Hepatitis B and C - Approach and Management : Updates 2020

1. HEPATITIS B
Chair person: Dr Ram S K
Associate professor
Dept of General Medicine
Student :Dr Tousif

2. HEPATITIS B
• INTRODUCTION
• 1965 Baruch Samuel Blumberg
Discovered hepatitis B surface antigen(HBs
AG) Autralia Ag, now a days known as
Hepatitis surface antigen
• 1970,Dane Cameron and Briggs Visualized the
hepatitis B virus (HBV) virion-Dane particle
• Block Tmet et al A historical perspective on the discovery and elucidation of the
hepatitis B virus. Antiviral Research. 2016 Jul

3. Baruch Samuel Blumberg
was an
American physician,
geneticist, and
co-recipient of the
1976 Nobel Prize in
Physiology or
Medicine (with Daniel
Carleton Gajdusek) for his
work on the hepatitis
B virus while an
investigator at the NIH
(National Institute of
health ,USA)

4. Introduction
• Hepatitis b virus is an hepadnavirus,
• Has a circular genome composed of partially
double standed DNA.
• The virus replicate through an RNA
intermediate form by reverse transcription
• Zlotnick A, et al A theoretical model successfully identifies features of hepatitis B
virus capsid assembly. Biochemistry. 1999

5. Continue
• Hepatits B virus(HBV) has been classified into ten
genotypes (A-J) based on genomic sequence
divergence.
• HBeAg expression last longer and liver disease is
more severe with graver outcome in carriers of
genotype C than B in Asia.
• Evidence indicate a better response to interferon
and lamivudine in patients with chronic hepatitis
B genome b rather than genome c
• Pujol F, et al Hepatitis B virus American genotypes: Pathogenic variants?. Clinics and
Research in Hepatology and Gastroenterology. 2020 Jun 15.

6. Prevalence
• 400 to 500 million carriers of HBV worldwide,
with chronic HBV infection at a rate of 5%.
• WHO report, HBsAg prevalence between 2%
and 8% in most studies.
• India, prevalence in general population
appears to less than 3-4%
• Jha AK et al Seroprevalence of Hepatitis B and C in the Eastern Himalayan
Region of India: A Population-Based Study. Tropical Gastroenterology. 2020
Jun

7. Morphological characteristics
• Lipid envelope
• Icosahedral nucleocapsid
• Core composed of proteins
• The nucleocapsid encloses the viral DNA
• DNA polymerase that has reverse transcriptase
activity.
• The outer envelope contains embedded proteins
helps entry into, susceptible cells.
• The virus is one of the smallest enveloped viruses
42nm

10. Liu H, Shen L, Zhang S, Wang F, Zhang G, Yin Z, Qiu F, Liang X, Wang F, Bi S. Complete genome analysis of
hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic diversity, and co-existence
of HBsAg and anti-HBs antibodies. Virology Journal. 2020 Dec;17(1):1-2.

11. Gene Regions Antigens
S
(Having three regions S,
Pre-S1 and Pre-S2)
S
S+ Pre S2
S + Pre S1 & S2
Small protens (S) surface antigen
Middle protein (M)
Large protein (L)-present only in virion
C
(having regions C and Pre –C)
C
C +Pre-C
Core antgen
HBeAg
P Dna polymerase(DNA dependent DNA
polymerases)
X HBXAg (nonparticulate antigen which leads
to enhance replication of HBV
Liu H et al Complete genome analysis of hepatitis B virus in Qinghai-Tibet plateau: the geographical distribution, genetic
diversity, and co-existence of HBsAg and anti-HBs antibodies. Virology Journal. 2020

18. Route of transmission
• Contaminated needles
• Sexual transmission
• Blood and blood products
• Vertical transmission
Hahné S et al Incidence and routes of
transmission of hepatitis B virus in England
and Wales, 1995–2000: implications for
immunisation policy. Journal of clinical
virology. 2004 Apr 1

19. High risk groups
• Multiple sex partners (>1 partner/6 months);
men who have sex with men;
• injecting drug users;
• imprioned persons; household and sex contacts
of HBV-infected persons;
• healthcare and public safety workers who have
exposure to blood in the workplace; and
haemodialysis patients
Mast EE et al Hepatitis B vaccination of adolescent and adult high-risk groups in the United
States. Vaccine. 1998 Nov

20. Acute Viral Hepatitis
Incubation period is prolonged than Hep A
lasting for 30-180 days (8-12weeks)
• CLINICAL FEATURES divided into
– Preicteric phase
– Icteric phase
– Post icteric phase or recovery phase

