Transcript Master slide

Epidemiology and Natural History of
Hepatitis C Virus Infection
Miriam J. Alter, Ph.D., MPH
Infectious Disease Epidemiology Program
Institute for Human Infections and Immunity
University of Texas Medical Branch
Galveston, Texas
May 5, 2009
Topics

History of discovery
– Virus and clinical characteristics

General population characteristics
– Prevalence
– Incidence

Natural history and role of co-factors
– Alcohol
– Metabolic factors
– HIV co-infection

Current and future morbidity and mortality
Viral Hepatitis - Overview


Primary infection of the liver caused by at
least five unrelated viruses: A, B, C, D, E
HAV and HEV
– Fecal-oral route
– Acute self-limited disease; no chronic infection

HBV, HCV, HDV
– Percutaneous or mucosal exposures to blood
– Chronic infection – major causes of cirrhosis and
hepatocellular carcinoma worldwide
Viral Hepatitis – Historical Perspective
“Infectious”
Viral hepatitis
“Serum”
A
Enterically
transmitted
E
NANB
B D
false-report
C
F, G,
?other
Parenterally
transmitted
Non-pathogenic
Clinical Features of Hepatitis
Common
 malaise
 anorexia
 nausea & vomiting
 fever
Less Common
 diarrhea
 arthralgias
jaundice
abdominal pain
hepatomegaly





pruritis
rash
Hepatitis C Virus Infection
Before Discovery


First identified as a clinical entity (non-A, non-B hepatitis) in
transfused patients late 1960s
Most risk factors identified before 1990 from cohort and
case-control studies of acute disease dx by exclusion
–
–
–
–
–
–

Whole blood transfusion, clotting factors
IDU
Iatrogenic (dialysis, unsafe injection techniques)
Occupational (needlesticks, frequent expos to blood)
Perinatal
Sex
“High” rate of chronic infection
– Persistence of abnormal ALT in NANB cohorts followed from onset
– High rate of transfusion-transmitted NANB hepatitis from apparently
healthy donors
Hepatitis C Virus

RNA Flavivirus (Hepacivirus)
– Discovery using recombinant DNA technology
reported in 1989
– Clinical entity (non-A, non-B hepatitis) in transfused
patients reported late 1960s
– Target organ liver


Bloodborne (primarily) and sexually-transmitted
No vaccine
– Mutations occur during viral replication
– Substantial heterogeneity (quasispecies) prevents
effective neutralization
Hepatitis C Virus Infection
After Discovery

RNA Flavivirus
– Mutations occur during viral replication
– Substantial heterogeneity (quasispecies) prevents effective
neutralization
– No vaccine



Serologic (Ab) followed by NAT (RNA)
Clinical symptoms of acute disease <20%
Chronic infection 60-85%
– Chronic hepatitis 70%
– Cirrhosis and liver cancer 5-20%
• Mortality 5%/year
– Most common indication for liver transplantation in US
HCV – A Product of The Twentieth Century
ABO and
anticoagulants
Hypodermic needle
invented by Sir
Christopher Wren, 1660
Blood banking
<20% of patients
received IV therapy
1st human-human
blood
transfusion, 1834
Transfusions, AHF,
plasmapheresis,
commercial IV solutions,
single use disposables,
vaccination
1650
1800
1850
1900
1950
2000
Injection drug use
HCV Accomplishments
During Past 15 Years





Determined burden of infection and morbidity
in the general population
Eliminated transfusion-associated infections
Documented >80% decline in incidence
Characterized the epidemiology
Implemented community-based prevention
Natural History of HCV Infection
How Selection of Study Population Affects Conclusions
Regarding Disease Progression
5-15%
All infections; many never
come to medical attention
including those that resolve
Biologic
Onset of
Disease
Pathologic
Evidence of
Disease if
Detected
Signs and
Symptoms
of Disease
20%
Broader spectrum of disease
severity; but milder cases
may not be referred
30-50%
High proportion
severe disease
Cirrhosis
Medical
Care
Sought
Diagnosis
by Referral
Natural History of HCV in Patients Referred for
Medical Care ~20 Years After Infection
Chronic hepatitis
Cirrhosis
HCC
Median percentage
60
50
Tx
40
30
UK
20
IDU
10
0
Kiyosawa
Exposure
30-50% transfused
Tong
All transfused
Niederau
Gordon
50% transfused
Natural History of HCV in Cohorts Followed for 20
Years by Age at Infection
Persistent infection
Chronic hepatitis
Cirrhosis
Median percentage
80
70
60
50
40
30
20
10
0
<10
20-29
Age at infection
Years followed
17
15-20
Median age at FU
20
40
Exposure
Transfusion
Anti-D; IDU
References
Losasciulli ‘97
Kenny-Walsh ’99; Wiese ‘00
Vogt ’99; Casiraghi ‘04 Thomas ‘00; Rodger ‘00
45+
8-20
67
Transfusion
DiBisceglie ‘91
Seeff ‘01
Co-factors Affecting Natural History

