gastroenterology topic

1. CHRONIC HEPATITIS B
G.PRUTHVI
PG IN GENERAL MEDICINE

2. OVERVIEW
 Introduction and epidemiology
 Virology
 Pathogenesis
 Natural History, Clinical features
 Diagnosis
 Liver Biopsy and Noninvasive Assessment
of Fibrosis
 Treatment

3. Introduction & Epidemiology
 Definition - Chronic necroinflammatory disease of the liver
caused by persistent infection with hepatitis B virus.
 Approximately one third of the world’s population has
serological evidence of past or present infection with HBV
and 350–400 million people are chronic HBV surface
antigen (HBsAg) carriers.
 Up to 2 million die each year from HBV infection, making it
the 9th leading cause of death worldwide.

4. Worldwide Prevalence of
Chronic Hepatitis B
HBsAg Prevalence
(%)
8: High
2-7: Intermediate
<2: Low
World Health Organization
Centers for Disease Control and Prevention.

5.  Hepatitis B is classified into 8 genotypes(A-H)
and 8subtypes.
 Genotype A & D are predominant in USA &
Europe.
 Genotype B & C are predominant in Asia.

6. Virology
 Hepatitis B belongs to family Hepadnaviridae.
 It contains circular partially single stranded &
partially double stranded DNA of 3.2 kb.
 HBV has compact genomic structure

7.  HBV infected cells produce 3 particulate forms
1.42nm, double shelled spherical particle(intact
virion),Dane particle.
2.27nm particle (nucleocapsid core).
3.22nm (spherical and filamentous
form),represent excess viral envelope protein.
 Concentration of HBsAg & virus particles in
blood may reach 500 µg/ml & 10 trillion
particles/ml respectively.

9. MOLECULAR VARIANTS
Pre -core mutant ,it occurs due to single base
substitution from G to A in the second last codon of
pre C gene at nucleotide 1896. This mutation
prevents translation of HBeAg.
2. Mutation in core promoter region prevents
transcription of the coding region of HBeAg &
results in HBeAg negative phenotype.
3. Escape mutants, it occurs due to single amino acid
substitution at position 145 of immunodominant a
determinant common to all subtypes of HBsAg. It
results in loss of neutralizing activity by anti HBs.
1.

10. PATHOGENESIS
 HBV virions bind to surface receptors and are




internalized.
Viral core particles migrate to the hepatocyte
nucleus, where their genomes are repaired to form a
covalently closed circular DNA (cccDNA) that is the
template for viral messenger RNA (mRNA)
transcription.
The viral mRNA that results is translated in the
cytoplasm to produce the viral
surface, core, polymerase, and X proteins.
There, progeny viral capsids assemble, incorporating
genomic viral RNA (RNA packaging).
This RNA is reverse-transcribed into viral DNA. The
resulting cores can either bud into the endoplasmic
reticulum to be enveloped and exported from the cell
or recycle their genomes into the nucleus for
conversion to cccDNA.

13. Natural History

15. 5 Phases of Chronic HBV Infection
Current Understanding of HBV Infection
HBeAg
Anti-HBe
ALT activity
HBV DNA
Phase
Liver
Immune
Tolerant
Immune
Clearance
Inactive
Carrier State
Minimal
inflammation
and fibrosis
Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Reactivation
Active
inflammation
Optimal treatment times
Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in
2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

16. 5 Phases of Chronic HBV
Infection

18. CLINICAL FEATURES
 They vary from asymtomatic infection to end




stage fatal hepatic failure.
Fatigue is most common symptom.
Persistent or intermitent jaundice is a feature of
advanced disease.
Acute exacerbations when superimposed on
cirrhosis leads to decompensation.
Extra hepatic manifestations include
arthritis, arthralgias,iummune complex
GN, generalized vasculitis (PAN).

