Hepatitis A

Hepatitis A
! The causative agent is hepatitis A virus
(HAV)

Studies in Pune (1982-98)

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.

! Earlier referred to as infectious

hepatitis.

! Major public health problem,

million cases each year worldwide.

1.4

The virus
! ! ! ! !
Picornaviridae, genus Hepatovirus. 27-30 nm diameter particles. Plus-stranded 7.5 Kb RNA genome. Seven genotypes / Single serotype. HAV grows slowly in cell culture without cytopathic effect. primates.
HAV Genome
5 NCR
LA LB

! In developing

countries, pediatric disease; in developed nations, disease of adults.

! Prevalence of hepatitis A is inversely

related to socioeconomic status.

Transmission
! Fecal-oral route. ! Person-to-person contact. ! Inadequately cooked food. ! Blood-products-associated
transmission noted in Europe.

Indigenously developed hepatitis A diagnostic kit Epidemiology

! Available animal models: Non human

Urban Lower-middle class
110 100 90 80

P1
1C 1D

P2
2A 2B 2C 3A 3B

P3
3C 3D

% anti-HAV

NCR 3 Poly A

Vpg

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.
18%

70 60 50 40 30 20 10 0

Disease
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.
Markers / symptoms during HAV infection
JAUNDICE ALT SYMPTOMS IgM ANTI- HAV IgG ANTI- HAV

Laboratory diagnosis
! IgM-anti-HAV is the diagnostic marker
for hepatitis A.

6-10

11-15 AGE GROUP

16-25 1982 1992

25+ 1998

! At NIV, Pune, IgM anti HAV capture

ELISA and Blocking ELISA tests have been developed and are routinely used to provide diagnosis of recent and past infection of hepatitis A virus.
Hep A

82%
110 100

Rural lower middle class

90 80

Non-A
% anti-HAV

Acute viral hepatitis

70 60 50 40 30 20 10 0

! ELISA based hepatitis A diagnostic

technology has been transferred to Hyderabad based industry. This is the first such transfer from NIV, Pune.
Hep A 40%

! Urine was found to be an alternative

test specimen for diagnosis of hepatitis A, useful especially in children.

FECAL HAV

Non-viral Hepatitis 48%

6-10 AGE GROUP

11-15 1983 1998

15+

Viral Hepatitis 52%

! Blood collection on filter paper disc

0 4 8 WEEKS AFTER EXPOSURE 12 16

Hep B or D 12%

proved to be satisfactory for anti-HAV detection.

52

Fulminant hepatitis
53

Higher socioeconomic class

110 100 90 80 70 60 50 40 30 20 10 0 6-10 11-15 AGE GROUP 16-25 1982 1998 25+

Year-round PCR-based HAV-RNA positivity 35 30 25 20 15 10 5 0 Affluent Sewage plant Effluent % PCR +ve

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 54 100 99 IN D 9 8 -7 /VP 1 IIIA IN D 0 1 - 10 /VP 1 IN D 9 6 - 3 /V P 1 N O R 21 L 0 7 7 2 4 Nepal L 0 7 7 2 5 India L 2 0 5 2 8 Japan 87 L 0 7 7 2 9 SierralL e o n e GenotypeVIIIB GenotypeVII GenotypeII GenotypeIA Genotype IIIA

%ANTI-HAV

Hepatitis A in adults
12 10

Prolonged fecal excretion and viremia observed in Indian patients and experimental monkey. Several animal species shown to be anti-HAV positive.

L07693France 78 98 100 53 L 0 7 7 3 2 Phillipines L 0 7 7 3 1 Indonesia 79 0.05 D00924Kenya Ab020564Japan M147 07 IN D 9 2 - 1 /V P 1 IN D 9 4 - 2 / V P 1 IB IN D 9 8 - 7 / V P 1 IB

GenotypeIB

% Hep A Cases

8 6 4 2 0

GenotypeV

Genotyping of HAV strains in sporadic cases from Pune

1978-81 1994-97

Isolates indicating mixed genotypes are shown in blue color. Scale indicates genetic distance

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.

