CHRONIC Hepatitis B

Dr CHANDRIMA PATTADAR
JUNIOR RESIDENT
 EPIDEMIOLOGY

 HBV infection is an important public health problem with approx. 240 million people
are HBsAg positive throughout the world.
 Prevalence is more in:
1.High endemic zone: Southest Asia and china, Africa, prevalence is 6%.lifetime risk of
infection 60%-80%
2.Intermediate risk : Eastern and southern Europe ,middle east, japan, India , northern
Africa . Life time risk of infection 20%-40%.
3.Low risk: North America, western Europe, central part of south America, Australia .
Lifetime risk of infection is less than 20%.
 84% 5year survival rate = patient with compensated cirrhosis due to HBV
 14% 5 year survival rate = patient with decompensated cirrhosis due to HBV
TRANSMISSION

 Effectively transmitted by percutaneous and mucous membrane exposure to

infectious body fluids.
 HBV is 50 to 100 times as infectious as HIV and 10 times as infectious as HCV.
 HBV replicates in hepatocyte primarily, other reservoir, adrenal gland, testis,
colon, nerve ganglia, skin.
Natural History and Nomenclature for
Chronic State
 Depends on HBV replication and host immune response.
 Rate of progression from acute to chronic hep B depends on age of acquired infection. 90% for a
perinatally acquired infection, 20 to 50% for infections between the age of 1 and 5 years,
and less than 5%for an adult-acquired infection.
 Natural history divided into five phases depends on
1.HBeAg
2.HBV DNA level
3.S.ALT level.
CLINICAL FEATURES

 Asymptomatic 2/3rd
 Fatigue
 Poor appetite
 Malaise
 Features of cirrhosis
 1% acute liver failure
EXTRAHEPATIC MANIFESTATION
 Uncommon but may happen in chronic or acute hepatitis B.
 Arthritis dermatitis
 Polyarteritis nodosa : <1% HBV affected, and less seen in Asia ; treatment :
antiviral therapy + plasmapheresis .
 Glomerulonephritis : membranous glomerulonephritis ,
membranoproliferative glomerulonephritis are the most common. Renal
biopsy shows immune complex deposition and cytoplasmic inclusion in
glomerular basement membrane.
 Cryoglobulinemia : type 2 and type 3
Initial assessment for Chronic HBV
infection
 History and complete physical examination for liver disease activity
 Severity and marker of HBV infection:
 1.S.AST,ALT,ALP,Bilirubin,PT,CBC,KFT
 2.USG W/A
 3.Liver biopsy or non-invasive test for hepatic fibrosis ( AST:platelet, fibroscan )
 4.HBeAg and anti HBeAg, Hep B DNA level,Serum HbsAg quantification
 5.anti HCV,HIV and other comorbidities like alcoholism, metabolic syndrome.
 Goal for treatment

 The ultimate goals for treatment of patients with chronic hepatitis B is long-
term suppression of HBV replication and arrest of progression of liver
disease, prevention of late complications, and improvement in survival.
 Several studies have now documented the long-term benefits of treatment,
such as reversal of cirrhosis and reductions in the frequency of HCC and the
need for liver transplantation (LT).
 Classical endpoints of treatment include suppression of serum HBV DNA,
HBeAg seroconversion in HBeAg-positive patients, serum ALT normalization,
and histologic improvement.
 However, the most desirable endpoint is HBsAg loss or seroconversion, which
has been associated with improved survival.
 Indication of Treatment

EASL and AASLD guideline For treatment of Hep B

Simplified version of treatment

 All adults, adolescents and children with CHB and evidence of

compensated or decompensated cirrhosis should be treated, regardless of
ALT levels, HBeAg status or HBV DNA level.
 Treatment requires for those patient who has HBV DNA (>2,000 IU/ml),
elevated ALT and/or at least moderate histological lesions.
Drugs for Hep B infection

