8. Hepatitis
⢠Hepatitis: Inflammation of Liver
⢠Viral, Alcohol, Immune, Drugs & Toxins
⢠Biliary obstruction â Gall stones.
⢠Acute, Chronic & Fulminant - Types
⢠Viral Hepatitis â
⢠Specific â Hepatitis A, B, C, D, E, & others Non A-E = TT/GBV-C/HGV/SEN-V
⢠Systemic - CMV, EBV, other.
9. ď > 6 months; Similar features with acute hepatitis
ď Pathologic classification:
1. Chronic Persistent hepatitis
-Mononuclear infiltration
2. Lobular hepatitis = prolonged /slowly resolving hepatitis
-Multifocal hepatonecrosis; periportal fibrosis
3. Chronic active hepatitis = mild-severe necroinflammation
-Mono infiltration
-Piecemeal & bridging necrosis
Classification of Chronic Hepatitis
10. Chronic Hepatitis
⢠Recent classification using All criteria
ďśCause
ďśGrading=periportal, piecemeal, bridging necrosis.
ďśStaging with fibrosis : Histology/Fibroscan
⢠Hepatic activity index(HAI score=22):Knodell-Ishak score: Mild-Moderate-
Severe.
11. ⢠Hepatitis B, Hepatitis B plus D, or Hepatitis C;
⢠Autoimmune hepatitis, including several subcategories, I and
II (perhaps III),
⢠Serologic distinctions; drug-associated chronic hepatitis; and
⢠Unknown cause, cryptogenic chronic hepatitis
Cause
12. Grade
⢠Degree of periportal necrosis and disruption of the
limiting plate of periportal hepatocytes by inflammatory
cells - piecemeal necrosis /interface hepatitis.
⢠Degree of confluent necrosis that forms bridges between
vascularâreferred to as bridging necrosis.
⢠Degree of hepatocyte degeneration and focal necrosis
⢠Degree of portal inflammation.
⢠Scoring system ; mild, moderate , severe
⢠Histologic Activity Index (HAI), and
⢠METAVIR score
13. ⢠Level of progression based on degree of hepatic fibrosis
⢠When fibrosis is so extensive that fibrous septa surround
parenchymal nodules and alter the normal architecture of the
liver lobule, the histologic lesion is defined as cirrhosis .
⢠Staging is based on the degree of fibrosis as categorized on a
numerical scale from 0â6 (HAI) or 0â4 (METAVIR) .
Stage
14. Histologic Staging/ METAVIR staging system
14
No Fibrosis Portal Fibrosis Few septa
Stage 0 Stage 1 Stage 2
Numerous septa
Stage 3
Cirrhosis
Stage 4
15. FibroScan
15
2.5 cm
4 cm
1 cm ď
Explored volume
LB: 1/50,000 of the liver
FibroScan: 1/500 of the liver
The probe induces an
elastic wave through
the liver
The velocity of the wave is evaluated in a
region located from 2.5 to 6.5 cm below the
skin surface
16. Viral Hepatitis
⢠All types of viral hepatitis produce clinically similar illnesses.
⢠Range from asymptomatic and in apparent to fulminant and fatal acute
infections common to all types,
⢠On the other hand, from subclinical persistent infections to rapidly progressive
chronic liver disease with cirrhosis and even hepatocellular carcinoma(HCC).
⢠Specific â Hepatitis A, B, C, D, E, & others Non A-E = TT/GBV-C/HGV/SEN-V
⢠Systemic - CMV, EBV, other.
February 24, 2018 Kassa Tameru,MD 16
20. Global Impact of Hepatitis B
.
World
population
7 billion
2 billion with past/present
HBV infection
350â400 million with
chronic hepatitis B
15-40% develop
cirrhosis, liver failure
or HCC
~1 million/year die from HBV-associated
liver disease
February 24, 2018 20
21. Hepatitis B - Epidemiology
- 400 Million people chronically infected
- 2 billion with evidence of âpastâ infection
- Over 1 million deaths annually
ďś Ethiopia has 10.8% HBV prevalence.
22. Why Are So Many People Infected
with HepB?
