Hepatitis B is one of the most prevalent viral diseases affecting the liver. They mainly present as chronic hepatitis B (CHB) and depend on the time of acquisition of infection and rarely with acute hepatitis B/acute liver failure. They may also have extrahepatic manifestations. Tenofovir and entecavir are the most commonly used anti-viral drugs. It may occur in association with various other diseases and may require special care in such populations.Hepatitis B is one of the most common viral diseases that affect the liver. It primarily presents as chronic hepatitis B (CHB), depending on when the infection is acquired, and occasionally as acute hepatitis B or acute liver failure. Additionally, there may be extrahepatic manifestations of the disease. The most commonly used antiviral medications for treatment are tenofovir and entecavir. Hepatitis B can also occur alongside various other conditions, which may necessitate special care for affected individuals.

1. MANAGEMENT OF
HEPATITIS B
Dr. Ajay Kumar Yadav
DM resident Gastroenterology, NAMS
2081/09/10

2. Contents
• Epidemiology, Introduction, Prevalence, Structure and Life cycle
• Natural History
• Clinical manifestations
• Extrahepatic manifestations
• Assessment of Hepatitis B infection
• Approved Therapies and Indications for CHB treatment
• Goals and Endpoints of Therapy
• Special Populations
• Emerging Therapies

3. Epidemiology of HBV infection
• Worldwide, an estimated 296 million people are chronic carriers of HBsAg. Overall,
almost half the global population lives in areas of high endemicity and mainly d/t
perinatal transmission. (1)
• In 2022, hepatitis B caused an estimated 1.1 million deaths. (1)
1-WHO Global hepatitis report 2024: Action for access in low- and middle- income
countries
• Acute hepatitis B is usually a self-limiting disease with a CFR of 0.5–1%.
• Chronic Hepatitis B (CHB): HBsAg > 6months
• Chronicity is common following acquisition in neonate or childhood

4. Introduction
• In 1965, Blumberg et al  antibody in two multiply transfused hemophilic patients that reacted with
antigen in serum sample from an Australian aborigine.
• Australian antigen HBsAg
• In 1976, Blumberg was awarded Nobel Prize in Physiology or Medicine for discovery of causative
agent of Hepatitis B
• Hepatitis B is a preventable and treatable condition
• Lack of reverse transcriptase proofreading activity  frequent mutations of viral genome
• HBV: Hepadnaviridae family, Virion (Dane particle)  42 nm particle with an outer envelope (HBsAg)
surrounding a nucleocapsid that contains small DNA genome.
• HBV genome: circular, partially ds DNA of approx. 3.2 kb base pairs

5. HBV Prevalence
Lifetime risk of CHB infection: 60-80% 20-60%
<20%

6. HBV structure and life-cycle
Source: Sherlock’s disease of
liver and Biliary system 13 E

7. HBV Genotypes
Genotype classification does
not generally lead to
difference in management
10
ge
n
ot
yp
es

8. Infectivity
MOT: MTCT, Sexual, Blood/products
Infectiousness: HBV > HCV > HIV (100:10:1)
Extrahepatic localization
• Explains high rate of HBV transmission from organ donnors positive for anti-HBc

9. Outcome of Hepatitis B infection by
age at infection
Age at infection Risk of CHB
infection
• Perinatal • 95%
• 0.5-5 years • 30%
• Adults • 2-5%
The age at which a person
becomes infected with HBV is
the principal determinant of the
clinical outcome
Source: WHO Guideline for CHB infection
2024

10. Natural History of CHB infection
Source: EASL 2017
VIRAL CYTOPATHIC
EFFECT
HOST IMMUNOLOGICAL RESPONSE

11. Source: Sleisinger and Fordtran’s GI and Liver Disease 11th
Edition

12. Outcomes of CHB infection
• Untreated CHB  cirrhosis (8-20%/5 Y)
• Cirrhosis  decompensation (20%
annually)
• CHB  HCC (<1% to 5% annually)
• CHB responsible for 80% of primary liver
cancer globally
Source: Sherlock’s disease of liver and Biliary
system 13 E

13. Clinical manifestations
• vary from subclinical hepatitis, anicteric hepatitis, and icteric hepatitis
to fulminant hepatitis during the acute phase, and from inactive carrier
state to chronic hepatitis, cirrhosis, hepatic decompensation, and HCC
during the chronic phase.
• Acute HBV infection:
• IP: 1-4 months
• Prodromal phase f/b malaise, anorexia, nausea, RUQ pain, s/t fever, vomiting,
and jaundice
• Severe injury: TB >3 mg/dl, INR >1.5; ALF: +ascites, HE
• Clinical symptoms and jaundice usually disappear after 1- months
• Chronic HBV infection:
• Normal  stigmata of CLD

