2. Outline
• Definition
• Life Cycle
• Diagnosis
• Management ( Noncirrhosis vs Cirrhosis)
• Management pertaining to special population
3. Introduction
• A major health problem affecting approx. 350
million people worldwide.
• Prevalence worldwide has declined minimally
from 4.2% in 1990 to 3.7% in 20051 despite
evolution of vaccine and viral suppressing
drugs.
• Treatment is still handicapped with regards to
curative intent.
1. Ott JJ, et al. Vaccine 2012;30:2212-9.
4.
5. Definition of HBV cure
HBsAg Anti HBsAb Viraemia cccDNA
Functional
Cure - + - +
Complete
Cure - + - -
Zeisel MB et al. Gut 2015;64:1314–26.
6. STRUCTURE OF HBV
Outer lipid
envelope
containing HBsAg
Core protein
containing
HBcAg & HBeAg
HBV DNA
DNA Polymerase with reverse
transcriptase activity
7. HBV genome
• Circular partially double
stranded DNA
• 4 overlapping genes
Gene S – HBsAg
Gene C – HBcAg & HBeAg
Gene P – DNA Polymerase
Gene X – function not
defined
12. HBV Life cycle
Entry inhibitors
ccc DNA
inhibitors
Polymerase
inhibitors
Nucleocapsid
assembly
inhibitors
RNA interference
Direct acting antivirals
Host targeting agents
IFNs
Immune modulators
13. Diagnosis
Easy to make owing to serological markers.
Some difficulty in differentiating acute vs
chronic vs reactivation of chronic hepatitis
(acute on chronic) infection
Decision on treatment : A herculean task
Different agencies have set different
guidelines
No clear guidelines from Indian agencies
14. Serological Tests
• HBsAg/Anti HBsAb
• HBeAg/AntiHBe ab
• Anti HBc Ab ( IgM/IgG/ Total)
• HBV DNA (quantitative)
• HBsAg ( quantitative)
15. HBsAg
• A marker of Hepatitis B infection
• Present in both acute and chronic infection.
• Appear in serum 1-10 wks after acute exposure ,
2-6 wks before onset of hepatitis and rise in ALT.
• Become undetectable in 4-6 months in acute
infection
• Can be absent from beginning in acute infection
(Approx. 20-30 % cases)
• Assessed both qualitatively and quantitatively.
16. Anti HBsAb
• Marker of recovery of Acute hepatitis B
• Persist for life
• Also present in vaccinated persons
17. HBeAg/AntiHBeab
• Markers of HBE replication and infectivity
• HBeAg positive status :Associated with florid
infection, high HBV DNA levels
• Anti HBeAb positive : Result due to
seroconversion from HbeAg, associated with
less infectivity
18. HBcAg and HBcAb (IgM/IgG/Total)
• HBcAg: Not present in blood, only present in
liver
• IgM anti HBcAb: Present in acute infection,
most reliable test for acute infection and
reactivation of hepatitis B
• IgG anti HBcAb: Indicates chronic infection
• Total Anti HBcAb: May be raised in acute or
chronic infection or reactivation.
19. HBV DNA
• Reflect viral load of the patient
• Qualitative presence is of no value as far as
therapeutic strategy is concerned
• High viral load associated with increased risk
of transmission and liver damage.
• The current used NUCs are targeted therapy
for decrease of DNA levels
23. Natural History of hepatitis B
• Interplay between the
Virus (HBV replication, HBV genotype, and
viral variants),
Host (age, gender, race/ethnicity, genetic
make-up, and immune response),
Environment (alcohol, concomitant infection
with other viruses – HCV, HDV,HIV and
carcinogens such as aflatoxin)
24. • The overall rate of progression from acute to
chronic (persisting for >6 months) HBV
infection has been estimated to be 5–10%.
• The risk is inversely proportional to the age
at infection: 90% for perinatal infection, 20%
for childhood infection, and less than 5% for
adult infection
25. • The annual rate of progression from chronic
hepatitis to cirrhosis has been estimated to be 2–
5% for HBeAg positive and 3–10% for HBeAg-
negative patients.
• The annual rate of progression from
compensated cirrhosis to hepatic
decompensation has been estimated to be 3–5%
• Survival after the development of compensated
cirrhosis is favorable initially (85% at 5 years) but
decreases dramatically after the onset of
decompensation to 55–70% at 1 year and 14–
35% at 5 years .
