6. VIRAL HEPATITIS
Viral hepatitis needs detail discussion as
• It is responsible for more than 90% cases of
hepatitis
• Very important from public health point of view –
as preventable
• Types A and E cause only acute hepatitis and
spread by feaco-oral route
• Types B,C,D and G cause both acute & chronic
hepatitis and are transmitted by blood and blood
products and body fluids
6
7. 7
HEPATITIS VIRUSES
• Hepatitis A (HAV) Picornaviridae (1973)
• Hepatitis B (HBV) Hepadnaviridae (1963)
• Hepatitis C (HCV) Flaviviridae (1988)
• Hepatitis D (HDV) ? (1977)
• Hepatitis E (HEV) (Caliciviridae) (1983), Hepeviridae
• Hepatitis F – Not separate entity – Mutant of B Virus.
• Hepatitis G (HGV) Flaviviridae (1995)
10. Hepatitis A
Patients may present with jaundice, dark urine, nausea, diarrhea,
and severe malaise.
Acute hepatitis A is usually a self-limited illness, but a small
number of patients develop fulminant hepatitis.
11.
12. Endemicity
Disease
Rate
Peak Age
of Infection Transmission Patterns
High Low to
High
Early
childhood
Person to person;
outbreaks uncommon
Moderate/
intermediate
High Late
childhood/
young adults
Person to person;
food and waterborne
outbreaks
Low Low Young adults Person to person;
food and waterborne
outbreaks
Very low Very low Adults Travelers; outbreaks
uncommon
Global Patterns of
Hepatitis A Virus Transmission
13. 13
HAV:
Picornavirus
(formerly known as
Enterovirus 72, now
put in its own family:
heptoviridae )
Non-enveloped
Single-stranded RNA
in protein shell
Only one serotype
but multiple
genotypes
Agent factors
14. 14
• HAV is extremely resistant.
• It survives:
– at 70°C for up to 10 min
– acid treatment (pH 1 for 2
h at room temperature)
– Not affected by detergents
• Can be stored at –20°C for
years
• inactivated by:
– Heating to 85°C for 1 min
– Autoclaving (121°C for 20
min)
– Ultraviolet Radiation
– Chlorine (free residual
chlorine concentration of
2.0 to 2.5 mg/l for 15 min)
– Shellfish from
contaminated areas should
be heated to 90°C for 4
min or steamed for 90 sec
Agent factors
15. 15
• RESERVOIR OF
INFECTION
– Human
case(asymptomatic
/anicteric
infections
especially children
• PEROID OF
INFECTIVITY
– 2weeks before to
one week after
onset of jaundice
• INFECTIVE
MATERIAL
– Mainly feces
• VIRUS EXCRETION
– 2weeks before to 2
week after onset
Agent factors
16. • AGE
– CHILDREN:
frequent, 90%
infected by age 10
yr, mild,ratio to
anicteric12:1 vs 1:3
in adults but short
fecal excretion
• SEX- Equal
• IMMUNITY
– Life long,
– second attacks
in 5%
HOST factors
18. Modes of
TRANSMISSIO
N
• Fecal-oral
– direct: person-to-
person contact (e.g.,
household contact,
sex contact, child day
care centers)
– Waterborne
– Food borne(e.g.,
infected food
handlers, raw
shellfish)
• Parenteral-rare
– (e.g., injecting drug
use, transfusion)
• Sexual transmission:
homosexual
19. 19
PATHOGENESIS - HAV
HAV invade into human body by fecal-oral route, multiplies
in the intestinal epithelium & reaches the liver by
hematogenous spread.
After one week, the HAV reach liver cells replicate within.
Then enter intestine with bile and appear in feces.
After HAV replicating and discharging, liver cells damage
begin
INCUBATION PERIOD :
30 days (range: 10-50 days).
20. 20
Prodromal or Preicteric phase :
(symptoms: fatigue, joint- and
abdominal pain, malaise,
vomiting, lack of appetite,
hepatomegaly)
Icteric phase: Icterus: jaundice (skin,
sclera, mucous membranes,
cause: elevated bilirubin level,
bilirubinuria: dark urine, pale stool)
21. DIAGNOSIS :
Acute hepatitis A is confirmed by a positive
serum IgM anti-HAV titer that is detectable
within 5-10 days after the onset of symptoms
and persists for up to 6 months after
infection.
Previous HAV infection is evidenced by (IgG
anti-HAV-positive & IgM anti-HAV-
negative).
22. TREATMENT :
No effective antiviral therapies are available
for acute hepatitis A.
