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Hepatitis b
1. Management of Hepatitis B
Ajay Kumar Yadav
PGY2,Internal medicine
IOM-TUTH, Kathmandu
2074/11/09
2. Hep-B virus
Hepadnaviridae family
Enveloped
Primarily hepatotropic
DNA viruses : Small - 3.2 kb : partially ds : relaxed circular(rc) --> HBV nucleocapsid is
transported to the nucleus to release the rcDNA genome rcDNA is converted into a
covalently closed circular DNA (cccDNA) : transcription template for all viral transcripts
viral proteins.
lack of reverse transcriptase proofreading activity : HBV mutants
Nine genotypes (A-I) and several sub-genotypes
3. Hep-B cont..
Encode 7 proteins:
• HBeAg
• HBcAg
• HBV Pol/RT
• PreS1/PreS2/HBsAg (large, medium, and small surface envelope glycoproteins)
• HBxAg : regulator of transcription required for the initiation of infection).
Immunity
• Acute infections : immune response efficient and timely
• Chronic infections : impairment of T cell immunity
11. Natural history cont..
• Infection at birth is associated with clinically silent acute infection but a 90%
chance of chronic infection.
• Infection in young adulthood in immunocompetent persons is typically associated
with clinically apparent acute hepatitis but a risk of chronicity of only approx. 1%.
• The likelihood in a patient with HBeAg-reactive chronic hepatitis B of converting
spontaneously from relatively replicative to nonreplicative infection is approx.
10−15% per year
12. Natural history cont..
The 5 yr cumulative incidence of cirrhosis in untreated CHB : 8% to 20%
The 5-year cumulative risk of hepatic decompensation among those with
cirrhosis is 20%.
The annual risk of HCC in patients with cirrhosis has been reported to be
2–5%.
Hepatitis B responsible for 80% of primary liver cancer globally
In Asia, upto 40% of HCC related to Chronic HBV infection without
cirrhosis
13. Natural history cont..
• The risk of developing HCC is higher in patients with one or more factors that relate to the host :
Cirrhosis
Chronic hepatic necroinflammation on tissue biopsy
Older age
Male sex
African origin
Alcohol abuse
Chronic co-infections with other hepatitis viruses or HIV
Diabetes or metabolic syndrome
Active smoking
Positive family history
High HBV DNA and/or HBsAg levels
HBV genotype C > B
Specific mutations
14. Goals of treatment
Main goal
• improve survival and quality of life by preventing disease
progression, and consequently HCC development.
Additional goals
• Prevent mother to child transmission
• Prevent hepatitis B reactivation
• Prevention and treatment of HBV-associated extrahepatic
manifestations.
15. HBV-induced HCC
• Suppress HBV replication to induce the stabilisation of HBV-induced liver disease
and to prevent disease progression
• Reduce the risk of HCC recurrence after potentially curative HCC therapies.
Acute hepatitis B
• Preventing the risk of acute or subacute liver failure
16. Initial assessment in pts with chronic Hep-B
infection
History/physical
examination
Routine lab tests Serology/Virology
studies
Imaging/Staging
studies
All pts. Symptoms/signs of
cirrhosis
Alcohol and
metabolic risk
factors
Family history of
HCC
Vaccination status
CBC including
platelet count,
AST, ALT, total
bilirubin,
alkaline
phosphatase,
albumin, INR
HBeAg/anti-HBe
HBV DNA
quantitation
Anti-HAV to
determine need
for vaccination
Abdominal
ultrasound
Vibration-controlled
transient
elastography or
serum fibrosis
panel (APRI, FIB-4,
or FIbroTest)
Selected pts. Tests to rule out
other causes of
chronic liver
diseases if
elevated liver
test(s)
AFP, GGT
HBV genotype
Anti-HDV
Anti-HCV
Liver biopsy
17. Initial assessment cont..
The diagnostic accuracy of all non-invasive methods is better at excluding than confirming
advanced fibrosis or cirrhosis
HBeAg and anti-HBe detection are essential for the determination of the phase of chronic HBV
infection.
Measurement of HBV DNA serum level is essential for the diagnosis, establishment of the phase of
the infection, the decision to treat and subsequent monitoring of pts.
Sr. HBsAg quantification can be useful, particularly in HBeAg-negative chronic HBV infection and in
patients to be treated with interferon-alfa (IFNa).