14. Extrahepatic manifestations
• About 20% people with
hepatitis B develop major
EHM
• Pathogenesis: Ag-Ab complex
 complement activation
• Major EHM:
 Arthritis-Dermatitis
 PAN (PAN 30% infected
with HBV, CHB  < 1%
PAN)
 GN: membranous GN,
MPGN  Nephrotic
syndrome
 Cryogolulinemia: Type
II/III
• Arthritis/GN can effectively
disappear after reduction of
HBV replication

15. Assessment of Hepatitis B
Serological diagnosis
• HBsAg, HBeAg, Anti-HBc (IgM/IgG), anti-HBeAg, anti-HBsAg, HBV-DNA
ALT
• EASL/APASL: 40 U/L (both for men and women)
• AASLD: 35 U/L for men and 25 U/L for women
• WHO: 30 U/L for men and 19 U/L for women
Liver Biopsy/Non-invasive tests
• Necroinflammatory activity, Fibrosis/cirrhosis
• Non-invasive measurement of liver fibrosis: APRI, FiB-4, Transient elastography, Fibroscan, Fibrotest
HCC Surveilance
• US±AFP

16. Initial assessment of HBV infection

17. Serology in
Hepatitis B

18. Quantitative HBsAg
• Although qHBsAg reflects cccDNA and intrahepatic DNA levels, it also measures HBsAg that
arises from integrated DNA, thereby reducing its specificity as a biomarker for viral
replication.
• The levels of HBsAg are generally higher in HBeAg-positive patients than HBeAg-negative
patients
• Higher qHBsAg levels have been a/w progression to cirrhosis and HCC.
• In HBeAg-negative patients, low qHBsAg (<1,000 IU/mL) and low HBV DNA (2,000 IU/mL)
suggest inactive CHB.
• qHBsAg <1,000 IU/mL predicts spontaneous HBsAg clearance in HBeAg-negative patients with a
low viral load

19. Serological profile of acute Vs chronic
Hepatitis B infection

20. New biomarkers of HBV infection
Viral cccDNA
• Quantification of cccDNA will be important in clinical trials evaluating novel treatment concepts to cure
HBV infection.
Hepatitis B core-related antigen (HBcrAg)
• Composite biomarker: HBcAg, HBeAg, and prec22 precursor protein
• may partly reflect the amount of intrahepatic DNA and cccDNA in hepatocytes especially in HBeAg-positive patients.
Circulating HBV RNA
• strong correlation with intrahepatic cccDNA
• interesting marker to study cccDNA transcriptional activity

21. Histopathology of HBV infection
• Mononuclear cell
infiltration
• Ground glass
hepatocytes
• HBsAg particles
• Specific
• ~viral replication

22. • Necroinflammator
y activity A2
≥
• Fibrosis F2
≥
• APRI >0.5
• TE >7Kpa
Indications for
treatment

24. Some definitions
HBV reactivation:
• loss of HBV immune control in HBsAg-positive, antiHBc–positive or HBsAg-negative, anti-
HBc–positive patients receiving IST for a concomitant medical condition; a rise in HBV
DNA compared to baseline (or an absolute level of HBV DNA when a baseline is
unavailable); and reverse seroconversion (seroreversion) from HBsAg negative to HBsAg
positive for HBsAg-negative, anti-HBc–positive patients
Hepatitis flare:
• ALT increase 3 times baseline and >100 U/L
Resolved CHB:
• sustained loss of HBsAg in a person who was previously HBsAg positive, with
undetectable HBV-DNA levels and absence of clinical or histological evidence of active
viral infection
Virological breakthrough:
• >1 log10 (10-fold) increase in serum HBV DNA from nadir during treatment in a patient
who had an initial virological response and who is adherent

25. Drugs for treatment of HBV
1992:
Conventional
IFN-α
1998:
Lamivudine
2002:
Adefovir
2005:
Entacavir (ETV)
2006:
Nucleos(t)ide analogs (NA)
• target HBV replication
through inhibition of
the reverse
transcriptase function
of HBV DNA polymerase
PegIFN
• both antiviral and
immunomodulatory
activities

26. Approved Therapies for CHB
Dose: 0.5 mg/day; 1 mg in
lamivudine or telbivudine
exposed and decompensated
cirrhosis

27. Goals of treatment
Main goal
Improve survival and QOL by preventing disease progression, and
consequently HCC development.

28. Endpoints of treatment
Functional cure: sustained HBsAg loss
Most desirable endpoint
Suppression of HBV-DNA
Histological improvement
without detioration of fibrosis
HBeAg positive pts:
HBeAg loss
ALT normalization

30. PEG-INFα
• Short fixed duration of therapy
• No renal toxicity
• Has stopping and continuation rules
• Chance of sustained HBV DNA suppression <20%
• HBsAg loss < 10%
• Interferons have anti-proliferative properties and should not be used
during pregnancy.
• PEG-IFNα should not be used in advanced/decompensated cirrhosis,
mood disorders.

