Hepatitis C in Hepatitis C in PakistanPakistan

Rashid A. ChotaniRashid A. ChotaniAssistant Professor & Director,Assistant Professor & Director,The Global Infectious Disease Surveillance & Alert SystemThe Global Infectious Disease Surveillance & Alert SystemThe Johns Hopkins Bloomberg School of Public HealthThe Johns Hopkins Bloomberg School of Public Health

AA““Infectious”Infectious”

““Serum”Serum”

Viral Viral hepatitishepatitis

EntericallyEntericallytransmittedtransmitted

ParenterallyParenterallytransmittedtransmitted

otherother

EE

““NANB”NANB”

BB DD

CC

A Historical A Historical PerspectivePerspective

The Hepatitis C VirusThe Hepatitis C Virus

Spherical, enveloped, single-stranded RNA vSpherical, enveloped, single-stranded RNA virusirus

Family FlaviviridaeFamily Flaviviridae HCV may produce ~ 1 trillion new viral particlHCV may produce ~ 1 trillion new viral particl

es each dayes each day RNA polymerase lacks proofreading capabiliRNA polymerase lacks proofreading capabili

tiesties Encodes a single polyprotein of 3011 amino Encodes a single polyprotein of 3011 amino

acids that is processed into 10 structural and acids that is processed into 10 structural and regulatory proteinsregulatory proteins

A single A single HCV HCV

floating amonfloating among hepato-g hepato-

cytescytes

The Hepatitis C VirusThe Hepatitis C Virus

Hepatitis C: Basic FactsHepatitis C: Basic Facts Hepatitis C is a global health problem affecting over 170 Hepatitis C is a global health problem affecting over 170

million people worldwide. million people worldwide. There is wide geographic variation in both prevalence and There is wide geographic variation in both prevalence and

genotype distribution of hepatitis C virus on a global level. genotype distribution of hepatitis C virus on a global level. Transmitted: Transmitted:

Body fluidsBody fluids Parenterally Parenterally

Hepatitis C is a leading cause of end-stage liver disease Hepatitis C is a leading cause of end-stage liver disease and hepatocellular carcinoma. and hepatocellular carcinoma.

Despite a declining incidence of new infections, the burden Despite a declining incidence of new infections, the burden of disease, both in terms of mortality and in terms of cost, of disease, both in terms of mortality and in terms of cost, is expected to increase over the next decade.is expected to increase over the next decade.

The prevalence is increasing worldwideThe prevalence is increasing worldwide WHO estimates ~ 200 million infected, 3.3% of the world’s poWHO estimates ~ 200 million infected, 3.3% of the world’s po

pulationpulation Infection due to HCV accounts for (worldwide):Infection due to HCV accounts for (worldwide):

20% of cases of acute hepatitis20% of cases of acute hepatitis 70% of cases of chronic hepatitis 70% of cases of chronic hepatitis 40% of cases of end-stage cirrhosis40% of cases of end-stage cirrhosis 60% of cases of hepatocellular carcinoma60% of cases of hepatocellular carcinoma 30% of liver transplants.30% of liver transplants.

170 million hepatitis C virus (HCV) carriers present worldwide170 million hepatitis C virus (HCV) carriers present worldwide 3 to 4 million new cases per year3 to 4 million new cases per year

Prevalence of HCV Prevalence of HCV WorldwideWorldwide

Prevalence of Hepatitis C Prevalence of Hepatitis C 20032003

>10% 2.5-9.9%

1-2.4%0-0.9%

Features of Hepatitis C Features of Hepatitis C Virus InfectionVirus Infection

Incubation periodIncubation period Average 6-7 Average 6-7 weeksweeks

Range 2-26 Range 2-26 weeksweeks

Acute illness (jaundice)Acute illness (jaundice) Mild (Mild (≤≤20%)20%)

Case fatality rateCase fatality rate LowLow

Chronic infectionChronic infection 60%-85%60%-85%

Chronic hepatitisChronic hepatitis 10%-70% 10%-70% (most (most asx)asx)

CirrhosisCirrhosis <5%-20%<5%-20%

Mortality from CLDMortality from CLD 1%-5%1%-5%

Age-related

Chronic Hepatitis C Factors Chronic Hepatitis C Factors Promoting Progression or Promoting Progression or SeveritySeverity

Increased alcohol intakeIncreased alcohol intake Age 30-49 years at time of infectionAge 30-49 years at time of infection

Those infected at a younger age have Those infected at a younger age have much better prognosismuch better prognosis

HIV co-infectionHIV co-infection OtherOther

Male genderMale gender Chronic HBV co-infectionChronic HBV co-infection

Serologic Pattern of Acute Serologic Pattern of Acute HCV Infection with RecoveryHCV Infection with Recovery