 Currently, there are two main treatment options for CHB patients: treatment
with a NA or PegIFNa.
 The NAs that have been approved for HBV treatment include lamivudine
(LAM), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (TBV), tenofovir
disoproxil fumarate (TDF) and tenofovir alafenamide (TAF).
 classified into those associated with low barrier against HBV resistance (LAM,
ADV, TBV) and those with high barrier to HBV resistance (ETV, TDF, TAF).
 Selection of antiviral drug for CHB
 In all adults, adolescents and children aged 12 years or older in whom antiviral therapy
is indicated, the NAs which have a high barrier to drug resistance (tenofovir or entecavir)
are recommended.
 In woman of childbearing age Tenofovir may be preferred as the drug of choice in the
eventuality of a pregnancy. Entecavir is not recommended in pregnancy.
 Tenofovir is preferred in patients who have been exposed to lamivudine who have a
potential for Entecavir resistance.
 Entecavir is recommended in children aged 2–11 years.
 Entecavir and TAF may be preferred over TDF in:
 Age > 60 years; bone disease due to chronic steroid use or use of other medications that
worsen bone density history of fragility fracture, osteoporosis
 altered renal function with eGFR < 60 mL/min/1.73 m2 or albuminuria > 30 mg /24 hr.
 Tenofovir alafenamide fumarate ( TAF) is the drug of choice in patients with reduced
renal function or bone disease bone toxicities, where entecavir is contraindicated .
When To Stop Treatment

 All persons with cirrhosis require lifelong treatment with NAs, and should not
discontinue antiviral therapy because of the risk of reactivation, which can
also cause severe acute-on-chronic liver injury.
 NAs should be discontinued after confirmed HBsAg loss, with or without anti-
HBs seroconversion .
 NAs can be discontinued in non-cirrhotic HBeAg positive CHB patients who
achieve stable HBeAg seroconversion and undetectable HBV DNA and who
complete at least 12 months of consolidation therapy. Close post-NA
monitoring required.
 Discontinuation of NAs in selected non-cirrhotic HBeAg-negative patients who
have achieved long term (P3 years) virological suppression under NA(s) may
be considered if close post-NA monitoring can be guaranteed .
 MONITORING
NOT ON TREATMENT:
 Frequent monitoring with monthly ALT and 3 monthly HBeAg/Anti HBeAg
and HBVDNA quantitative would be required in those with fluctuating ALT
and HBV DNA 2000-20,000 IU/mL, who are as yet not on treatment.
 In active chronic B with persistently normal ALT and HBV DNA<20,000 IU may
be monitor annually.
ON TREATMENT:
 More frequent 3-6 monthly assessment is required initially in those with
advanced liver disease in the first year.
DISCONTINUED TREATMENT:
 Careful long term monitoring for reactivation with serial 3-6 monthly HBeAg,
ALT and HBVDNA levels is mandatory in those who have discontinued
treatment for consideration of retreatment .
 Monitoring for disease progression and treatment response in persons with
CHB prior to, during and post-treatment It is recommended that the
following be monitored at least annually.
 ALT levels (and AST for APRI), HBsAg, HBeAg, and HBV DNA levels (where HBV
DNA testing is available).
 Non-invasive tests (APRI score, FIB-4 or FibroScan) to assess for the worsening
of fibrosis/presence of cirrhosis, in those without cirrhosis at baseline.
 If on treatment, adherence should be monitored regularly and at each visit.
 Monitoring for tenofovir and entecavir toxicity:
 Measurement of baseline renal function and assessment of baseline risk for
renal dysfunction should be considered in all persons prior to initiation of
antiviral therapy.
 Renal function should be monitored annually in persons on long-term
tenofovir or entecavir therapy,
 growth monitored carefully in children.
Definition of Response
Virological responses for NA therapy :
 Virological response during NA is defined as undetectable HBV DNA by a sensitive
polymerase chain reaction (PCR) assay with a limit of detection of 10 IU/ml.
 Primary nonresponse is defined by a less than one log10 decrease of serum HBV
DNA after 3 months of therapy.
 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 12 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 DNA level on-
therapy.
 Definition of Response
 In patients who discontinue NA, sustained off-therapy virological response could be
defined as serum HBV DNA levels <2,000 IU/ml for at least 12 months after the end
of therapy.
 Serological responses: for HBeAg are HBeAg loss and HBeAg seroconversion(HBeAg
patient) and for HBsAg are HBsAg loss and HBsAg seroconversion(All patient)
 Biochemical response: is defined as a normalisation of ALT levels based on the
traditional ULN (40 IU/L).
 Histological response is defined as a decrease in necroinflammatory activity (by P2
points in histologic activity index or Ishak’s system) without worsening in fibrosis
compared to pretreatment histological finding.
Management of patients with NA
failure
 Prevention of resistance should rely on the use of first line therapy with high
barrier to resistance NAs.
 Compliance to NA therapy should be checked in all cases of treatment failure.
 Management of treatment failure should be based on NAs cross-resistance
data.
 Treatment adaptation should be performed as soon as virologic failure under
NAs is confirmed .
Monitoring for hepatocellular carcinoma (HCC):

