Hepatitis C Update

Report
Hepatitis Update 2013
Brendan M. McGuire, MD
UAB Liver Center
Introduction
• Hepatitis - Inflammation of the liver
• Five types
–
–
–
–
–
A
B
C
D
E
Characteristics of Hepatitis Viruses
Virus
Genome
Family
Major mode of Chronicity
Transmission
Fecal - oral
No
HAV
RNA
Picornavirus
HBV
DNA
Hepadnavirus
Blood
Yes
HCV
RNA
Flaviviridae
Blood
Yes
HDV
RNA
Satellite
Blood
Yes
HEV
RNA
Caliciviridae?
Fecal - oral
No
14
Hepatitis A
12
10
8
6
4
Hepatitis B
Hepatitis C
2
2000
1998
1996
1994
1992
1990
1988
1986
1984
0
1982
Cases / 100,000 population
US Incidence of Reported Cases of Acute
Viral
Hepatitis,
1982-2001
16
Mortality Rate for acute hepatitis is approximately 0.2%
US Esimates of Acute & Chronic Disease
Burden for Viral Hepatitis
HAV
HBV
HCV
New Infections
25,000
43,000
17,000
Chronic Infections
0
1.2 million
3.2 million
Chronic liver
disease deaths/year
0
3,000
12,000
Based on CDC estimated annual incidence 2007
Hepatitis A
•
•
•
•
Usually a self-limiting disease
Severity of illness increases with age
Transmission is fecal-oral
Rarely transmitted by
blood to blood transfer
• Incubation period is about
28 days
• Diagnosis by anti-HAV
IgM
http://ocw.jhsph.edu/imageLibrary
Geographic Distribution of HAV Infection
Symptoms & Signs of HAV Infection
• Some persons, particularly young children, are
asymptomatic.
• When symptoms are present, can include:
– Constitutional: fever, fatigue & joint pain
– Gastrointestinal: loss of appetite, nausea & emesis
– Hyperbilirubinemia: jaundice, dark urine & claycolored bowel movements
Concentration of HAV in
Various Body Fluids
Body Fluids
Feces
Serum
Saliva
Urine
100
102
104
106
108
1010
Infectious Doses per mL
Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
Risk Factors Associated with Reported
HAV in the US (1990-2000)
Source: National Notifiable Diseases Surveillance System
Unknown 45%
Personal
contact 14%
IVD
use 6%
Food/waterborne
outbreaks 4%
International
travel 5%
Other 8%
Daycare
centers
8%
Men who have
sex with men 10%
Sequence of Serologic Changes in
Acute HAV
Relative Concentration
Jaundice
Symptoms
ALT
HAV
Stool
Anti-HAV
Anti-HAV IgG
Anti-HAV IgM
Viremia
TIME
Persons at Risk for Acquiring HAV
• Travelers to regions with intermediate or high rates of
HAV
• Sex contacts of infected persons
• Household members or caregivers of infected persons
• Injection & non-injection illegal drug users
• Persons working with nonhuman primates susceptible
to HAV infection
Prevention of HAV
• Hygiene
– Hand washing
• Sanitation
– Clean water source
• Immune globulin
– Pre-exposure
– Post-exposure
• Hepatitis A vaccine
HAV Prevention Immune Globulin
• Pre-exposure
– Travelers to intermediate & high HAVendemic regions without enough time for HAV
vaccine
• Post-exposure (within 14 days)
– Household & other intimate contacts
– Selected situations in institutions & common
source exposure
HAV Vaccine
• Two single-antigen vaccines are available
(HAVRIX® & VAQTA®)
• A combination vaccine, TWINRIX®,
contains both HAV & HBV antigens
• All are inactivated vaccines
• Schedule is 0 and 6 months
• Not recommended for children < 1 years old
Persons Currently Considered to Have an
Indication for HAV Vaccine by ACIP
• All children ages 12-23 months
• Travelers to countries with intermediate & high
rates of disease
• Individuals who engage in high risk behaviors
– Homosexual activities
– Intravenous drug use
• Chronic liver disease
• Individuals with occupational risk of disease
– Primate handlers
Advisory Committee on Immunization Practices (ACIP) Recommendations 2006
Advisory Committee on Immunization Practices = ACIP
Hepatitis B Virus (HBV)
• DNA virus
• Worldwide: 350 million infected
& 620,000 die annually from
HBV-related liver disease
• 1.2 million persons in the US
with chronic HBV infection
• Incubation period is 120 days
• Causes acute & chronic disease
http:ocw.jhsph.edu/imageLibrary
www.cdc.org
Prevalence of Chronic HBV Infection
www.cdc.org
Symptoms & Signs of HBV Infection
• Most children < 5 years old are asymptomatic.