21. 1.Pre-icteric Phase/prodromal stage: 3-9 days
• anorexia, nausea and vomiting,
• fatigue, malaise, arthralgias, myalgias,
• headache, photophobia,
• pharyngitis, cough, and coryza
• may precede the onset of
jaundice by 1–2 weeks,
• Examination; fever with relative
bradycardia + enlarged liver

22. 2.Icteric Phase: 2-4 weeks
Increase jaundice with decrease
fever and improvement of general
condition and constitutions symptoms
• Dark coloured urine due to bilirubinuria
• Clay coloured stools due to cholestasis
• Loss of weight
• Pruritis as a result of elevated serum bile
acid/salt
(Large percentage of patient never become
icteric)

23. 3. Post-icteric Phase (recovery phase)
• disappearance of jaundice
• urine and stools colour become normal
• appetite improve
• GI symptoms disappears
Complete recovery of liver may take up to
6months

24. Laboratory features
• The serum AST and ALT increase to a variable
degree during the prodromal phase,
• and precede the rise in bilirubin level.
• these enzymes does not correlate degree of
liver cell damage.
• levels vary from 400–4000 IU or more; these
levels are usually reached at the time the patient
is clinically icteric and diminish progressively
during the recovery phase of acute hepatitis.

25. • Bilirubin->2.5 mg/dL.
• When jaundice appears levels will ranging 5–20
mg/dL which may continue to rise despite falling
serum aminotransferase levels.
• In most instances, the total bilirubin is equally
divided between the conjugated and
unconjugated fractions.
• Bilirubin levels >20 mg/dL is associated with
severe disease
Harrison 20th Edition

26. • Neutropenia and lymphopenia
• Lymphocytosis
• Prolong prothrombin time
• Hypoglycemia
• Steatorrhea
• slight microscopic hematuria and minimal
proteinuria.

27. At 6 month 95%
becomes HBsAg
negative
Window period

28. Wai CT et al US Acute Liver Failure Study Group. Clinical outcome and virological characteristics of
hepatitis B‐related acute liver failure in the United States. Journal of viral hepatitis. 2005 Mar
>95%

31. Management
• When to give AntiVIRAL treatment ?
• Fulminant hepatitis
• Severe hepatitis – defined as 2 of the following 3 criteria
– bilirubin >5.8mg/dl
– PT(INR) 1.6
– liver encephalopathy
• Long-lasting symptoms or increased bilirubin for over 4
weeks
• Immunocompromized patients
active viral replication (documented by measurable
HBVDNA C1 9 104 copies/ml);

32. Fulminant hepatitis
• Diagnosis of fulminant hepatitis B was based on
the following criteria:
• (a) histologically proven acute hepatitis
• (b) severe coagulation disorders;
• (c) hepatic encephalopathy within 2 months after
the onset of jaundice
• (d) presence of IgM anti-HBc in the earliest serum
sample collected after the onset of hepatic
encephalopathy
• Bernuau J et al Multivariate analysis of prognostic factors in fulminant hepatitis B.
Hepatology. 1986 Jul

33. How long we should continue
teatment
• Treatment with ETV, TDF or TAF is primarily
recommended until HBsAg is undetectable. If
HBsAg is still detectable, treatment should be
discontinued after 6-12 months.
• Future need of treatment should then be
assessed according to the same guidelines as
for chronic hepatitis B.
• Interferon is contraindicated in acute hepatitis
B, due to the risk of liver decompenzation.
• Flisiak R et al Recommendations for the treatment of hepatitis B in 2017. Clinical and
experimental hepatology. 2017 Jun.

34. • At present, there are no unambiguous results
from controlled trials on the effectiveness of
NA therapy in acute hepatitis B with a severe
(including fulminant) course.
• NA therapy may be considered only if liver
transplantation is an option.
• Treatment should be started with NA drugs
which show potent antiviral activity and high
genetic barrier: ETV, TDF or TAF . However,
patient management should be oriented
primarily toward actions leading to liver
transplantation.
Flisiak R et al Recommendations for the treatment of hepatitis B in 2017. Clinical and experimental hepatology. 2017

