This document discusses the history, virology, transmission, diagnosis, and treatment of hepatitis B virus (HBV) infection over several pages. It notes that HBV was discovered in 1965 and its virus particle identified in 1970. HBV is transmitted through blood and bodily fluids and can be prevented through vaccination. Diagnosis involves testing for various hepatitis B antigens and antibodies. Treatment goals are to prevent disease progression and complications through suppression of HBV replication. First-line treatments include interferons and nucleoside analogues administered for at least 12 months after HBeAg seroconversion or lifelong in cirrhosis.

1. Dr. (Maj) Ajay Kandpal
MD,DNB

2.  Introduction
 The virus
 The disease
 Spectrum
 Special scenarios
 Treatment considerations
 Prevention

3.  BC 2000 - Some ancient records showed epidemic
of hepatitis.
 1883 - Lurman found that people vaccinated for
small pox with lymph from other people suffered
from hepatitis (known as serum hepatitis at that
time).
 Many similar outbreaks happened when treating
syphilis with reused needles in 1909.

4.  1965 - Baruch Blumberg discovered ‘Australian
antigen (now known as HBs Antigen)
 1970 - D.S. Dane and others discovered the virus
particle with electron microscope.
 1980-81 – HBV vaccine derived from serum was
developed by Hilleman and collegues, proved
effective and licensed for use.
 1983-86 - William Rutter and colleagues
developed HBV vaccine derived from yeast using
recombinant DNA technology.

5.  2010 – Clément Gilbert and Cédric Feschotte found
the fragments of HBV genes in the 19-millions-old
fossils of songbirds.
 2012 - Korean and Islraeli scientists can map the
entire genome of HBV found in the preserved liver of
16th century Korean mummified child

7.  HBV is a member of smallest virus family
Hepadnaviridae.
 It measures 42 nm.
 Enveloped (surface Ag), – Outer lipoprotein
 Primarily hepatotropic
 It can survive for 15 years at -20ºC, for 24 months
at-80ºC, for 6 months at room tempature, and 7
days at 44ºC.

8.  Encodes 7 proteins:
 HBeAg
 HBcAg
 HBV Pol/RT
 PreS1/PreS2/HBsAg (large, medium, and small
surface envelope glycoproteins)
 HBxAg : regulator of transcription required for the
initiation of infection).

9.  There are 4 open reading frames derived from the same
strand (the incomplete + strand)
 S - the 3 polypeptides of the surface antigen (preS1, preS2
and S - produced from alternative translation start sites.
 C - the core protein
 P - the polymerase
 X - a transactivator of viral transcription and cellular genes.
 HBx is conserved in all mammalian (but not avian)
hepadnavirus.
 Though not essential in transfected cells, it is required for
infection in vivo.

13.  Include HBsAg, anti-HBs, pre-s1,s2 antigen and
anti-pres1, s2
 HBsAg appears 1-2 weeks (late to 11-12
weeks)after exposure, persists for 1-6 weeks( even
5 months) in acute hepatitis B.
 In chronic patients or carrier, HBsAg persists for
many years.
 HBsAg confers antigencity but no infectivity.

14.  HBeAg is a soluble antigen
 HBeAg is a reliable indicator of active replication of
HBV
 Anti-HBe is a marker of reduced infectivity. If exist
long may be a marker of integration of HBV into
liver cell.

15.  HBcAg can be found in the nuclei of liver cells, no
free HBcAg is found in serum
 HBcAg is the marker of replication of HBV
 The stage called window phase
 Anti-HBc IgM is a marker of acute infection and
acute attack of chronic infection of HBV.
 Anti-HBc IgG is the marker of past infection, high
titer means low level replication of HBV.

16.  HBsAg: Present in acute or chronic infection.
 HBsAb:Present in recovery or immunization.
 Anti -HB Core: May be “Total” (IgG&IgM) or IgM.
Lifelong marker of past and active infection in
either acute or chronic.
 HBeAg: Present in Acute infection, and extremely
infectious.
 Anti-Hbe: Usually prognostic for resolution.

