Approach to case of chronic hepatitis B after suspicion or establishment of an acute Hepatitis B- covering diagnosis, management, medications available, vaccination and followup.
Circulatory Shock, types and stages, compensatory mechanisms
Chronic hepatitis B
1. DIAGNOSIS AND
MANAGEMENT OF
CHRONIC HEPATITIS B
A PRESENTATION BY DR. AISHWARYA JOSHI
MODERATOR: DR. PRAMOD KUMAR TUDU
IMS AND SUM HOSPITAL,
BHUBANESWAR
2. DEFINITION:
CHRONIC HBV INFECTION: DEFINED AS PERSISTENCE OF HEPATITIS B
SURFACE ANTIGEN FOR SIX MONTHS OR MORE AFTER ACUTE
INFECTION WITH HBV.
3. HEPATITIS B :
• It is an infection caused by the hepatitis B virus
effecting 0.3 % of world population, 75% of which is
Asian.
• Baruch Blumberg, in 1965 discovered the Australia
antigen –now called the HBsAg.
• D.S. Dane discovered the viral particle in 1970 by
electron microscopy.
4.
5.
6. Acute HBV infection:
•New onset hepatitis B infection that may or may not
be icteric or symptomatic.
• Diagnosis is based on detection of hepatitis B
surface antigen (HBsAg) and IgM antibodies to
hepatitis B core antigen (anti-HBc).
•Recovery is accompanied by clearance of HBsAg
with seroconversion to anti-HBs (antibodies to
hepatitis B surface antigen), usually within 3
months.
7. TRANSMISSION/MODE OF INFECTION:
HORIZONTAL TRANSMISSION
CONTAMINATED NEEDLES
HEALTH CARE WORKERS
SEXUAL
TRANSFUSION OF BLOOD PRODUCTS
VERTICAL
TRANSMISSIO
N
MOTHER
INFANT
8. ACUTE HEPATITIS B
• Incubation period: 30-180 days
• Symptoms: fever, fatigue, anorexia, jaundice
In 5-10% individuals, serum sickness like features of arthralgia,
rash, angioedema, proteinuria, hematuria may occur.
9. •Dark urine followed
by dark colored
stools.
•Jaundice and right
upper abdominal
pain.
Icteric phase
•Symptoms and
icterus resolve
•Liver enzymes revert.
Convalescent
phase
• Clinically asymptomatic,
• Hepatic serological and
enzyme markers present.
Replication
phase
• Fever, nausea, anorexia,
arthralgia, fatigue, malaise,
urticaria, pruritis.
Prodromal
phase
C
L
I
N
I
C
A
L
F
E
A
T
U
R
E
S
11. • In acute stage of viral hepatitis, antibodies to smooth muscle
and other cellular components may be present, low titres of
rheumatoid factor, nuclear antibody and heterophile antibody
can also be present.
• Transient neutropenia/ lymphopenia can show up.
13. SUSPICION OF CHRONIC HEPATITIS:
• Persistence of anorexia, fatigue and weight loss after
an acute attack of HBV
• Persistent hepatomegaly on clinical examination
• Neonates- 95%
• Adults-1-5%
14. CLINICAL FEATURES IN CHRONICITY:
• Mild features of hepatocellular disease.
• Serum bilirubin, aspartate transaminase and gamma
globulin show a moderate rise.
• Normal level of serum albumin.
18. Anti HBc antibody
No HBc antigen can be detected in serum
ðIgM is an early indicator
ðIt is an indicator of past or existing infection, in immune
individual or a chronic carrier.
ðIn chronic hepatitis B, IgM anti HBc will be negative and IgG HBc
will be positive.
19. HBe Antigen
• Correlates with ongoing viral synthesis and infectivity.
• Persistence beyond 6 weeks is an indicator of chronicity
20. ANTI HBsAg
• 10-20% cases of chronic cases harbour this antibody.
• It is the only serological marker to appear after vaccination
• Anti HBs >12 mIU is protective.
