Hepatitis A
Studies in Pune (1982-98)
Hepatitis A
The disease is hyper endemic and the
pattern of HAV infection in urban lower
middle and rural lower middle classes
has remained unchanged. Better
hygiene and non-exposure to HAV in
higher middle and upper class young
population renders them susceptible.
Thus the possibility of HAV epidemic
amongst them exists. Hepatitis A
appears as an emerging infection in
adults. Substantial increase in number of
hepatitis A cases in higher age group
from high socio-economic status has
been recorded.
! The causative agent is hepatitis A virus
(HAV)
! Earlier referred to as infectious
hepatitis.
! Major public health problem,
1.4
The virus
million cases each year worldwide.
!
!
!
!
!
! In developing
countries, pediatric
disease; in developed nations, disease
of adults.
! Prevalence of hepatitis A is inversely
related to socioeconomic status.
Transmission
Plus-stranded 7.5 Kb RNA genome.
Seven genotypes / Single serotype.
HAV grows slowly in cell culture
without cytopathic effect.
primates.
Epidemiology
P1
5’ NCR
LA
LB
1C
P3
P2
1D
2A 2B
2C
3A 3B
3C
3D
Vpg
Laboratory diagnosis
Disease
! IgM-anti-HAV is the diagnostic marker
Ninety percent infections in children lead
to subclinical presentation. Proportion of
clinical cases increases with age.
Fulminant hepatic failure is a rare
serious complication. Does not lead to
chronicity.
80
70
60
50
40
30
20
10
0
6-10
SYMPTOMS
! Urine was found to be an alternative
IgG ANTI- HAV
test specimen for diagnosis of hepatitis
A, useful especially in children.
! Blood collection on filter paper disc
proved to be satisfactory for anti-HAV
detection.
16
WEEKS AFTER EXPOSURE
52
11-15
16-25
1982
AGE GROUP
82%
25+
1992
1998
Rural lower middle class
110
100
Hep A
90
Non-A
80
Acute viral hepatitis
! ELISA based hepatitis A diagnostic
ALT
12
90
% anti-HAV
ELISA and Blocking ELISA tests have
been developed and are routinely
used to provide diagnosis of recent
and past infection of hepatitis A virus.
technology has been transferred to
Hyderabad based industry. This is the
first such transfer from NIV, Pune.
8
100
18%
! At NIV, Pune, IgM anti HAV capture
JAUNDICE
4
110
for hepatitis A.
Markers / symptoms during HAV infection
0
NCR 3’
Poly A
Urban Lower-middle class
In India, Hepatitis A virus is the main
causative agent of acute hepatitis in
children. It accounts for significant
number of FHF cases in children.
% anti-HAV
HAV Genome
transmission noted in Europe.
IgM ANTI- HAV
Indigenously
developed
hepatitis A
diagnostic
kit
27-30 nm diameter particles.
! Available animal models: Non human
! Fecal-oral route.
! Person-to-person contact.
! Inadequately cooked food.
! Blood-products-associated
FECAL HAV
Picornaviridae, genus Hepatovirus.
70
60
50
40
30
20
10
0
Non-viral
Hepatitis
48%
Hep A
40%
Viral Hepatitis
52%
AGE GROUP
Hep B or D
12%
Fulminant hepatitis
53
15+
11-15
6-10
1983
1998
Higher socioeconomic class
Year-round PCR-based HAV-RNA positivity
%ANTI-HAV
% PCR +ve
110
100
90
80
70
60
50
40
30
20
10
0
6-10
11-15
AGE GROUP
16-25
1982
Dendrogram depicting nucleotide sequence identity among HAV strains in
VP1/2A region of HAV genome
L07730 PANAMA
54
52 IN D 9 4 -2 /V P 1 IIIA
54
54
Effluent
L 0 7 7 2 4 Nepal
L 0 7 7 2 5 India
L 2 0 5 2 8 Japan
L 0 7 7 2 9 SierralL e o n e
87
Several animal species shown to be
anti-HAV positive.
6
4
Genotyping of HAV strains
in sporadic cases from Pune
2
1994-97
Co-circulation of subgenotypes IB and
IIIA with predominance of IIIA detected.
Mixed infection with IB and IIIA identified
in inidividual hepatitis A patients.