 Routine surveillance for HCC with abdominal ultrasound and alpha-fetoprotein

testing every six months is recommended for:
1. Persons with cirrhosis, regardless of age or other risk factors
2. Persons with a family history of HCC.
3. Persons aged over 40 years (lower age may apply according to regional
incidence of HCC), without clinical evidence of cirrhosis (or based on APRI
score ≤2), and with HBV DNA level >2000 IU/mL (where HBV DNA testing is
available).
Treatment of patients with
decompensated cirrhosis
 Patients with decompensated cirrhosis should be immediately treated with a
NA with high barrier to resistance, irrespective of the level of HBV
replication, and should be assessed for liver transplantation.
 PegIFNa is contraindicated in patients with decompensated cirrhosis.
 Patients should be closely monitored for tolerability of the drugs and the
development of rare side effects like lactic acidosis or kidney dysfunction.
HIV-HBV coinfection

 All HIV-positive patients with HBV co-infection should start antiretroviral

therapy (ART) irrespective of CD4 cell count.
 HIV-HBV co-infected patients should be treated with a TDF- or TAF-based
ART regimen.
 HCV co-infected patient

 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 should be 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.
HDV-HBV coinfection

 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.
Treatment 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.
 Treatment in Pregnancy

 Screening for HBsAg in the first trimester of pregnancy is strongly

recommended .
 Pregnant women with CHB and advanced fibrosis or cirrhosis, therapy with
TDF is recommended.
 In pregnant women already on NA therapy, TDF should be continued while
ETV or other NA should be 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 week 24–
28 of gestation and continue for up to 12 weeks after delivery .
 Breast feeding is not contraindicated in HBsAg-positive untreated women or
on TDF-based treatment or prophylaxis .
Prevention of HBV recurrence after
liver transplantation
 All patients on the transplant waiting list with HBV related liver disease
should be treated with NA .
 Combination of hepatitis B immunoglobulin (HBIG) and a potent NA is
recommended after liver transplantation for the prevention of HBV
recurrence.
 Patients with a low risk of recurrence can discontinue HBIG but need
continued monoprophylaxis with a potent NA.
 HBsAg-negative patients receiving livers from donors with evidence of past
HBV infection (anti-HBc positive) are at risk of HBV recurrence and should
receive antiviral prophylaxis with a NA.
Health care worker