17.  Serology: - acute:
 HBsAg+ (HBsAb-) = acute infection or chronic
carrier
 HBeAg+ = highly infectious
 HBsAb = immune – naturally or vaccine
 Window = HBsAg- and HBsAb will be HBcAb+ (IgM
– acute)

22.  It can be inactivated in 10 minutes when heated at
80ºC.
 HBV is 100 times more infectious than HIV. Very minute
amount of blood can be infectious
 lack of reverse transcriptase proofreading activity : HBV
mutants
 Nine genotypes (A-I) and several sub-genotypes
 – All HBV subtypes share one common antigenic
determinant - "a.“Thus, antibodies to the
"a"determinant confer protection to all HBV subtypes.

23.  About 2 billion people have been infected with HBV
infection around the world.
 > 2 million people have chronic HBV infection.
 About 600 000 die every year due to the acute and
chronic consequences of HBV. (WHO 2012).
 About 25% (20-30%) of chronic infection results in
cirrhosis or liver cancer.

25.  High (>8%): 45% of global population lifetime risk
of infection >60%, early childhood infections
common.
 Intermediate (2%-7%): 43% of global population
lifetime risk of infection 20%-60%, infections occur
in all age groups.
 Low (<2%): 12% of global population lifetime risk of
infection <20%, most infections occur in adult risk
groups.

26.  Falls in intermediate endemicity group
 HBsAg prevalence between 2% to 7%.
 Estimated 43-45 million cases per year.
 40 million carriers.
 100,000 death annually by disease related to HBV
infection.
 Of 25 million newborn annually, 1 million runs
lifetime risk of HBV infection.

28.  Transmitted by blood, semen and vaginal fluid of an
infected person.
 Unprotected sexual contact with infected person
 Infectious blood and blood related instruments
 Blood transfusion
 Unsterilized/under-sterilized needles and syringes
 Needle stick injury
 Toothbrush and razor
 From mother to child (esp. during childbirth) (Common in
South- East Asia)

32.  Infection at birth is associated with clinically silent
acute infection but a 90% chance of chronic
infection.
 Infection in young adulthood in immunocompetent
persons is typically associated with clinically
apparent acute hepatitis but a risk of chronicity of
only approx. 1%.
 The likelihood in a patient with HBeAg-reactive
chronic hepatitis B of converting spontaneously
from relatively replicative to nonreplicative infection
is approx 10−15% per year.

33.  The 5 yr cumulative incidence of cirrhosis in
untreated CHB : 8% to 20%
 The 5-year cumulative risk of hepatic
decompensation among those with cirrhosis: 20%.
 Annual risk of HCC in patients with cirrhosis: 2–5%.
 Hepatitis B responsible for 80% of primary liver cancer
globally
 In Asia, upto 40% of HCC related to Chronic HBV
infection without cirrhosis.

38. Acute Hepatitis B:
 It refers to the conditions following transmission of
HBV.
 Usually lasts for 4-8 weeks.
 Two third (2/3) of patients are asymptomatic.
(don’t suffer from anything)
 Chance of progression to chronic HBV depends on
age of acquiring HBV.

42.  Progress of chronic hepatitis B to cirrhosis and Liver
cancer can be as high as 20-30%.
 Factors influencing disease progress are:
 High HBV DNA in blood
 Precore mutant HBV (HBe Ag negative chronic HBV)
 Male patients
 Alcohol and other hepatotoxic agents/drugs use
 Smoking
 Coinfection with HIV and/or HCV
 Genotype of HBV (e.g., genotype C)
 Immune status of the patient

43.  HBsAg-positive >6 months
 Serum HBV DNA >20,000 IU/mL (105copies/mL), lower
values 2,000-20,000 IU/mL (104-105 copies/mL) are
often seen in HBeAg-negative chronic hepatitis B
 Persistent or intermittent elevation in ALT/AST levels
 Liver biopsy showing chronic hepatitis with moderate or
severe necrosis and inflammation (AASLD: Chronic
Hepatitis B: Update 2009)

44.  Chronic Hep B carrier
 To know the disease progression and need for
treatment ALT, Ultrasound should be checked every
3-6 months.
 If available and affordable, better to check HBV DNA.
 Should avoid risk factors (alcohol, smoking, liver toxic
agents) and should be vaccinated against Hepatitis A
& E.)
 If HBV DNA is high enough to start treatment,
decreasing HBV DNA with drugs is needed to prevent
further liver damage from HBV.

