viral hepatitis- facts and treatment guidelines.

Viral Hepatitis- The Silent
Disease
Facts and Treatment
Guidelines
(NCDC/ASSLD / EASL / WHO
2015)Dr Shivaraj Afzalpurkar
KIMSDU
Dr Shivaraj

Introduction
• Viral hepatitis is a systemic infection affecting predominantly
the liver and causing its inflammation.
• The most common clinical consequence of infection with HAV
or HEV is an illness characterized by sudden onset of fever
and systemic symptoms, which is followed a few days later by
jaundice.
• Majority of people with acute viral hepatitis recover
spontaneously within a few weeks.
• However in some persons, the illness is complicated by
occurrence of acute liver failure (ALF), or chronic hepatitis.
Dr Shivaraj

Viral hepatitis
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Enteral route of transmission
Parenteral route of
transmission
By Ways of transmission
Hepatitis E
Dr Shivaraj

Hepatitis A and E
• Hepatitis A and E viruses are transmitted by the faeco-oral
route.
• Hepatitis A and E cause self - limiting acute infections.
• Hepatitis E may in rare instances, mainly in transplant
recipients, result in chronic infection.
• Acute liver failure is uncommon except in pregnant
women infected with hepatitis E.
• Vaccines have been developed to prevent hepatitis A and E.
Dr Shivaraj

Disease Burden-
• Cases in developed countries usually occur in
individuals returning from visits to high endemic
areas such as South East Asia, Indian subcontinent
and Mexico.
• More recently, sporadic hepatitis E has been
reported in residents of developed countries who
have not travelled abroad; in these cases the
mechanism of spread is unknown.
Dr Shivaraj

Indian Scenario
Viral hepatitis, caused by hepatitis viruses A through E, still
remains a major public health problem in India.
• HAV and HEV are an important cause of acute viral hepatitis
and acute liver failure in India.
• Since 1955, several epidemics of hepatitis have been
reported.
• 315 outbreaks of viral hepatitis were reported from 2010 to
2013.
• In India, HEV has been responsible for most of these
epidemics.
Dr Shivaraj

• HAV is responsible for 10-30% of acute hepatitis and 5-15% of
acute liver failure cases in India.
• HEV is responsible for 10-40% of acute hepatitis and 15-45%
of acute liver failure in India.
• Acute HEV has inordinately high mortality rate of 15 to 25
percent in women in the third trimester.
• Superimposed HEV is responsible for 10-15% of cases of
acute on chronic liver failure in India.
Dr Shivaraj

HEPATITIS A
 Hepatitis A (formerly known as “infectious” hepatitis or
epidemic jaundice) is an acute infectious disease caused
by Hepatitis A virus (HAV).
 It accounts for 20-25 % of clinical hepatitis in developed
world.
 The disease is heralded by non-specific symptoms such
as fever, chills, headache, fatigue, generalized weakness
and aches and pains, followed by anorexia, nausea,
vomiting, dark urine and jaundice.
 The disease is benign with complete recovery in several
weeks.
Dr Shivaraj

Epidemiological determinants
 Agent factors
a) AGENT: The causative agent, the hepatitis A virus, is an
enterovirus of the Picornaviridae family. It multiplies only in
hepatocytes.
a) RESISTANCE: The virus is fairly resistant to heat and chemicals.
-Withstands heating to 600 C for 1 hr. and is not affected by
chlorine in doses usually employed for chlorination.
-Formalin is stated to be an effective disinfectant.
- Virus inactivation- UV rays, 2% glutaraldehyde or sodium
hypochlorite and autoclaving.
Dr Shivaraj

c) RESERVOIR OF INFECTION: The human cases are the only
reservoir of infection.
d) PERIOD OF INFECTIVITY : The risk of transmitting HAV is
greatest from 2 weeks before to 1 week after the onset of
jaundice.
e) INFECTIVE MATERIAL : Mainly man’s faeces.
f) VIRUS EXCRETION: HAV is excreted in the faeces for about 2
weeks before onset of jaundice and for up to 2 weeks
thereafter.
Dr Shivaraj

 Host factors
a) AGE: Infection with HAV is more frequent among children
than in adults. However, people from all ages may be
infected if susceptible.
b) SEX: Both sexes are equally susceptible.
c) IMMUNITY: Immunity after attack probably lasts for life.
Environmental factors
 Cases may occur throughout the year.
 In India the disease tends to be associated with periods of
heavy rainfall.
Dr Shivaraj

Mode of Transmission
Incubation period
10-50 days (usually 25 to 30 days).
a) FAECAL-ORAL ROUTE: Major route of transmission.
-By contaminated water, food or milk.
b) PARENTERAL ROUTE (Rarely):
-By blood and blood products or by skin penetration through
contaminated needles.
c) SEXUAL TRANSMISSION:
-May occur mainly among homosexual men because of oral-
anal contact.
Dr Shivaraj