31. PEG-
IFNα Vs
NA
combination therapy of
PegIFN and
nucleos(t)ide analogs
cannot be
recommended in
general clinical practice

32. TDF Vs TAF
TAF is non-inferior to TDF in terms of outcome in
HBeAg-positive and HBeAg negative patients

33. Advantage of TAF over TDF
Greater plasma stability than TDF
Efficient delivery of active drug to hepatocytes at reduced systemic exposure
Safe and well tolerated
Less renal and bone toxicity

34. When is ETV or TAF preferred over
TDF?
Age >60 Y
Bone disease
Renal disease

35. Who should be treated?
WHO (2024) >2000 >ULN (30 U/L for men and 19 U/L for women)
Significant fibrosis or cirrhosis
(HBsAg Positive) Coinfection/Immunosuppression/co-
morbidities/EHM

36. ALT <2 UNL
HBV-DNA <
2000 (HBsAg
–ve) or
<20,000
(HBsAg +ve)
T/t can be
considered if:
age >40 Y,
family h/o
HCC,
presence of
EHM or
cirrhosis
AASLD 2018

38. EASL
2017

39. Monitoring of Patients of CHB
• 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 is repeated to confirm the result.
• HBsAg: yearly.
• Screening for HCC : US±AFP
• Adverse reactions to drugs

40. Cessation criteria for CHB treatment

41. How long treatment should be
continued?
• At least 4-5 years of t/t
• Cirrhotic patients:
• Life-long therapy
• Non-cirrhotic:
• HBeAg Positive CHB
• At least 12 months after HBeAg seroconversion
• Some advice treatment until loss of HBsAg
• HBeAg Negative CHB
• Confirmed loss of HBsAg

44. Responses to HBV Therapy
Virological Serological
Biochemica
l
Histological

45. Virological response
NA therapy
• Virological response: undetectable HBV DNA by a sensitive PCR assay with a limit of detection of 10 IU/ml.
• Primary nonresponse: defined by < 1 log10 decrease of serum HBV DNA after 3 months of therapy.
• Partial virological response: defined as a decrease in HBV DNA of > 1 log10 IU/ml but detectable HBV
DNA after at least 12 months of therapy in compliant patients.
• Virological breakthrough: defined as a confirmed increase in HBV DNA level of > 1 log10 IU/ml (10 fold)
compared to the nadir(lowest value) HBV DNA level on-therapy
PegIFNa therapy
• Virological response: defined as serum HBV DNA levels <2,000 IU/ml evaluated at 6 months and at the
end of therapy.
• Sustained off-therapy virological response: defined as serum HBV DNA levels <2,000 IU/ml for at least
12 months after the end of therapy.

46. Cont..
Serological responses for HBeAg
• HBeAg loss and HBeAg seroconversion
Serological responses for HBsAg :
• HBsAg loss and HBsAg seroconversion
Biochemical response :
• Normalization of ALT
Histological response
• Defined as a decrease in necroinflammatory activity (by 2 points in histologic activity index or Ishak’s system) without worsening in fibrosis compared to
pretreatment histological findings

47. Resistance in
HBV infection
• For pts on antiviral
therapy, the 1st
manifestation of
antiviral resistance
is virological
breakthrough

48. Management
of resistant
HBV

49. Flare of hepatitis in CHB

50. WHO 2024 Algorithm for management of Chronic
Hepatitis B

52. Chronic Hepatitis-B in Special
Populations

53. Pregnancy with CHB
• 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 28–32 wop and
continued at least upto delivery, preferably for up to 12 weeks after delivery.
• The infants of all HBsAg-positive women should receive immunoprophylaxis (HBV vaccination
and/or HBIG.
• Breast feeding is not contraindicated in HBsAg-positive untreated women or on TDF-based
treatment or prophylaxis

54. Pregnant women with HBV Infection:
assessment, prophylaxis and treatment
Starting at
28-32 wop

55. HBIG±HBV vaccine
Within 24 hrs: WHO
Within 12 hrs: EASL, AASLD, APASL
Only monovalent vaccine s/b used for preterm or
term infants <6 weeks

57. Decompensated cirrhosis
• Patients with decompensated cirrhosis should be referred for consideration of LT.
Concurrently, antiviral therapy should be started.
• Indefinite therapy is recommended
• Despite successful t/t with antivirals  high risk for HCC  should continue long-term HCC
surveillance.
• Peg-IFN is contraindicated (↑infections/sepsis, cytopenias)
• Entecavir or TDF >TAF are recommended as preferred first-line agents.
• Lactic acidosis remains a rare but serious S/E

58. HBV-HIV Coinfection (10%)
• Progression of liver disease to cirrhosis and HCC is accelerated
• All HIV-positive patients with HBV co-infection should start ART
irrespective of CD4 cell count
• Recommended regimens include:
• Tenofovir-based regimen (TDF or TAF) in combination with either lamivudine
or emtricitabine  to avoid the development of HIV resistance to tenofovir
• ART that includes an HBV-active medication such as TDF or TAF
should not be discontinued due to the risk of HBV relapse.