46.  Acute infection
 HBsAg positive and anti-HBcAg IGM
 Rarely, IgM anti-HBc only marker
 Usually seen in acute fulminant Hep B
 Chronic infection
 HBsAg positive and anti-HBcAg
 Previous Infection
 HBsAg negative
 anti-HBs positive
 IgG anti-HBc positive

47.  Arthritis
 PAN
 Glomerulonehrites
◦ MGN
◦ MPGN , NS
 Cryoglobinemia

48.  WHAT NEXT
 WHY NEXT

53.  Goals of treatment
 Main goal
 Improve survival and quality of life by
preventing disease progression, and
consequently HCC development.
 Additional goals
 Prevent mother to child transmission.
 Prevent hepatitis B reactivation.
 Prevention and treatment of HBV-associated
extrahepatic manifestations.

54.  HBV-induced HCC
• Suppress HBV replication to induce the stabilisation
of HBV-induced liver disease and to prevent
disease progression.
• Reduce the risk of HCC recurrence after potentially
curative HCC therapies.
 Acute hepatitis B
• Preventing the risk of acute or subacute liver
failure.

56.  The diagnostic accuracy of all non-invasive methods
is better at excluding than confirming advanced
fibrosis or cirrhosis.
 HBeAg and anti-HBe detection are essential for the
determination of the phase of chronic HBV infection.
 Measurement of HBV DNA serum level is essential for
the diagnosis, establishment of the phase of the
infection, the decision to treat and subsequent
monitoring of pts.

57.  Sr. HBsAg quantification can be useful, particularly
in HBeAg-negative chronic HBV infection and in
patients to be treated with interferon-alfa (IFNa).
 HBV genotype is not necessary in the initial
evaluation : selected pts to be treated with IFNa :
prognostic information : response to IFNa therapy
and the risk of HCC.
 Pts with negative anti-HAV should be advised to be
vaccinated against HAV.

63.  Interferons
• Interferon alfa (IFN-a)
• Pegylated interferon alfa 2a (Peg-IFN-a 2a)
 Nucleos(t)ide analogues (NA)
• Tenofovir (also useful in patients resistant to other NAs)
• Entecavir
• Lamivudine
• Adefovir
• Telbivudine
 These are not recommended for initial monotherapy.

68.  How long treatment s/b continued?
At least four to five years of treatment
 Cirrhotic patients:
Life-long therapy with oral agents is typically
administered to reduce the risk of clinical
decompensation if a relapse occurs
 Non Cirrhotic:
• HBeAg-positive : At least 12 months after HBeAg
seroconversion. Some advice treatment until loss of
HbsAg
• HBeAg-Negative : confirmed loss of HBsAg

69.  Virological
 Serological
 Biochemical
 Histological

74.  HBV DNA : every three months until undetectable for at least two
consecutive visits, then decrease the frequency to every six
months.
 ALT : every three months, the frequency can be decreased to every
six months in patients with an undetectable HBV DNA or
normalized ALT.
 HBeAg and anti-HBe : every six months in HBeAg-positives to
determine if seroconversion has occurred. If HBeAg seroconversion
has occurred test repeated to confirm result.
 HBsAg : be tested yearly.
 Screening for HCC : USG and AFP
 Adverse reactions to drugs

76.  HIV co-infected patients
 All HIV-positive patients with HBV co-infection
should start ART irrespective of CD4 cell count
 Should be treated with a TDF- or TAF-based ART
regimen
 Entecavir may generate HIV mutations

