Viral Hepatitis

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Viral Hepatitis

• Paul Martin M.D.
• Medical Director, Liver Transplant Cedars-Sinai
• Professor of Medicine, UCLA

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Viral Hepatitis

• 5 major hepatitis viruses A-E
• Hepatitis indicates biochemical hepatic
  dysfunction, not necessarily due to a virus
• Hepatitis can also occur as part of multisystem
  viral disorder

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• 95 of viral hepatitis due to the 5 major
  hepatitis
• Other viruses ( EBV, CMV, HSV, etc.,) cause
  hepatitis as part of systemic illness
• Hepatitis like picture can also result from
  other etiologies e.g. drugs, autoimmune process

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• Older terms such as infectious hepatitis
  (fecal-oral spread) and serum hepatitis are
  becoming obsolete as diagnostic testing readily
  identifies specific virus

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Acute Hepatitis

• Malaise, nausea, abdominal discomfort, jaundice
  typical but not invariable
• Acute hepatitis can occur with any of the 5 major
  viruses
• Recovery usual in acute hepatitis
• Fulminant course with liver failure a concern

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Acute Viral Hepatitis
Source CDC
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Chronic Hepatitis

• Implied by persistence of hepatitis gt 6 mos
• Occurs with hepatitis B, C and D
• Hepatitis A and E do not become chronic
• Spectrum of findings from mild biochemical
  dysfunction to advanced cirrhosis

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Hepatocellular Carcinoma Secondary to
Childhood-acquired HBV Infection
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Diagnosis of viral hepatitis

• Based on serological workup
• Liver biopsy does not distinguish one type from
  another, mainly used in chronic hepatitis to
  assess prognosis
• Biochemical tests, ALT and AST, reflect hepatic
  necrosis

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Role of Liver Biopsy
Assess severity of necro-inflammation

• Confirm clinical diagnosis

Evaluate possible concomitant disease processes
Assess therapeutic intervention
Assessfibrosis
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Hepatitis A Virus Transmission

• Close personal contact(e.g., household contact,
  sex contact, child day care centers)
• Contaminated food, water(e.g., infected food
  handlers, raw shellfish)
• Blood exposure (rare)(e.g., injecting drug use,
  transfusion)

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Hepatitis A Virus Transmission

• Close personal contact(e.g., household contact,
  sex contact, child day care centers)
• Contaminated food, water(e.g., infected food
  handlers, raw shellfish)
• Blood exposure (rare)(e.g., injecting drug use,
  transfusion)

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Average Hepatitis A Rates by State 1987-1997
Rate gt20/100,000
Rate 10-20/100,000
Rate lt10/100,000
Adapted from Advisory Committee on Immunization
Practices MMWR 199948(RR12)1-37.
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Hepatitis A Virus Infection
Typical Serologic Course
Symptoms
Total anti-HAV
ALT
Titer
Fecal HAV
IgM anti-HAV
0
1
2
3
4
5
6
12
24
Months after Exposure
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Hepatitis E - Clinical Features

• Incubation period Average 40 days
• Range 15-60 days
• Case-fatality rate Overall, 1-3 Pregnant
  ,1525
• Illness severity Increased with age
• Chronic sequelae None identified

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Hepatitis E - Epidemiologic Features

• Most outbreaks associated withfecally
  contaminated drinking water
• Minimal person-to-person transmission
• U.S. cases usually have history of travel to
  HEV-endemic areas

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Global Distribution of Chronic HBV Infection

• 350 million chronic carriers worldwide
• Ninth leading cause of death
• Nearly 75 of HBV chronic carriers are Asian

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Transmission of Hepatitis B Infection
Transfusion and transplant recipients
Newborns of long-term carriers
Individuals with multiple sexual partners
Intravenousdrug users
Healthcare workers
Prisoners and other institutionalised people
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Estimated Incidence of Acute Hepatitis B United
States, 1978-1995
Infant immunization recommended
Vaccine licensed
OSHA rule enacted
Cases per 100,000 Population
Decline among homosexual men HCWs
Decline among injecting drug users

Provisional date
Health Care Workers http//www.cdc.gov/ncidod/di
seases/hepatitis/slideset/hep_b/slide_15.htm.
Accessed 11-02-02.
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Risk of Developing Chronic Hepatitis B by Age at
Infection
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Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBeAg
anti-HBe
Total anti-HBc
Titer
anti-HBs
IgM anti-HBc
HBsAg
0
4
8
12
16
24
28
32
52
100
20
36
Weeks after Exposure
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Progression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
Acute (6 months)
Chronic (Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
IgM anti-HBc
Years
0
4
8
12
16
20
24
28
32
36
52
Weeks after Exposure
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Hepatitis D - Clinical Features