27. Immunotolerant Phase
• Characterized by high levels of HBV
replication: the presence of HBeAg and high
levels of HBV DNA in serum (106–1010 IU/mL),
normal ALT, and minimal changes on liver
biopsy
• A mild degree of liver injury despite high levels
of HBV replication is believed to be due to
immune tolerance to HBV.
28. • Very low rate of spontaneous HBeAg clearance.
• The persistence of high levels of viremia
in adolescents and young adults accounts for the
high frequency of maternal–infant transmission
of HBV in Asia.
• In patients with childhood or adult-acquired HBV
infection, the immune tolerant phase is short-
lived or absent
29. Immune Active Phase/HbeAg
positive chronic hepatitis
• Characterized by the presence of HBeAg, high levels of
serum HBV DNA, and active liver disease (elevated ALT
and necroinflammation on liver biopsy).
• In patients with perinatally acquired HBV infection,
transition from the immune tolerant to the immune
clearance phase usually occurs during the second to
fourth decades of life.
• Most patients with childhood or adult-acquired
HBV infection are already in the immune clearance
phase at presentation
• Spontaneous HBeAg clearance occurs at an annual rate
of 10–20%
30. Inactive Carrier Phase
• Characterized by the absence of HBeAg,
presence of anti-HBe, persistently normal ALT
levels and low or undetectable serum HBV
DNA (usually <103 IU/mL)
31. Reactivation of Hepatitis B
• Reactivation may occur
Spontaneously
As a result of immunosuppression,
May be due to wild-type HBV or HBV variants
that abolish or downregulate HBeAg
production.
32. • Characterized by the absence of HBeAg,
presence of anti-HBe, detectable serum HBV
DNA, elevated ALT, and chronic inflammation
± fibrosis on biopsy.
• Patients are usually older and have more
advanced liver disease because this represents
a later phase in the course of chronic HBV
infection.
• Serum HBV DNA levels are lower than in
HBeAg positive patients but may reach 108-
109IU/mL.
35. When to Treat?
• Most challenging task
• Inadvertent use of drugs associated with
resistance, side effect
• Delay of therapy – lead to progressive liver
damage.
36. Parameters to be looked
• SGPT (ALT) levels : Denotes liver injury
• HBV DNA levels: Denotes Viral load
• HbeAg/ AntiHBeab status: Denotes infectivity,
precore/core mutant
• Liver Biopsy: Denotes cellular level of injury
• Cirrhosis : Itself an indication of Cirrhosis
37. Drugs in the Armamentarium
• Interferons
• Nucleos(t)ide Analogues (NUCs)
• IFN + NUCs
38. Timeline of milestones in chronic
hepatitis B treatment ( IFN and
Polymerase inhibitors)
41. PITFALLS OF CURRENT THERAPY
• NUCLEOS(T)IDE ANALOGUES
Potent HBV DNA suppressors but little effect on
HBsAg & ccc DNA levels
Need lifelong therapy
• IFN THERAPY
Finite duration but limited response
More side effects
42.
43.
44. How Long to treat?
• Lifelong?
• HbsAg loss : Yes, an indication for cessation of
therapy
• HBeAg Seroconversion with undetectable DNA
levels : Difference of opinion among different
authorities
• I recommend lifelong therapy
45. Definition of Response
• Biochemical:
Normalization of ALT levels
• Virological:
Sustained disappearance of HBV DNA from
serum after 6 month of therapy
• Histological :
>2 point improvement in necroinflammatory
score without worsening fibrosis
47. Antivirals and Acute hepatitis B
• No consensus till now in acute Hepatitis B
infection
• 95-99% clear virus with 1% going into
chronicity
• Recommended for patients with
encephalopathy, deep jaubdice > 4 wks, INR >
1.5
• Stop therapy after 3 months of HBsAg
becoming negative
52. A
D
C
B
At 48 wks, decline in mean
HbsAg titres was significantly
more in group A (p<0.05) as
compared to all groups
53. • The study also showed that combination
therapy, can induce HBsAg loss at a similar
frequency in all major genotypes and
inrespective of HBeAg status
Combination therapy with TDF plus
peginterferon for 48 weeks resulted in
higher rates of HBsAg loss than either
monotherapy.
55. Hepatitis B and Pregnancy
• Associated with transplacental spread
• 10-30 % vs 5-7 % risk of transmission (HBeAg +
vs HBeAg –ve).
• High viral load associated with increased
chances of infection to infant
• Immunoprphylaxis and vaccination reduce risk
to < 1 %
62. Take Home Message
• HBV Infection: Dreadful one
• Proper diagnosis and treatment : Life saving
• Needs still unmet in terms of poor response
of available therapy to HBsAg loss.