Co-circulation of subgenotypes IB and IIIA with predominance of IIIA detected. Mixed infection with IB and IIIA identified in inidividual hepatitis A patients.

Emergence of epidemic hepatitis A

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.

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
0.2

54

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
Supply of safe potable water. High standards of public and personal hygiene. Education of food handlers. 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

Novel process of Hepatitis A

vaccine preparation has been filed.

Hepatitis B

56

Hepatitis B
! The causative agent is hepatitis B virus
(HBV).

The risk factors

! Transfusion of unscreened blood. ! Improperly sterilized syringes /
needles / dental / other equipments.

Based on transmission modes, several high-risk groups have been identified.

Mentally compromised children Orphans Asthamatics Health care personnel Leprosy patients Family contacts of carriers Paid blood donors Haemodialysis patients Prisoners STD patients Dental auxiliary staff Dentists Voluntary blood donors 0 10 20 30 40 50 60 70 80 90 100

Hepatitis B vaccination introduced for tribals of Andaman and Nicobar Islands

HBV Epidemiology in and around Pune (1982-1998)
Urban
25

! Earlier referred as Serum Hepatitis. ! 350 million carriers of the virus

worldwide.

! Close contact with HBV positive

individual.

% Positive

! 34 million HBsAg carriers in India. ! 200-fold higher risk of primary

hepatocellular carcinoma.

HBsAg
20

HBsAg+anti-HBc

! Shared razors, toothbrushes with

carrier.

15

! Wide spectrum of clinical presentations.

! Tattooing. ! Sexual contact with HBV positive

individual.

10

! Several transmission modes. ! Efficacious vaccine available since

1982.
Hepadnavirus

! Multiple sex partners. ! Infected mother to infant.

HBsAg

anti-HBc

Percentage

1982

1992 Children

1998

1982

1992 Adults

1998

Year

These high risk individuals must be considered for vaccination

Percentage

35 30 25 20 15 10 5 0

Rural
HBsAg anti-HBc

Electron micrograph of 42 nm HBV from a blood donor in Pune

Cultural practices make tribals a high-risk category

Tribal populations and exposure to HBV (%)
Dhule

Infection with HBV may lead to ! Subclinical infection.

Children
1983

Aduilts

Children
1998

Adults

! Acute self-resolving hepatitis. ! Fulminant hepatitis. ! Asymptomatic carrier state. ! Chronic hepatitis. ! Cirrhosis. ! Hepatocellular carcinoma.

Maharashtra

Bhiwandi

Thane

HBV prevalence in Pune was determined according to socio-economic status viz. lower middle class status (LMS) and higher socio-economic status (HS).
HBV exposure according to socio-economic status, Pune 1998
LMS HS

Pune

10

20

30

40

50

60

70

HBsAg

anti-HBc
Percent Positives

30 25 20 15 10 5 0

Andaman & Nicobar islands

Transmission routes
Parenteral Inapparent parenteral Sexual Vertical Horizontal

Onges

Shompens

6-10

11-15

16-25

25+

Age Groups
Nicobarese

58

Andamanese

10

20

30

40

50

60

70

80

90

100

HBsAg

anti-HBc

HBV Pre-Core mutant and clinical presentation

Asymptomatic HBsAg Carriers
2%

Diagnostics
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. In 1981, again for the first time, ELISA for the detection of anti-HBs antibodies was developed.

Delta Rn vs Cycle No HBV Standard

Chronic Hepatitis B
2% 16%

36%

39%

Delta Rn

23%

82%

Acute Hepatitis B
14%

Fulminant Hepatitis B
13%

Cycle Number

HBV DNA quantitation is a national facility available at NIV

86%

Assessment of screening tests / vaccines

87%

! Evaluation of commercially available

Mixture

Negative

Mutants

Wild

! To assess the presence of replicating

virus, PCR for the detection of HBV DNA was standardized in 1990.

assays as part of WHO-SEARO designated national reference center.

