1. 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

2. A Historical Perspective
Enterically
transmitted
“Infectious” A E
Viral hepatitis
“NANB” C
Parenterally
transmitted B D
“Serum”
other

3. 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

4. floating among hepato-
The Hepatitis C Virus
A single
HCV
floating among hepato-
cytes

5. 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.

6. 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

7. Prevalence of Hepatitis C 2003
>10% %
1-2.4%
0-0.9%

8. 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%
Chronic hepatitis 10%-70% (most asx)
Cirrhosis <5%-20%
Mortality from CLD 1%-5%
Age-
related

9. Chronic Hepatitis C Factors Promoting Progression or Severity
Increased alcohol intake
Age 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

10. Serologic Pattern of Acute HCV Infection with Recovery
anti-HCV
Symptoms +/-
HCV RNA
Titer
ALT
Normal 1 2 3 4 5 6 1 2 3 4
Months
Years
Time after Exposure

11. Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection
anti-HCV
Symptoms +/-
HCV RNA
Titer
ALT
Normal 1 2 3 4 5 6 1 2 3 4
Months
Years
Time after Exposure

12. 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

13. Pakistan GDP per capita (Intl $, 2001): 2,146
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): /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
Figures are for 2002 unless indicated. Source: The world health report 2003

14. 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)

15. Risk Factors Persons Risk of Infection Testing Recommended?
Injecting drug users
High
Yes
Recipients of clotting factors made before 1987
High
Yes
Hemodialysis patients
Intermediate
Yes
Recipients of blood and/or solid organs before 1992
Intermediate
Yes
People with undiagnosed liver problems
Intermediate
Yes

16. Only after known exposure
Risk Factors
Persons
Risk of Infection
Testing Recommended?
Infants born to infected mothers
After months old
Intermediate
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

17. Prevalence of anti-HCV amongst blood donors*
Anti-HCV Prevalence
* Anti-HCV prevalence by EIA-1 or EIA-2 with supplemental testing; based on data
available in January, 1995
>5% - High
1.1-5% - Intermediate
0.2-1% - Low
£0.1% - Very Low
Unknown 14

18. 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

19. Risk Factor: Unsafe injections
1995: Aamir Javed Khan et al.
Investigated relationship between hepatitis B and C and injections in peri-urban 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

20. Risk Factor: Tattooing
CDC found that in Pakistan, 7% of those with tattoos were positive for HCV

21. Risk Factor: Body Piercing
In Pakistan, 7% of those with body piercing tested positive for HCV (Luby et. al)

22. 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”)

23. 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

24. 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

25. 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

26. 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.

27. 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
Source: (NIH, Fried MW et al., Manns MP et al., Hadziyannis SJ et al.)

28. General Prevention Strategies
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:
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.

29. Prevention Strategies in Pakistan
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

30. Future Research
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

31. Future Research
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