21. HBV DNA DETECTION
•Signal amplification
assay
•DNA amplification assay
by PCR
These markers are useful in following the course of HBV
replication in patients of chronic Hep B receiving
chemotherapy. It is the most sensitive index of viral
replication.
22. NEEDLE LIVER BIOPSY:
• Degree of necroinflammation and fibrosis becomes clear.
Chronic
hepatitis
Active
cirrhosis
HCC
23. METAVIR SCORE
Piecemeal necrosis score
absent 0
focal alteration of
the periportal plate
in some portal tracts
1
diffuse alteration of
the periportal plate
in some portal tracts
or focal lesion
around all portal
tracts
2
diffuse alteration of
the periportal plate
in all portal tracts.
3
Focal lobular necrosis score
0, less than one
necroinflammatory
foci per lobule
0
at least one
necroinflammatory
foci per lobule
1
several
necroinflammatory
foci per lobule or
confluent or bridging
necrosis
2
A0-no activity A1mild activity- A2-moderate activity A3- severe activity
F0-no fibrosis, F1-portal fibrosis without septa, F2-portal fibrosis with rare
septa F3- numerous septa without cirrhosis;F4- cirrhosis
24. ISHAK SCORING SYSTEM
0 No fibrosis
1 Expansion of some portal areas with or without septa
2 Expansion of most portal areas with or without septa
3 Expansion of most portal areas with occasional portal to portal bridging
4 Expansion of portal areas with marked bridging (portalportal and/or portal-
central)
5 Marked bridging with occasional nodules (incomplete cirrhosis)
6 Cirrhosis, probable or definitive
25. NON INVASIVE TESTS FOR CHRONIC HEP B
• Serum markers of fibrosis: APRI and FIB-4
APRI= X 100
• APRI score >1 has sensitivity of 71% and specificity of 72% to
predict cirrhosis.
MEASURED AST
UPPER LIMIT OF NORMAL
AST
PLATELET COUNT
26. FIB 4 SCORE
FIB-4 =
A FIB-4 score of >3.25 has 97% specificity.
FIBROSCAN : TRANSIENT ELASTOGRAPHY
>90% accuracy for early cirrhosis and fibrosis
AGE IN YEARS X
AST[U/L]
TPC X ALT[U/L]√
27. GOAL OF THERAPY IN CHRONIC HBV
INFECTION
TO ACHIEVE TOTAL SUPPRESSION OF HBV DNA WITH LONG TERM
ANTIVIRAL THERAPY AND KEEP DNA UNDETECTED.
28. PEGYLATED INTERFERON: THE FIRST LINE
DRUG
• It requires finite duration of therapy: 48
weeks, achieves highest rate of HBeAg
response after a year of therapy and does not
cause viral mutations.
• Subcutaneous administration, more intense
monitoring are drawbacks. Also, not as
effective as NA in high HBV DNA levels.