HBV genotype is not necessary in the initial evaluation : selected pts to be treated with IFNa :
prognostic information : response to IFNa therapy and the risk of HCC.
Pts with negative anti-HAV should be advised to be vaccinated against HAV.
18. Candidates of treatment
AASLD (2015) APASL (2015) EASL (2017)
HBeAg-positive HBV DNA > 20,000 20,000 2000
HBeAg-negative 2000 2000 2000
ALT cutoff level U/L 30 for men
19 for women
Traditional cutoff
value of 40 U/L
Traditional cutoff
value of 40 U/L
19. T/t of HBeAg (+) CHB
AASLD (2015) APASL (2015) EASL (2017)
HBV DNA>20,000 IU/mL,
ALT >2xULN
Monitor for 3-6months. Treat
if no spontaneous HBeAg loss.
Liver biopsy before treatment
is optional
HBV DNA>20,000 IU/mL ,ALT
>2xULN
Monitor for 3months. Treat if
no spontaneous HBeAg loss.
Histology should be obtained
or assessed noninvasively
HBV DNA>20,000 IU/mL, ALT
>ULN) : Treat
HBV DNA>2000 IU/mL, ALT
>ULN : Monitor for 3-6months.
Liver biopsy (or noninvasive
markers of fibrosis) is
recommended.
Treat if no spontaneous HBeAg
loss and biopsy shows
moderate-severe
inflammation
HBV DNA>20,000 IU/mL,
ALT≤2xULN : Monitor every 3-
6months. Consider biopsy (>40
years, ALT persistently 1-
2ULN,or family h/o of HCC).
Treat if moderate/severe
inflam. or significant fibrosis
Similar to AASLD except age
cut off for biopsy > 35 years
HBV >20,000 IU/mL, ALT
persistently Normal :
May be treated if age > 30
years depending on underlying
liver injury.
<30 yrs : monitor 3 – 6 months
20. T/t of HBeAg (-) CHB
AASLD (2015) APASL (2015) EASL (2017)
HBV DNA>20,000 IU/mL,
ALT >2xULN : Treat
Biopsy optional .
HBV DNA>20,000 IU/mL ,ALT
>2xULN :Treat
Biopsy optional
HBV DNA>20,000 IU/mL, ALT
>ULN : Treat
Biopsy optional
HBV DNA 2000-20,000 IU/mL,
ALT 1-2xULN :
Consider liver biopsy.
Treat if liver biopsy shows
moderate/severe
inflammation or significant
fibrosis.
HBV DNA >2000IU/mL, ALT 1-
2xULN : Monitor ALT and HBV
DNA every
1-3 months.
Biopsy if ≥40years.
Treat if moderate/severe
inflammation or fibrosis.
HBV DNA >2000IU/mL, ALT>
ULN
Liver biopsy(or non invasive
markers of fibrosis) is
recommended Treat if biopsy
shows moderate- severe
inflammation and/or at least
moderate fibrosis.
HBV DNA≤2000 IU/mL,
ALT≤ULN : Monitor
HBV DNA≤2000 IU/mL,
ALT≤ULN : Monitor
HBV DNA≤2000 IU/mL,
ALT≤ULN : Monitor
21. T/t of HBV induced cirrhosis
Cirrhosis AASLD (2015) APASL(2015) EASL (2017)
Compensated HBV
DNA>2000IU/mL:
Treat regardless of ALT
level
HBV DNA<2000IU/mL
: Treat regardless of
ALT level
HBV DNA>2000IU/mL
: Treat regardless of
ALT level
HBV DNA<2000IU/mL
: Treat if ALT >ULN.
HBV DNA detectable :