Multivariate analysis identified lower
middle socioeconomic status (22.9
fold), age > 15 years (8.9 fold) and
family size > 4 (1.6 fold) as independent
risk factors influencing exposure to HAV.
Thirty percent HAV RNA positivity in neat
sewage samples documents extremely
high viral load in the environment. This
also represents a potential threat for
contamination of drinking water leading
to endemicity and extensive outbreaks.
54
GenotypeII
GenotypeIA
M147 07
98
100
IN D 9 2 - 1 /V P 1
IN D 9 4 - 2 / V P 1 IB
GenotypeIB
IN D 9 8 - 7 / V P 1 IB
L 0 7 7 3 2 Phillipines
L 0 7 7 3 1 Indonesia
79
D00924Kenya
GenotypeV
0.05
˜ Isolates indicating mixed genotypes are shown in blue color. Scale indicates genetic distance
0
1978-81
GenotypeVII
Ab020564Japan
78
53
8
GenotypeVIIIB
L07693France
Prolonged fecal excretion and viremia
observed in Indian patients and
experimental monkey.
10
Genotype IIIA
IN D 9 6 - 3 /V P 1
N O R 21
100
99
Sewage plant
12
IN D 9 8 -7 /VP 1 IIIA
IN D 0 1 - 10 /VP 1
Affluent
25+
1998
Hepatitis A in adults
% Hep A Cases
35
30
25
20
15
10
5
0
Emergence of epidemic
hepatitis A
All epidemic HAV isolates from Pune (prefix 03) and
around Pune (red) belong to genotype IIIA.
0314456
0313824
12 037108
0313832
26 037082
26 0314447
037107
0314484
IIIA
3
DAUND-B2
DAUND-S1
DAUND-SW
8
9 DAUND-B1
M34084
44
DAUND-S2
037114
49
0313267
AY032861 VII
88 AF268396
88 M14707
IB
77
AF314208
85 M20273
54
AF357222
AF485328
83
K02990
IA
48
AB020565
33
X75215
39
81 X83302
D00924 V
M59286 IV
An outbreak of hepatitis A in day-care
centers for children in Pune emphasizes
importance of such centers in the
transmission of HAV. From 2003,
hepatitis A is assuming epidemic
proportions, especially in rural and
semi-urban settings. Source remains
contaminated water supply.
0.2
Vaccines
! Both killed and attenuated hepatitis A
vaccines are available. Most countries
do not have definite policies for
hepatitis A vaccination.
! NIV studies suggested that 9 months is
the appropriate age for hepatitis A
vaccination.
! Isolated an Indian strain of HAV in
tissue culture and transferred to
industry for vaccine preparation.
Prevention
Ÿ Supply of safe potable water.
Ÿ High standards of public and personal
hygiene.
Ÿ Education of food handlers.
Ÿ Vaccination of high-risk individuals:
§ Children from high socioeconomic status.
§ Young food handlers.
§ Siblings of hepatitis A patients.
§ HBV/HCV carrier children.
Patent
A patent on
Hepatitis B
“Novel process of Hepatitis A
vaccine preparation”
has been filed.
56
The risk factors
! The causative agent is hepatitis B virus
! Transfusion of unscreened blood.
! Improperly sterilized syringes /
(HBV).
! Earlier referred as Serum Hepatitis.
! 350 million carriers of the virus
needles / dental / other equipments.
Based on transmission modes, several
high-risk groups have been identified.
Mentally compromised children
! Close contact with HBV positive
worldwide.
individual.
! 34 million HBsAg carriers in India.
! 200-fold higher risk of primary
! Shared razors, toothbrushes with
carrier.
! Tattooing.
! Sexual contact with HBV positive
hepatocellular carcinoma.
! Wide spectrum of clinical presentations.
individual.
! Several transmission modes.
! Efficacious vaccine available since
HBV Epidemiology in and around
Pune (1982-1998)
Orphans
Asthamatics
Health care personnel
Urban
Leprosy patients
25
Family contacts of carriers
Paid blood donors
20
HBsAg
HBsAg+anti-HBc
Haemodialysis patients
% Positive
Hepatitis B
Hepatitis B vaccination
introduced for tribals
of Andaman and
Nicobar Islands
Prisoners
STD patients
Dental auxiliary staff
Dentists
Voluntary blood donors
HBsAg
1982.