• Dose: 180 mcg SC/ week
• It should be used in patients without
cirrhosis, normal ALT levels and HBV DNA
29. TREATMENT: FIRST LINE
drug dose
Tenofovir 300 mg once daily
entecavir(adult with compensated liver
disease and lamivudine naive)
0.5 mg once daily
Entecavir (adult with decompensated liver
disease)
1 mg once daily
Tenofovir plus emtricitabine (in HIV) Tenofovir 245 mg; emtricitabine 200 mg
34. clinical HBV DNA
[IU/mL]
ALT RECOMMENDATION
-CHRONIC
HEPATITIS
-CIRRHOSIS
COMPENSATED
-CIRRHOSIS
DECOMPENSATED
>2X104
>2X104
>2X103
<2X103
DETECTABLE
UNDETECTABL
E
<2 X ULN
>2 X ULN
< OR > ULN
>ULN
<OR> ULN
<OR> ULN
NO TREATMENT. IN PT >40 AND FAMILY
H/O HCC AND/OR ALT PERSISTENTLY
HIGH AT 2FOLD RANGE , LIVER BIOPSY
MAY BE HELPFUL TO DECIDE TO TREAT
TREAT
TREAT WITH ORAL AGENTS [NOT PEG
INF]
CONSIDER TREATMENT
TREAT WITH ORAL AGENTS, NOT PEG
INF, REFER
LIVER TRANSPLANT
OBSERVE, REFER FOR LIVER
TRANSPLANTATION
IF HBe AG IS REACTIVE
35. CLINICAL HBV DNA [IU/Ml] ALT RECOMMENDATION
-CHRONIC
HEPATITIS
-CHRONIC
HEPATITIS
-CIRRHOSIS
COMPENSATED
-CIRRHOSIS
DECOMPENSATED
<2X103
>103
>104
>2X103
<2X103
DETECTABLE
UNDETECTABLE
<ULN
1 TO >2 X ULN
>2 X ULN
<OR> ULN
>ULN
<OR> ULN
<OR>ULN
INACTIVE CARRIER,
NO TREATMENT
LIVER BIOPSY-TREAT
IF MOD-SEV
INFLAMMATION OR
CIRRHOSIS
TREAT
TREAT WITH ONLY
ORAL AGENTS
CONSIDER
TREATMENT
TREAT WITH ORAL
AGENTS, REFER FOR
LIVER TRANSPLANT
OBSERVE, REFER FOR
TRANSPLANT
If HBe ag negative
36. WHO TO TREAT ?
• All cases with proven cirrhosis regardless of ALT levels, HBeAg
status or HBV DNA levels.
• adults with CHB who do not have clinical evidence of cirrhosis
(or based on APRI score ≤2 in adults), but are aged more than
30 years, and have abnormal ALT levels HBV DNA >20 000
IU/mL, regardless of HBeAg status.
37. • Existing recommendation for HBV/HIV-coinfected
persons:
In HBV/HIV-coinfected individuals, ART should be initiated in all
those with evidence of chronic liver disease , regardless of CD4
count; and in all those with a CD4 count ≤500 cells/mm3 ,
regardless of stage of liver disease.
38. -WHO NOT TO TREAT BUT CONTINUE TO
MONITOR
1. ANTIVIRAL THERAPY IS NOT RECOMMENDED IN PERSONS
WITHOUT CLINICAL EVIDENCE OF CIRRHOSIS (OR BASED ON APRI
SCORE ≤2 IN ADULTS), AND WITH PERSISTENTLY NORMAL ALT
LEVELS AND LOW LEVELS OF HBV REPLICATION (HBV DNA
<2000IU/ML) REGARDLESS OF HBEAG STATUS OR AGE.
2.PERSONS WITHOUT CIRRHOSIS AGED 30 YEARS OR LESS, WITH
HBV DNA LEVELS >20 000 IU/ ML BUT PERSISTENTLY NORMAL
ALT;
3. HBEAG-NEGATIVE PERSONS WITHOUT CIRRHOSIS AGED 30
YEARS OR LESS, WITH HBV DNA LEVELS THAT FLUCTUATE
BETWEEN 2000 AND 20 000 IU/ML, OR WHO HAVE
INTERMITTENTLY ABNORMAL ALT LEVELS.
39. PREREQUISITES IN MANAGEMENT:
Assessment
of the
severity of
liver disease :
USG, LFT,
TPC, PT.
Assessment of the
level of viral
replication: using
quantification of
serum HBV DNA and
HBeAg and anti-HBe
serostatus.
Assessment for the presence of
comorbidities: evaluation for the
presence of other comorbidities,
including coinfection with HIV,
HCV or HDV, impaired glucose
tolerance, dyslipidemia, non-
alcoholic fatty liver disease,
alcoholic liver disease, iron
overload and drug/toxin-induced
injury.