Treat regardless of ALT
level
Decompensated Regardless of HBV
DNA or ALT level
Treat and refer for
liver transplantation
Same Same
HCC surveillance US every 6 months US and AFP every 6
months
US every 6 months
Presence of extrahepatic manifestations: treatment irrespective of liver disease
severity
22. How long treatment s/b continued?
At least four to five years of treatment
Cirrhotic patients:
• life-long therapy with oral agents is typically administered to reduce the
risk of clinical decompensation if a relapse occurs
Non Cirrhotic:
• HBeAg-positive :
o At least 12 months after HBeAg seroconversion
o Some advice treatment until loss of HbsAg
• HBeAg-Negative : confirmed loss of HBsAg
25. Drug Dose in adults Dose in
children
Potential A/E Monitoring
Peg-IFN-2a(adult)
IFN-a-2b
(children)
180 mcg weekly ≥ 1 year
Dose: 6 million
IU/m2
Flu-like symptoms,
fatigue, mood
disturbances,
cytopenias,
autoimmune
disorders in adults
Anorexia and
weight loss in
children
CBC (monthly to
every 3 months)
TSH (every 3
months)
Clinical monitoring
for autoimmune,
ischemic,
neuropsychiatric,
and infectious
complications
Lamivudine 100 mg daily ≥ 2 years
Dose: 3 mg/kg daily
to max 100 mg
Pancreatitis
Lactic acidosis
Amylase if
symptoms
Lactic acid levels if
clinical concern
Telbivudine 600 mg daily Creatine kinase
elevations and
myopathy
Peripheral
neuropathy
Lactic acidosis
Creatine kinase if
symptoms
Cinical evaluation if
symptoms
Lactic acid levels if
clinical concern
26. Drug Dose in adults Dose in
children
Potential A/E Monitoring
Entecavir 0.5 or 1.0 mg daily ≥ 2 years
Dose: weight-based
to 10-30 kg; above
30 kg : 0.5 mg daily
Lactic acidosis Lactic acid levels if
clinical concern
Adefovir 10 mg daily ≥ 12 years 10 mg
daily
Acute renal failure
Fanconi syndrome
Nephrogenic
diabetes insipidus
Lactic acidosis
Creatinine clearance at
baseline
If at risk for renal
impairment, creatinine
clearance, serum
phosphate,
urine glucose, and protein
at least annually
Consider bone density study
at baseline and during
treatment in persons
with history of fracture or
risks for osteopenia
Lactic acid levels if clinical
concern
Tenofovir 300 mg daily ≥ 12 years 300 mg
daily
Nephropathy,
Fanconi syndrome
Osteomalacia
Lactic acidosis
As above
27.
28.
29.
30. PEG IFN, entecavir, or tenofovir are recommended as first-line therapy
PEG IFN requires finite-duration therapy, achieves the highest rate of HBeAg responses
after a year of therapy, and does not support viral mutations, but it requires subcutaneous
injections and is associated with inconvenience and intolerability
Oral nucleoside analogues require long-term therapy in most patients, and when used
alone, lamivudine and telbivudine foster the emergence of viral mutations, adefovir
somewhat less so, and entecavir (except in lamivudine-experienced patients) and tenofovir
rarely at all.
Oral agents do not require injections, are very well tolerated, lead to improved histology in
50−90% of patients, suppress HBV DNA more profoundly than PEG IFN, and are effective
even in patients who fail to respond to IFNbased therapy.
31. Peg Inteferon 2 alpha
Short fixed duration therapy ( 48-52 wks)
No renal toxicity
Ideal patients with high ALT and medium to low DNA
Has stopping rules and continuation rules
Chance of DNA suppression long term in less than 20%
Loss of HBsAg less than 10%
• Interferons have antiproliferative properties and should not be used during pregnancy
• PEG IFN should not be used in patients with compensated or decompensated cirrhosis
32.
33. Entecavir
Nucleoside analogue, inhibits reverse transcriptase
0.5 mg/day : 1 mg/day in lamivudine or telbivudine exposed and
decompensated COL
Over 97% of treatment-naıve patients could achieve maintained HBV DNA
suppression on entecavir after 2–3 years
34. Advantages of TAF over TDF
Greater plasma stability than TDF
Efficient delivery of active drug to hepatocytes at reduced systemic tenofovir
exposures
Safe and well tolerated; declines in HBV DNA similar to TDF at all doses
evaluated
Less renal and bone toxicity
35. Indications for selecting ETV or TAF over TDF
Age >60 years
Bone disease
• Chronic steroid use or use of other medications that worsen BMD
• History of fragility fracture
• Osteoporosis
Renal alteration
• eGFR <60 ml/min/1.73 m2
• Albuminuria >30 mg/24 h or moderate dipstick proteinuria
• Low phosphate (<2.5 mg/dl)
• Hemodialysis
37. Responses cont..
• Virological responses
• 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 a less than one log10 decrease of serum HBV DNA after 3 months of therapy.
