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 Enterically transmitted “Infectious” A E Viral hepatitis “NANB” C Parenterally transmitted B D “Serum” 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

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

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

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 anti-HCV Symptoms +/- HCV RNA Titer ALT Normal 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure

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

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 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): 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 Figures are for 2002 unless indicated. Source: The world health report 2003

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 Hemodialysis patients Intermediate Yes Recipients of blood and/or solid organs before 1992 Intermediate Yes People with undiagnosed liver problems Intermediate Yes

Only after known exposure Risk Factors Persons Risk of Infection Testing Recommended? Infants born to infected mothers After 12-18 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

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

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 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

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

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.

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

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

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