Clinical presentation
• The classic presentation of infectious hepatitis involves four
phases, as follows:
• Phase I (viral replication phase): Patients are asymptomatic
during this phase. Laboratory studies demonstrate serological
and enzyme markers of hepatitis.
• Phase II (prodromal phase): Patients experience anorexia,
nausea, vomiting, alterations in taste, arthralgia, malaise,
fatigue, urticaria, and pruritus.
• When seen by a health care provider during this phase,
patients are often diagnosed as having gastroenteritis or a
viral syndrome.
Dr Shivaraj

• Phase III (icteric phase): Patients note dark urine, followed by
pale-colored stools, in addition to the predominant
gastrointestinal symptoms and malaise.
• Patients become icteric and may develop right upper
quadrant pain with hepatomegaly (smooth tender edge) and
spleenomegaly (20 %).
• Pruritis, indicating a cholestatic phase, may appear transiently
for few days.
• Phase IV (convalescent phase): Symptoms and icterus resolve
and liver enzymes return to normal.
Dr Shivaraj

Diagnosis
1. Demonstration of Virus in feces, blood, bile:
By: Immunoelectron microscopy.
2. Virus Isolation:
3. Detection of Antibody :By ELISA
4. Biochemical tests:
i) Alanine aminotransferase (ALT)
ii) Bilirubin
iii) Protein
5. Molecular Diagnosis : RT PCR of feces
Dr Shivaraj

Biochemical changes
• Total serum bilirubin levels range widely. Deep jaundice
generally implies a prolonged clinical course.
• An increase in conjugated bilirubin is early, even when the
total bilirubin level is still normal.
• Serum alkaline phosphatase level is usually less than three
times the upper limit of normal and indicates a cholestatic
hepatitis.
• Serum albumin and globulin are quantitatively unchanged.
• The serum iron and ferritin levels are raised.
Dr Shivaraj

Typical biochemical changes in acute
hepatitis:-
Dr Shivaraj

• Serum transaminase estimations are useful in early
diagnosis, in detecting the anicteric case and for detection of
inapparent cases in epidemics.
• The peak level is found 1 or 2 days before or after onset of
jaundice.
• Later in the course the level falls, even if the clinical condition
is worsening. The estimation cannot be used prognostically.
• Haematological changes- leucopenia, atypical lymphocytes,
raised ESR (inc in preicteric phase and falls in icteric phase),
rarely aplastic anemia.
Dr Shivaraj

Prevention:-
-hygienic measures and sanitation.
Passive immunization –
• Human Immunoglobulin given before exposure to virus or
early during the incubation period, will prevent or attenuate a
clinical illness.
• It must be given within 2 weeks following exposure (0.02
ml/kg IM).
• In this situation it is 80-90 % effective.
Dr Shivaraj

Groups for which the hepatitis A vaccine is
recommended
• Children in endemic areas or areas with high risk of
infection
• Travellers to or those working in endemic areas
• Occupational exposure
• Men who have sex with men
• Intravenous drug users
• Patients with clotting factor disorders
• Military
• Missionaries.
• Chronic liver disease (HCV)
• ? Immunosuppressed individuals
Dr Shivaraj

History
• In 1978 there was a vast epidemic of icteric viral hepatitis in
the Kashmir Valley involving 52000 cases with 1650 fulminant
forms and 1560 deaths.
• Serology for hepatitis A and B in these patients was negative.
• In 1983 Balayan demonstrated that this virus, at difference of
non-A non-B virus, is transmitted by fecal-oral route.
• He himself ingested fecal suspensions from affected patients
and contracted the disease
Dr Shivaraj

Hepatitis E virus
 HEV is spherical nonenveloped virus, 29-nm to 32 nm in
diameter, with a ssRNA genome.
 The Virus is very labile.
 It has been classified in the genus Hepevirus under the
family Hepeviridae.
Incubation Period
2-9 weeks
Animal Reservoir: Pigs
Dr Shivaraj

Signs and Symptoms
 After a short prodromal phase symptoms lasting from days to
weeks follow. They may include jaundice, fatigue and nausea.
 Viral RNA becomes detectable in stool and blood serum during
incubation period.
 Serum IgM and IgG antibodies against HEV appear just before
onset of clinical symptoms.
 Recovery leads to virus clearance from the blood, while the virus
may persist in stool for much longer.
 Recovery is also marked by disappearance of IgM antibodies and
increase of levels of IgG antibodies.
Dr Shivaraj

Symptoms
ALT IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Hepatitis E Virus Infection
Typical Serologic Course
Titer
Weeks after ExposureDr Shivaraj