Treatment efforts are largely supportive.
Immunoglobulin in severe cases
23. Prevention & CONTAINMENT:
a.control of reservoir
-complete bedrest with disinfection of feces
b.control of transmission:
Personal & community hygiene
clean drinking water/boiled
c. control of susceptible population:
human IgG
d. Vaccine
24. VACCINE
• Hepatitis A vaccine highly immunogenic vaccine
• 2 types
– Live attenuated: single, subcut
– Formaldehyde inactivated: two-shot series, 6-12 months
apart , i.m
• For >=12 months
• Two brands of hepatitis A vaccine (HAVRIX®
formulated with a preservative; and a bivalent
combination vaccine, TWINRIX®, containing
hepatitis A (HAVRIX®) and hepatitis B
(ENGERIX-B®) antigens, given on a 0, 1, 6-month
schedule, and is equally effective.
• As preexposure prophylaxis before travel to
countries with high and intermediate
25. • Pre-exposure
– travelers to intermediate and high
HAV-endemic regions
• Post-exposure (within 14 days)
Routine
– household and other intimate contacts
Selected situations
– institutions (e.g., day care centers)
– common source exposure (e.g., food prepared by infected food
handler)
Hepatitis A Prevention - ImmuneGlobulin
27. Virology
• Single-stranded RNA icosahedral virus
• Genus Hepevirus
• HEV has a fecal-oral transmission route
• First documented in New Delhi in 1955 when 29000 cases
of icteric hepatitis occurred
28. Stability
• These properties are comparable to HAV though
authentic literature is NOT available
• This too is probably destroyed by chlorination of water
• The virus is very sensitive to salt
29. Epidemiology
• HEV infections account for >50% of acute viral
hepatitis in India.
• More than 70% acute hepatitis occurring in Pediatric
population in Indian subcontinent are caused by HEV
30.
31. Epidemiology…
• 16 of the 17 epidemics in India were retrospectively found
to have been caused by hepatitis E viruses
Large epidemics:
1. The Delhi Epidemic 1955-56
2. Ahmedaban, India 1975-76
3. Pune, India 1978
4. Kashmir 1980
5. 400 cases reported from Rohtak in 2000
retrospective analysis confirmed HEV
32. Symptoms
ALT IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
Hepatitis E Virus Infection
Typical Serologic Course
Titer
Weeks after Exposure
33. The Disease
• Incidence is highest in ages b/n 15 & 40
• Children are less frequently symptomatic
• Self-limiting disease comparable to hepatitis A
• Occasionally develops into an acute severe liver disease,
and is fatal in about 2% of all cases
• Pregnant women, especially those in the third trimester,
suffer around 20% mortality(fulminant
34. The Disease…
• Four distinct genotypes have been reported.
Genotypes 1 and 2 :
restricted to humans.
In developing countries
Genotypes 3 and 4 infect humans, pigs and other animal species
As zoonotic disease from undercooked or raw meat
In developed countries
• Transmission may occur rarely
from pregnant mother to fetus
From transfusion of infected blood products
35.
36.
37. The Disease
• Mostly acute disease but genotype 3or 4 HEV may cause
chronic hepatitis E in
– immunosuppressed people esp. organ transplant
receipts on immunosuppressive drugs
38. Treatment
• No specific treatment
• Hospitalization generally not required but
should be considered in high risk esp pregnant
mothers
• Chronic hepatitis E: ribavirin, interferon
41. INTRODUTION
• Hepatitis B initially called as serum hepatitis is an acute
systemic illness with major pathology in liver.
• HBV infection is the 10th leading cause of death
• HBV related hepatocellular carcinoma(HCC ) is the 5th
most frequent cancer worldwide.
• Globally, HBV causes 60 - 80% of the world’s primary
liver cancers.
• 5% of adults and 90% of children infected become carries
• 25% of adults who become chronically infected during
childhood die from hepatitis B-related liver cancer or
cirrhosis;
42. PROBLEM STATEMENT : WORLD
•2 billion people have been infected (1 out of 3 people).
•350 million people are chronically infected.
•10-30 million will become infected each year.
•An estimated 1 million people die each year from hepatitis B
and its complications.
•Approximately 2 people die each minute from hepatitis B.
Source-(WHO, hepb.org)
43. Prevalence of Chronic HBV Infection, Worldwide, 2006
• Source: CDC and Prevention. MMWR
2008;57(RR-8):1-20.
