Occult hepatitis B virus infection

phases HBeAg HBV DNA

level

Aminotransfer

ases levelsliv.necroinf-

lamation

Fibrosis

progression

Immunotolerant + High normal No or mild No

Immunoreactive + High Increased or

fluctuating

Moderate to

severe

Rapid

Inactive carier st. _ Low Normal Very low

HBeAg - CHB _ High High Yes

HBsAg – phase

(Occult BI)

Very low or

undetectable

?? ??

recovered (immune) subjects following self limited acute HB

Occult hepatitis B virus infection (OBI)

Definition of OBI

HBs AG Undetectable

Intrahepatic HBV DNA

HBV DNA Detectable +/-

HBsAG - & HBV DNA +

80% 20%Seropositive OBI Seronegative OBI

( anti-HBc+ (+/-) anti-HBs+) ( anti-HBc - , anti- Hbs -)

higher DNA level lower DNA level

recovered (immune) subjects following self limited acute HB

Seropositive

Anti-HBc positive

HBsAg lost after

self-limiting acute

hepatitis

HBsAg lost after

years of chronic

carriage

Anti-HBV never

present

(Iry occult infection)

Seronegative

Anti-HBc negative

Anti HBV antibodies

progressively

disappear over time

OBI

“False” OBI

HBsAg negative & positive serum DNA levels comparable to levels in overt HBV infection.

Infection with HBV mutations in S gene (escape mutants ), producing a modified HBsAg that is not recognized by some or all commercially available detection assays

Raimondo G, et al,. J Hepatol 2008; 49: 652-65

the use of multivalent anti-HBs antibodies in the HBsAg assays is strongly recommended for optimal detection of these variants

Long lasting persistence of HBV ccc –DNA.Levrero M, et al. J Hepatol 2009; 51: 581-592

Viral replication is strongly suppressed:-High HBV-specific immunological pressure- Co-infection with other pathogens- Epigenetic factors

Zerbini A, et al, . Gastroenterology 2008; 134: 1470-1481

Larrubia JR .World J Gastroenterol 2011 March 28; 17(12): 1529-1530,

Recovered (immune) subjects following self limited acute HB

Gold Standard : Analysis of liver tissue and blood for HBV DNA

HBV DNA in blood by nested-PCR, real-time PCR, and transcription based mediated amplification (TMA)

Anti-Hbc is a less than ideal surrogate marker when HBV DNA measurement is not feasible.

Raimondo G, et al,. J Hepatol 2008; 49: 652-65

Auther Diagnosis of OBI Target population OBI Prevalence

El-shaarawy,et al, 2007 Anti-HBc 40 pat. With HCV CLD 50%

El-Sherif, et al, 2009 Anti-HBc/

DNA

71HCV pat.+ Anti-HBc+

29 HCV pat.+ Anti-HBc -

22.5%

0%

Said, et al, 2009 DNA 100 child with

haematological dis.

38%

Ismail, et al, 2010 DNA Haemodialysis

46 HCV RNA +

52 HCV RNA-

6.3%

3.8%

Emara, et al, 2010 DNA 156 HCV pat. On peg-INF 3.9%

Hassan, et al, 2011 DNA 40 HCC : tissue

serum

62.5%

22.5%

Selim, et al, 2011 DNA HCV : 30 enzyme flare

30 no enzyme flare

63.3%

13.3%

Abu-elmakarem,

et al,2012

DNA 145 haemodialysis 4.1%

Said, et al, 2013 Anti-HBc/

DNA

3167 blood donors

303 Anti-HBc +

Anti-HBc +14.2%

17.2%

Transmission Of HBV infection

HCC OBI HBVdevelopment reactivation

Liver disease progression

Target populations.

Antiviral Therapy.

OBI is a phenomenon essentially attributed to the long-lasting presence of HBV cccDNA into the hepatocytes and to a strong inhibition of HBV replication and protein synthesis.

Considering the very low levels of serum HBV DNA, its detection requires the use of a highly sensitive and specific molecular biology techniques.

The inhibition of HBV replication may be reversible and the occult infection may be reactivated, leading to acute and severe forms of classical hepatitis B, which may also occur after transmission of OBI by blood transfusion or organ transplantation.

The long-term persistence of the virus in the liver may induce a very mild but continuing necroinflammation that if other causes of liver injury co-exist - may favor the progression of the chronic liver disease toward cirrhosis.

Moreover, OBI seems to maintain the tumorigenic properties typical of the overt infection, and it is in fact an important risk factor for HCC development.