Diagnosis
ELISA kits are available for IgG and IgM
antibodies, using recombinant and synthetic
peptide antigens.
Prevention
Sanitation:
Avoid drinking water of unknown purity, uncooked
shellfish, and uncooked fruit/vegetables.
Dr Shivaraj

Hepatitis E and Pregnancy
• In men and non pregnant women, the disease is usually self-
limited and has a case-fatality rate of less than <0.1%.
• However in pregnant women particularly from certain
geographic areas in India, HEV infection is more severe, often
leading to fulminant hepatic failure and death.
• In contrast, reports from Egypt, Europe and the USA have
shown no difference in mortality in pregnant and non-
pregnant women.
• The high mortality rate in pregnancy -hormonal (estrogen and
progesterone) changes during pregnancy and consequent
immunological changes. Dr Shivaraj

HEV genotypes and severity
• Characterization of HEV genomes from geographically distinct locations
has identified at least four major genotypes (that may differ up to 20% at
the nucleotide level)
• Genotype 1 includes isolates from Asia, the Middle East, and North Africa.
• Genotype 2 has been found in Mexico and Nigeria.
• Genotype 3 was recovered from humans in North and South America,
Europe, Japan and China.
• Genotype 4 was found in humans and swine in Asia.
• Accumulating evidence suggests that genotypes 3 and 4 are less
pathogenic in humans, while genotype 1 isolated has been shown to be
more pathogenic.
• This explains the high severity of infection in India where genotype 1 is
the commonest subtype in comparison to US, where genotype 3 is the
commonest type seen.
Dr Shivaraj

Management of hepatitis E in pregnancy
• The mechanism of liver injury in hepatitis E is not clear and all
the hypotheses put forth has not been yet conclusively proved.
• All the studies have shown that pregnant women have the
differential immune response which triggers fulminant liver
failure.
• So the logical treatment should be to deliver the fetus as soon
as possible.
• Unfortunately, very few such studies have been undertaken in
this field.
Dr Shivaraj

• In a retrospective study from India, Banait et al, studied 42
patients with HEV induced liver failure, there was no
difference in maternal mortality in pregnant women who
delivered and those who did not questioning the role of
therapeutic termination.
• The literature at present is not supportive of the fact that
delivery of the baby may decrease the maternal mortality.
• However this was a small retrospective study and must not
discourage physicians from pursuing that option considering
that HEV infection produces immunological changes in the
fetus too.
Dr Shivaraj

WHO data
About 2 billion people are infected with HBV infection worldwide
Around 400 million persons are living with chronic HBV infection
There are 4 million people with HBV infection in the USA
58% of HIV infected patients have co infection with HBV (AntiHBc
total)
From 5 to 20% of Asian population is infected with HBV
HBV Prevalence and Incidence
Dr Shivaraj

WHO data
HBV associated morbidity and mortality
Around 1 000 000 patients die due to end stage liver disease caused
by HBV annually
About 550 000 persons die due to liver cancer caused by chronic
HBV infection annually
This accounts 2800 deaths everyday
This is 1-2 deaths every minute
Annually tens of thousand persons with chronic HBV infection
undergo liver transplantationDr Shivaraj

Indian scenario
• India has “intermediate to high endemicity” for Hepatitis B
surface antigen and an estimated 40 million chronic HBV
infected people, constituting approximately 11% of the
estimated global burden.
• Population prevalence of chronic HBV infection in India is around
3-4 %.
• There is a wide variation in HBsAg prevalence in different
geographical regions in India with highest prevalence recorded
in natives of Andaman and Arunachal Pradesh.
Dr Shivaraj

• In one meta-analysis, the point prevalence of hepatitis B in
non-tribal populations was found to be 2.1 per cent (95% CI
1.8 to 2.5) and this corresponded to a chronic HBV infection
HBV infection rate of 1.7 per cent.
• Chronic HBV infection account for 40-50% of HCC and 10-20%
cases of cirrhosis in India.
• Outbreaks of acute and fulminant hepatitis B still occur
mainly due to inadequately sterilized needles and syringes, as
demonstrated by the recent outbreak of acute hepatitis B in
Modasa town of Gujarat.
Dr Shivaraj

Prevalence of Hepatitis B carriers
. Worldwide prevalence of hepatitis B carriers and primary hepatocellular carcinoma. (Courtesy
Centers for Disease Control and Prevention, Atlanta.)
Dr Shivaraj

Properties of HBV
• A member of the hepadnavirus group.
• Circular partially double-stranded DNA viruses.
• Replication involves a reverse transcriptase.
• Endemic in the human population in many parts of
the world.
Dr Shivaraj

Genotype Geographical distribution
A Africa, India, North Europe, USA.
B Asia, USA
C Asia, USA
D
India, Near East, South Europe, USA.
E West and South Africa.
F Central and South Africa.
G Europe, USA.
H Central and South America. Califrnia, USA.
HBV Genotypes
Dr Shivaraj