• 30-50% of persons > 5 years of age have signs
& symptoms.
• Symptoms when present can include:
– Constitutional: fever, fatigue & joint pain
– Gastrointestinal: loss of appetite, nausea & emesis
– Hyperbilirubinemia: jaundice, dark urine & claycolored bowel movements
– Decompensated cirrhosis
Concentration of HBV in Body Fluids
High
 Blood
 Serum
 Wound
exudate
Moderate
 Semen
 Vaginal fluid
 Saliva
Low/not detectable
 Urine
 Feces
 Sweat
 Tears
 Breast milk
Reported Risk Factors for Acute
HBV in the US (1990-2000)
Heterosexual activity 45%
Men who have
sex with men 13% Other
6%
IVD use 21%
Other include household contact, institutionalization,
hemodialysis, blood transfusion, occupational exposure
Unknown 15%
Source: CDC
Natural History of HBV in Infants
Acute HBV infection
5%
95%
Recovery and immunity
Chronic HBV
Replication
High
Low
Progressive liver injury
Fibrosis and cirrhosis
Asymptomatic infection
Hepatocellular carcinoma
Natural History of HBV in Adults
Acute HBV infection
95%
5%
Recovery and immunity
Chronic HBV
Replication
High
Low
Progressive liver injury
Fibrosis and cirrhosis
Asymptomatic infection
Hepatocellular carcinoma
Cellular Immune Responses to HBV
NEJM 2004;350:1118
Acute HBV with Recovery
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titer
HBsAg
0
4
8
IgM anti-HBc
12
16
20
24
28
32
36
Weeks after Exposure
anti-HBs
52
100
Serological Markers of Acute HBV Infection
Clinical Significance
HBsAg
HBsAb
Early
+
-
Window
-
Recovery
+
HBeAg
+
-
-
HBeAb
-
+
+
HBcAb IgM
+
+
-
HBcAb IgG
HBV DNA
+++
-
+
-
Progression to Chronic HBV Infection
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Titer
Total anti-HBc
IgM anti-HBc
0
4
8 12 16 20 24 28 32 36
52
Weeks after Exposure
Years
Chronic HBV Disease Types
• HBeAg positive
– Also known as “wild type”
– Antibody to HBeAg is negative
– HBV DNA > 20,000 IU/mL (> 105 copies/mL)
• HBeAg negative
– Also known as “precore mutant”
– Antibody to HBeAg is positive
– HBV DNA > 2000 IU/mL (> 104 copies/mL)
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
Chu CJ, et al. Gastroenterology. 2003;125:444-451.
4 Phases of Chronic HBV
Current Understanding of HBV Infection
HBeAg
Anti-HBeAg
ALT activity
HBV DNA
Phase
Liver
Immune
Tolerant
Immune
Clearance
Inactive
Carrier State
Minimal
inflammation
and fibrosis
Chronic active
inflammation
Mild hepatitis
and minimal
fibrosis
Yim HJ, et al. Hepatology. 2006;43:S173-S181.