Symptoms +/-

Time after Exposure

Tit

er

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4YearsMonth

s

HCV RNA

Serologic Pattern of Acute Serologic Pattern of Acute HCV Infection with HCV Infection with Progression to Chronic Progression to Chronic InfectionInfection

Symptoms Symptoms +/-+/-

Time after ExposureTime after Exposure

Tit

er

Tit

er

anti-anti-HCVHCV

ALTALT

NormaNormall

00 11 22 33 44 55 66 11 22 33 44YearsYearsMonthMonth

ss

HCV RNA HCV RNA

Sources of Infection forSources of Infection forPersons with Hepatitis CPersons with Hepatitis C

Sexual 15%Sexual 15%

Other* 5%Other* 5%

Unknown 10%Unknown 10%

Injecting Injecting drug use drug use

60%60% Transfusion 10%Transfusion 10%(before screening)(before screening)

* Hemodialysis; health-care work; perinatal* Hemodialysis; health-care work; perinatal

Source: Centers for Disease Control and PreventionSource: Centers for Disease Control and Prevention

PakistanPakistan Total population: 149,911,000 Total population: 149,911,000 GDP per capita (Intl $, 2001): 2,146GDP per capita (Intl $, 2001): 2,146 Life expectancy at birth M/F (years): 61.1/6Life expectancy at birth M/F (years): 61.1/61.61.6 Healthy life expectancy at birth M/F (years):Healthy life expectancy at birth M/F (years): 54.2/52.3 54.2/52.3 Child mortality M/F (per 1,000): 105/115Child mortality M/F (per 1,000): 105/115 Adult mortality M/F (per 1,000): 227/201Adult mortality M/F (per 1,000): 227/201 Total health expenditure per capita (Intl $, Total health expenditure per capita (Intl $, 2001): 852001): 85 Total health expenditure as % of GDP (200Total health expenditure as % of GDP (2001): 3.91): 3.9

Burden of diseases in Burden of diseases in PakistanPakistanStudies in Pakistan have found Studies in Pakistan have found HCV:HCV:

60% among liver cancer patients 60% among liver cancer patients (Ahmed et al., 1995)(Ahmed et al., 1995)

51% among beta thalassemia major 51% among beta thalassemia major patients patients (Ahmed et al., 1995)(Ahmed et al., 1995)

46% among chronic liver disease pa46% among chronic liver disease patients tients (Mujeeb et al., 1998)(Mujeeb et al., 1998)

18% among cirrhotic patients 18% among cirrhotic patients (Mujeeb et (Mujeeb et

al., 1998)al., 1998)

20% among commercial blood dono20% among commercial blood donors rs (Mujeeb et al., 1998)(Mujeeb et al., 1998)

Risk FactorsRisk Factors

YesYesIntermediateIntermediatePeople with undiagnosed People with undiagnosed liver problemsliver problems

YesYesIntermediateIntermediateRecipients of blood and/or Recipients of blood and/or solid organs before 1992solid organs before 1992

YesYesIntermediateIntermediateHemodialysis patientsHemodialysis patients

YesYesHighHighRecipients of clotting Recipients of clotting factors made before 1987factors made before 1987

YesYesHighHighInjecting drug usersInjecting drug users

Testing Testing Recommended?Recommended?

Risk of Risk of InfectionInfection

PersonsPersons

Risk FactorsRisk Factors

NoNoLowLowPeople having sex with a People having sex with a steady partnersteady partner

NoNoLowLowPeople having sex with People having sex with mutiple partnersmutiple partners

Only after Only after known exposureknown exposure

LowLowHealthcare/public safety Healthcare/public safety workersworkers

After 12-18 After 12-18 months oldmonths old

IntermediateIntermediateInfants born to infected Infants born to infected mothersmothers

Testing Testing Recommended?Recommended?

Risk of Risk of InfectionInfection

PersonsPersons

1.1-5% - Intermediate

Anti-HCV Prevalence

>5% - High

0.2-1% - Low0.1% - Very Low

Unknown

Prevalence of anti-HCV amongst blood donors*

Risk Factor: Risk Factor: Unsafe injectionsUnsafe injections

1993: Luby et al.1993: Luby et al. 6.5% antibodies positive for HCV in Hafizaba6.5% antibodies positive for HCV in Hafizaba

d, Pakistand, Pakistan Shows an increased prevalence in Pakistan cShows an increased prevalence in Pakistan c

ompared to worldompared to world 1994: Luby et al.1994: Luby et al.