10
20
30
40
50
60
70
80
90
100
0
Percentage
anti-HBc
1982
These high risk individuals
must be considered for
vaccination
35
1998
1982
Year
1992
1998
Adults
HBsAg
anti-HBc
25
Cultural practices make tribals
a high-risk category
Electron micrograph of
42 nm HBV from a
blood donor in Pune
1992
Children
Rural
30
Percentage
Hepadnavirus
10
5
0
! Multiple sex partners.
! Infected mother to infant.
15
20
15
10
5
Tribal populations and exposure to HBV (%)
0
Infection with HBV may lead to
! Subclinical infection.
Children
Dhule
Maharashtra
! Acute self-resolving hepatitis.
! Fulminant hepatitis.
! Asymptomatic carrier state.
! Chronic hepatitis.
! Cirrhosis.
! Hepatocellular carcinoma.
Children
Adults
1998
HBV prevalence in Pune was determined
according to socio-economic status viz.
lower middle class status (LMS) and higher
socio-economic status (HS).
Bhiwandi
Thane
Pune
0
10
20
30
58
40
50
60
70
30
anti-HBc
Percent Positives
Transmission
routes
Andaman & Nicobar islands
HBsAg
Ÿ Parenteral
Ÿ Inapparent parenteral
Ÿ Sexual
Ÿ Vertical
Ÿ Horizontal
Aduilts
1983
Onges
Shompens
25
HBV exposure according to
socio-economic status, Pune 1998
LMS
HS
20
15
10
5
0
6-10
11-15
16-25
Age Groups
Nicobarese
Andamanese
0
10
20
30
40
HBsAg
50
60
anti-HBc
70
80
90
100
25+
Asymptomatic HBsAg Carriers
Chronic Hepatitis B
2%
2%
16%
39%
36%
Delta Rn vs Cycle No HBV Standard
Diagnostics
HBV Pre-Core mutant and clinical presentation
As early as 1980, highly sensitive and
specific ELISA for the detection of HBsAg
was developed at NIV. This represents
the first indigenously developed HBsAg
ELISA in India. These ELISA reagents
were certified by WHO.
Delta Rn
In 1981, again for the first time, ELISA
for the detection of anti-HBs antibodies
was developed.
82%
23%
Acute Hepatitis B
Fulminant Hepatitis B
Cycle Number
13%
14%
HBV DNA quantitation is
a national facility
available at NIV
Assessment of screening
tests / vaccines
86%
87%
Negative
Mutants
Wild
! Evaluation of commercially available
Mixture
Ÿ Risk of Chronic hepatitis 4.3-fold higher with HBV pre-C wild
Ÿ 3.2 fold higher chances of asymptomatic carrier state with pre-C mutants
Ÿ Pre-C mutant not associated with fulminant hepatitis
assays as part of WHO-SEARO
designated national reference center.
! To assess the presence of replicating
virus, PCR for the detection of HBV
DNA was standardized in 1990.
! From 1985, worked closely with blood
banks from Pune in verifying efficiency
of the tests used for donor screening.
! An important
development was
standardization of Quantitative Real
Time HBV DNA PCR assay employing
primers and probes designed at NIV.
! Immune response to several plasmaderived and recombinant vaccines
evaluated in Indian population.
HBV Genotypes
! Follow up of vaccinated persons for 14
§ Genotype D predominant
GNTYP-B
GNTYP-C
38
GNTYP-E
GNTYP-D
38
60 ASC1027 (19)
99
CLD2235 (25)
56 FHF2376 (5)
65 AVH1164 (8)
GNTYP-F
99
GNTYP-H
0.01
60
years.
in western India.
§ Did not influence outcome
of HBV infection.
§ Genotype D
highly prevalent in tribes
from Andaman and
Nicobar islands
61
One orphan selected by needy
parents and born to HBsAg carrier
mother was vaccinated, followed
for seroconversion and
finally adopted
Creation of awareness
about hepatitis B
! Children from several urban and
rural schools.