Reactivation
Active
inflammation
Optimal treatment times
Hepatitis B Viral (HBV) Markers
Laboratory
Results
HBsAg +
HBsAb +
HBeAg +
HBeAb +
Comments
HBcAb IgM +
HBcAb IgG +
HBV DNA +
Acute or prior exposure
Prior exposure
Active viral replication
Active viral replication
Prior exposure or immunity
Active viral replication
Acute or prior exposure or chronic infection
Markers of Chronic HBV Infection
Clinical Significance
Phase
Replicative
Low,
Flare of
or
nonreplicative, chronic HBV
or inactive
Reactivation
carrier
Precore/core
promotor
mutants
HBsAg
HBsAb
+
-
+
-
+
-
+
-
HBeAg
+
+/-
+/-
-
HBeAb
-
-/+
-/+
+
HBcAb IgM
-
-
+/-
-
HBcAb IgG
HBV DNA
+
+++
+
+/-
-/+
++
+
+
The Replication Cycle of HBV
NEJM 2004;350:1118
Therapeutic Approaches to HBV
• Interferon
• Nucleoside analogues
– Lamivudine & Entecavir
• Nucloetide analogues
– Adefovir & Tenofovir
• Monoclonal antibody to HBsAg
• Vaccination for prevention
Hepatitis B Immune Globulin (HBIG)
• Prepared from plasma containing high titers of antibody
to HBsAg
• Used for post-exposure prophylaxis to prevent infection
from:
– Perinatal
– Sexual
– Occupational
• Must be given within 2 weeks of exposure to be
effective
• Confers no protection against future exposure
Hepatitis B Vaccine
• Became available in 1981.
• All are produced with yeast & recombinant
techniques to generate the HBsAg protein.
• Advisory Committee on Immunization Practices
recommended universal vaccinations of
– All infants, in 1991.
– All adolescents, in 1995.
– All persons up to age 18, in 1999.
Adults Considered to Have an
Indication for HBV Vaccine By ACIP
•
•
•
•
•
•
•
•
•
•
Sexual or household contacts of people infected with HBV
Multiple sexual partners
IVD user
Job that involves contact with blood or blood products
Prisoner in a correctional facility
Residents/staff in institutions for the developmentally disabled
Travelers to countries with high rates of HBV
HIV positive
Chronic liver disease, renal failure or dialysis
Unvaccinated adults with diabetes ages 19 - 59 years
HCV: RNA Genomic Organization
0
3000
6000
9000
NEJM 2001;345:41
Hepatitis C Virus (HCV)
• RNA virus
• 17,000 cases new annually
in the US (2007)
• Approximately 12,000
deaths each year in the US
secondary to chronic HCV
www.cdc.org
Identifying Estimated 170 Million Persons
With HCV Infection Worldwide
Americas
13.1 million
(1.7%)
Europe
8.9 million
(1.03%)
Africa
31.9 million
(5.3%)
W Pacific
62.2 million
(3.9%)
SE Asia
E
Mediterranean 32.3 million
(2.15%)
21.3 million
(4.6%)
World Health Organization (WHO). Wkly Epid Rec .1999;74:425-427. WHO. Hepatitis C:
Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126.
Wasley A, et al. Semin Liver Dis. 2000;20:1-16.
Prevalence of Chronic HCV Infection
In the US, 2.7–4 million people are living with
chronic HCV infection;
75% are unaware they are infected
CDC & Prevention. HCV. Available at:
http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Accessed June 26, 2011.
Institute of Medicine. Hepatitis & Liver Cancer: A National Strategy for Prevention
& Control of Hepatitis B & C; 2010.
Epidemiology of HCV in the US
• 2.7-4 M Americans infected (2%)
• High prevalence rates
– 2.5% of males
– 3.2% of African Americans
– 2.1% of Hispanic Americans
– People born between 1946 - 1964
Two-Thirds of Those With Chronic HCV in the U.S.
Were Born Between 1946 & 1964
Individuals (n)
Estimated Prevalence by Age Group
1.6M
1.4M
1.2M
1M
800k
600k
400k
200K
0
<1920
19201929
19301939
19401949
19501959
19601969
1970- 19801979 1989
1990+
Birth Year Group
Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby
Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009.
Natural History of HCV Infection
A cute H C V Infection (100)
R ecov ery & C learance
of H C V (20)
M ild (24)
C hronic H epatitis
C hronic Infection
(8 0 )
M oderate (32)
S ev ere (24)
C irrhosis
E nd-S tage Liv er
D isease
H epatocellular
CA
Clin Liver Dis 2005;9:383-398. Eur J Gastroenterol Hepatol 1996;8:324-328. Hepatology 2002;36(suppl):S1-S2.