Partial virological response : 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 : 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
• 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.
38. Responses cont..
• Serological responses for HBeAg :
HBeAg loss and HBeAg seroconversion
• Serological responses for HBsAg :
HBsAg loss and HBsAg seroconversion
• Biochemical response :
Normalisation of ALT
• Histological response :
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 findings.
40. Antiviral Options for Management of Antiviral
Resistance
Antiviral Resistance Switch Strategy Add Strategy:
2 Drugs Without Cross-Resistance
Lamivudine-resistance Tenofovir Continue lamivudine : add
tenofovir (or alternative
emtricitabine-tenofovir)
Telbivudine-resistance Tenofovir Continue telbivudine : add
tenofovir
Adefovir-resistance Entecavir Continue adefovir : add entecavir
Entecavir-resistance Tenofovir Continue entecavir : add tenofovir
(or alternative emtricitabine-
tenofovir)
Multi-drug resistance Tenofovir Combined tenofovir and entecavir
41. Monitoring of Patients
• 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 : be tested yearly.
• Screening for HCC : USG and AFP
• Adverse reactions to drugs
42. Endpoints in therapy
Ideal endpoint : sustained off-
therapy HBsAg loss, with or
without seroconversion to anti-HBs
More realistic endpoint : induction
of sustained or maintained off
therapy virological remission
Sustained or maintained on
therapy virological remission
43. Treatment in special patient groups with HBV
infection
HIV co-infected patients
• All HIV-positive patients with HBV co-infection should start ART irrespective of CD4 cell count
• HIV-HBV co-infected patients should be treated with a TDF- or TAF-based ART regimen
• Entecavir may generate HIV mutations
HDV co-infected patients
• 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
44. HCV co-infected patients
• 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 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
45. Acute hepatitis B
• More than 95% of adults with acute HBV hepatitis do not require specific treatment,
because they will fully recover spontaneously
• Only patients with severe acute hepatitis B, characterised by coagulopathy or
protracted course(i.e., persistent symptoms or marked jaundice for [4 weeks), or signs
of ALF s/b treated with NA and considered for liver transplantation
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
46. Healthcare workers
• 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
47. Pregnancy
• 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 24–28 wop and continue for up to 12 weeks after delivery
• The infants of all HBsAg-positive women should receive immunoprophylaxis (HBV vaccination and/or
hepatitis B immunoglobulin )
• Breast feeding is not contraindicated in HBsAg-positive untreated women or on TDF-based treatment or
prophylaxis
48. • Patients undergoing immunosuppressive therapy or chemotherapy
• All candidates for chemotherapy and immunosuppressive therapy s/b tested for
HBV markers prior to immunosuppression
• 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
49. 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
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
Found in aborigines
The hepatitis B virion (aka Dane particle) is a 42-nm particle with an outer envelope (HBsAg) surrounding a nucleocapsid that contains a small DNA genome
A genotype – responds to inteferon – african origin
B,C – most commonly asians ( no genotype A)
Sandwiched between China, a country with high prevalence of hepatitis B surface antigen (HBsAg) and 30% of the world's HBsAg carriers, and India which has intermediate HBsAg prevalence and 10% of the world's carriers, Nepal has the lowest prevalence of hepatitis B virus (HBV) infection in Asia, with an HBsAg carrier rate of 0.9%.
The HBsAg prevalence among pregnant women in Nepal is low (0.5%)
During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis; during the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations can also occur with both acute and chronic infection.
immune tolerance phase usually lasts 10 to 30 years.
Approximately 70 percent of patients with acute hepatitis B have subclinical or anicteric hepatitis. 5% develop chronic hepatitis
Active disease most commonly develop HCC.
HBV is a carcinogen. Screening mandatory even in inactive carriers.
Tests to be done at least 2 months apart.
only a small minority of patients (approximately 5 percent) lose HBsAg after five years of continued therapy.
APASL guideline state that treatment may be withdrawn after completing at least 2 years of treatment with undetectable HBV DNA documented on three occasions 6 months apart.
only the MELD and not the Child–Pugh score was correlated with the development of lactic acidosis, suggesting that renal impairment may be an important contributor
Lamivudine, entecavir and tenofovir have activity against both HIV and HBV and are contraindicated as single agents for hepatitis B in coinfected patients because of the risk of HIV resistance