HBsAg Prevalence
>8% = High
2-7% = Intermediate
< 2% = Low
44. PROBLEM STATEMENT : INDIA
• India has over 40 million HBV carriers and accounts
for 10–15% of the entire pool of HBV carriers of the
world.
• Estimated 43-45 million new cases per year.
• 100,000 death annually by disease related to HBV
infection.
• Of 25 million newborn annually, 1 million run
lifetime risk of HBV infection.
Source-1) API 2)World Health Organization (2012)
45. Acute hepatitis B: Case Definition
• A clinical case of acute viral hepatitis is an
acute illness that includes
– discrete onset of symptoms and
– jaundice or elevated serum aminotransferase
levels (>2.5 times the upper limit of normal)
• A confirmed case of hepatitis B is a suspected
case that is laboratory confirmed:
– HBsAg positive or Anti-HBc-IgM positive and
– Anti-HAV-IgM negative.
46. AGENT
• Hepatitis B virus belongs
to hepadnavirdae family
• Complex 42 nm. Double
stranded
• Enveloped DNA virus
(DNA polymerase with
reverse transcriptase
activity)
• Known as “Dane”
particle.
• Has affinity for liver and
hepatocytes
47. AGENT FACTORS
Reservoir of infection
– Human cases or carriers
– Carrier state defined as
persistence of HBsAg > 6
months
Resistance of virus:
– Quite stable, can survive for
days in environmental
conditions.
– Can be destroyed by sodium
hypochlorite
– Also by autoclaving for 30 to
60 minutes
Period of communicability:
– From incubation period upto
disappearance of HBsAg and
appearance of antibody.
48. HOST FACTORS
AGE:
• Acute Hepatitis B occurs in 1%
perinatal, 10% early childhood
(1-5 yrs) and 30% in older
children (>5 yrs age)
• Development of chronic
infection inversely related to
age.
– 90%if infected perinatally;
– 30% if <6yrs
– 5% if >6yrs
• Mortality from fulminant
Hepatitis B -70%
49. HOST FACTORS
High Risk groups
1. Health care workers and
laboratory personnel
2. High risk sexual behaviour
3. Frequent blood transfusion
recepient
4. Injectable drug users
5. Immunocompromised
individuals
6. Infants of HBV carrier mothers
50. ROUTES OF TRANSMISSION
1) Vertical transmission
2) Sexual transmission
3) Parenteral transmission
Needle stick injury
Household
contacts
52. Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Weeks after Exposure
Titre
53. IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
Titre
Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
54.
55. DIAGNOSIS
• HBsAg - used as a general marker of infection.
• HBsAb - used to document recovery and/or immunity to
HBV infection.
• anti-HBc IgM - marker of acute infection.
• anti-HBcIgG - past or chronic infection.
• HBeAg - indicates active replication of virus
• Anti-Hbe - virus no longer replicating. However, the patient
can still be positive for HBsAg which is made by integrated
HBV.
• HBV-DNA - indicates active replication of virus, more
accurate than HBeAg. Used mainly for monitoring response
to therapy.
56. Acute hepatitis B infection
Asymptomatic
Or
Subclinical
infection(33%)
Clinical infection
-jaundice
-flu like
symptom(66%)
Fulminant
hepatitis
(0.5%)
Death
Chronic
Carrier
(5-10%)
Recovery
Immunity
(85-90%)
Minimal
liver
Disease
(70-90%)
Chronic
Hepatitis
(10-30%)
Primary
hepatocellular
carcinoma
cirrhosis
DEATH
Reactivation
57. Hepatitis B and HIV
• Around 10 percent of 40 million people infected with HIV are
coinfected with Hep B.
• HBV infection has minimal effect on progression of HIV.
• But HIV markedly increases the risk of developing cirrhosis
and hepatocellular CA.
• HIV treatment can be used safely and effectively if coinfected
with hepatitis B.
58. Hepatitis B in Pregnancy
• Risk of transmission ranges from 10% in 1st trimester to about
90% in 3rd trimester.
• If a pregnant woman tests positive for hepatitis B, the newborn
child must be given - 1st dose of hepatitis B vaccine and one
dose of hepatitis B immune globulin (HBIG).
• Given within 12 hours of life, a newborn has 95% chance of
being protected against a lifelong hepatitis B infection.
• If not given in time - > 90% possibility that the baby will
become chronically infected.
• According to WHO, it is safe for an infected woman to
breastfeed her child since the benefits of breastfeeding
outweigh the potential risk of transmitting the virus through
breast milk.
60. Non-invasive tests (NITs)
• for evaluating and staging liver fibrosis, which reduces the
need for liver biopsy in persons with an established cause of
liver disease.