Persistence
–
–
–
–

Older age at infection
Male gender
Black race
Immunosuppression
Progression
–
–
–
–
–
–
–
–
–
Older age at infection
Immunosuppression
Co-infection (HIV, HBV)
Metabolic syndrome
Heavy alcohol intake
Diabetes
Obesity
Male gender
Genotype?
Metabolic and Other Co-Factors in Liver
Disease Progression -- Independent and
Synergistic for Cirrhosis and HCC
Factor
Obesity
Metabolic syndrome
Diabetes
Heavy Alcohol
NAFLD
HCV infection
Prevalence US
Adult Gen Pop
38.6%
23%
9.3%
7-15%
6-14%
3-14%
Annual hepatitis C mortality rates (95% CI) for
selected age groups, United States, 1995-2004.
Wise M et al., Hepatology;47:1128-1135
Estimated Future HCV-Related Disease Burden
Davis GL et al. 2009 unpublished data
Predicted HCV-Related Deaths
UK 1996-2004
Sweeting MJ, et al. J Viral Hepatitis,
2007, 14, 570–576
Australia
1990-2020
Law MG. Intern J Epidemiology 2003;32:717–724
USA
2005-2025
Note: Similar trends predicted for France by same authors
S. Deuffic-Burban,et al. J Viral Hepatitis, 2007, 14, 107–115
Greece
1990-2030
Sypsa V et al. Journal of Viral Hepatitis, 2005, 12, 543–550
Viral Hepatitis-Related ESLD Mortality
Worldwide
Deaths
Total Deaths
Cirrhosis
Liver Cancer
HBV-related HCV-related
563,000
235,000
328,000
Perz J et al. Journal of Hepatology 45 (2006) 529–538
366,000
211,000
155,000
Hepatitis C Virus Infection
United States
New infections per year 1985-89
2006
242,000
20,000
Deaths from acute liver failure
Rare
Persons ever infected (1.6%)
4.1 million (3.4-4.9)*
Persons with chronic infection
3.1 million (2.5-3.7)*
HCV-related chronic liver disease 40% - 60%
Deaths from chronic disease/year 8,000-10,000
* 95% confidence interval (data from 1999-2002)
Risk Factors Associated With
Acquiring HCV Infection
Cohort and Acute Case Control Studies






Transfusion, transplant from infectious donor
Injecting drug use
Occupational blood exposure (needle sticks)
Birth to an infected mother
Infected sex partner
Multiple heterosexual partners
HCV Infection
Estimated Past Incidence and Future Prevalence
140
Decline in cases among IDUs
Infections
per 100,000
120
100
80
60
Incidence
40
20
Prevalence
0
2.0%
Overall prevalence
1.5%
1.0%
Infected
20+ years
0.5%
0.0%
1960
1970
1980
Armstrong GL et al. Hepatology 2000;31
1990
2000
2010
2020
2030
Posttransfusion Hepatitis
% of Recipients Infected
40
All volunteer donors
HBsAg
30
20
NANB
10
Donor Screening for HIV Risk Factors
Anti-HIV
3rd generation
HBsAg
ALT/Anti-HBc
Anti-HCV
HCV RNA
HBV
0
1964
1968
1972
1976
1980
1984
Year
Adapted from HJ Alter
1988
1992
1996
2000
Injecting Drug Use and HCV


Accounts for most (50-80%) infections in Western
countries, particularly in persons <50 yrs old.
Cumulative infection rates have slowed
– 30% prevalence after 2-3 years (vs. 80% in 1989)