Clinical Importance of HBV genotypes
A Interferon therapy is effective
B
Slow progression of disease.
Low incidence of hepatocelular carcinoma.
Interferon therapy is effective
C
Rapid progression of disease.
High incidence of hepatocelular carcinoma.
Low response to Interferon therapy
D Low response to Interferon therapy
Dr Shivaraj

Structure of hepatitis b virus
Dr Shivaraj

HBV Structure & Antigens
Dr Shivaraj
Dane particle
HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown

Hbv – serology interpretation
• Acute infection
– HBsAg positive and anti-HBcAg
IGM
– Rarely, IgM anti-HBc only marker
• Usually seen in acute fulminate
Hep B
• Chronic infection
– HBsAg positive and IgG anti-
HBcAg
• Previous Infection
– HBsAg negative
– anti-HBs positive
– IgG anti-HBc positive
Dr Shivaraj

Clinical outcomes of Hepatitis B infections
Dr Shivaraj

Screening – Who?
• Who should be screened
– Persons born in hyper endemic areas
– Men who have sex with men
– Injection drug users
– Patients on dialysis
– HIV infected patients
– Pregnant women
– Family and household contacts and sexual contacts of
HBV-infected persons.
• Testing should be performed by obtaining an HBsAg and
anti-HBs.
Dr Shivaraj

HEPATITIS B MARKERS:
• HBsAg: Present in acute or chronic infection.
• HBsAb: Present in recovery or immunization.
• Anti -HB Core: May be “Total” (IgG&IgM) or IgM.
Lifelong marker of past and active infection in
either acute or chronic.
• HBeAg: Acute infection, and extremely infectious.
• Anti-Hbe: Usually prognostic for resolution.
Dr Shivaraj

0
10
20
30
40
50
60
1 2 3 4 5 6 7 8 9 10
Months after exposure
Titer
Anti-HBsAb
Anti-HBeAb
Anti-HBcAb
HBeAg
HBsAg
Elevated ALT
JaundiceIncubation Recovery IMMUNE
“Window”
HEPATITIS B
Serologic Markers During Acute HBV Hepatitis and Recovery
Dr Shivaraj

Phases of Chronic HBV Infection
Dr Shivaraj

Phase Immune
Tolerant
Immune
Clearance
Inactive Carrier
State
Reactivation
Liver
Minimal
inflammation and
fibrosis
Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Active
inflammation
Optimal treatment times
Anti-HBe
HBV DNA
ALT activity
Current Understanding of HBV Infection
Phases of Chronic HBV Infection
HBeAg
Dr Shivaraj

CLINICAL FEATURES
• They vary from asymptomatic infection to end stage fatal hepatic
failure.
• Fatigue is most common symptom.
• Persistent or intermitent jaundice is a feature of advanced disease.
• Acute exacerbations when superimposed on cirrhosis leads to
decompensation.
• Extra hepatic manifestations include arthritis, arthralgias, immune
complex GN, generalized vasculitis (PAN).
Dr Shivaraj

LABORATORY FEATURES
• Aminotransferase elevations tend to be modest for chronic
hepatitis B but may fluctuate in the range of 100–1000 units.
• Alanine aminotransferase (ALT) tends to be more elevated
than aspartate aminotransferase (AST); however, once
cirrhosis is established, AST tends to exceed ALT.
• Alkaline phosphatase activity tend to be normal or only
marginally elevated.
• In severe cases, moderate elevations in serum bilirubin (3–10
mg/dL)] occur.
Dr Shivaraj

What Is an Elevated ALT Level ?
• Reference ranges for ALT laboratories-
– Men: 4-60 IU/L; women: 6-40 IU/L
• Both AASLD and US treatment algorithms recommend lower
ULN levels for ALT when making treatment-initiation decisions.
– 30 IU/L for men
– 19 IU/L for women
Dr Shivaraj

AST to Platelet Ratio Index (APRI)
• Poor man’s biopsy
• Calculation =
Patient’s AST/ULN AST (40) x 100
Platelet counts (109/L)
• Interpretation :-
< 0.5 rule out significant fibrosis (Metavir F0-F1)
> 1.5 rules in significant fibrosis (Metavir F2-F4)
> 2.0 probable cirrhosis (Metavir F4)
• Repeat yearly, track APRI trend
Dr Shivaraj

HISTOPATHOLOGY
• Histologic features in chronic hepatitis are increase in size of
hepatocytes and ground glass appearance.
• Abundant ground glass appearance indicates active viral
replications.
• Immunofluorescence and electron microscopy shows HBcAg
inside hepaocyte nuclei of affected cell.
Dr Shivaraj