Risk of Chronic hepatitis 4.3-fold higher with HBV pre-C wild 3.2 fold higher chances of asymptomatic carrier state with pre-C mutants Pre-C mutant not associated with fulminant hepatitis

! 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 Genotype D predominant

38
GNTYP-E GNTYP-D GNTYP-B GNTYP-C

! Follow up of vaccinated persons for 14

years.

38 99

60 ASC1027 (19)
CLD2235 (25)

56 FHF2376 (5) 65 AVH1164 (8)

GNTYP-F

99

GNTYP-H

0.01

in western India. Did not influence outcome of HBV infection. Genotype D highly prevalent in tribes from Andaman and Nicobar islands
61

60

Creation of awareness about hepatitis B

! Children from several urban and
rural schools.

! Family contacts of HBsAg carriers.

One orphan selected by needy parents and born to HBsAg carrier mother was vaccinated, followed for seroconversion and finally adopted

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 < Based on NIV results immunization of dental students and dentists was made mandatory in Maharashtra < Orphans screened for HBsAg before adoption

Hepatitis C

62

Hepatitis C
! Earlier known as post-transfusion
non A-non B hepatitis (PT-NANB).

! At present, no confirmatory immunoassays are obligatory.

! Presence of HCV RNA by nested RT

PCR employing primers from 5'NTR.

Experimental transmission
! So far, chimpanzee is the only animal
model for HCV.

! 170 million hepatitis C virus (HCV)

infected individuals worldwide.

A new subtype of HCV, 3i, first identified in western India, was later found in other parts of the country.

! Nested RT-PCR assay (1990) was

standardized at NIV. Screening of clinical samples from all over India for HCV RNA is ongoing.

! No convenient cell-culture system is

available.

Transmission
! Parenteral
transmission important mode. is the

The disease
! Mostly subclinical. ! High chronicity potential (>70%). ! 50-70% of chronically infected
individuals develop chronic liver disease.

! At NIV, attempts to infect rhesus

monkeys and insect cell lines susceptible for other flaviviruses, were not successful.

! Other modes like sexual, vertical

and intrafamilial are infrequent.

! Quantitation of HCV viral load is a

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.

Genotypes
Samples from 149 HCV RNA positive patients from different parts of India were genotyped on the basis of phylogenetic analysis.
WEST
2.82%

! In dialysis units, a new patient usually

gets infected with HCV within six months, mainly through nosocomial spread.

! Not a major cause of acute or

fulminant hepatitis.

! Important cause for primary

hepatocellular carcinoma.

! First, 2nd and 3rd generation ELISAs

evaluated in Indian population immediately after availability in the market.

Epidemiology
! Anti-HCV prevalence among age
stratified general population is low.

The virus
Belongs to family Flaviviridae; positive sense, ssRNA genome (~9.4 kb). Classified into 6 genotypes.

45.07% 52.11%

! Prevalence was low in rural and

tribal populations.

! At present, several host and viral

factors are being investigated for chronicity potential and success of interferon therapy.
Delta Rn vs Cycle

! Anti-HCV positivity in commercial

blood donors was high.
3.33% 33.33%

NORTH

! Dialysis patients and hemophiliacs

are at higher risk of getting infection.

! Blood donors from a commercial

63.33%

Electron Micrograph of HCV

Delta Rn

SOUTH
25.00% 38.89%

plasmapheresis unit had shown 90% anti-HCV positivity, most antibody positives being HCV RNA positive.
14 12

Diagnosis
! No marker distinguishes between
acute and chronic infections.
36.11%
Cycle Number

Commercial blood donors

! Detection of anti-HCV antibodies by

3 generation screening ELISAs.
rd

75.00%

4
Genotype 4 Nontypable

HCV Genome Organization

P22
5 NTR C

gp35
E1

gp70
E2

P7
Ns1

P23
Ns2

P70
Ns3

P8
Ns4A

P27
NS4B

P56/58
NS-5A

P68
NS-5B 3 NTR

Genotype 1 Genotype 3

2 0

Percentage

Blood products being imported in India are screened for HCV RNA at NIV.