 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 (EASL
guideline).
 Regular activities can be maintained if serum HBV DNA <1000 IU/mL and if
above it then may be treat with long term NA therapy(CDC guideline).
HBV Reactivation During
Immunosuppressive Therapy
 HBV-r can be defined as an increase in HBV DNA replication (e.g.,>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
followed by elevation of serum aminotransferase levels, with or without
jaundice or other signs of liver failure.
 More chance of HBV-r in patient with HBsAg positive than HBsAg negative
patient.
 Recommended serologic screening tests include HBsAg and anti-HBc for all
patient . In HBsAg-positive patients, testing for serum HBV DNA, HBeAg,
and anti-Hbe(AGA,AASLD guideline).
 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.
 Prophylaxis should be initiated at least one week before the start of
immunosuppression and should be continued for at least 6 to 12 months
after withdrawal of immunosuppression; most guidelines extend this
duration to more than 12 months with B-cell depleting anti-CD20 agents.
Future treatment

 There are no drug till now for complete cure of all patient with chronic
hepatitis B.
 A functional cure of HBV is defined as HBsAg loss and, unfortunately, occurs in
only 2% to 10% of patients with chronic hepatitis B treated with available
antiviral agents.
 Therefore, novel antiviral agents, likely in combination, targeting multiple
steps in the viral life cycle will be required to achieve cure of HBV infection
in most patients.
 Prevention of Hep B infection

 Immunoprophylaxis against HBV can be by passive immunization using HBIG

or active immunization using HBV vaccine.
 Active immunization gives long-term immunity, whereas passive
immunization confers only immediate and short-lived protection
 Hepatitis B Immune Globulin: There are established efficacy of HBIG in
preventing HBV infection in high-risk persons, such as hemodialysis patients,
sexual partners of persons with chronic hepatitis B, and newborn infants of
HBsAg-positive mothers within 12 hours of birth along with simultaneous
vaccination.
Hepatitis B Vaccine
 Currently marketed HBV vaccines use recombinant DNA technology by introducing the
S gene encoding HBsAg into the genome of yeast cells.
 HBV vaccines typically achieve an anti-HBs titer greater than 100 mIU/mL. Antibody
titers >100 mIU/mL is 100% protection against HBV infection, and a lower antibody
titer (up to 10 mIU/mL) is seroprotective.
 Studies in different populations have demonstrated that anti-HBs titers decrease to
nonprotective levels in at least 25% to 50% of recipients over a period of 5 to 10
years.
 Although protective anti-HBs response rates after HBV vaccination occur in
approximately 90% patient and 5% to 8% of HBV vaccine recipients do not achieve
detectable anti-HBs levels (“nonresponders”).
Preexposure prophylaxis

 Causes of nonresponder: Smoking, obesity, injection into the buttock, chronic liver
disease, presence of HLA-DR3, DR7, and DQ2 alleles, absence of the HLA-A2 allele, and
older age .
 In a large randomized study of stable HIV-infected patients on antiretroviral therapy, the
proportion of patients given a 4-dose HBV vaccine regimen who had a durable response
(anti-HBs>10 mIU/mL) was 71%.
 Vaccination Schedule: The typical vaccination schedule is 0, 1, and 6 months after birth.
 In immunocompromised patients and those undergoing hemodialysis, 4 vaccine doses are
recommended, with the fourth dose given to maximize the anti-HBs titer response.
 If vaccination is interrupted, the second dose should be administered as soon as possible
after the first.
 If the third dose is not given on schedule, it should be given at least 2 months after the
second dose
Recommendations for vaccination

 In 2018, updated recommendations for HBV vaccication:

 universal infant vaccination,
 revaccination of nonresponder infants,
 serologic testing of infants whose maternal HBsAg status is unknown,
 HBV DNA testing in all HBsAg positive pregnant women, and vaccination of
patients with chronic liver disease.
 Previously, the CDC had also recommended HBV vaccination in persons 19 to
59 years of age with DM patient.
References

1. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B

virus infection
2. National guideline for Diagnosis & Management of Viral Hepatitis by
MOHF,Govt of India
3. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B:
AASLD 2018 Hepatitis B Guidanc
4. Sleisenger and Fordtran’s Gastrointestinal and Liver Diseases.11 th edition.
THANK YOU