Incidence remains high in new users in many
countries
– 15%-20% annual rate

Associated with sharing cookers and cotton
independent of needles/syringes.
– Need to include in harm reduction messages
Prevalence and Incidence of HCV Infection in
IDUs, 1995-2001
Age <30 years
New York City
Chicago
Vancouver, BC
Italy (Veneto region)
UK
Prevalence
40-50%
27%
46%
37%
13-20%
Incidence/100 PY
9-34
10
37
--
Any age
Seattle
Italy (Veneto region)
Ireland
UK
86%
74%
66%
48-76%
21
-24.5
14
Diaz T Am J Pub Health 2003; Des Jarlais DC Am J Epi 2003; Thorpe L Am J Epi 2002;
Hahn JA JID 2002; Miller Hepatology 2002; Hagan H Am J Epi 1999; Quaglio J Viral Hep 2003;
Bird SM J Epi Biostat 2001; Grogan L Irish J Med Sci
HCV by Frequency of IDU among 5282 College
and University Students, US
IDU history (% total)
HCV Prevalence
Never injected (98%)
Ever injected (2%)
Once or twice
Daily, regular, sporadic *
* Sporadic = more than once or twice but not long term
0.5%
22.6%
9.0%
29.0%
Occupational Transmission of HCV


Inefficient by occupational exposures
Incidence <0.5%-2% following needle stick
from HCV-positive source
– Associated with hollow-bore needles, deep injury


Case reports of transmission from blood
splash to eye; one from exposure to nonintact skin
Prevalence 1-2% among health care workers
– Lower than adults in the general population
– 10 times lower than for HBV infection
Perinatal Transmission of HCV

Only from women HCV-RNA pos. at delivery
– Average rate of infection 4-6%
– Higher (17%) if woman co-infected with HIV
– Role of viral titer unclear
• Threshold for transmission not consistent among studies

Risk factors
– Internal fetal scalp monitoring (7-fold increased risk)
– Prolonged rupture of membranes (9-fold increased risk)

No association
– Delivery method
– Breastfeeding
Perinatal Transmission of HCV
Potential risk factor
No. Infants
Tested
Type of Delivery
Vaginal
C-section
336
107
10%
8%
Type of Feeding*
Breast-fed
Bottle-fed
157
74
5%
8%
* Includes only infants born to HIV-negative mothers
% Infants
Infected
Exposures Not Associated With Acquiring HCV
Case Control Studies of Acute Hepatitis C, U.S., 1979-85
Exposure (prior 6 months)
Cases
n=148
Controls
n=200
Medical care procedures
Dental work
Health care work (no blood contact)
Ear piercing
Tattooing
Acupuncture
Incarceration
Foreign travel
Military service
30.4%
24.3%
4.1%
2.7%
0.7%
0
4.1%
4.1%
1.3%
29.5%
23.5%
5.0%
3.0%
0.5%
1.0%
1.0%
2.5%
4.9%
Sources: JID 1982;145:886-93; JAMA 1989;262:1201-5.
Identification of Rare Events Associated with
HCV Transmission

Healthcare procedures in the U.S.
– Patient-to-patient and HCW-to-patient
• Difficult to detect
• Identified in in-patient, out-patient, dialysis and home-therapy
• Increasingly recognized in context of outbreaks
– Mostly due to unsafe injection practices
• Re-use of syringes and needles
• Contaminated multiple dose medication vials