Hepatology 2002;36(suppl):S35-S46. Ann Intern Med 2000;132:296-305. Gastroenterology 1997;112:463-472.
Immunopathogenesis of HCV CD4
T-Helper Cells
HCV Antigen
APC
MHC Class II
TCR/CD3
CD-4
Th1
IL-12
INF-g
Th0
IL-4
Th3
TGF-b, IL-10
Th2
IL-2, TNF-a/b, IFN-g
IL-4, IL-6, IL-6, IL-10
Greater Immunopathology
Lesser Immunopathology
Number of cases
Projected Cases of Hepatocellular Carcinoma &
Decompensated Cirrhosis Due to HCV
160,000
140,000
120,000
Decompensated
100,000
cirrhosis
80,000
60,000
40,000
Hepatocellular
cancer
20,000
0
1950 1960 1970 1980 1990 2000 2010 2020 2030
Year
Gastroenterology 2010;138:513-521
Patient Survival Rates with HCV (+) &
HCV (–) After Liver Transplantation
HCV (+) 4439
HCV (-) 6597
3035
4784
1951
3343
1134
2117
519 98
1003 220
Gastro 2002;122(4):889.
Risk Factors for HCV
• Transfusion of blood
or blood products
before 1992
• Intravenous drug use
• Intranasal cocaine
• Hemodialysis
• High-risk sexual
contact
• Tattooing or body
piercing
• Occupational exposure
to blood or blood
products
• An organ, graft, or
tissue transplant from
an HCV+ donor
Reported Risk Factors for Acute
HCV in the US, 2007
•
•
•
•
•
Injection drug use – 48%
Multiple sex partners – 42%
Men who have sex with men – 10%
Sex with someone known to have HCV -10%
Risk factors are not mutually exclusive
Low Risk of HCV Transmission
Between Monogamous Sexual Partners
• 776 serodiscordant spouses followed for 10 yrs
– Intercourse mean: 1.8/wk
– No condom use, no anal sex
– 3 new infections (incidence 0.37/1000 pt-yrs), but
all 3 differed from partner’s strain
– Net incidence of transmission: 0
Vandelli C, et al. Am J Gastroenterol. 2004;99:855-859
Counseling HCV Patients
• Potentially infectious
• Keep cuts and skin lesions covered
• Potential for sexual transmission
• Potential for perinatal transmission
– no evidence to advise against pregnancy or breastfeeding
• Should not
• Donate blood, organs, tissue, or semen
• Share household articles (e.g., toothbrushes, razors)
Typical Course for Resolution of Acute HCV
Symptoms
Titer
anti-HCV
Normal
0
1
2
3
Months
4
5
6
1
2
3
4
ALT
HCV RNA
Years
Time after exposure
Hepatology. 2002;36:S65-S73.
Typical Course for Chronic HCV Infection
HCV RNA
Symptoms
Titer
anti-HCV
ALT
Normal
0
1
2
3
Months
4
5
6
1
2
3
4
Years
Time after exposure
Hepatology. 2002;36:S65-S73.
Enzyme Immunoassay (EIA)
anti-HCV
• Main screening test
• Detects circulating antibodies – 2 months after
exposure
• Advantages are ease of use, low variability, ease of
automation & relatively low expense
• Sensitivity is 97-100%
• Positive predictive value varies on prevalence
– 95% with risk factors & elevated ALT
– 50% without risk factors & normal ALT
Quantitative HCV RNA by PCR
• Important for measuring the level of circulating HCV
RNA (viral load)
• Diagnosis within 1 to 2 weeks after exposure
• Evaluation of patients with false positive EIA
• Diagnosis of patients who fail to develop antibodies
• Detection limit > 12 IU/ml
Hepatology. 2009;49:1335-1374.
False Negative Molecular Tests
• Ribonucleases are ubiquitous & makes RNA
inherently unstable
• Serum specimens should be separated from whole
blood < 4 hours of venipuncture
• Rapid storage of serum specimens at -70 oC
• Minimal freezing & thawing
Nucleic Acid Testing For HCV
• Allows very small amounts of RNA to be detected by a
process of massive copying of a gene fragment.
