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Hepatitis C in Pakistan
Rashid A. Chotani
Assistant Professor & Director,
The Global Infectious Disease Surveillance & Alert System
The Johns Hopkins Bloomberg School of Public Health
A Historical Perspective
“Infectious”
Viral
hepatitis
“Serum”
A
“NANB”
E
Enterically
transmitted
C
Parenterally
transmitted
B D
other
The Hepatitis C Virus





Spherical, enveloped, single-stranded RNA
virus
Family Flaviviridae
HCV may produce ~ 1 trillion new viral
particles each day
RNA polymerase lacks proofreading
capabilities
Encodes a single polyprotein of 3011 amino
acids that is processed into 10 structural
and regulatory proteins
The Hepatitis C Virus
A single
HCV
floating
among
hepatocytes
Hepatitis C: Basic Facts
 Hepatitis
C is a global health problem
affecting over 170 million people worldwide.
 There is wide geographic variation in both
prevalence and genotype distribution of
hepatitis C virus on a global level.
 Transmitted:
 Body fluids
 Parenterally
 Hepatitis
C is a leading cause of end-stage
liver disease and hepatocellular carcinoma.
 Despite a declining incidence of new
infections, the burden of disease, both in
terms of mortality and in terms of cost, is
expected to increase over the next decade.
Prevalence of HCV Worldwide

The prevalence is increasing worldwide
 WHO estimates ~ 200 million infected, 3.3% of the
world’s population
 Infection due to HCV accounts for (worldwide):
 20% of cases of acute hepatitis
 70% of cases of chronic hepatitis
 40% of cases of end-stage cirrhosis
 60% of cases of hepatocellular carcinoma
 30% of liver transplants.
 170 million hepatitis C virus (HCV) carriers
present worldwide
 3 to 4 million new cases per year
Prevalence of Hepatitis C 2003
>10%
2.5-9.9%
1-2.4%
0-0.9%
Features of Hepatitis C
Virus Infection
Incubation period
Average 6-7 weeks
Range 2-26 weeks
Acute illness (jaundice)
Mild (≤20%)
Case fatality rate
Low
Chronic infection
60%-85%
AgeChronic hepatitis
related 10%-70% (most asx)
Cirrhosis
<5%-20%
Mortality from CLD
1%-5%
Chronic Hepatitis C Factors
Promoting Progression or Severity
 Increased
alcohol intake
 Age 30-49 years at time of infection
 Those
infected at a younger age have
much better prognosis
 HIV
co-infection
 Other
 Male
gender
 Chronic HBV co-infection
Serologic Pattern of Acute HCV
Infection with Recovery
antiHCV
Symptoms
+/-
Titer
HCV RNA
ALT
Normal
0
1
2
3 4
Months
5
6
1
Time after Exposure
2 3
Years
4
Serologic Pattern of Acute HCV
Infection with Progression to
Chronic Infection
antiHCV
Symptoms
+/-
Titer
HCV RNA
ALT
Normal
0
1
2
3 4 5 6 1 2 3
Years
Months
Time after Exposure
4
Sources of Infection for
Persons with Hepatitis C
Sexual 15%
Injecting
drug use
60%
Transfusion 10%
(before screening)
Other* 5%
Unknown 10%
* Hemodialysis; health-care work; perinatal
Source: Centers for Disease Control and Prevention
Pakistan
 Total population: 149,911,000
 GDP per capita (Intl $, 2001): 2,146
 Life expectancy at birth M/F (years):
61.1/61.6
 Healthy life expectancy at birth M/F (years):
54.2/52.3
 Child mortality M/F (per 1,000): 105/115
 Adult mortality M/F (per 1,000): 227/201
 Total health expenditure per capita (Intl $,
2001): 85
 Total health expenditure as % of GDP
(2001): 3.9
Burden of diseases in Pakistan
Studies in Pakistan have found HCV:

60% among liver cancer patients
(Ahmed et al., 1995)



51% among beta thalassemia major
patients (Ahmed et al., 1995)
46% among chronic liver disease
patients (Mujeeb et al., 1998)
18% among cirrhotic patients (Mujeeb et
al., 1998)

20% among commercial blood
donors (Mujeeb et al., 1998)
Risk Factors
Persons
Risk of
Infection
Testing
Recommended?
Injecting drug users
High
Yes
Recipients of clotting
factors made before 1987
High
Yes
Intermediate
Yes
Recipients of blood and/or Intermediate
solid organs before 1992
Yes
People with undiagnosed Intermediate
liver problems
Yes
Hemodialysis patients
Risk Factors
Persons
Infants born to infected
mothers
Risk of
Infection
Intermediate
Testing
Recommended?
After 12-18
months old
Healthcare/public safety
workers
Low
Only after
known exposure
People having sex with
mutiple partners
Low
No
People having sex with a
steady partner
Low
No
Prevalence of anti-HCV
amongst blood donors*
Anti-HCV
Prevalence
>5% - High
1.1-5% - Intermediate
0.2-1% - Low
0.1% - Very Low
Unknown
Risk Factor:
Unsafe injections
1993: Luby et al.
6.5% antibodies positive for HCV in
Hafizabad, Pakistan
Shows an increased prevalence in
Pakistan compared to world
1994: Luby et al.
Follow up case control study to identify
risk factors
Positive individuals were 8.2 times more
likely to receive > 5 injection per year
Risk Factor:
Unsafe injections
1995: Aamir Javed Khan et al.
Investigated relationship between
hepatitis B and C and injections in periurban Karachi
44% hepatitis C positive
Those who received more injections
were more likely to be hepatitis C
infected
94% of the needles/syringes were reused
Risk Factor:
Tattooing