TREATMENT OF HEPATITIS B
Dr Shivaraj

Indications for treatment- ASSLD
Treatment strongly recommended
• Acute liver failure
• Decompensated cirrhosis and detectable serum HBV DNA
• Compensated cirrhosis and serum HBV DNA > 2000 IU/mL
• Severe exacerbations of chronic hepatitis B
Treatment should be considered
• HBeAg - positive chronic hepatitis, ALT persistently > 2 × ULN and
HBV DNA > 20 000 IU/mL
• HBeAg - negative chronic hepatitis, ALT persistently > 2 × ULN and
HBV DNA > 20 000 IU/mL
Treatment should be individualized
• HBeAg - positive, ALT 1 – 2 × ULN or age > 40
• HBeAg - negative, ALT 1 – 2 × ULN and/or HBV DNA 2000 – 20 000
IU/mL
Dr Shivaraj

Indications for treatment- WHO
• As a priority, all adults, adolescents and children with CHB and
clinical evidence of compensated or decompensated cirrhosis (or
cirrhosis based on APRI score >2 in adults) should be treated,
regardless of ALT levels, HBeAg status or HBV DNA levels.
• Treatment is recommended for adults with CHB who do not have
clinical evidence of cirrhosis (or based on APRI score ≤2 in adults),
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/mL), regardless of HBeAg status.
• Where HBV DNA testing is not available: consider treatment based
on abnormal ALT levels alone, regardless of HBeAg status.
Dr Shivaraj

Treatment not indicated-
• Antiviral therapy is not recommended and can be deferred in
persons –
 Without clinical evidence of cirrhosis (or based on APRI score
≤2 in adults),
 With persistently normal ALT levels,
 Low levels of HBV DNA 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.
Dr Shivaraj

Continued monitoring is necessary :
• Persons without cirrhosis aged 30 years or less
with
 HBV DNA levels >20 000 IU/mL but
 Persistently normal ALT levels;
• HBeAg-negative persons without cirrhosis aged 30 years or
less,
with
 HBV DNA levels between 2000 and 20 000 IU/mL,
 Intermittently abnormal ALT levels;
Dr Shivaraj

INTERFERON -α
• IFN- α was the first approved therapy for chronic hepatitis B.
• It is no longer used to treat hepatitis B.
• For immunocompetent adults with HBeAg-reactive chronic hepatitis
B, a 16-week course of IFN given subcutaneously at a daily dose of
5 million units, or three times a week at a dose of 10 million units is
used.
• Complications of IFN therapy include systemic "flu-like" symptoms;
marrow suppression; emotional lability , autoimmune reactions
(especially autoimmune thyroiditis); alopecia, rashes, diarrhea, and
numbness and tingling of the extremities.
Dr Shivaraj

Pegylated Interferon
• PEG IFN alpha- 2a ,is administered SC
180 µg weekly for 48 weeks.
• PEG IFN alpha-2b-
0.5 or 1.0 μg per kg per week
Dr Shivaraj

When to Consider Peg-IFN ?
• Favorable predictors of
response-
In HBeAg+ve CHB
– Low HBV DNA
– High ALT
– Genotype A or B > C or D
– Not advanced disease.
 Specific patient demographics
– Generally young people
– Young women wanting
pregnancy in near future
– Absence of comorbidities
 Patient preference
 Concomitant HCV infection
Dr Shivaraj

Nucleos(t)ide Analogs
• Lamivudine (100mg)
• Adefovir (10mg)
• Entecavir (0.5mg),(1mg)
• Telbivudine (600mg)
• Tenofovir (300mg)/(245mg)
Dr Shivaraj

Nucleos(t)ide Analogs
Dr Shivaraj

DEFINITION OF ANTIVIRAL RESPONSE
• Responses can be divided into biochemical, serological,
virological and histological.
• Biochemical response is defined as normalisation of ALT
levels.
• Serological response for HBeAg applies only to patients with
HBeAg-positive CHB and is defined as HBeAg loss and
seroconversion to anti-HBe.
• Serological response for HBsAg applies to all CHB patients and
is defined as HBsAg loss and development of anti-HBs.
Dr Shivaraj

Virological responses on IFN/PEG-IFN therapy:
• Primary non-response has not been well established.
• Virological response is defined as an HBV DNA concentration of
less than 2000 IU/ml.
• It is usually evaluated at 6 months and at the end of therapy as
well as at 6 and12 months after the end of therapy.
• Sustained off-treatment virological response is defined as HBV
DNA levels below 2000 IU/ml for at least 12 months after the
end of therapy
Dr Shivaraj

EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283.
Lok AS, et al. Hepatology. 2009;50:661-662.
Treatment of hepatitis B in
special situations :-
Dr Shivaraj

TREATMENT IN HIV CO-INFECTED PATIENTS
• In HBV/HIV-coinfected individuals :- (WHO)
 ART should be initiated in all those with evidence of severe
chronic liver disease, regardless of CD4 count;
 and in all those with a CD4 count ≤500 cells/mm3, regardless of
stage of liver disease
• In agreement with recent HIV guidelines, it is recommended that
most co-infected patients should be simultaneously treated for
both HIV and HBV de novo
Dr Shivaraj