19. LABORATORY FEATURES
 Aminotransferase elevations tend to be modest for




chronic hepatitis B but may fluctuate in the range of
100–1000 units.
Alanine aminotransferase (ALT) tends to be more
elevated than aspartate aminotransferase (AST);
however, once cirrhosis is established, AST tends to
exceed ALT.
Alkaline phosphatase activity tend to be normal or
only marginally elevated.
In severe cases, moderate elevations in serum
bilirubin (3–10 mg/dL)] occur.
Hyperglobulinemia and detectable circulating
autoantibodies are distinctly absent in chronic
hepatitis B (in contrast to autoimmune hepatitis).

20. HISTOPATHOLOGY
 Histologic features in chronic hepatitis are increase in
size of hepatocytes and ground glass appearance.
 Abundant ground glass appearance indicates active viral
replications.
 Immunofluorescence and electron microscopy shows
HBcAg inside hepaocyte nuclei of affected cell.

21. DIAGNOSIS
Serological assays for various Hepatitis B
antigens & antibodies.
2. HBV DNA by Southern hybridization, in-situ
hybridization, or PCR.
3. Detection of HBsAg or hepatitis B core antigen
(HBcAg) in liver tissues by
immunohistochemical staining.
1.

24. Liver biopsy and non invasive
monitoring of hepatic fibrosis
 There are three primary reasons for performing a liver biopsy:
1) it provides helpful information on the current status of the
liver injury,
2)it identifies features useful in the decision to embark on
therapy,
3) it may reveal advanced fibrosis or cirrhosis that
necessitates surveillance.
 The biopsy is assessed for grade and stage of the liver
injury, but also provides information on other histological
features that might have a bearing on liver disease
progression.
 The grade defines the extent of necroinflammatory
activity, while the stage establishes the extent of fibrosis or
the presence of cirrhosis

25. Non invasive monitoring of
fibrosis
 aspartate aminotransferase:platelet ratio index (APRI)
and
 commercially available assays of : α2macroglobulin,α2-globulin, γ-globulin, apolipoprotein
A-I, γ-glutamyltransferase, total bilirubin, and
hyaluronic acid.
 the assays are typically much better at detecting
advanced fibrosis and cirrhosis than mild-to-moderate
fibrosis.
 Combining assays(e.g., APRI and FibroSURE or
HepaScore) appears to increase the diagnostic
accuracy and may eliminate the need for liver biopsy
in more than half of patients.

26. TREATMENT

27. Goals and End Points of Hepatitis
B Treatment
 Prevention of long-term negative clinical outcomes
(eg, cirrhosis, liver transplantation, HCC, death) by
durable suppression of HBV DNA.
 Ideal end point is induceing HBsAg loss or seroconversion.
 Sustained decrease in serum HBV DNA level to
undetectable.
 Decrease or normalize serum ALT
 Improve liver histology
 Induce HBeAg loss or seroconversion in HBeAg-positive
disease

28. DEFINITION OF ANTIVIRAL
RESPONSE
 Responses can be divided into
biochemical, serological, virological and
histological.
 Biochemical response is defined as normalisation
of ALT levels.
 Serological response for HBeAg applies only to
patients with HBeAg-positive CHB and is defined
as HBeAg loss and seroconversion to anti-HBe.
 Serological response for HBsAg applies to all
CHB patients and is defined as HBsAg loss and
development of anti-HBs.

29. Virological responses on IFN/PEGIFN therapy:
 Primary non-response has not been well established.
 Virological response is defined as an HBV DNA
concentration of less than 2000 IU/ml. It is usually
evaluated at 6 months and at the end of therapy as
well as at 6 and12 months after the end of therapy.
 Sustained off-treatment virological response is defined
as HBV DNA levels below 2000 IU/ml for at least 12
months after the end of therapy

30. Virological responses on NA therapy:
 Primary non-response is defined as less than 1
log10 IU/ml decrease in HBV DNA level from
baseline at 3 months of therapy.
 Virological response is defined as undetectable HBV
DNA by a sensitive PCR assay. It is usually
evaluated every 3– 6 months during therapy
depending on the severity of liver disease and the
type of NA.
 Partial virological response is defined as a decrease
in HBV DNA of more than 1 log10 IU/ml but
detectable HBV DNA after at least 6 months of
therapy in compliant patients.
 Virological breakthrough is defined as a confirmed
increase in HBV DNA level of more than 1 log10
IU/ml compared to the nadir (lowest value) HBV

31.  Histological response is defined as decrease in
necroinflammatory activity (by ≥2 points in HAI or
Ishak’s system) without worsening in fibrosis
compared to pre-treatment histological findings.
 Complete response is defined as sustained offtreatment virological response together with loss
of HBsAg.