Follow up case control study to identify risk fFollow up case control study to identify risk factorsactors

Positive individuals were 8.2 times more likelPositive individuals were 8.2 times more likely to receive > 5 injection per yeary to receive > 5 injection per year

Risk Factor: Risk Factor: Unsafe injectionsUnsafe injections

1995: Aamir Javed Khan et al.1995: Aamir Javed Khan et al. Investigated relationship between hepatitInvestigated relationship between hepatit

is B and C and injections in peri-urban Kis B and C and injections in peri-urban Karachiarachi

44% hepatitis C positive44% hepatitis C positive Those who received more injections were Those who received more injections were

more likely to be hepatitis C infected more likely to be hepatitis C infected 94% of the needles/syringes were reused94% of the needles/syringes were reused

Risk Factor: Risk Factor: TattooingTattooing

CDC found that in Pakistan, 7% of CDC found that in Pakistan, 7% of those with tattoos were positive those with tattoos were positive for HCVfor HCV

Risk Factor: Risk Factor: Body PiercingBody Piercing

In Pakistan, 7% of those with body In Pakistan, 7% of those with body piercing tested positive for HCV piercing tested positive for HCV (Luby et. al)(Luby et. al)

Tests for HCV: Tests for HCV: VVirological markersirological markers Detection of HCV antibodiesDetection of HCV antibodies

Enzyme immunoassays (EIA)Enzyme immunoassays (EIA) Enzyme-linked immunosorbent assays (ELISA)Enzyme-linked immunosorbent assays (ELISA) Detect a mixture of antibodies directed against various Detect a mixture of antibodies directed against various

viral epitopes viral epitopes HCV genotype determinationHCV genotype determination

Phylogenetic analysis can distinguish HCV types, subtPhylogenetic analysis can distinguish HCV types, subtypes and isolates on the basis of average sequence divypes and isolates on the basis of average sequence divergence rates ergence rates

Sequence-based assaySequence-based assay testing for type-specific antibodies with a competitive testing for type-specific antibodies with a competitive

EIA (so-called “serotyping”)EIA (so-called “serotyping”)

Tests for HCV: Tests for HCV: Virological markersVirological markers Assessment of HCV replicationAssessment of HCV replication

The presence of HCV RNA in peripheral bloThe presence of HCV RNA in peripheral blood is a reliable marker of active HCV od is a reliable marker of active HCV replicationreplication

HCV RNA is detectable within one to HCV RNA is detectable within one to two weeks after infectiontwo weeks after infection

HCV RNA levels are stable over time HCV RNA levels are stable over time in patients with chronic infection in patients with chronic infection (Nguyen TT, (Nguyen TT, et al.) et al.)

The HCV RNA level may increase slightly afThe HCV RNA level may increase slightly after several years of chronic infection. ter several years of chronic infection.

HCV RNA can be detected and/or quantified HCV RNA can be detected and/or quantified in serum or plasma by means of various catin serum or plasma by means of various categories of amplification techniquesegories of amplification techniques

HCV Spot TestHCV Spot Test

Diagnosis of HCV Diagnosis of HCV InfectionsInfections

Acute hepatitis C Acute hepatitis C Should be tested for anti-HCV by means of EIA Should be tested for anti-HCV by means of EIA Detection of HCV RNA without anti-HCV is strongly Detection of HCV RNA without anti-HCV is strongly

indicative of acute hepatitis Cindicative of acute hepatitis C Acute hepatitis C is unlikely if both markers are Acute hepatitis C is unlikely if both markers are

absent. absent. Chronic hepatitis CChronic hepatitis C

Certain in a patient with chronic liver disease when Certain in a patient with chronic liver disease when both anti-HCV and HCV RNA are detected both anti-HCV and HCV RNA are detected

High optical density ratio in EIA: true-positive High optical density ratio in EIA: true-positive result,result,

Low optical density ratio in EIA: no conclusion can Low optical density ratio in EIA: no conclusion can be drawn because anti-HCV antibody titers may fall be drawn because anti-HCV antibody titers may fall gradually after spontaneous clearance of the virusgradually after spontaneous clearance of the virus

Diagnosis of HCV Diagnosis of HCV InfectionsInfections

Mother-to-infant transmission Mother-to-infant transmission Should be based on HCV RNA detection Should be based on HCV RNA detection

with a sensitive technique rather than on with a sensitive technique rather than on anti-HCV detectionanti-HCV detection

Antibodies are passively transferred Antibodies are passively transferred in in uteroutero and remain detectable for several and remain detectable for several months to more than a year after delivery, months to more than a year after delivery, regardless of whether viral transmission regardless of whether viral transmission occurs occurs

Assessment of disease severity and prognosisAssessment of disease severity and prognosis Virologic tests have no prognostic valueVirologic tests have no prognostic value

Treatment of Treatment of Acute Hepatitis CAcute Hepatitis C

The optimal treatment schedule remains to be The optimal treatment schedule remains to be established for acute hepatitis C, and no established for acute hepatitis C, and no recommendations can yet be made regarding the use of recommendations can yet be made regarding the use of virologic tests in the decision to treat (Hoofnagle JH)virologic tests in the decision to treat (Hoofnagle JH)

Virologic response assessed at the end of therapy by Virologic response assessed at the end of therapy by means of a sensitive HCV RNA technique means of a sensitive HCV RNA technique If HCV RNA is negative, the sustained or transient If HCV RNA is negative, the sustained or transient

nature of the response is assessed 24 weeks laternature of the response is assessed 24 weeks later Negative HCV RNA detection at this second test Negative HCV RNA detection at this second test

indicates that therapy has been successful.indicates that therapy has been successful.