TREATMENT IN HDV CO-INFECTION
• Chronic infection after acute HBV-HDV hepatitis is less common,
while chronic delta hepatitis develops in 70–90% of patients with
HDV superinfection.
• Active co-infection with HDV is confirmed by detectable HDV
RNA, immuno-histochemical staining , IgM anti-HDV.
• (PEG-)IFN is the only drug effective against HDV.
• The efficacy of (PEG-)IFN therapy can be assessed by measuring
HDV RNA levels.
• More than 1 year of therapy may be necessary, as there may be
some benefit from treatment prolongation.
Dr Shivaraj

TREATMENT IN HCV CO-INFECTION
• In HBV-infected patients, HCV co-infection accelerates
liver disease progression and increases the risk of HCC.
• HBV and HCV replicate in the same hepatocyte without
interference.
• However, HBV DNA level is often low or undetectable
and HCV is responsible for the activity of chronic
hepatitis in most patients.
• Thus, patients should usually receive treatment for HCV.
Dr Shivaraj

Treatment in Pregnant Women
Dr Shivaraj

Pre-emptive therapy before immunosuppressive
therapy or chemotherapy
HBsAg Anti HBc HBV DNA Treatment
Positive Positive/Negative Any levels
Pre-emptive NA during and
for 12 months after
cessation of therapy.
Negative Positive Detectable -’’-
Negative Positive Undetectable
Monitor ALT and HBV DNA
levels, initiate treatment
once HBV DNA levels are
detected.
Dr Shivaraj

Hepatitis B Vaccines-
RECOMBIVAX HB ENGERIX-B
INFANTS &CHILDREN<11 YRS 5µg(0.5ml) 10µg(0.5ml)
CHILDREN 11-19 5µg(0.5ml) 10µg(0.5ml)
ADULTS >20 10µg(1ml) 20µg(1ml)
HEMODIALYSIS&
IMMUNOCOMPROMISED
(<20 yrs)
(≥20 yrs)
5µg(0.5ml)
40µg(4ml)
10µg(0.5ml)
40µg(2ml)
Dr Shivaraj

CDC ESTIMATES ~385,000
SHARPS INJURIES ANNUALLY
AMONG HOSPITAL-BASED
HEALTHCARE PERSONNEL.
(>1,000 INJURIES/DAY)
POST EXPOSURE PROPHYLAXIS OF NEEDLE STICK
INJURY

INFECTIONS TRANSMITTED
• The major blood-borne pathogens of concern associated with needle
stick injury are:
– hepatitis B virus (HBV) 6-30%
– hepatitis C virus (HCV) ≈ 2%
– human immunodeficiency virus (HIV). 0.3%
• However, other infectious agents also have the potential for
transmission through needle stick injury. These include:
– hepatitis D virus, hepatitis G virus (GB virus or GBV-C)
– cytomegalovirus (CMV)
– Epstein Barr Virus (EBV)
– West Nile Virus (WNV)
– malarial parasites

PREVENTION
• Use devices with safety features
to isolate sharps.
• Safe recapping system.
• Do not recap needles or
scalpels & dispose them
through effective disposal
system.
• Plan for safe handling and
disposal of sharps before
using them.

EXAMPLES OF SAFER NEEDLE
DEVICES
• Self-sheathing
system
• Retractable
technology.
• Add on safety
features

MANAGEMENT
• Report the incident immediately.
• Wash the area immediately under running water.
• Make the wound bleed for three to four minutes while continuing
to wash the area. Dry area with paper towel.
• Cover the wound with a water-impermeable sticking plaster and
consider double gloving any hand injury if continuing to work.
• The source patient should be identified and arrangements made
for a blood sample to be obtained, with informed consent. This
should be tested for the presence of the blood borne viruses
hepatitis B, hepatitis C and HIV.

MANAGEMENT (continue….)
• Arrangements should be made for blood samples to be taken from
the staff member (victim) with informed consent.
• The sample is analyzed to determine the hepatitis B antibody level.
• Further assessment, treatment and follow up of the victim
• Counseling, reassurance and information may be required and
arrangements for accessing this should be in place as appropriate.
• Appropriate records must be kept.