62. Who to treat
With clinical evidence of
compensated or
decompensated cirrhosis (or
cirrhosis based on APRI score
>2 in adults)
• all adults, adolescents and
children with CHB and
regardless of ALT levels,
HBeAg status or HBV DNA
levels.
Without clinical evidence of
cirrhosis (or based on APRI
score ≤2 in adults)
• adults with CHB, but are
aged more than 30 years (in
particular), and have
persistently abnormal ALT
levels and evidence of high-
level HBV replication (HBV
DNA >20 000 IU/mLf),
regardless of HBeAg status
63. Who to treat - HBV/HIV-coinfected
persons
ART should be initiated in
• all those with evidence of
severe chronic liver
disease, regardless of CD4
count;
• in all those with a CD4
count ≤500 cells/mm3,
regardless of stage of liver
disease.
64. Who not to treat but continue to
monitor
• without clinical evidence of cirrhosis (or based on APRI score
≤2 in adults), and with persistently normal ALT levels and low
levels of HBV replication (HBV DNA <2000 IU/mL), regardless
of HBeAg status or age.
• Where HBV DNA testing is not available: Treatment can be
deferred in HBeAg-positive persons aged 30 years or less and
persistently normal ALT levels.
65. PREVENTION AND CONTROL
Strategies:
• Hepatitis B vaccination.
• Screening of blood, plasma and organ donor-
National Blood Policy, 2002
• Infection control precautions-Universal precautions.
• Safe injection practices
• Safer sex practices
66. HEPATITIS B VACCINATION
• Active immunization
• Passive immunization
ACTIVE IMMUNIZATION
• Two types of vaccine
1. Plasma derived vaccine
2. Recombinant DNA vaccine
67. Recombinant DNA Vaccine
• Introduced in 1986 in USA.
• Has replaced plasma derived vaccine.
• Cost effective
• Available as monovalent or combined vaccine
Active substance:
-HBsAg derived from culture of yeast or mammalian cells
Adjuvant:
- Alum or thiomersal
Storage:
-2 to 8°C
HEPATITIS B VACCINATION
68. Age :
• Ideal first dose at birth ( within 24 hours)
• Next 2 or 3 dose according to immunization schedule
No. of doses:
• 3 or 4
• First at birth , second and third with DPT1 and DPT3.
• First at birth, second, third and fourth with DPT
• Adults 3 doses at 0, 1 month, 6 month
• No need of booster dose.
HEPATITIS B VACCINATION
69. • Neither pregnancy nor lactation is a contraindication for its use.
• Usually provides life long immunity
Adverse reactions:
• Infrequent and rare
• transient fever(1-5%) , local reaction(5%),myalgia
• Very rarely anaphylactic reaction .
HEPATITIS B VACCINATION
70. PASSIVE IMMUNIZATION
• Hepatitis B immunoglobulin used for temporary post-exposure
prophylaxis.
• Combined active and passive vaccination is advised in following
cases:
- Newborn of HBsAg +ve mother
- Percutaneous exposure
- Sexual exposure
- After liver transplant in case of recurrent HBV infection
• Time :
within 6 hours of exposure and maximum upto 48 hours.
• Dose: 0.05 to 0.07 ml. / kg. body weight.
• Provides short term passive immunity for 3 months.
HEPATITIS B VACCINATION
73. PROBLEM STATEMENT: WORLD
• According to WHO estimates
– 3% of world population infected with HCV
– 170 million are chronic carriers
• 3–4 million new infections per year
• more than 350 000 people die every year from hepatitis C-
related liver diseases
• Highest – Egypt(15%)
• Most common cause of chronic liver disease in
the United States and the most common
indication for liver transplantation
74.
75. PROBLEM STATEMENT:INDIA
• HCV prevalence-1.5%
• About 12 million chronic carriers
• HCV antibodies found in 2% of voluntary blood donors.
• 42% of patients with hepatocellular CA had markers of
HCV infection.
Source-WHO, http://www.epidemic.org
76. HIGH RISK GROUPS
• Current or former i.v. drug users
• Recipients of clotting factor concentrates
• Recipients of blood transfusions or donated organs before July
1992
• Persons with known exposures to HCV (e.g., healthcare
workers after needlesticks , recipients of blood or organs from
a donor who later tested positive for HCV)
• Infants born to infected mothers
77. ACUTE HEPATITIS C:
Case Definition
• Acute illness typically including acute jaundice, dark urine,
anorexia, malaise, extreme fatigue, and right upper quadrant
tenderness.