78.  HDV co-infected patients
 PegIFNa for at least 48 weeks is the current
treatment of choice in HDV-HBV co-infected
patients with compensated liver disease.
 In HDV-HBV co-infected patients with ongoing HBV
DNA replication, NA therapy should be considered
 PegIFNa treatment can be continued until week 48
irrespective of on-treatment response pattern if
well tolerated

79.  HCV co-infected patients:
 Treatment of HCV with direct-acting antivirals
(DAAs) may cause reactivation of HBV. Patients
fulfilling the standard criteria for HBV treatment
should receive NA treatment
 HBsAg-positive patients undergoing DAA therapy
s/b considered for concomitant NA prophylaxis
until week 12 post DAA, and monitored closely
 HBsAg-negative, anti-HBc positive patients
undergoing DAA should be monitored and tested
for HBV reactivation in case of ALT elevation

80. Adults:
 More than 95% of adults with acute HBV hepatitis
do not require specific treatment, because they will
fully recover spontaneously.
 Only patients with severe acute hepatitis B,
characterised by coagulopathy or protracted
course(i.e., persistent symptoms or marked
jaundice for >4 weeks), or signs of ALF s/b treated
with NA and considered for liver transplantation.

81. Children
 In children, the course of the disease is generally
mild, and most of the children do not meet standard
treatment indications. Thus, treatment should be
considered with caution
 In children or adolescents who meet treatment
criteria, ETV, TDF, TAF, and PegIFNa can be used in
this population

82. Healthcare workers
 HBV infection alone should not disqualify infected
persons from the practice or study of surgery,
dentistry, medicine, or allied health fields
 Healthcare workers performing exposure prone
procedures with serum HBV DNA >200 IU/ml may
be treated with NA to reduce transmission risk

83. Pregnancy
 In a woman of childbearing age without advanced
fibrosis who plans a pregnancy in the near future, it
may be prudent to delay therapy until the child is born.
 Pregnant women with CHB and advanced fibrosis or
cirrhosis,therapy with TDF is recommended.
 In pregnant women already on NA therapy, TDF s/b
continued while ETV or other NA s/b switched to TDF.
 In all pregnant women with high HBV DNA levels
(>200,000 IU/ml) or HBsAg levels [>4 log10 IU/ml,
antiviral prophylaxis with TDF should start at 24–28
wop and continue for up to 12 weeks after delivery.

84.  The infants of all HBsAg-positive women should
receive immunoprophylaxis (HBV vaccination and/or
hepatitis B immunoglobulin )
 Breast feeding is not contraindicated in HBsAg-
positive untreated women or on TDF-based treatment
or prophylaxis.

85. Patients undergoing immunosuppressive
therapy or chemotherapy
 All candidates for chemotherapy and
immunosuppressive therapy s/b tested for HBV
markers prior to immunosuppression.
 All HBsAg-positive patients should receive ETV or TDF
or TAF as treatment or prophylaxis.
 HBsAg-negative, anti-HBc positive subjects should
receive anti-HBV prophylaxis if they are at high risk of
HBV reactivation.

86. Dialysis and renal transplant patients
 HBsAg-positive dialysis patients who require treatment
should receive ETV or TAF.
 All HBsAg-positive renal transplant recipients should
receive ETV or TAF as prophylaxis or treatment.
 HBsAg-negative, anti-HBc positive subjects s/b
monitored for HBV infection after renal transplantation.
Extrahepatic manifestations
 Pts with replicative HBV infection and extrahepatic
manifestations should receive antiviral treatment with NA.
 PegIFNa should not be administered in patients with
immune-related extrahepatic manifestations.

88.  Antiviral drugs are not usually needed to prevent
transmission to baby from infected mother.
 Nucleos(t)ide analogues are recommended to start
at last 3 months of pregnancy only if maternal HBV
DNA is high and HBeAg (+).
 Every baby born to HBsAg has to be vaccinated with
both Hepatitis B Immunoglobulin (HBIG) and
Hepatiti B vaccine.
 Babies who had prophylaxis and vaccine are
unlikely to get HBV from breastfeeding

95. THANK YOU