! Family contacts of HBsAg carriers.
l Several family contacts
immunized
l Several HBsAg carriers
counselled at a young age
l Immunized would-be spouses
before marriage
l Immunized children at birth,
born to HBsAg positive mothers
Hepatitis C
< Based on NIV results
immunization of dental
students and dentists was
made mandatory
in Maharashtra
< Orphans screened for HBsAg
before adoption
62
! At present, no confirmatory immuno-
! Earlier known as post-transfusion
non A-non B hepatitis (PT-NANB).
assays are obligatory.
! Presence of HCV RNA by nested RT
! 170 million hepatitis C virus (HCV)
infected individuals worldwide.
PCR employing primers from 5'NTR.
! Nested RT-PCR assay (1990) was
The disease
! Mostly subclinical.
! High chronicity potential (>70%).
! 50-70% of chronically infected
individuals develop chronic liver
disease.
! Not a major cause of acute or
fulminant hepatitis.
standardized at NIV. Screening of
clinical samples from all over India
for HCV RNA is ongoing.
very important parameter in disease
staging and response to antiviral
therapy. Quantitative real time PCRbased assay was standardized in
2003 on the basis of viral genotypes
circulating in India.
evaluated in Indian population
immediately after availability in the
market.
hepatocellular carcinoma.
The virus
! At present, several host and viral
Belongs to family Flaviviridae; positive
sense, ssRNA genome (~9.4 kb).
Classified into 6 genotypes.
! So far, chimpanzee is the only animal
model for HCV.
factors are being investigated for
chronicity potential and success of
interferon therapy.
Transmission
! No convenient cell-culture system is
! Parenteral
transmission
important mode.
available.
! At NIV, attempts to infect rhesus
! Quantitation of HCV viral load is a
! First, 2nd and 3rd generation ELISAs
! Important cause for primary
Experimental transmission
!
! In dialysis units, a new patient usually
gets infected with HCV within six
months, mainly through nosocomial
spread.
Samples from 149 HCV RNA positive
patients from different parts of India
were genotyped on the basis of
phylogenetic analysis.
Epidemiology
! Anti-HCV prevalence among age
stratified general population is low.
2.82%
! Prevalence was low in rural and
45.07%
tribal populations.
52.11%
! Anti-HCV positivity in commercial
blood donors was high.
NORTH
3.33%
! Dialysis patients and hemophiliacs
are at higher risk of getting infection.
33.33%
Delta Rn vs Cycle
! Blood donors from a commercial
plasmapheresis unit had shown 90%
anti-HCV positivity, most antibody
positives being HCV RNA positive.
63.33%
Delta
Rn
Electron
Micrograph
of HCV
SOUTH
25.00%
38.89%
14
Diagnosis
12
! No marker distinguishes between
36.11%
acute and chronic infections.
Cycle Number
! Detection of anti-HCV antibodies by
rd
3 generation screening ELISAs.
Blood products
being imported
in India are
screened for
HCV RNA at NIV.
EAST
25.00%
8
6
4
HCV Genome Organization
5 NTR
gp35
gp70
P7
P23
P70
C
E1
E2
Ns1
Ns2
Ns3
Structuralprotins
P8
P27
P56/58
P68
Ns4A
NS4B
NS-5A
NS-5B
3’ NTR
Commercial
blood
donors
10
75.00%
P22
the
and intrafamilial are infrequent.
Genotypes
WEST
is
! Other modes like sexual, vertical
monkeys and insect cell lines
susceptible for other flaviviruses,
were not successful.
Genotype 1
Genotype 4
Genotype 3
Nontypable
2
Percentage
Hepatitis C
A new subtype of HCV,
3i, first identified in
western India, was later
found in other parts
of the country.
0
1982
Nonstructural proteins
1983
Year
65
1986
Voluntary Blood Donors
1 / 217
0 / 346
1 / 180
0 / 178
0 / 400
0 / 259
0 / 445
Other studies
Association with blood banks
As serological tests for HCV were still
evolving (1st, 2nd & 3rd generations), the
NIV together with local blood banks
sorted out the problems of specificity
and sensitivity, based on the use of
confirmatory Recombinant Immunoblot Assay (RIBA) and PCR tests.
Similar trend continues till 2004
25
Anti-HCV positivity in different
categories
15
20
Interferon treatment
A national facility for the detection of
HCV RNA, employing nested RT PCR
was set up in July 1995. Samples from
different parts of India were screened
as a prerequisite for the initiation of
interferon therapy as well for the
assessment of success of therapy.