HIV-positive MSM through high risk sexual activities
HCV Prevalence by Age, NHANES,
U.S. General Population, 1988-94 vs. 1999-02
Percent Anti-HCV Positive
1990 (1988-1994)
7
(1.8%)
3.9 million
6
2000 (1999-2002)
(1.6%)
4.2 million
5
4
3
2
1
0
6-11
12-19 20-29 30-39 40-49 50-59 60-69
70+
Age in Years
Alter MJ, NEJM 1999;341:556-562; Armstrong GL, Ann Intern Med 2006;144:705-714
HCV Prevalence by Gender, Age and Race,
NHANES, U.S. General Population, 1999-2002
Females
NH Black
Mex Amer
16
14
12
10
Percent Anti-HCV Positive
Males
Percent Anti-HCV Positive
NH White
8
6
4
2
0
8
6-19
20-29
30-39
40-49
50-59
60-69
70+
6-19
20-29
30-39
40-49
50-59
60-69
70+
6
4
2
0
Age in Years
Armstrong GL, Ann Intern Med 2006;144:705-714
Distribution of HCV Genotypes in the
General Population, 1990 vs. 2000, US
80
Percentage positive
70
1990 (1988-1994)
60
2000 (1999-2002) *
50
40
30
20
10
0
Genotype 1
Genotype 2
Nainan OV. Gastroenterol 2006;131:478-484
*CDC, preliminary unpublished data
Genotype 3
Others
HCV Genotypes in the US General Population
by Percentage US-Born, 1988-1994
All US-born Blacks
Percentage US-born
100
80
60
40
20
All Asian-born
0
1
2
3
Genotype
Nainan OV. Gastroenterol 2006;131:478-484
4
6
Demographics Independently Associated with
HCV Infection among Participants Age 20-59
Variable
Ethnicity
Non-Hispanic white
Non-Hispanic black
Mexican American
Place of birth
Within United States
Outside of United States
Ratio of income to poverty threshold
2.0
1.0–1.9
0.0–0.9
Armstrong GL, Ann Intern Med 2006;144:705-714
Adjusted OR (95% CI)
1.0
1.9 (0.9–3.8)
2.6 (1.2–5.8)
1.0
0.2 (0.08–0.7)
1.0
3.5 (1.9–6.4)
9.1 (4.5–18.2)
Risk Factors Independently Associated with
HCV Infection among Participants Age 20-59
Variable
Blood transfusion before 1992
No
Yes
Drug Use
Never
Non-injection drug use
Injection drug use
Lifetime number of sexual partners
0–1
2–19
>20
Armstrong GL, Ann Intern Med 2006;144:705-714
Adjusted OR (95% CI)
1.0
2.6 (0.9–7.3)
1.0
3.7 (1.7–7.9)
148.9 (44.9–494)
1.0
1.4 (0.3–6.0)
5.2 (1.5–18.2)
Factors Independently Associated with HCV
Infection among Participants Age >60 Years
Variable
Ethnicity
Non-Hispanic white
Non-Hispanic black
Mexican American
Blood transfusion before 1992
No
Yes
Armstrong GL, Ann Intern Med 2006;144:705-714
Adjusted OR (95% CI)
1.0
4.3 (1.9–9.6)
1.6 (0.6–4.0)
1.0
4.9 (1.7–14.1)
Risk Factors For Persons with
Acute or Chronic Hepatitis C 1999-2002, U.S.
Chronic (Prevalent)
Acute (Incident)
Injection Drug Use
50%
Injection Drug Use
60%
Unk
10%
Other*
10%
Transfusion
10%
Sexual
20%
Unk
10%
Other*
10%
* Other includes occupational, nosocomial, iatrogenic, perinatal
Armstrong GL, Ann Intern Med 2006;144:705-14; CDC Sentinel Counties, unpublished data
Sexual
20%
Summary

Most HCV-positives can be identified based on 2-3 major
characteristics
– “Laundry lists” of risk factors distract attention from those that should
be used for testing
– Generic risks demand their own messages regardless of risk
• Don’t use illegal drugs
• Anything that pierces your skin should be sterile

Less than half of HCV infected patients have been identified
– Unrealistic to expect healthcare professionals to ascertain risk
histories or individualize preventive services