59. HBV-HCV Coinfection
• Treatment of HCV with 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.

60. HBV-HDV Coinfection
• When to suspect co-infection? • Diagnosis of HDV coinfection:
• anti-HDV in serum
• active disease is confirmed by a
positive HDV RNA testing
• The only approved therapy for
HBV-HDV coinfection is PegIFNα
given for at least 48 weeks.
• sustained response: 20% to 50%
pts after one year of t/t with
PegIFN
• late relapses: common

61. Sherlock’s disease of liver and Biliary system 13 E

62. Acute Hepatitis B
• More than 95% of adults with acute HBV hepatitis do not require specific
treatment, because they will fully recover spontaneously
• Antiviral treatment is indicated only for those who have ALF or who have a
protracted (>4 wks), severe course, as indicated by TB >3 mg/dL, INR >1.5,
encephalopathy, or ascites and considered for LT.
• Entecavir, TDF, or TAF are the preferred antiviral drugs.
• Treatment should be continued until HBsAg clearance is confirmed or indefinitely in
those who undergo LT.
• Peg-IFN is contraindicated.

63. CHB in 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

64. Healthcare workers
• Healthcare workers performing exposure prone procedures with
serum HBV DNA >200 IU/ml may be treated with NA to reduce
transmission risk

65. Hepatitis B with 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.

66. Patients undergoing
immunosuppressive therapy (IST) or
chemotherapy
• Definition of HBV reactivation during IST:
• increase in HBV DNA replication (>1 log) from baseline or
• reappearance of HBV DNA in serum and/or HBsAg seroreversion (reappearance of
HBsAg in the serum) in HBsAg negative persons, sometimes f/b elevation of ALT,
with or without jaundice or other signs of liver failure.
• Risk of HBV-r:
• higher in HBsAg-positive individuals (10-50%) Vs HBsAg-negative, anti-
HBc-positive individuals (3-41%)
• also depends on the specific IS regimen and the presence of underlying
cirrhosis

67. Antiviral prophylaxis following
immunosuppression

68. • Significant reduction in HBV-r, by 80% to 100%, while also decreasing
the risk of HBV-associated hepatitis with antivirals.
• 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
• Timing:
• Prior to IST: at least 1 weeks prior

69. 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

70. Liver Transplant Recipients
• Entecavir, TDF, and TAF are preferred antivirals because of their high potency and
low rate of drug resistance.
• Therapy should be continued post-transplant indefinitely, regardless of HBeAg or
HBV DNA status.
• All HBsAg-positive pts undergoing LT should receive prophylactic therapy with NAs
with or without HBIG post-transplantation regardless of HBeAg status or HBV-DNA
level pre-transplant.
• All HBsAg-negative patients who receive HBsAg-negative but anti-HBc–positive grafts
should receive long-term antiviral therapy to prevent viral reactivation

72. Prevention (Immunoprophylaxis)
against HBV
HBIG
• Passive immunization
HBV vaccine
• Active immunization

73. HBV vaccination

74. • Recombinant vaccines: by
introducing S gene encoding
HBsAg into genome of yeast cells
• Anti-HBs titre >10 mIU/ml
(mostly protective); >100 mIU/ml
(100% protective)
• For those who are
immunocompromised, including
those with HIV, on dialysis, or
with cirrhosis  double dose
recommended↑anti-HBs titer +
duration of protection

75. Post-exposure Prophylaxis for HBV: ?
vaccination status
HBIG:
anti-HBs titre
of 1:100,00
Timing of
prophylaxis:
• Preferably
within 24
hours
• No later than 7
days for PC
exposure and
14 days for
sexual
exposure

76. Recommendations for Infected
Persons Regarding Prevention of
Transmission

77. Developing new therapeutics for
CHB

80. References
• Sleisinger and Fordtran’s GI and Liver Disease 11th Edition
• Sherlock’s disease of liver and Biliary system 13 E
• WHO Guidelines 2024 for the prevention, diagnosis, care and treatment for
people with chronic hepatitis B infection
• EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus
infection.
• Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD
2018 Hepatitis B Guidance
• Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015
update
• Leowattana et al Chronic hepatitis B: New potential therapeutic drugs target 2022

81. Thought of the day