Treatment of Treatment of Chronic Hepatitis CChronic Hepatitis C

Based on a combination of:Based on a combination of: pegylated interferon (IFN) alfa, pegylated interferon (IFN) alfa, either pegylated IFN alfa-2a either pegylated IFN alfa-2a

or pegylated IFNalfa-2bor pegylated IFNalfa-2b and ribavirinand ribavirin

General Prevention StrategiesGeneral Prevention Strategies Communication of information about HCV to health Communication of information about HCV to health

care and public health professionals care and public health professionals Education of the public and persons at risk for infectionEducation of the public and persons at risk for infection Integration of prevention and control activities into Integration of prevention and control activities into

public health programs to:public health programs to: Identify, counsel, and test persons at risk for HCV infectionIdentify, counsel, and test persons at risk for HCV infection Provide referral for medical evaluation of those found to be Provide referral for medical evaluation of those found to be

infected infected Conduct outreach and community-based activities to address Conduct outreach and community-based activities to address

practices that put people at risk for HCV infectionpractices that put people at risk for HCV infection Surveillance to monitor acute and chronic disease Surveillance to monitor acute and chronic disease

trends and evaluate the effectiveness of strategiestrends and evaluate the effectiveness of strategies Epidemiologic and laboratory investigations to better Epidemiologic and laboratory investigations to better

guide prevention efforts. guide prevention efforts.

Prevention Strategies Prevention Strategies in Pakistanin Pakistan

Methadone treatment programsMethadone treatment programs Needle and syringe exchange programsNeedle and syringe exchange programs Comprehensive risk-modifying educational proComprehensive risk-modifying educational pro

gramsgrams Ensuring access to sterile syringes through phEnsuring access to sterile syringes through ph

ysician prescription and pharmacy sales of syrysician prescription and pharmacy sales of syringes to IDUs inges to IDUs

IDUs should be educated about:IDUs should be educated about: the importance of hand washing before and after givthe importance of hand washing before and after giv

ing injectionsing injections not using the others' injection equipmentnot using the others' injection equipment avoiding any contact with blood from other personsavoiding any contact with blood from other persons

Future ResearchFuture Research Development of reliable, reproducible, and efficient Development of reliable, reproducible, and efficient

culture systems for propagating HCVculture systems for propagating HCV Role of genetic factors in the pathogenesis of HCVRole of genetic factors in the pathogenesis of HCV Development of less-toxic therapies and molecular-Development of less-toxic therapies and molecular-

based agents that specifically inhibit viral replication based agents that specifically inhibit viral replication and/or translation of viral RNA. and/or translation of viral RNA.

Directed investigation examining the development and Directed investigation examining the development and progression of hepatic fibrosis progression of hepatic fibrosis

Establishment of Hepatitis Clinical Research Network Establishment of Hepatitis Clinical Research Network to conduct of research related to the natural history, to conduct of research related to the natural history, prevention, and treatment of hepatitis C. prevention, and treatment of hepatitis C.

Examine the pattern of HCV disease progression in Examine the pattern of HCV disease progression in persons infected for at least two decades, including persons infected for at least two decades, including those infected as infants and as childrenthose infected as infants and as children

Future ResearchFuture Research Analysis of effectiveness of infection-control strategiesAnalysis of effectiveness of infection-control strategies Better understanding of factors that might predict Better understanding of factors that might predict

transmission transmission Understanding side effect management and increasing Understanding side effect management and increasing

patient adherence to therapy. patient adherence to therapy. Analysis of effect of health insuranceAnalysis of effect of health insurance Clearly establish the role of liver biopsy in the Clearly establish the role of liver biopsy in the

therapeutic management of patients with chronic therapeutic management of patients with chronic hepatitis C. hepatitis C.

International standardization of viral RNA titers International standardization of viral RNA titers Role of fatty liver, obesity, diabetes, and hepatic iron Role of fatty liver, obesity, diabetes, and hepatic iron

stores in the natural history of hepatitis C and stores in the natural history of hepatitis C and responses to therapy. responses to therapy.

Better understand HIV co-infected patientsBetter understand HIV co-infected patients