ďśRoutes of transmission
ďśVertical (Maternal-Fetal)
ďśEarly Horizontal (mom to kids, kids to kids)
ďśMedical Misadventure
ďśThe other usual suspects - sexual, IDU etc
ďśThe wide range in HBV carrier rate in different parts of the
world is largely related to differences in the age at infection, &
mode of transmition, which is inversely related to the risk of
chronicity
ďśThe route matters because Age matters
23.
24. ⢠Nationwide Seroepidemiological study of Hepatitis B markers prevalence conducted
among 5,270 Young males from all regions of Ethiopia.
⢠Overall prevalence rates were 10.8% for HBsAg and 73.3% for âat least one marker
positiveâ.
⢠A remarkable geographical and ethnic variability of marker prevalence was observed,
reflecting the wide differences existing in Ethiopia in sociocultural environment and
activities such as tribal practices and traditional surgery.
Epidemiology in Ethiopia
25. Prevalence studies
ďśOf 1562 autopsies in a hospital in Addis Ababa,7.5% had
liver cirrhosis
ďśThe prevalence of HBsAg was estimated to be 8-12% and
the overall HBV marker prevalence about 50-79%.
ďśA recent study from Addis Ababa reported HCV-antibody
prevalence of 4.5% among HIV positives and 0.8% among
HIV-negative subjects
27. ď§ dsDNA ; accounts for 45 % acute viral hepatitis.
ď§ Transmission ; blood, sexual,perinatal
⢠According to the World Health Organization, the hepatitis B virus
is fifty to one hundred times more infectious than HIV.
ď§ Incubation period ; 6 wks â 6 mos (mean 12-14 wks)
ď§ Acute infection ; 70 % subclinical,30 % jaundice, < 1 % fulminant
(Up to 60 % mortality)
⢠Risk of HCC ; 25-40 % highest w/perinatal & inc. HBV DNA
ďśDiagnosis:
⢠HBsAg ; appears before SSx ,used to screen blood donors, persist
> 6 mo = chronic HBV.
Hepatitis B
29. Surface Antigen
Core Antigen Polymerase
(RNA â DNA)
dsDNA
RNA
HBV Genome
Oncogene???
February 24, 2018 29
Precore Antigen
HBV achieves its genomic
economy by relying on an
efficient strategy of
encoding proteins from
Four overlapping genes:
S, C, P, and X
HBsAg/Anti-HBs
Anti- HBc IgM/IgG
HBe Ag/Anti-HBe
HBV DNA
30. 1. Replication
occurs in the
nucleus
2. Genomic
integration can
occur
3. Reverse
transcriptase
(RNA to DNA)
done in particles
in cytoplasm
February 24, 2018 Kassa Tameru,MD 30
31. Viral Proteins and Particles:
⢠The concentration of HBsAg and virus particles in the blood may reach 500 ug/ml
and 10 trillion particles per milliliter, respectively
⢠The antigen expressed on the surface of the nucleocapsid core is referred to as
hepatitis B core antigen (HBcAg), and its corresponding antibody is anti-HBc.
⢠HBeAg is immunologically distinct from intact HBcAg but is a product of the same
C gene.
⢠HBcAg particles remain in the hepatocyte, where they are readily detectable by
immunohistochemical staining.
⢠A third HBV antigen is hepatitis B e antigen (HBeAg), a soluble, nonparticulate,
nucleocapsid protein
⢠The secreted nucleocapsid protein, HBeAg, provides a convenient, readily
detectable, qualitative marker of HBV replication and relative infectivity.
February 24, 2018 31
Hepatitis B Virus Particles
33. ⢠HBsAg-positive serum containing HBeAg is more likely to be highly infectious than
HBeAg-negative or anti- HBe-positive serum.
⢠Persistence of HBeAg in serum beyond the first three months of acute infection
may be predictive of the development of chronic infection.
⢠The presence of HBeAg during Chronic Hepatitis B is associated with
ď Ongoing viral replication
ď Infectivity, and
ď Inflammatory liver injury
February 24, 2018 33
Hepatitis B Virus Particles
34. Unique Features of HBV
1. cccDNA
ďŽ By âdisguisingâ itself as a host chromosome, manages to persist and evade
immune response
ďŽ Stays in the host, probably FOREVER!!!
ďŽ Even with HBsAg loss, there is still cccDNA present so term âpast infectionâ is
really a misnomer.
2. Reverse transcription (RNA dependent DNA polymerase)
ďŽ Strange for a DNA virus to use this pathway â itâs the only one!!