5
10
ICMR's multi- centric trial for
combination therapy
NIV is responsible for all the
virological aspects of this trial,
including detection and quantitation
of HCV RNA and sequencing-based
genotyping.
Voluntary Blood Donors
Patients undergoing Hemodialysis
Multiply transfused Patients
Chronic Liver Disease Patients
Leprosy Patients
Acute Viral non-A,non-B Hepatitis Patients
Health Care Personnel
Patients suffering from Sexually Transmitted Diseases
Dentists
Institutionalised children with high HBV exposure
Normal Pregnant Women
0
Expression of recombinant
core antigen
Highly immunoreactive recombinant
HCV core antigen was expressed in
baculovirus system.
Prevention
In the absence of possibility of vaccine
for hepatitis C in the near future, strict
adherence to universal precautions in
relation to parenteral transmission
mode seems the best available choice.
66
Hepatitis E
Recognition
During 1980, joint efforts of NIV, Pune
and NIH, USA led to the recognition of
a novel clinical entity, enterically
transmitted non-A, non-B or
waterborne or epidemic NANB
hepatitis, distinctly different from
paranterally transmitted non-A, nonB hepatitis identified in the west.
Virus-like particles were identified at
NIV employing Immune Electron
Microscopy in the feces of a NANB
patient. Association of this virus with
the disease was subsequently
confirmed after experimental
infection of chimpazees (in
collaboration with NIH, USA). In
1990 the virus was named as
hepatitis E virus.
Electron
micrograph
of HEV
The virus
! Recently classified as a member of a
Acute, self-limiting; occasionally leads
to fulminant hepatitis. No chronicity
recorded. Usually affects young
adults; high mortality among
pregnant women, especially in the
third trimester.
The disease was believed to be
restricted to developing countries
wherein both epidemic as well as
sporadic forms exist. However, recent
studies have documented hepatitis E
among persons from several
developed countries without any
history of travel to endemic countries.
Detection of IgM-anti-HEV by ELISA. In
very early acute cases, IgM antibodies
may not be detectable, HEV RNA by
nested RT PCR may be the method of
choice.
! 27-30nm spherical particles.
! The genome is a single-stranded,
positive sense RNA of about 7.2 kb.
ORF-3: 369 nt
Epidemiology
Diagnosis
newly designated Hepeviridae
family.
5’
The disease
3’
Studies conducted at NIV and in
different countries have shown that
HEV has predilection for young adults.
However, an outbreak of hepatitis E
among residential school children at
Talegaon, India (1988) was recorded.
Moreover, ~ 70% anti-HEV positivity
among children from Shompen tribe
from Andaman and Nicobar Islands
was also documented.
Diagnostic test development
! ORF-2
ORF-2: 2 kb
ORF-1: 5 kb
Genotypes
HEV strains are classified into 4
79
93
AF103940
52
99
98
98
IND-SW2
IND-SW1
IND-SW3
IND-SW4
98
TAIWAN
CH-T11
88
44
AF134812
63
TW6310E
TW8E-2
57
100
43
TW6196E
TW2494E
US2
US-SW
100
US1
68
MEX86
87
99
41
Epidemics of
HEV in India
be used to detect both type 1 and 4
HEV infections.
! Sporadic HEV cases could be dia-
CH-T21
29
hepatitis E.
! Swine and human HEV antigens can
4
HF-030
HF-054
57
100
collected during all HEV
epidemics (1976-2004) showed
anti-HEV IgM and IgG antibodies.
TW74SW
67
Hepatitis E is the major cause of
epidemic hepatitis in India. NIV has
investigated over 100 outbreaks of
! Sera
TW32SW
TW5483E
80
protein (both swine and
human HEV) expressed in baculovirus system proved to be a highly
reactive antigen for ELISA. Based on
recombinant ORF-2 antigen, ELISA
could efficiently detect both IgM and
IgG-anti-HEV antibodies.
NAFR83
49
D11092
96 L08816
3
2
gnosed. NIV ELISA was comparable
with the commercially available,
Genelab ELISA.