32. Indications for treatment
 Serum HBV DNA levels.
 Serum ALT levels.
 Severity of liver disease.
 May also take into account are age,health
status,family history of HCC, cirrhosis & extra
hepatic manifestations.

33. What Is an Elevated ALT Level?
 Reference ranges for ALT laboratories
 Men: 4-60 IU/L; women: 6-40 IU/L
 Both AASLD and US treatment algorithms recommend
lower ULN levels for ALT when making treatment-initiation
decisions
 30 IU/L for men
 19 IU/L for women
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
Prati D, et al. Ann Intern Med. 2002;137:1-10. Lok AS, et al. Hepatology. 2009;50:661-662.

34. Asian-Pacific consensus statement
on the management of chronic
hepatitis B: a 2012 update

38. Current Guideline
Recommendations for First-line
Therapy
• Peginterferon alfa-2a
– Exceptions: pregnancy, chemotherapy
prophylaxis, decompensated cirrhosis, acute infection
• Entecavir
• Tenofovir
EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283.
Lok AS, et al. Hepatology. 2009;50:661-662.

39. INTERFERON -α
 IFN- α was the first approved therapy for chronic hepatitis




B.
It is no longer used to treat hepatitis B.
For immunocompetent adults with HBeAg-reactive
chronic hepatitis B, a 16-week course of IFN given
subcutaneously at a daily dose of 5 million units, or three
times a week at a dose of 10 million units is used.
In HBeAg-negative chronic hepatitis B, more protracted
courses, lasting up to 11/2 years, have been reported to
result in sustained remissions documented to last for
several years.
Complications of IFN therapy include systemic "flu-like"
symptoms; marrow suppression; emotional lability
, autoimmune reactions (especially autoimmune
thyroiditis); alopecia, rashes, diarrhea, and numbness and
tingling of the extremities. With the possible exception of
autoimmune thyroiditis, all these side effects are

40. Pegylated Interferon
 PEG IFN- 2a ,is administered SC 180 µg
weekly for 48 weeks.

41. When to Consider PegIFN
• Favorable predictors of
response
In HBeAg+ve CHB
– Low HBV DNA
– High ALT
– Genotype A or B > C or
D
– Not advanced disease.
 Specific patient
demographics
– Generally young people
– Young women
wanting pregnancy in
near future
– Absence of
comorbidities
 Patient preference
 Concomitant HCV infection
1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL,
et al, Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al.
Am J Gastroenterol. 2006;101:297-303.

42. Nucleos(t)ide Analogs
 Lamivudine (100mg)
 Adefovir (10mg)
 Entecavir (0.5mg),(1mg)
 Telbivudine (600mg)
 Tenofovir (300mg)/(245mg)

43. Nucleos(t)ide Analogs

44. Nucleos(t)ide Analogs

45. Nucleos(t)ide Analogs

46. Nucleos(t)ide Analogs

50. Response – HBe Ag +ve

51. Response – HBe Ag +ve

52. Response – HBe Ag +ve

53. Response – HBe Ag - ve

55. •
•
•
•
•
•
Potential Barriers to HBV
Treatments
Patient resistance or cultural beliefs about treatment
Potential adverse effects (particularly interferon)
Challenges with long-term therapy
Understanding endpoints and monitoring strategies
Lack of symptoms
Lack of ability to cure disease with current regimens in
most patients
• Adherence

56. PREDICTORS OF RESPONSE

57. For IFN/PEG-IFN based
treatment
 In HBeAg-positive CHB, predictors of anti-HBe
seroconversion are low viral load (HBVDNAbelow
2000 IU/ml), high serum ALT levels (above 2–5
times ULN), HBV genotype and high activity
scores on liver biopsy (at least A2). HBV
genotypes A and B have been shown to be
associated with higher rates of anti-HBe
seroconversion and HBsAg loss than genotypes
D and C, respectively, after treatment with PEGIFN.