New strategies need to be developed for efficient delivery of
preventive services
Global Differences in
HCV Transmission Patterns
Exposures among
prevalent infections
Contribution of exposures to disease
burden by HCV prevalence
Low
Injecting drug use
++++
Transfusions before testing
-
Unscreened transfusions
+
+
+
++
Unsafe therapeutic injections
Occupational
Perinatal
High-risk sex
Moderate
++
+/++++
+
+
+
High
+
+++
+++
++++
+
+
+/-
Estimated HCV Prevalence by Region
E Europe
11.6 million
N/W/S Europe
6.2 million
No. America
5 million
E Med
1.4 million
So/Central America
7.8 million
Africa
29.4 million
Southeast Asia
24 million
Western Pacific
41.4 million
< 1.0%
1.0% - 1.9%
2.0% - 2.9%
> 2.9%
Not included in a WHO region
Global Anti-HCV Prevalence 2.2%
130,000,000 Positives
J Perz et al., Journal of Hepatology 45 (2006) 529–538
Geographic Patterns of Age-specific
Prevalence of HCV Infection, 2000-2005
Percent Anti-HCV Positive
15
Italy/Japan (1-1.9)
10
Taiwan (2-2.9)
5
Turkey (1.5)
US/WEur/AU (1-1.9)*
0
0-9
10-19
20-29
30-39
40-49
Age Group (Years)
* Numbers in parentheses refer to region specific prevalences
50+
Geographic Patterns of Age-specific
Prevalence of HCV Infection, 2000-2005
Egypt (>2.9)
Percent Anti-HCV Positive
45
40
35
30
25
15
Japan
hyperendemic
areas (1-1.9)
10
Italy/Japan (1-1.9)
20
Taiwan (2-2.9)
Turkey (1.5)
US/WEur/AU (1-1.9)*
5
0
0-9
10-19
20-29
30-39
40-49
Age Group (Years)
* Numbers in parentheses refer to region specific prevalences
50+
Incidence of HCV Infection by Selected
Geographic Areas, 1995-2000
Mean age 35y
32y
50y
40y 60y
<20y
Italy
Donors
Taiwan
Japan
Egypt *
Hyperendemic communities
Infections per 10,000
70
60
50
40
30
20
10
0
US
Gen pop
* Background HCV prevalence differed between areas studied, 9% vs. 24%.
Source: Prati, Hepatol 1997; Sun, J Med Virol 2001; Fukuizumi, Scand J Infect Dis 1997;
Okayama, J Viral Hep 2002; Mohamed, Hepatol 2005
Global Burden of Hepatitis Infections Attributable
to Contaminated Health Care Injections
HBV
Annual number of infections (million) 21
Attributable fraction for injections
Projected deaths 2000-2030
Disability adjusted life years (million)
Source: Hauri et al., Int J STD & AIDS 2004;15:7-16
32%
HCV
2
40%
75,000 24,000
3
0.3
Use of Injections Worldwide
Immunization injections
Most vaccine are
administered by injections
Measles
Eradication
Source: WHO
Therapeutic injections
Most medications used in
primary care can be
administered orally
Unsafe Injection Practices





Inadequate supplies of sterile syringes
Inadequate sterilization of reusable syringes
and needles
Administration by non-professionals at home
Syringes shared with others (family,
neighbors)
Overuse of therapeutic injections
Children Handling Medical Waste, Bangladesh
Current and Future Issues

Identification of infected persons
– Screening and testing not routinely performed
– Lack effective methods for reaching those whose risk was in the
remote past
• Risk factor ascertainment in routine healthcare visits is rare

Therapy regimens less than ideal, especially those with
genotype 1
– In US, treatment offered to low % of HCV-positives

Implications of multiple co-factors on liver disease
progression and response to therapies not well understood
– Impact likely to grow creating an even greater challenge

Need to be alert to changes in epidemiology
Role of Therapeutic Management in Global
Control of Viral Hepatitis




Major advances over past 5 years in the
therapautic management of HBV and HCV
Good news: promise of further advances
Bad news: COSTS, side effects,
contraindications
Challenge: how to extend benefits to the vast
numbers of persons who could benefit
– Address affordability issues head-on
Remaining Challenges: International
Prevention Efforts





Obtaining and maintaining funding and
infrastructure for vaccine program implementation
Integrating into routine childhood schedules in
harmony with other vaccines
Delivery of vaccine to infants born out of hospital
Demonstrating impact of programs
Reducing transmission due to unsafe injection
practices (healthcare-related and illicit drug use)
Most Common (>10%) HCV Genotypes by
Region
1,2,3
1,3
1,2
1,3

1,3,4
1,2,3
4
4
1,3
3
3
SE Asia: 6
1,3
4
1
5
1
Distribution of HCV Genotypes in
France (2001) and US (1999-2002)
60
Percentage positive
France
United States
50
40
30
20
10
0
1a
1b
Payan C, J Viral Hepatitis 2005;12:405-413
CDC, NHANES 1999-2002, unpublished data
2
3
Other
HCV Genotypes 1, 2 and 3 by Age
United States and Western Europe
1a
Percentage
70
1b
2
3a
60
50
40
30
20
10
0
<50 y.o.
50+ y.o.
United States
<50 y.o
50+ y.o.
Western Europe
Alter MJ. NEJM 1999;341:556-62; Nainan OV. Hepatology June 1996; Pawlotsky JID
1995;171:1607;Simmonds J Hepatol 1996;24:517; Zeuzem et al. J Hepatol 1996;24:3.
HCV Genotypes in the US General Population
by US and Foreign Birth
1
2
3
4
6
Percentage with genotype
100%
80%
60%
40%
20%
0%
US born
Source: Nainan OV, Gastroenterology 2006;131:478–484
Foreign-born
HCV Genotypes in French Patients by
Geographic Origin
Payan C, J Viral Hepatitis 2005;12:405-413