Maharashtra State
3
L25595
61
87
BUR83
BUR89
45
AKL90
AKL90
76
HYD87
64 TK4-95
49
NEP4-94
2
2
INDFHFL
INDFHFL
MAD93
70
1
2
PAK87
8
1
5
1
3
8
1
1
1999-2000
2002-03
Indian strains:
All human strains - genotype 1
All swine strains - genotype 4
1
69
Goa
45
40
50
40
30
25
the US and strong possibility of
zoonotic spread to humans was
suspected. Wherever examined, all
countries showed anti-HEV positivity
in pigs.
10
5
0
6-10
11-15
Age group
Affluent
Effluent
Sewage Plant
30
! In 1997, swine HEV was discovered in
1998
20
0
35
and bonnet (19.1%) monkeys from
India were shown to be anti-HEV
positive.
16-25
HSS
25+
LMSS
Rural
! In 2001, anti-HEV antibodies were
20
0
Adults
! 2/37 anti-HEV negative transfusion
Proportion of sporadic hospitalized
hepatitis E cases in Pune
recipients sero-converted, 4 and 5
weeks post-transfusion.
Though high mortality in pregnant
women is the characteristic feature of
hepatitis E, in sporadic situation, nonpregnant women as well as men were
shown to succumb to fulminant
hepatitis E.
100
90
80
70
60
40
30
10
! Transfusion associated hepatitis E
Risk factors
Multivariate analysis showed that age
> 15 yrs (5.7 fold), lower middle
socioeconomic status (2.4 fold) and
are
well water usage (1.9 fold)
important risk factors for contracting
infection.
Transmission
Water contamination
Leaky water/drainage pipelines
running in close proximity or other
means of contamination at the source
of water reservoirs results in explosive
outbreaks.
200
100
0
0
6-10
11-15
AGE GROUP
16-25
1982
1992
% POSITIVE
0.2
0.4
0.6
0.8
300
200
100
0
0
1
1998
0.2
60
40
20
0
0
0.2
0.4
0.6
0.6
Optcal Density (ELISA)
11-15
AGE GROUP
16-25
1983
0.8
1
25+
Pune HSS urban
110
0
0
0.2
0.4
0.6
Optcal Density (ELISA)
In contrast to other countries, different
genotypes circulate in humans
(genotype-I, 1976-2004) and pigs
(genotype IV, 1985-2000) in India.
80
70
60
50
40
30
20
10
0
6-10
11-15
AGE GROUP
70
16-25
1982
The complete genome of Indian swine
HEV was sequenced.
25+
1998
71
1
100
100
90
0.8
200
Anti-HEV positivity documented in pigs
from states of Maharashtra,
Karnataka and Andaman & Nicobar
Islands. Mean age of pigs for
seroconversion was 4.8 + 1.6 months.
1998
1
300
Swine HEV
6-10
0.8
Rodents
Dogs
110
100
90
80
70
60
50
40
30
20
10
0
0.4
Optical Density (ELISA)
Optical Density (ELISA)
25+
Pune didtrict, rural
During epidemics, the estimated ratio
of clinical:subclinical infections
based on serology was shown to be
1:26 in pregnant women.
300
0
may occur in countries endemic for
HEV.
Intra-familial spread
Based on the study of 49 families
during an epidemic of hepatitis E, the
intra-familial spread was shown to be
negligible.
Cattle
Pigs
50
20
% POSITIVE
Children
detected in pigs, dogs, cattle,
rodents, and chickens from India.
Goats were negative.
Pune urban LMSS
No of Pigs
5
110
No of Dogs
10
% POSITIVE
Parenteral transmission
! 1.5% (3/200) voluntary blood
donors from Pune positive for HEV
RNA.
15
No of Cattle
15
HEV as zoonosis
! In 1994, wild caught rhesus (36.7%)
60
% ANTI-HEV+VE
% PCR +ve
20
10
% HEV Cases
HEV antibody prevalance in
and around Pune
About 15% of neat sewage samples
collected year round were HEV RNA
positive, 7-fold higher risk of infection
in sewage workers was documented.
No of Rodents
Initial studies conducted by NIV
showed that ~ 60% of the sporadic
hepatitis cases among adults are of
NANB type. With the availability of
ELISA for IgM-anti-HEV detection, over
40% of sporadic cases among adults
were diagnosed as hepatitis E.