35. Chronic Hepatitis B

37. Immune tolerant phase
• The AASLD suggests that ALT levels be tested at least every 6months
for adults with immunotolerant CHB to monitor for potential
transition to immune-active or inactive CHB.
• Antiviral treatment is usually not recommended. The patient should be
monitored one to two times per year (
The AASLD suggest antiviral therapy in selected group of
Adults >40 yr of age with normal ALT
Elevated HBV DNA (1,000,000 IU/mL)
Liver biopsy showing significant necroinflammation or fibrosis
Management of hepatitis B virus infection, updated Swedish guidelines by Johan Westin,
infectous disease
American Association for the study of Liver diasease

38. Immune tolerance phase
• HBsAg +ve
• HBeAg +ve
• HBV DNA –elevated
• ALT-normal
• Asymptomatic

39. Immune clearance phase
• Seroconversion of HBeAg
• HBV DNA fluctuation
• ALT-elevated
• Active inflammation

40. Inactive carrier state
• Anti HBe +ve
• HBV DNA-low
• ALT-normal
• Mild inflammation and minimal fibrosis

41. Immune active phase
Immune Active CHB is defined by
• An elevation of ALT >2 ULN
OR
• evidence of significant histological disease
plus
• Elevated HBV DNA above 20,000 IU/mL
• (HBeAg positive)
• AASLD recommends Peg-INF ,Entecavir,or
Tenofovir as prefered initial therapy for adults
with immune-active CHB.

42. • Additional factors included in the decision to
treat persons with immune active CHB but ALT
<2 ULN and HBV DNA below thresholds are:
• Age: Older age (>40 years ) is associated with
higher likelihood of significant histological
disease.
• Family fistory of HCC
• Presence of extra hepatic manifestation

43. Extrahepatic manifestation
• Vasculitis (polyarteritis nodosa)
• skin rash (purpura),
• joint pain,
• peripheral neuropathy,Acute dorsal myelitis
• Glomerulonephritis leading to chronic kidney
disease ( HBsAg,immunoglobulina,C3
deposition )
• Cryoglobinemia
• Han SH et al Extrahepatic manifestations of chronic hepatitis B. Clinics in liver
disease. 2004 May

44. Polyarteritis nodusa

45. Cryoglobulinemia
• Essential mixed cryoglobulinemia
– reported initially to be associated with hepatitisB.
– arthritis,
– cutaneous vasculitis (palpable purpura),
– glomerulonephritis (AKI)
– presence of circulating cryoprecipitable immune
complexes of more than one immunoglobulin class( LOW
C4 and LOW C3)
• Type 1 MPGN
• 75% presented after >10 years of HBV infection
• Predominantly type 3 cryoglobulinemia (polyclonal
IgM-polyclonal IgG )

52. Treatment options
Eligibility of chronic hepatitis B infections
• HBsAg must be consistently detectable for at
least six months, and at least two out of the three
criteria below (evaluated concurrently) must be
met:
– 1) HBV-DNA > 2,000 IU/ml;
– 2) ALT level exceeding the upper limit of normal;
– 3) signs of liver inflammation or fibrosis.
Inflammation should be evaluated by histological
examination of liver biopsy specimens,
Flisiak R et al Recommendations for the treatment of hepatitis B in 2017. Clinical and
experimental hepatology. 2017 Jun

53. Treatment in CIRRHOSIS
1. Entecavir and tenofovir are preferred drugs.
2. Peg-IFN is contraindicated in persons with
decompensated cirrhosis owing to safety
conserns.
3. Concurrent consideration for liver
transplantation is indicated in eligible persons.
• Treatment with antivirals does not eliminate
the risk of HCC and survellance for HCC should
be continued.

54. • All individuals must evaluated at least every 6
months for a history and examination ,
metabolic panel with renal and liver function
tests, CBC, HBV DNA level, and serological
tests for HBeAg and HBsAg. Patients with
increasing HBV DNA and ALT levels should be
evaluated more frequently
• Tang LS et al. Chronic hepatitis B infection: a review. Jama. 2018 May

55. Duration of treatment
• The AASLD suggest that HBeAg-positive adult
without cirrhosis with CHB who seroconvert to
anti-Hbe on therapy discontinued NAs after
period of treatment consolidation.
• The period of consolidation therapy generally
involves treatment for at least 12months of
persistently normal ALT levels and
undetectable serum HBV DNA levels

56. • Persons with cirrhosis who stop antiviral
therapy should be monitored closely (e.g
montly first 6 months ,then every 3 montly)
for recurrrent viremia, ALT flares,
seroreversion,and clinical decompensation.
Tang LS et al Chronic hepatitis B infection: a review. Jama. 2018 May