ďŽ Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse
transcription (effected by the DNA polymerase) of minus-strand DNA from a
"pregenomic" RNA intermediate.
ďŽ Very relevant for HIV co-infected patientsâŚdrugs are the same
ďŽ Occurs AFTER protein production - so can be DNA negative but HBsAg
(and HBeAg) +ve.
(NAâs)
35. Immune Clearance
ďŽHBV is non-cytopathic; not cytolytic-naked virus, rather it is persistent
productive virus (generally)
ďŽLiver damage caused by immune response to virus
ďŽBattle takes place in the liver and hepatocytes are the innocent bystanders that
take all the hits!!!
ďŽA potent immune response may cause more short-term damage but ultimately
leads to clearance (similar to scenario with acute HBV)
36. ⢠The first Virologic marker detectable in serum within 1â12 weeks, usually
between 8â12 weeks, is HBsAg.
⢠Circulating HBsAg precedes elevations of serum aminotransferase activity and
clinical symptoms by 2â6 weeks and remains detectable during the entire icteric
or symptomatic phase of acute hepatitis B and beyond.
⢠In typical cases, HBsAg becomes undetectable 1â2 months after the onset of
jaundice and rarely persists beyond 6 months.
⢠After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in
serum and remains detectable indefinitely thereafter.
February 24, 2018 36
Hepatitis B Serologic and Virologic
Markers
37. ⢠Because HBcAg is intracellular and, when in the serum, sequestered
within an HBsAg coat, naked core particles do not circulate in serum.
⢠Anti- HBc is readily demonstrable in serum, beginning within the first 1â2
weeks after the appearance of HBsAg and preceding detectable levels of
anti-HBs by weeks to months
⢠A gap of several weeks or longer may separate the disappearance of
HBsAg and the appearance of anti-HBs. During this "gap" or "window"
period, anti-HBc may represent the only serologic evidence of current or
recent HBV infection.
February 24, 2018 37
Hepatitis B Serologic and Virologic
Markers
38. ⢠Infrequently, in 1â5% of patients with acute HBV infection, levels of
HBsAg are too low to be detected; in such cases, the presence of IgM
anti- HBc establishes the diagnosis of acute hepatitis B.
⢠Recent and remote HBV infections can be distinguished by
determination of the immunoglobulin class of anti-HBc i.e IgM/IgG
⢠Generally, in persons who have recovered from hepatitis B, anti-HBs
and anti-HBc persist indefinitely.
February 24, 2018 38
Hepatitis B Serologic and Virologic
Markers
39. ⢠Persons with anti-HBs in serum are protected against
reinfection with HBV suggests that anti-HBs is the protective
antibody.
⢠Appearance of HBeAg coincides temporally with high levels of virus
replication and reflects the presence of circulating intact virions and
detectable HBV DNA, i.e. in acute infection or chronic active hepatitis .
ďśIn chronic HBV infection, HBsAg remains detectable beyond six months,
anti-HBc is primarily of the IgG class, and anti-HBs is either undetectable
or detectable at low levels.
February 24, 2018 39
Hepatitis B Serologic and Virologic
Markers
40. ⢠HBeAg is a qualitative marker and HBV DNA a quantitative marker of
replicative phase, during which HBV circulate
⢠Over time, the replicative phase of chronic HBV infection gives way to a
relatively nonreplicative phase. This occurs at a rate of 10% per year and
is accompanied by seroconversion from HBeAg positive to anti-HBe-
positive.
⢠Seroconversion coincides with a transient, acute hepatitis-like elevation
in aminotransferase activity, believed to reflect cell-mediated immune
clearance of virus-infected hepatocytes
February 24, 2018 40
Hepatitis B Serologic and Virologic
Markers
41. ⢠In reality, the designations replicative and nonreplicative are only relative
⢠Even in the so-called nonreplicative phase, HBV replication can be
detected at levels of 103 virions.