POST EXPOSURE PROPHYLAXIS OF HEPATITIS B
Dr Shivaraj

Efficacy of HBV PEP
Dr. Shivaraj SA
Regimen
1) Multiple doses of
HBIG alone when
1st dose initiated
within 1 week
2) Hepatitis B vaccine
series alone
3) Combination of HBIG
and vaccine series
Prevention of HBV
Infection
70-75%
70-75%
85-95%

Learning Points-
• Patients with chronic HBV infection are at risk of developing cirrhosis,
liver failure and hepatocellular carcinoma especially when there is
persistent presence of HBeAg or persistently high serum HBV DNA
levels.
• There are seven approved therapies for chronic hepatitis B: two
formulations of interferon and five orally administered nucleos(t)ide
analogues, lamivudine, adefovir dipivoxil, entecavir, telbivudine and
tenofovir disoproxil fumarate.
• Antiviral treatment suppresses but does not eradicate HBV; in the
absence of HBsAg loss most patients require long - term treatment.
Long - term treatment of nucleos(t)ide analogues is associated with
risks of antiviral drug resistance.
Dr Shivaraj

HCV
• Genus Hepacivirus.
• Family Flaviviridae,
• 6 genotypes worldwide (~ 35% difference at RNA sequence
level)
• > 100 subtypes (20-25% sequence difference) & isolates
based on nucleotide diversity.
• Quasispecies within individual
Dr Shivaraj

HCV Infection: Epidemiology
• Prevalence of anti-HCV among blood
donors-
– UK 0.01%
– USA 0.3%
– Japan 2.2%
– India 0.2%-0.85%
Dr Shivaraj

Burden of HCV infection
 Worldwide 180 million
 USA 1.6% 4.1 million
 UK 1% 0.2 million
 India ~1% ~12 million
 Major cause of death
 Leading indication for Liver transplantation.
Dr Shivaraj

Prevalence of HCV in India
Dr Shivaraj

Transmission sources
Dr Shivaraj

Clinical Features
ACUTE
Malaise
Muscle and joint pain
Fever
Loss of appetite
CHRONIC
Malaise, tiredness
END STAGE LIVER
Malaise, tiredness, weakness
Weight loss
Peripheral oedema
Ascites
Hematemesis
Dr Shivaraj

Diagnosis of Hepatitis C
HCV antibody test
• Screening for infection
HCV RNA detection test
• Confirmation of infection
PCR
• Viral load for HCV infection
HCV genotype testing
• Determines choice of treatment
Dr Shivaraj

Liver Biopsy
• Current status of the liver injury
• Identifies features useful in the decision to
embark on therapy
• Reveal advanced fibrosis or cirrhosis that
necessitates surveillance for HCC and/or
screening for varices
Dr Shivaraj

Others laboratory tests
IL-28B genotype testing
• Predictor of response to IL therapy
Complete Blood Count
• Evaluate side effects of therapy
Liver function test
• High level of enzymes indicates ongoing damage
Ultrasound scan
• Size of the liver and presence of ascites
Fibro scan
• Evaluate extent of cirrhosis in patients
Dr Shivaraj

AASLD/IDSA: When and in whom to initiate HCV therapy
• ALL pts are candidates for HCV therapy, regardless of disease stage.
• In regions where limited resources preclude treatment of all pts,
the following groups should be prioritized for therapy:
Highest Priority (based on highest risk for disease complications)
– Advanced fibrosis (F3) or compensated cirrhosis (F4)
– Organ transplant
– Type 2 or 3 essential mixed cryoglobulinemia with end-organ
manifestations
– Proteinuria, nephrotic syndrome, or membranoproliferative
glomerulonephritis
AASLD/IDSA. HCV Management. http://www.hcvguidelines.org.Dr Shivaraj

High Priority (based on high risk for disease
complications) –
– HIV-1 coinfection
– Fibrosis (Metavir F2)
– HBV coinfection
– Debilitating fatigue
• Other coexistent liver disease (eg, NASH)
• Type 2 DM (insulin resistant)
• Porphyria cutanea tarda
Dr Shivaraj

a -Treatment may be shortened to 8 weeks in treatment-naive persons without cirrhosis if their
baseline HCV RNA level is below 6 million (6.8 log) IU/mL. The duration of treatment should be
shortened with caution.
b- If platelet count <75 x 103/μL, then 24 weeks’ treatment with ribavirin should be given.
Dr Shivaraj

Genotype 1 HCV Treatment Naive
• AASLD-IDSA guidelines
– 3 regimens recommended
Ledipasvir/
Sofosbuvir*
Ombitasvir/
Paritaprevir/ Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir
Genotype 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV
Genotype 1a, cirrhosis 12 wks 24 wks + RBV 24 wks ± RBV
Genotype 1b, no cirrhosis 12 wks 12 wks 12 wks
Genotype 1b, cirrhosis 12 wks 12 wks + RBV 24 wks
http://www.hcvguidelines.org
*Ledipasvir/sofosbuvir for 8 wks can be considered in naive, noncirrhotic pts with baseline HCV RNA < 6
million IU/mL.
Dr Shivaraj

