been classified as the “HBsAg negative phase” in the course of chronic infection
- HBV DNA may persist in the liver, with undetectable or fluctuating very low level viremia
HBV clearance and persistence
- clinical recovery does not necessarily indicate a complete cure of HBV infection, as a small amount of HBV genome, covalently closed circular DNA (cccDNA) as well as integrated viral DNA, may persist in the nucleus of hepatocytes
- HBV persistence can be regarded as a shift from an “overt” to an “occult” state, depending on the detection of viral markers
- overt state, known as chronic infection - defined as persistence of HBsAg for six months or more after acute infection with HBV
- occult infection - defined as the presence of HBV genome in the liver, with the loss of detectable serum HBsAg
- presence of cccDNA that is fully replication competent is essential to establish occult HBV infection
- theoretically, a complete cure is possible when HBV cccDNA is eradicated, and thereby the potential for viral replication is impossible
- HBV reactivation can occur spontaneously or
as a complication of therapy for a concomitant medical condition
- HBV reactivation starts with viral replication, followed by liver injury that results from a delayed immune reconstitution
- severity of liver injury varies greatly among ndividuals, ranging from an asymptomatic rise in alanine transaminase levels to severe hepatitis, or even liver failure
Therefore the definitions of HPV clearance and persistence are:
- Resolution of HBV infection
- sustained, undetectable HBsAg and HBV DNA in serum with or without seroconversion to anti-HBs after resolution of acute infection, or recovery from chronic infection either spontaneously, or following antiviral therapy (also known as “functional cure” in this setting)
- Complete cure—complete eradication of HBV cccDNA and integrated DNA from each hepatocyte
- Overt infection—detectable HBsAg in serum
- Chronic infection—sustained, detectable HBsAg for at least six months in serum
- Occult infection— presence of replication competent HBV DNA (ie, episomal HBV cccDNA) in hepatocytes in absence of detectable serum HBsAg
Reference:
- Shi Y, Zheng M. Hepatitis B virus persistence and reactivation. BMJ 2020;370:m2200