⢠Below the above replication threshold, liver injury and infectivity of HBV
are limited to negligible
February 24, 2018 Kassa Tameru,MD 41
Hepatitis B Serologic and Virologic
Markers
47. Possible Outcomes of HBV Infection
Acute Hepatitis B Infection
Chronic HBV Infection
3-5% of adult-
acquired
infections
95% of Infant-
acquired
infections
Cirrhosis
Chronic Hepatitis
12-25% in 5 years
Liver failureHepatocellular
carcinoma
Liver transplant
6-15% in 5 years
20-23% in 5 years
DeathDeath
48. 48
HBV - Natural History
Modulating Factors in Hepatitis B
HOST
Gender
Age
Immune Response
VIRUS
Genotype
Molecular Variants
ENVIRONMENT
Alcohol
HCV, HDV, HIV
Carcinogens
56. Risk of Chronicity
Age at Acquisition %
Neonate 70 - 90
1 â 5 yrs 20 - 30
Adolescent 6
Adults 1 - 5
Elderly 59
Lavanchy J Vir Hep 2004
Source Matters Too
Mom HBeAg +ve - 85-90% transmission
Mom HBeAg -ve - 10-31% transmission
Immune
Status
Viral Load
HBeAg Itself
57. 57
HBV - Epidemiology
Risk of chronic infection
Age at Infection
0
20
40
60
80
100
Neonates Infants Children Adults
%
Risk
Risk of Chronic Infection
58. From the Patientâs PerspectiveâŚ
ďŽ Patients feel perfectly fine!!!
ďŽ Almost always entirely asymptomaticâŚuntil itâs too late
ďŽ Even if they have cirrhosis
HBsAg
59. CLINICAL SYMPTOMS
⢠Fatigue is a common symptom
⢠Persistent or intermittent jaundice
ď Complications of cirrhosis
⢠Ascites
⢠Edema
⢠Bleeding gastroesophageal varices
⢠Hepatic encephalopathy
⢠Coagulopathy or
⢠Hypersplenism.
60. Extrahepatic Manifestations
⢠Immune complexâmediated (type III hypersensitivity reaction) tissue damage
appears to play a pathogenetic role in the extrahepatic manifestations of acute
hepatitis B
⢠Glomerulonephritis with the nephrotic syndrome is observed occasionally
⢠Generalized vasculitis (polyarteritis nodosa) develops in considerably fewer than
1% of patients with chronic HBV infection.
⢠Essential mixed cryoglobulinemia (EMC), was reported initially to be associated
with hepatitis B,but the majority related to HCV
February 24, 2018 60
61. Complications of
Chronic HBV Infection
⢠Cirrhosis
⢠Decompensated liver disease
⢠Hepatocellular carcinoma
⢠Death
62. Prognosis and survival
ďźThe estimated five year rates of progression (Fattovich
2008):
ďźChronic hepatitis to cirrhosis â 10-20%
ďźCompensated cirrhosis to hepatic decompensation â 20-30%
ďźCompensated cirrhosis to hepatocellular carcinoma â 5-15%
ďźAccordingly, the survival rates are:
ďźCompensated cirrhosis â 85% at five years
ďźDecompensated cirrhosis - 55-70% at one year and 15-35% at five
years
63. Risk Factors for HCC
Factor Adjusted HR P-value
Male 2.1 .03
Age 1.09 per yr <0.001
E Positive 2.6 <0.001
Cirrhosis 9.1 <0.001
HBV DNA
<300 IU
300-10E4 IU
10E4-10E5 IU
10E5-10E6 IU
>10E6 IU
1.0
1.1
2.3
6.6
6.1
.86
.02
<0.001
<0.001
Chen JAMA 2006
64. 64
HBV - Natural History
Fattovich, et al., Hepatology 1995; 21:77
Cumulative Probability of Developing HCC in
Patients with HBsAg + Compensated
Cirrhosis
0
100 987654321
%
Year
20
25
15
65.
66. Treatment: Chronic Hepatitis B
⢠Progression occurs with Active HBV replication.
ďSuppressing Viral Replication; Eradication HBV DNA; Seroconversion
HBeAg/HBsAg; Histology/Liver enzymes normalization or stabilization.