• A rapid test to determine RNA in the blood.
• Can identify RNA in the blood 12 days after exposure.
• Used by organ and blood banks for identifying acute
cases of HCV from donors.
Transfusion 2010; 50:1495–1504
Prevalence of HCV Genotypes &
Subtypes in the USA
1&2 3 4
2b
2a
1a & 1b
1b (39%)
1a (36%)
Patterns of Virologic Response
PegIFN alfa & RBV
HCV RNA (log10 IU/mL)
7
Null Response*
6
5
Partial Response*
4
3
Relapse
2
1
Undetectable
0
-8
-4
-2
0
*Subset of Nonresponse
RVR
4
EVR
8
12
ETR
16
20
24
32
40
48
SVR
52
60
72
Wks After Start of Therapy
4 weeks - RVR: rapid virological response
12 weeks - eRVR: extended RVR & EVR: early virological response
24 - 48 weeks - ETR: end of treatment response
24 weeks after treatment - SVR: sustained virological response Hepatology 2009;49:1335-1374.
Treatment Evolution of HCV
Sustained Viral Response (SVR)
100
1999
1991
2001
2002
2011
70-80%
80
54-56%
60
40
34%
42%
39%
16%
20
6%
0
IFN
6m
IFN
12m
IFN/RBV
6m
IFN/RBV
12m
Peg-IFN
12m
Peg-IFN/
RBV 12m
Peg-IFN/
RBV + PI
6-12m
IFN: Interferon; m: months; RBV: Ribavirin; Peg: Pegylated; PI: Protease inhibitor
Adapted from Strader DB et al. Hepatology 2004;39:1147-1171
Guidelines for HCV Testing:
Acute Infection Suspected
• Baseline HCV Ab
• 4-6 weeks - HCV antibody & HCV RNA
• 2-3 months – HCV RNA
– If positive, consider treatment
• 4-6 months - HCV antibody & HCV RNA
JAMA. 2007;297:724-732.
Spontaneous Clearance for Symptomatic
Acute HCV High, Justifies Treatment Delay
• 60 patients with acute HCV (36 genotype 1) followed[1]
– Spontaneous clearance in 52% of 51 symptomatic cases
• No asymptomatic patient cleared virus spontaneously
– SVR achieved in 81% of symptomatic patients without
spontaneous clearance who were treated > 3 mos after
symptom onset with IFN ± RBV
• Recent study showed similar SVR rates in symptomatic
adherent patients who delayed therapy for 12 wks vs
those who received immediate treatment[2]
1. Gerlach JT, et al. Gastroenterol. 2003;125:80-88. 2. Deterding K, et al. EASL 2009. Abstract 1047.
Randomized Trial of Treatment for Acute
HCV at Variable Times After Onset
– 37% genotype 1
– 41% genotype 4
• Randomized to treatment at
Wk 8, 12, or 20
• Treatment with pegIFN alfa2b 1.5 µg/kg/wk x 12 wks
100
95*
92
76
80
SVR (%)
• 129 patients entered treatment
for lack of spontaneous
clearance within 8 wks of
presentation
60
40
20
0
43
43
43
8 wks
12 wks
20 wks
Time of Treatment Initiation
*SVR rates significantly higher for genotype 1 patients
who received treatment after 8 wks vs either 12 or 20
wks (P = .01 and P = .004, respectively).
Gastroenterol. 2006;130:632-638.
Acute HCV Infection:
Summary of Recommendations
• Patients with acute HCV infection should be
considered for IFN-based therapy (either standard or
pegIFN).
• Treatment can be delayed 8-12 weeks after acute
onset to allow for spontaneous resolution
• No definitive recommendation about optimal
duration of treatment for acute HCV; however, it is
reasonable to treat for ≥ 12 weeks, & 24 weeks may
be considered
• Decision to use RBV made on a case-by-case basis
Ghany MG, et al. Hepatology. 2009;49:1335-1374.

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