• Biological signs include
– increased urine urobilonogen and
– >2.5 times the upper limit of serum alanine
aminotransferase.
• Laboratory criteria for diagnosis:
– Hepatitis C: Positive for anti-HCV
• Confirmed Case: a suspected case that is laboratory
confirmed.
78. Agent
• HCV is a
– Small(55-65nm) enveloped,
– single-stranded, RNA virus
– Flaviviridae family
• Classified into 6 genotypes
• Genotype 2 and 3 in India.
• No resemblance to HBV or HDV.
79. Clinical Course
• Incubation period- mean 6-7 wks
• 85% of individuals, the clinical course of the acute infection
is asymptomatic and easily missed
• Persistent infection and chronic hepatitis are the hallmarks
of HCV infection, despite the generally asymptomatic
nature of the acute illness- 75% to 85% of cases.
• Immunity-no protective antibody response
80. ROUTES OF TRANSMISSION
1) Intravenous drug use:
sharing of needles and syringes
2) Sexual transmission
3) Blood transfusion
4) Vertical transmission
5) Needlestick injury
82. Symptoms
anti-HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Hepatitis C Virus Infection
Typical Serologic Course
Titre
Months Years
Time after
Exposure
83. DIAGNOSIS
• Diagnosis of acute infection is often missed because a
majority of infected people have no symptoms.
• Anti- HCV antibodies by ELISA : indicates infection.
• Recombinant immunoblot assay (RIBA) and hepatitis C
virus RNA testing : confirm the diagnosis.
• Chronic Hepatitis C- anti HCV> 6 months
84. Natural history of HCV infection
Exposure
(Acute Phase)
Chronic
Cirrhosis
HCC
Transplant
Death
Resolved
Stable
Slowly Progressive
85%(85)
80%(68) 20%(17)
25%(4)
75%(13)
15%(15)
HIV and
Alcohol
85. TREATMENT
• New DAA drugs(direct acting antiviral)
– Sofosbuvir with ribavirin :cure in 90%
– Sofosbuvir with daclatasvir: pangenotypic effect
• Cirrhosis, liver cancer patients-
– liver transplant
86. PREVENTION
Primary prevention
• There is no vaccine for hepatitis C.
• The risk of infection can be reduced by avoiding:
– unnecessary and unsafe injections;
– unsafe blood products;
– unsafe sharps waste collection and disposal;
– use of illicit drugs and sharing of injection equipment;
– unprotected sex with hepatitis C-infected people;
– sharing of sharp personal items that may be contaminated
with infected blood;
– tattoos, piercings and acupuncture performed with
contaminated equipment.
87. PREVENTION
Secondary prevention:
• For people infected with the hepatitis C virus, WHO
recommends:
– education and counselling on options for care and
treatment;
– immunization with the hepatitis A and B vaccines to
prevent coinfection;
– early and appropriate medical management including
antiviral therapy if appropriate; and
– regular monitoring for early diagnosis of chronic liver
disease.
89. Virology
• Hepatitis delta virus
• Single-stranded, closed, circular, partially double
stranded RNA
• With a genome of approximately 1700 nucleotides, HDV is
the smallest "virus" known to infect animals.
90. Epidemiology
• Worldwide, more than 10 million people are infected with
HDV
• HDV is rare in most developed countries and much more
common in Mediterranean countries, sub-Saharan Africa,
the Middle East, and countries in the northern part of
South America
91.
92. Transmission
• Transmission of HDV can occur either via simultaneous
infection with HBV (coinfection) or via infection of an
individual previously infected with HBV (superinfection).
• It is mostly associated with intravenous drug use.
• Both superinfection and coinfection with HDV results in
more severe complications compared to infection with
HBV alone
• In combination with hepatitis B virus, hepatitis D has the
highest mortality rate of all the hepatitis infections of
20%
95. Hepatitis G virus
• Hepatitis G virus (HGV), belongs to Flaviviridae
family
• Known to infect but is not known to cause human
disease.
• There have been reports that HIV patients coinfected
with GBV can survive longer
96. • 1 in every 12 people worldwide are living with
either chronic Hepatitis B or Hepatitis C.
• World hepatitis day on July 28
97. 1. What percentage of people
living with chronic hepatitis
KNOW they are infected?
a) Less than 5%
b) 30%
c) 50%
d) More than 90%
2. What percent of people can
be cured of hepatitis C?
a) More than 90%
b) 75%
c) 50%
d) Less than 25%