Seven drugs : PEGylated Interferon; and the NAâs [oral agents]
⢠Tenofovir Disoproxil Fumarate [TDF]
⢠Entecavir [ETV]
⢠Tenofovir Alafenamide [TAF]
⢠Telbivudine [TBV]
⢠Adefovir Dipivoxil [ADV]
⢠Lamivudine [LAM]
67. 67
Nucleos(t)ide analogues Immunomodulatory
Oral administration Subcutaneous
Potent HBV DNA suppression
Less potent HBV DNA
suppression
Not immunomodulatory
Antiviral and
immunomodulatory
Few side effects Frequent side effects
Risk of resistance development No resistance
HBsAg seroconversion rare
HBsAg seroconversion
more common
Long-term therapyâpotential for
drug fatigue
Lower short-term cost
Finite therapy duration
Higher initial cost
82. Treatment Refractory
â˘Primary treatment
failure
⢠Failure to reduce HBV DNA by
âĽ1 log10 IU/mL within 3 months
⢠Inadequate potency
⢠A priori viral resistance
⢠Noncompliance
⢠Poor absorption
Treatment-Emergent
Resistance
â˘Secondary treatment
failure
⢠Caused by mutation(s) in the
DNA polymerase gene
⢠Viral breakthrough occurs with
âĽ1 log10 IU/mL rise in HBV DNA
compared with nadir in patients
with an initial treatment effect
⢠Confirmed on 2 assessments at
a 1-month interval
82
83. ⢠Genotypic Resistance
⢠Emergence of novel substitutions in the
presence of agent
⢠Phenotypic Resistance
⢠Decrease in susceptibility level compared
with a reference strain, usually expressed
as âfold changeâ
⢠Viral Breakthrough or
Rebound
⢠Confirmed increase in plasma HBV DNA
âĽ1 log10 IU/mL from nadir
83
84. Prevention
⢠Vaccination
⢠Health care workers/EPI/Neonates of HBsAg positive mother.
⢠Hepatitis B Immunoglobulin
⢠HBIG may be used to protect persons who are exposed to hepatitis B.
ďś It is particular efficacious within 48 hours of the incident.
⢠Other measures
⢠Screening of blood donors, blood and body fluid precautions.
1st shot â
at any time
2nd shot â
1 month
after the 1st
3rd shot â
6 months
after the 1st
85. ⢠New Biomarkers???
⢠Quantification of HBsAg is not a perfect biomarker for intrahepatic
Viral cccDNA.
⢠Hepatitis B core-related antigen (HBcrAg) is a composite biomarker
comprising several antigens expressed from the Precore/-
Core gene: HBcAg, HBeAg, and prec22 precursor protein
⢠Hence, HBcrAg quantification may provide additional information
concerning the translational activity of the HBV infection beyond
HBsAg quantification.
⢠How to best use this new assay in the management of patients with
chronic HBV infection is still a matter of debate.
EASL 2017
86. ⢠Future treatment Options???
⢠The novel treatment options under pre-clinical and early clinical
evaluation can be categorized into direct antivirals and
immunotherapeutic agents.
⢠Direct-acting antivirals include HBV entry inhibitors, drugs aiming at
cccDNA destruction or silencing, approaches targeting viral transcripts
by siRNA or anti-sense oligonucleotides, nucleocapsid assembly
modulators, approaches to decrease HBsAg release in serum.
⢠Among Immunotherapeutic Agents, Toll-like receptors 7 (TLR7)
agonists have been the most explored, but other strategies that restore
IFNa responsiveness or other antiviral innate pathways are under
investigation
EASL 2017
87. Unresolved Issues & Unmet Needs
⢠When to start antiviral therapy in patients with HBeAg positive chronic
HBV infection?
⢠Stopping rules for HBeAg-negative patients treated with NA?
⢠Retreatment criteria after NA discontinuation?
⢠How to accelerate HBsAg decline in long-term NA treated patients?
⢠Better baseline or on-treatment predictors of sustained treatment in
patients treated with PegIFNa?
88. ⢠Definition of the residual risk of HCC in patients on long-term NA therapy
and impact on surveillance?
⢠Unmet need: new treatments with finite duration and high cure rates?
⢠How to define a cure of HBV infection? Definition of novel endpoints?
⢠Biomarkers for the cure of infection and for the cure of the liver disease?
Unresolved Issues & Unmet Needs
89. References
⢠EASL 2017 Clinical Practice Guidelines on the management
of hepatitis B virus infection
⢠Harrisons principles of Internal Medicine 19th edition.
⢠Up to date 21.6
⢠Summary Table of Different HBV treatment Guidelines by
Wondwossen Amogne.
⢠Silisinger and fortadon 10th edition
2/24/2018 89