57. Pharmacological management
• There are currently two main options for
treating chronic HBV infection:
• Nucleos(t)ide analogues (NA) or
• Alpha-interferon (IFN)

58. Nucleoside/nucleotide Analogues
• Six different NAs are approved for the
treatment of HBV:
• lamivudine(LAM),
• adefovir (ADV),
• telbivudine (TBV), (2nd line Treatment)
• entecavir (ETV),
• tenofovir disoproxil fumarate (TDF)
• tenofovir alafenamide (TAF)

59. • ETV, TDF or TAF, which all have a high barrier to
drug resistance, are recommended as preferred
treatments of HBV infection,
• while LAM, ADV, TBV (which have a low barrier
to drug resistance) are no longer recommended
• NAs are used in 90% of the cases internationally.
ongoing therapy most patients achieve non-
detectable HBV-DNA levels, histological
improvement, and normalization of ALT values
• effect of the treatment is usually not persistent
and lifelong treatment required

60. Nucleos(t)ide Analogue
• The nucleos(t)ide analogues inhibit the RNA-
dependent DNA polymerase reverse transcriptase
• Adverse effects
– The most common adverse effects were fatigue (3.3%-
10.4%), dizziness (5.0%-6.6%), headache (4.9%-
15.5%), and nausea(3.0%-10.0%)
lactic acidosis
– and severe hepatomegaly
Gilead Sciences. VIREAD (tenofovir disoproxil fumarate) package insert. https://www.accessdata
.fda.gov/drugsatfda_docs/label/2012 /021356s042,022577s002lbl.pdf. Accessed June 20, 2017.

61. Lamivudine
• Seroconversion in 20% of patients
• Delaying of Fibrosis and HCC
• Useful in HBe Ag –ve CHB
• Useful in decompensated hepatitis
• YMDD mutation in virus leads to 70%of
patient after 5yeasr become resistance
• Haptavir(100mg) brand name
• Cost ~3000/ anum

62. Entecavir (ETV)
• Dose 0.5mg OD
• in HBeAg postive patients, 6 log10 units reduction
in HBV DNA after 48 weeks of treatment
• HBeAg-negative patients, a reduction of HBV DNA
by more than 5 log10 units is achieved at week 48
• less than 1% of previously untreated patients,
resistance to ETV has developed after 3 years of
treatment.
• Cross resistance exsist with those who developed
resistance againt LAM

63. • The ETV dose should be reduced in patients with
renal impairment (creatinine clearance <50
mL/min).
• Prefered in patients resistance to Adefovir
• Yearly cost is nearly ~13,200/-INR or more
(X-VIR Brand )
• Johan Westin, et al ;Management of hepatitis B virus infection,updated
Swedish guidelines 2019

64. Tenofovir disoproxil fumarate (TDF)
• Monotherapy Approved for HBV and in combination
therapy is approved for HIV.
• Dose 300mg OD
• 4-6 log10 reduction of HBV DNA after 48 weeks of
treatment
• Nephrotoxic ,so RFT should be monitored every 6
months
• Crcl 30-49 300mg in 48hrs
• Crcl 10-29 300mg in 72-96hr
• If patient on hemodialysis 300mg in 7days is
recommended

65. • TDF also has an impact on bone density; hence,
patients with increased risk of pathological
fractures (high age, post-menopausal women,
steroid treatment, impaired renal function)
should be monitored regarding bone density
• Cost per anum ~18,000/-INR( TENVIR brand
CIPLA)
• Johan Westin, et al ;Management of hepatitis B virus infection,updated Swedish guidelines
2019

66. Tenofovir alafenamide (TAF)
• Recently approved for CHB
• Dose 25mg OD
• dose does not need to be adjusted for
patients with renal insufficiency, but is not
recommended in patients with creatinine
clearance below 15 mL/min, who are not on
haemodialysis

67. • Expenditure per anum ~18,000/-INR
(TENVIR AF 25mg brand CIPLA)
Johan Westin, et al ;Management of hepatitis B virus infection,updated
Swedish guidelines 2019

68. Alpha-interferon (IFN)
• weaker antiviral effect
• Approximately 11% of HBeAg-positive patients
and 6% of HBeAg-negative patients achieve
HBsAg clearance
• important advantage is that a persistent effect
can be achieved with a finite treatment
• 48 weeks of treatment is given by subcutaneous
injections once per week,
• No role in Asian population, immunosuppresed,
decompensated CHB,minimal ALT,HbeAg neagtive
patient

69. • Efficacy of Pegylated Interferon | In randomized
clinical trials, pegylated interferon achieved
higher rates of HBeAg loss (30% vs 21% with
lamivudine,P < .001).
• and higher incidence of HBsAg loss,improved liver
histology, and a reduction in cirrhosis and
hepatocellular carcinoma compared with
untreated controls.
Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the
combination for HBeAg-positive chronic hepatitis B. N Engl J Med.
2005;352(26):2682-2695.