10
EAST
25.00%

8 6

Structuralprotins

Nonstructural proteins

1982

1983

1986

Year
65

Voluntary Blood Donors 1 / 217 0 / 346 1 / 180 0 / 178 0 / 400 0 / 259 0 / 445
Similar trend continues till 2004

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. 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. 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.

Anti-HCV positivity in different categories

25 5 10 15 20

Acute Viral non-A,non-B Hepatitis Patients

Dentists

Leprosy Patients

Chronic Liver Disease Patients

Institutionalised children with high HBV exposure

Patients suffering from Sexually Transmitted Diseases

Multiply transfused Patients

Normal Pregnant Women

Health Care Personnel

Patients undergoing Hemodialysis

Voluntary Blood Donors

Expression of recombinant core antigen

Highly immunoreactive recombinant HCV core antigen was expressed in baculovirus system.

Hepatitis E

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

The disease 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

Epidemiology
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. 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. Hepatitis E is the major cause of epidemic hepatitis in India. NIV has investigated over 100 outbreaks of

The virus
! Recently classified as a member of a
newly designated Hepeviridae family. ! 27-30nm spherical particles. ! The genome is a single-stranded, positive sense RNA of about 7.2 kb.
5 ORF-1: 5 kb ORF-3: 369 nt 3 ORF-2: 2 kb

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.

Diagnosis
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. Diagnostic test development

! ORF-2

Genotypes
HEV strains are classified into 4

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. collected during all HEV epidemics (1976-2004) showed anti-HEV IgM and IgG antibodies.

79 80 93 67 52

TW32SW TW5483E TW74SW AF103940

! Sera

hepatitis E.

99 98

98 88 57 44 63 29 57 100 43 100 68 CH-T21

IND-SW2 IND-SW1 IND-SW3 IND-SW4 98

! Swine and human HEV antigens can

4

TAIWAN CH-T11 HF-030 HF-054 AF134812 TW6310E TW8E-2 TW6196E TW2494E US2 US-SW US1 MEX86 NAFR83 49 D11092 96 L08816 L25595 PAK87

be used to detect both type 1 and 4 HEV infections.

Epidemics of HEV in India

! Sporadic HEV cases could be dia3 2

gnosed. NIV ELISA was comparable with the commercially available, Genelab ELISA.
2

Maharashtra State
3 2 2 8 1

87 99 100 41

INDFHFL INDFHFL
70 87

MAD93
61 BUR83 BUR89 45 AKL90 AKL90 76 HYD87 64 TK4-95 49 NEP4-94

1
8 1

5 3

1999-2000 2002-03

Indian strains: All human strains - genotype 1 All swine strains - genotype 4

69

Goa

% ANTI-HEV+VE

% PCR +ve

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.
45 40 35

About 15% of neat sewage samples collected year round were HEV RNA positive, 7-fold higher risk of infection in sewage workers was documented.
20 15 10 5 0 Affluent Effluent Sewage Plant

HEV antibody prevalance in and around Pune

60 50 40 30 20 10 0 6-10 11-15 16-25 25+

HEV as zoonosis
! In 1994, wild caught rhesus (36.7%)
and bonnet (19.1%) monkeys from India were shown to be anti-HEV positive.

1998

! In 1997, swine HEV was discovered in

the US and strong possibility of zoonotic spread to humans was suspected. Wherever examined, all countries showed anti-HEV positivity in pigs.

Age group

HSS

LMSS

Rural

% HEV Cases

30 25 20 15 10 5 0

Children

Adults

% POSITIVE

Parenteral transmission ! 1.5% (3/200) voluntary blood donors from Pune positive for HEV RNA.