Genotype 1 HCV PegIFN/RBV Treatment
Experienced
– 3 regimens recommended
Ledipasvir/
Sofosbuvir
Ombitasvir/
Paritaprevir/
Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir
Genotype 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV
Genotype 1a, cirrhosis 24 wks
12 wks + RBV
24 wks + RBV 24 wks ± RBV
Genotype 1b, no cirrhosis 12 wks 12 wks 12 wks ± RBV
Genotype 1b, cirrhosis 24 wks
12 wks + RBV
12 wks + RBV 24 wks ± RBV
http://www.hcvguidelines.org Dr Shivaraj

Genotype 1 HCV Previous PI Failure
– 1 regimen recommended
Ledipasvir/
Sofosbuvir
Ombitasvir/
Paritaprevir/
Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir ±
Ribavirin
Genotype 1a, no cirrhosis 12 wks None None
Genotype 1a, cirrhosis 24 wks
12 wks + RBV
None None
Genotype 1b, no cirrhosis 12 wks None None
Genotype 1b, cirrhosis 24 wks
12 wks + RBV
None None

Genotypes 2 and 3
Genotype 2 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin
+ Sofosbuvir
Treatment naive 12 wks
(16 wks for cirrhosis)
None
PegIFN/RBV nonresponders 12-16 wks 12 wks (alternative)
http://www.hcvguidelines.org
Genotype 3 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin
+ Sofosbuvir
Treatment naive 24 wks 12 wks (alternative)
PegIFN/RBV nonresponders 24 wks 12 wks (alternative)
Dr Shivaraj

Genotype 4 HCV Treatment
Experienced
Regimen Wks AASLD/IDSA Study SVR12
Sofosbuvir + pegIFN/RBV 12 Recommended NEUTRINO[1] 27/28*
(96%)
Sofosbuvir + ribavirin 24 Recommended Ruane et al2] 13/15 (87%)
Ledipasvir/sofosbuvir 12 Recommended Multiple[3,4]
19/20†[3];
20/22[4]
(91-95%)
Ombitasvir/paritaprevir/rito
navir, ribavirin
12 Recommended PEARL-I[5] 49/49
(100%)
1. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. 2. Ruane PJ, et al. J Hepatol. 2015;62:1040-1046.
3. Kapoor R, et al. AASLD 2014. Abstract 240. 4. Abergel A, et al. EASL 2015. Abstract O056. 5. Hézode C,
et al. Lancet. 2015;[Epub ahead of print].
*Study included treatment-naive pts only.
†Treatment-naive and treatment-experienced pts.
Dr Shivaraj

Genotype 5/6 HCV Treatment Naive
Recommended Regimen Duration
Genotype 5
Sofosbuvir + ribavirin +
peginterferon
12 wks
Genotype 6
Ledipasvir/
sofosbuvir
12 wks
Alternative Regimen Duration
Genotype 5 Peginterferon + ribavirin 48 wks
Genotype 6
Sofosbuvir + ribavirin +
peginterferon
12 wks

Measures of response
Rapid Virological Response:
Undetectable HCV RNA 4 weeks after the start of treatment
Early Virological Response:
More than 2 log reduction in HCV RNA viral load at week 12 of treatment
Delayed Virological Response:
More than 2 log decline in HCV RNA viral load but a detectable HCV RNA level at
week 12 of treatment and undetectable HCV RNA level at week 24 of treatment
Sustained Virological Response:
Undetectable HCV RNA 3 or 6 months after the end of treatment
Dr Shivaraj

OVERALL SAFETY
• Premature discontinuation of sofosbuvir-containing
treatment because of adverse events - uncommon
– 1—11% in various studies (combination treatment)
• Cirrhotics vs noncirrhotics: similar safety profile
• Patients co-infected with HIV-1 and in patients with HCC
awaiting liver transplantation – no adverse events
reported
Dr Shivaraj

Liver Transplantation
Dr Shivaraj

Transplantation for cirrhosis
CIRRHOSIS
Complications No Complications
Ascites / SBP / HRS
Encephalopathy
Variceal Bleed MELD score > 15
TRANSPLANTATION
Bilirubin > 3, INR > 1.5
Albumin < 3
Poor Quality of Life
Recurrent Cholangitis
HPS
Child Pugh B
Dr Shivaraj

Measures to Avoid Transmission of
HCV
• Avoid sharing toothbrushes and dental or
shaving equipment, etc
• Stop using illicit drugs
• Do not donate blood, body organs, other
tissue or semen, etc
• Appropriate contraceptive measures.
Dr Shivaraj

Who Should be Screened?
 Unexplained abnormal liver enzymes
 Ever injected drugs
 Received medical or dental treatment
 Children of infected mothers
 Sexual partners of infected people
 Exposed to blood where a risk of transmission
exists
 Received tattoos, piercings, or acupuncture with
poor infection control procedures
Dr Shivaraj

viral hepatitis- facts and treatment guidelines.

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