Delta & other
Hepatitis Viruses
! HDV is not an important cause of viral
Hepatitis Delta Virus (HDV)
hepatitis in western India.
! In 1987, normal immunoglobulin
HBsAg
preparations were shown to be antidelta positive.
d Ag
35 nm
TT virus
d RNA
Hepatitis G Virus (HGV)
! Discovered in 1995.
! Disease potential yet to be confirmed.
! HGV does not contribute to sporadic
Ÿ Defective RNA virus.
Ÿ Requires HBV
multiplication.
replication
for
Non-A, Non-E hepatitis in India.
its
72
! Not an important cause of chronic or
fulminant hepatitis.
Ÿ Occurs as co- or super-infection with
HBV.
62
! The virus belongs to the family
Flaviviridae.
Ÿ Leads to severe course of liver disease.
! Discovered in 1997 in Japan.
! Disease potential questionable.
! Parenteral and enteric modes of
Phylogenetic analysis of
HGV isolates (western India)
91
Ÿ Though HDV replication is HBV
dependent, its prevalence is not a
simple function of HBV prevalence.
Ÿ Parenterally transmitted.
IND2
IND5
Peru-72442
IND3
IND4
IND9
IND21
64 Germany-532
87 US7
IND1
69
IND6
94
IND20
HGV-VT58
GHP7
HGV-VT10
88
TH-K10
94
75 HGV-MY67
CHN-NJ1
KR3
TH-T80
III
NU60
GHP2
65
Kenya
98
GA9
GA22
IV
Zair9
94
Ed3
98
transmission.
The virus
DNA virus, belong to family Parvoviridae.
I
II
0.02
Prevalence of anti-delta positivity
C2
64
80
Fulminant Hepatitis
Prevalence of HGV RNA
Sporadic Acute Viral Hepatitis
79
Anti - delta virus antibodies were
detected only in blood dooners
Rural Area Adults
Paid plasma donors
NIV-50
NIV-52
64 NIV-49
NIV-53
NIV-74
NIV-51
NIV-69
NIV-70
68
F5
NIV-63
NIV-46
NIV-66
NIV-47
NIV-73
75 NIV-67
54
NIV-75
NIV-68
99
NIV-71
NIV-76
N22
99
NIV-72
93
96 TTVCHN1
TTV33
MONG969 1b
66
TX011
91
99
Be7
BLDN20
A3
3
JaM53
JaM18
JaM28
99
Hemophiliacs
Patients suffering
from FHF
Mentally Compromised Children
Voluntary Blood
Donors
Voluntary Donors
Commercial Donors
0
0
1
2
3
4
5
6
7
2
4
6
8
10
12
14
16
18
% HGV RNA Positivity
% anti-delta Positivity
76
2
H4
C1
75
NIV-48
0.05
Non-A-E acute viral
hepatitis patients
Leprosy Patients
CK7
JaM21
A4
93
Patients suffering
from liver disease(s)
Children
5
TS003
53
99
Institutionalised Children
77
1
4
56
Rural Area Children
1a
Phylogenetic
analysis showed
presence of
genotypes
1, 1a and 2.
6
TTV DNA positivity
! Though high prevalence of TTV DNA
was recorded, no disease association
could be shown.
! Ten percent neat sewage samples
were TTV DNA positive.
! Sewage treatment did not reduce TTV
DNA positivity.
HBsAg Carriers
HBV-DNA HCV-RNA
Negative CLD Patients
HBV-DNA Positive CLD
Patients
CLD Patients
Patients undergoing
Haemodialysis
Hemophiliacs
Paid plasma donors
Voluntary Blood Donors
0
5
10
15
20
25
30
% TTV DNA Positivity
Non-A to E agents
! Despite use of sensitive and specific
serological and molecular assays, all
acute viral hepatitis cases cannot be
diagnosed.
! Non-B, non-C chronic hepatitis cases
continue to occur.
! An epidemic of enterically transmitted
non-A, non-E hepatitis in a tribe of
Andaman and Nicobar islands in
December 1987 was investigated by
NIV. Subsequently shown to be TTV
DNA and HGV RNA negative. So far,
no etiologic agent identified.
Transmission experiments in rhesus
monkeys were unsuccessful.
78