58. For NAs treatment
 In HBeAg-positive CHB, factors predictive of anti-
HBe seroconversion are low viral load (HBV DNA
below 2 IU/ml), high serum ALT levels, high
activity scores on liver biopsy . HBVgenotype
does not influence the virological response to any
NA.

59. TREATMENT IN HIV CO-INFECTED
Pt’S
 HIV-positive patients with CHB were at increased risk
of cirrhosis and HCC .
 The indications for therapy are the same as in HIV-
negative patients, based on HBV DNA levels, serum
ALT levels and histological lesions.
 In agreement with recent HIV guidelines, it is
recommended that most co-infected patients should be
simultaneously treated for both HIV and HBV de novo
.
 Tenofovir combined with emtricitabine or lamivudine
plus a third agent active against HIV are indicated.

60.  In a small number of patients with CD4 count
>500/ml, HBV can be treated before the
institution of anti-HIV therapy; PEGIFN, adefovir
and telbivudine, which are not proven to be active
against HIV, should be preferred.
 However, if any of these two NAs with a low
barrier to resistance does not reach the goal of
undetectable HBV DNA after 12 months of
therapy, treatment of HIV infection should be
envisaged.

61. TREATMENT IN HDV COINFECTED Pt’S
 Chronic infection after acute HBV-HDV hepatitis is




less common, while chronic delta hepatitis develops
in 70–90% of patients with HDV superinfection.
Active co-infection with HDV is confirmed by
detectable HDV RNA, immuno-histochemical staining
for HDV antigen, or IgM anti-HDV.
(PEG-)IFN is the only drug effective against HDV.
The efficacy of (PEG-)IFN therapy can be assessed
during treatment (after 3–6 months) by measuring
HDV RNA levels.
More than 1 year of therapy may be necessary, as
there may be some benefit from treatment
prolongation.

62. TREATMENT IN HCV COINFECTED Pt’S
 In HBV-infected patients, HCV co-infection
accelerates liver disease progression and
increases the risk of HCC.
 HBV and HCV replicate in the same hepatocyte
without interference.
 However, HBV DNA level is often low or
undetectable and HCV is responsible for the
activity of chronic hepatitis in most patients.
 Thus, patients should usually receive treatment
for HCV.

63. Treatment in Pregnant Women

64. Pre-emptive therapy before immunosuppressive
therapy or chemotherapy
 HBsAg-positive candidates for chemotherapy and
immunosuppressive therapy should be tested for HBV
DNA levels and should receive pre-emptive NA
administration during therapy (regardless of HBV DNA
levels) and for 12 months after cessation of therapy.
 When HBV DNA levels are<2000IU/ml & finite and
short duration of immunosuppression is
scheduled,Lamivudine is used.otherwise Entecavir or
Tenofovir are used.
 HBsAg-negative, anti-HBc positive patients with
detectable serum HBV DNA should be treate similarly
to HBsAg positive patients.

65.  HBsAg-negative, anti-HBc positive patients with
undetectable serum HBV DNA and regardless of antiHBs status who receive chemotherapy and/or
immunosuppression should be followed carefully by
means of ALT and HBV DNA testing and treated with
NA therapy upon confirmation of HBV reactivation
before ALT elevation.