41. SECOND LINE THERAPY:
• Primary antiviral treatment failure may be defined as failure of
an antiviral drug to reduce HBV DNA levels by ≥1 x log10
IU/mL within 3 months. Secondary antiviral treatment failure
may be defined as a rebound of HBV DNA levels of ≥1 x log10
IU/mL from the nadir in persons with an initial antiviral
treatment effect (≥1 x log10 IU/mL decrease in serum HBV
DNA).
• In persons with confirmed or suspected antiviral resistance (i.e.
history of prior exposure or primary non-response) to
lamivudine, entecavir, adefovir or telbivudine, a switch to
tenofovir is recommended.
42. A NOTE ON INTERFERON THERAPY:
• IMPORTANT HISTORICALLY, NO LONGER USED
• Not effective in infants, immunosuppressed, minimal to mild
ALT elevation, decompensated chronic hepatitis B where it
was actually detrimental.
• Complications: flu like symptoms, bone marrow suppression,
irritability-anxiety, auto immune reactions like thyroiditis,
rashes, alopecia, diarrhoea.
44. WHEN TO STOP TREATMENT
• All persons with cirrhosis based on clinical evidence (or APRI score >2
in adults) require lifelong treatment with nucleos(t)ide analogues
(NAs), and should not discontinue antiviral therapy because of the risk
of reactivation, which can cause severe acute-on-chronic liver injury.
Discontinuation: Discontinuation of NA therapy may be considered
exceptionally in:
• Persons without clinical evidence of cirrhosis (or based on APRI score
≤2 in adults);
• AND if there is evidence of HBeAg loss and seroconversion to anti-HBe
(in persons initially HBeAg-positive) and after completion of at least
one additional year of treatment;
• AND in association with persistently normal ALT levels and
persistently undetectable HBV DNA
45. MONITORING
• It is recommended that the following be monitored at least
annually:
ALT levels (and AST for APRI),
HBsAg , HBeAg , and HBV DNA
levels
adherence should be monitored at
each visit
Non-invasive tests (APRI score or
FibroScan) to assess for the
presence of cirrhosis, in those
without cirrhosis at baselineRenal function should be
monitored annually in persons on
long-term tenofovir or entecavir
therapy, and growth monitored
carefully in children.
46. HCC MONITORING
Routine surveillance for HCC with abdominal ultrasound and
alpha-fetoprotein testing every six months is recommended for:
• persons with cirrhosis, regardless of age or other risk factors
• persons with a family history of HCC
• persons aged over 40, without clinical evidence of cirrhosis (or
based on APRI score ≤2), and with HBV DNA level >2000 IU/mL
47. RETREATMENT:
• Relapse may occur after stopping therapy with NAs.
Retreatment is recommended if there are consistent signs of
reactivation (HBsAg or HBeAg becomes positive, ALT levels
increase, or HBV DNA becomes detectable again)
48. PREVENTION: RECOMBINANT DNA-DERIVED
VACCINES
• Subunit vaccine
• Indefinite protection if completed
• VACCINATION IN ADULTS: 0, 1 AND 6
MONTHS
• IN CHILD: WITHIN 24 HOURS OF BIRTH,
6-10-14 WEEKS, 6 MONTHS.
49. SCREENING: HIGH RISK GROUP
1. household and sexual contacts of persons with CHB,
2. HIV-infected persons
3. persons who inject drugs
4. men who have sex with men
5. sex workers,
6. Blood and organ donors should also be screened for HBsAg
51. SOURCE:
• Sheila Sherlock’s Diseases of the Liver and Biliary system
• Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B:
AASLD 2018 Hepatitis B Guidance
• EASL 2017 clinical practise guidelines on the management of Hepatitis B
virus infection.
• WHO GUIDELINES FOR THE PREVENTION, CARE AND TREATMENT OF
PERSONS WITH CHRONIC HEPATITIS B INFECTION- MARCH 2015
• Harrisons principles of internal medicine- 20th edition
• HEPATITIS B ANNUAL, KALINGA GASTROENTEROLOGY FOUNDATION
• Davidsons principles and practise of medicine: 22nd edition