CDC found that in Pakistan, 7% of
those with tattoos were positive
for HCV
Risk Factor:
Body Piercing

In Pakistan, 7% of those with body
piercing tested positive for HCV
(Luby et. al)
Tests for HCV: Virological markers
Detection of HCV antibodies
Enzyme immunoassays (EIA)
Enzyme-linked immunosorbent assays (ELISA)
Detect a mixture of antibodies directed against
various viral epitopes
HCV genotype determination
Phylogenetic analysis can distinguish HCV
types, subtypes and isolates on the basis of
average sequence divergence rates
Sequence-based assay
testing for type-specific antibodies with a
competitive EIA (so-called “serotyping”)
Tests for HCV: Virological markers
 Assessment of HCV replication
The presence of HCV RNA in
peripheral blood is a reliable
marker of active HCV replication
HCV RNA is detectable within one
to two weeks after infection
HCV RNA levels are stable over
time in patients with chronic
infection (Nguyen TT, et al.)
The HCV RNA level may increase
slightly after several years of
chronic infection.
HCV RNA can be detected and/or
quantified in serum or plasma by
means of various categories of
amplification techniques
HCV Spot Test
Diagnosis of HCV Infections
Acute hepatitis C
Should be tested for anti-HCV by means of EIA
Detection of HCV RNA without anti-HCV is
strongly indicative of acute hepatitis C
Acute hepatitis C is unlikely if both markers
are absent.
Chronic hepatitis C
Certain in a patient with chronic liver disease
when both anti-HCV and HCV RNA are detected
High optical density ratio in EIA: true-positive
result,
Low optical density ratio in EIA: no conclusion
can be drawn because anti-HCV antibody titers
may fall gradually after spontaneous clearance
of the virus
Diagnosis of HCV Infections
Mother-to-infant transmission
Should be based on HCV RNA detection
with a sensitive technique rather than on
anti-HCV detection
Antibodies are passively transferred in
utero and remain detectable for several
months to more than a year after delivery,
regardless of whether viral transmission
occurs
Assessment of disease severity and
prognosis
Virologic tests have no prognostic value
Treatment of
Acute Hepatitis C


The optimal treatment schedule remains to be
established for acute hepatitis C, and no
recommendations can yet be made regarding the
use of virologic tests in the decision to treat
(Hoofnagle JH)
Virologic response assessed at the end of therapy
by means of a sensitive HCV RNA technique
 If HCV RNA is negative, the sustained or transient
nature of the response is assessed 24 weeks later
 Negative HCV RNA detection at this second test
indicates that therapy has been successful.
Treatment of
Chronic Hepatitis C

Based on a combination of:
 pegylated interferon (IFN) alfa,
 either pegylated IFN alfa-2a
or pegylated IFNalfa-2b
 and ribavirin
General Prevention Strategies

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Communication of information about HCV to
health care and public health professionals
Education of the public and persons at risk for
infection
Integration of prevention and control activities into
public health programs to:

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Identify, counsel, and test persons at risk for HCV
infection
Provide referral for medical evaluation of those found to
be infected
Conduct outreach and community-based activities to
address practices that put people at risk for HCV
infection
Surveillance to monitor acute and chronic disease
trends and evaluate the effectiveness of strategies
Epidemiologic and laboratory investigations to
better guide prevention efforts.
Prevention Strategies
in Pakistan
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Methadone treatment programs
Needle and syringe exchange programs
Comprehensive risk-modifying educational
programs
Ensuring access to sterile syringes through
physician prescription and pharmacy sales of
syringes to IDUs
IDUs should be educated about:



the importance of hand washing before and after
giving injections
not using the others' injection equipment
avoiding any contact with blood from other persons
Future Research

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Development of reliable, reproducible, and
efficient culture systems for propagating HCV
Role of genetic factors in the pathogenesis of
HCV
Development of less-toxic therapies and
molecular-based agents that specifically inhibit
viral replication and/or translation of viral RNA.
Directed investigation examining the
development and progression of hepatic fibrosis
Establishment of Hepatitis Clinical Research
Network to conduct of research related to the
natural history, prevention, and treatment of
hepatitis C.
Examine the pattern of HCV disease progression
in persons infected for at least two decades,
including those infected as infants and as
children
Future Research

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Analysis of effectiveness of infection-control
strategies
Better understanding of factors that might
predict transmission
Understanding side effect management and
increasing patient adherence to therapy.
Analysis of effect of health insurance
Clearly establish the role of liver biopsy in the
therapeutic management of patients with
chronic hepatitis C.
International standardization of viral RNA titers
Role of fatty liver, obesity, diabetes, and
hepatic iron stores in the natural history of
hepatitis C and responses to therapy.
Better understand HIV co-infected patients