66. Unresolved issues and unmet needs
(1) Improve knowledge and prognosis of the natural history
and indications for treatment, particularly in HBeAgpositive immunotolerant patients and HBeAg-negative
patients with serum HBV DNA levels below 20,000 IU/ml.
(2) Assess the role of non-invasive markers (serum and
biophysical) for the evaluation of the severity of liver
disease and for the follow-up of treated and untreated
patients.
(3) Further clarify the role of serum HBsAg levels in the
evaluation of the natural history, prediction of therapeutic
responses and treatment individualisation.
(4) Assess host genetic and viral markers to determine
prognosis and optimise patients’ management.
(5) Assess the impact of early diagnosis and early treatment
intervention.

67. (7) Identify markers that predict successful NA
discontinuation.
(8) Assess the safety and efficacy of the combination of
PEGIFN
with a potent NA (entecavir or tenofovir) to increase
anti-HBe and anti-HBs seroconversion rates.
(9) Develop and assess new drugs and therapeutic
approaches,
particularly immunomodulatory therapies, to enhance
loss
of HBeAg and HBsAg and subsequent seroconversion.
(10) Assess long-term impact of therapy on the
prevention of
cirrhosis and its complications and HCC.

68. (12) Develop effective and optimum treatment for
HDV
co-infection.

69. PROPHYLAXIS

70. RECOMMENDED DOSEING
RECOMBIVAX HB
ENGERIX-B
INFANTS &CHILDREN<11 YRS 5µg(0.5ml)
10µg(0.5ml)
CHILDREN 11-19
5µg(0.5ml)
10µg(0.5ml)
ADULTS >20
10µg(1ml)
20µg(1ml)
HEMODIALYSIS&
IMMUNOCOMPROMISE
D
5µg(0.5ml)
(<20 yrs)
40µg(4ml)
(≥20 yrs)
10µg(0.5ml)
40µg(2ml)

71. POST EXPOSURE PROPHYLAXIS OF HB IF
SOURCE IS HBSAG +
Vaccination status
Immune prophylaxis
unvaccinated
HBIG *1 dose(.06ml/kg)&initiate HBV
VACCINE
Previously vaccinated
Known responder
No treatment
Known non responder
HBIG *1 dose(.06ml/kg)&initiate HBV
vaccine or HBIG *2 doses,
revaccination
Antibody response not known
Test for antibodies if adequate no
treatment; if inadequate HBIG *1
dose(.06ml/kg)& HBV VACCINE
booster dose

72. HEPATITIS B PROPHYLAXIS OF NEW BORN TO
HBSAG + MOTHER
AGE OF INFANT
HBIG
VACCINATION
WITH IN 12 HOURS
.5ML IM
FIRST DOSE
1 MONTH
NONE
SECOND DOSE
6 MONTHS
NONE
THIRD DOSE

74. THANK YOU

75. REFERCENCES
 Asian-Pacific consensus statement on the
management of chronic hepatitis B: a 2012
update.
 EASL Clinical Practice Guidelines: Management
of chronic hepatitis B virus infection(2012).
 HARRISONS INTERNAL MEDICINE

76. Genotypes

78.  Some persons may test positive for anti-HBc but notHBsAg or
anti-HBs. The finding of isolated anti-HBc canoccur for a variety
of reasons. (1) Anti-HBc may be anindicator of chronic HBV
infection; in these persons,HBsAg had decreased to
undetectable levels but HBVDNA often remains detectable, more
so in the liver thanin serum. This situation is not uncommon
among personsfrom areas with high prevalence of HBV infection
and inthose with human immunodeficiency virus (HIV) or
hepatitisC virus (HCV) infection.27 (2) Anti-HBc may be amarker
of immunity after recovery from a prior infection.In these
persons, anti-HBs had decreased to undetectablelevels but
anamnestic response can be observed after onedose of HBV
vaccine.28 (3) Anti-HBc may be a false positivetest result
particularly in persons from low prevalenceareas with no risk
factors for HBV infection. These individualsrespond to hepatitis B
vaccination similar to personswithout any HBV
seromarkers.10,28,29 (4) Anti-HBcmay be the only marker of
HBV infection during thewindow phase of acute hepatitis B;
these persons shouldtest positive for anti-HBc IgM.