70. • However, overall responses remain
suboptimal in that only approximately one-
third of patients achieve HBeAg loss and fewer
achieve HBsAg loss.
• For HBeAg-positive patients, factors indicating
good probability of response are genotype A
or B (vs. C and D), high ALT levels, low viral
load, apparent necroinflammatory activity,
and low HBsAg levels,
• Cost per anum is ~4,00,000/-INR
(brand name EXXURA 180mcg/0.5mL)

72. Myrcludex B/Bulevirtide (BLV)
• Myrcludex B/Bulevirtide (BLV) is a first-in-class entry
inhibitor to treat HBV/HDV co-infected patients.
• BLV monotherapy/ combination with Tenofovir (TDF) or
PEG-interferon α-2a (PEG-IFNα) induced serum and
intrahepatic HDV RNA decline in two phase 2 clinical
trials .
• In a substantial number of patients HBsAg was
undetectable and seroconversion occurred
• Results in study shows HBsAg declined by > 1log10
IU/ml in two patients but was detectable further on.
Wedemeyer H et al ;Safety and Efficacy of 10 mg Myrcludex B/IFNa Combination Therapy in
Patients with Chronic HBV/HDV Co-Infection. Zeitschrift für Gastroenterologie. 2020 Jan

73. Treatment of CHB in pregnancy
• Telbivudine and Tenfovir are the safest.
• to reduce the risk of perinatal transmission in
HBsAg positive pregnant women with an HBV
DNA levels >200,000 IU/mL.
• 28-32 weeks of gestation.
• discontinued at birth to 3 months post partum
discontinuation of treatment ,
• women should be monitored for ALT flares every
3 months for 6 months.
• Breastfeeding is not contraindicated.

74. • Neonates born to hepatitis B infected mothers
should be immunised at birth and
immunoglobulin is given.

75. Combination therapy
• Studies of combination therapy of IFN-a or Peg IFN-a
and lamivudine compared with IFN-a or Peg IFN-a
alone or lamivudine alone in viral suppression and a
higher rate of sustained response than lamivudine
alone,
• but no difference in sustained off-treatment response
• To date, there has been no large clinical trial that
confirms the benefits of Peg IFN-a plus lamivudine
therapy over Peg IFN-a monotherapy.
• Piratvisuth et al Reviews for APASL guidelines: immunomodulator therapy of chronic
hepatitis B. Hepatology international.

76. Vaccination
• Unvaccinated persons ----0,1,6 months
• Perinatal exposure----HBIG 0.5 ml immediately
after BIRTH ,Hep B vaccine started within 12
hrs
• Percutaneus/Transmucosal ----HBIG 0.06
ml/kg, plus HEP B vaccine within week
• Sexual contact---- HBIG 0.06 ml/kg within 14
days + HEP B vaccine

77. Vaccination
• A series of 3 doses (0.5 ml each) on a 0,1,6 month
schedule.
• Alternative doseage shedule 0,1,2 and 12 months
if there is an interruption between doses of
hepatitis B vaccine no need to restart,
Interruption after 1st dose ,2nd dose should be given
as soon as possible and 3rd should be given at
least 8weeks after 2nd dose
If 3rd dosed missed it should be given as soon as
possible

78. Booster doses of vaccine
• For hemodialysis patient
• immunocompromised persons (HIV-infected
persons, hematopoitic stem-cell transplant
recipient,and persons receiving
chemotherapy)
• A booster dose should be administered when
anti-HBs levels decline to <100mIu/ml
• Jia Q et al ;Predictive effect of five hepatitis B virus markers on re-vaccination time of hepatitis B vaccine.
Experimental and Therapeutic Medicine.2017

81. POST exposure prophylaxis
• Unvaccinated persons /incomplete hepatitis B
vaccine series/ANTI-HBS <100 should receive
both hepatitis B immunoglobulin and Hepatitis B
as soon as possible.(preferably<24hrs).
• For sexual exposures,HBIG should not be be
administered more than 14 days after exposure.
• Hepatitis B vaccine is administered simultaniously
with HBIG in a separate injection site.

82. Thanking you