! In 2001, anti-HEV antibodies were

110 100 90 80 70 60 50 30 20 10 0 40
300 200 100 0 0 0.2 0.4 0.6 0.8 1

Pune urban LMSS

detected in pigs, dogs, cattle, rodents, and chickens from India. Goats were negative.
Pigs
No of Cattle No of Pigs
300 200 100 0 0 0.2 0.4 0.6 0.8 1

Proportion of sporadic hospitalized hepatitis E cases in Pune

! 2/37 anti-HEV negative transfusion

recipients sero-converted, 4 and 5 weeks post-transfusion.

Cattle

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. During epidemics, the estimated ratio of clinical:subclinical infections based on serology was shown to be 1:26 in pregnant women.

! Transfusion associated hepatitis E

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. 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.

6-10

11-15

16-25

25+

Optical Density (ELISA)

Optical Density (ELISA)

AGE GROUP

1982

1992

1998
No of Dogs
60 40 20 0 0 0.2

Dogs
No of Rodents
300 200 100 0 0 0.2

Rodents

Pune didtrict, rural

110 100 90 80 70 60 50 40 30 20 10 0

0.4

0.6

0.8

0.4

0.6

0.8

Optcal Density (ELISA)

Optcal Density (ELISA)

% POSITIVE

Swine HEV
6-10 11-15 16-25 25+

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.

AGE GROUP

1983

1998

Pune HSS urban

110 100 90 80 70 60 50 40 30 20 10 0

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. In contrast to other countries, different genotypes circulate in humans (genotype-I, 1976-2004) and pigs (genotype IV, 1985-2000) in India.

% POSITIVE

6-10

11-15

16-25

25+

AGE GROUP

1982

1998

The complete genome of Indian swine HEV was sequenced.

71

70

Delta & other Hepatitis Viruses

Hepatitis Delta Virus (HDV)

HBsAg

! HDV is not an important cause of viral

hepatitis in western India.

TT virus
Phylogenetic analysis of HGV isolates (western India)
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

! In 1987, normal immunoglobulin

preparations were shown to be antidelta positive.
d RNA

d Ag

! Discovered in 1997 in Japan. ! Disease potential questionable. ! Parenteral and enteric modes of
transmission.

35 nm

Hepatitis G Virus (HGV)

! Discovered in 1995. ! Disease potential yet to be confirmed. ! HGV does not contribute to sporadic
for its Non-A, Non-E hepatitis in India.
72 62

The virus
I

DNA virus, belong to family Parvoviridae.

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 A3 3 JaM53 JaM18 JaM28

Defective RNA virus. Requires HBV multiplication. replication

! Not an important cause of chronic or

fulminant hepatitis.

Occurs as co- or super-infection with HBV. Leads to severe course of liver disease. Though HDV replication is HBV dependent, its prevalence is not a simple function of HBV prevalence. Parenterally transmitted. Prevalence of anti-delta positivity
Fulminant Hepatitis

II

! The virus belongs to the family

Flaviviridae.
91

1a 1

0.02

C2 64 80 79
Paid plasma donors

Prevalence of HGV RNA

Sporadic Acute Viral Hepatitis Rural Area Adults Rural Area Children Institutionalised Children Mentally Compromised Children Children Leprosy Patients Voluntary Donors Commercial Donors
0 1 2 3 4 5 6 7

99 Be7 BLDN20

5
CK7 JaM21

Anti - delta virus antibodies were detected only in blood dooners

4
99

56
Hemophiliacs Patients suffering from FHF Patients suffering from liver disease(s) Non-A-E acute viral hepatitis patients Voluntary Blood Donors
0 2 4 6 8 10 12 14 16 18
0.05

53 99 93

TS003 A4 H4 C1 75 NIV-48

% HGV RNA Positivity

% anti-delta Positivity

Phylogenetic analysis showed presence of genotypes 1, 1a and 2.

76

77

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