• Coinfection
• severe acute disease
• low risk of chronic infection
• Superinfection
• usually develop chronic HDV infection
• high risk of severe chronic liver disease

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Hepatitis D Virus Modes of Transmission

• Percutanous exposures
• injecting drug use
• Permucosal exposures
• sex contact

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Hepatitis D (Delta)

• Incidence declining worldwide due to vaccination
  and clean needle programs
• Only found in HBV infected patients, consider
  when liver disease unusually severe

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Epidemiology of HCV

• In United States
• 3.9 million people have been infected, nearly 3
  million are chronically infected
• Incidence
• Most common blood-borne infection
• Worldwide,170 million persons have been
  HCV-infected

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HCV Prevalence by Selected Groupsin the United
States
Hemophilia
Injection-drug users
Hemodialysis
STD patients
General population adults
Surgeons, other HCWs
Pregnant women
Military personnel
0
10
20
30
40
50
60
70
80
90
Anti-HCV Positive
Centers for Disease Control and Prevention. MMWR.
199847(RR-18)1-39.
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Natural History of HCV Infection
Exposure (Acute phase)
85 (85)
15 (15)
Resolved
HIV and alcohol
Chronic
20 (17)
80 (68)
Cirrhosis
Stable
25 (4)
75 (13)
Slowly Progressive
HCC, Transplant, Death
Alter, MJ. Epidemiology of Hepatitis C in the
West. Semin Liver Dis. 1995 15
5-14. Management of Hepatitis C. NIH Consensus
Statement. 1997 March 24-26 15(3).
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Future Disease Burden Related to HCV 2008
Need for Liver Transplantation
528
Decompensation
279
Liver-related Deaths
223
HCC
68
Cirrhosis
61
0
100
200
300
400
500
600
Estimated Increase by the Year 2008
Davis GL. Hepatology. 199828(4 pt 2)390a.
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Viral Hepatitis

• Acute hepatitis can be caused by A-E viruses
• Presentation non-specific
• Chronic hepatitis and cirrhosis caused by B,C and
  D
• Specific diagnosis is by serology

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Outcome of HAV Superinfection in Patients With
Chronic Viral Hepatitis
6/7 died
Underlying Disease
Vento S et al. N Engl J Med. 1998338286.
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HAV Vaccination in CLDSeroconversion Rate
Keeffe EB, et al. Hepatology 199827881-886.
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HAVSummary

• Higher Mortality in older patients and those with
  preexisting liver disease
• Vaccine increasingly recommended for patients
  with liver disease

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Hepatitis BReported Cases per 100,000
Population, 1998
gt4.0
2.4-3.9
1.5-2.3
NYC DC PR
0.0-1.4
VI GUAM AM SAMOA CNMI
NA
NA
NA
MMWR. 1998 47No.5344.
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Childhood Acquired HBV
HBeAg/anti-HBe
HBeAg
Anti-HBe
HBV-DNA
ALT
Cirrhosis HCC
CPH
CAH
Immune tolerance to HBV
Residual Integrated HBV
Immune clearance of HBV
0 10 20 30 40 50 60 70
Years
Lok 1990
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Hepatitis B Mortality

• About 1/3 of chronic HBV infections in the United
  States start in perinatal and early childhood
• Except flu and pneumococcal infections, HBV kills
  more people/year than any other
  vaccine-preventable disease (VPD) (gt5,000 HBV
  deaths/year)
• HBV causes hepatocellular carcinoma that kills
  about 1,000 Americans annually

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Estimated HBV Infections among US Born Children
(aged lt10 years) of HBsAg-Negative Mothers, 1990
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Elimination of Hepatitis B Virus Transmission
United States
Strategy

• Prevent perinatal HBV transmission
• Routine vaccination of all infants
• Vaccination of children in high-risk groups
• Vaccination of adolescents
• all unvaccinated children at 11-12 years of age
• high-risk adolescents at all ages
• Vaccination of adults in high-risk groups

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HBV who to treat

• Patients with chronic HBV
• Hepatic Inflammation ALT gt 2 upper limit of
  normal
• Active HBV replication HBV DNA /- HBeAG
• Symptoms not a factor

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Asia-Pacific Guidelines for Management of
Hepatitis B

• APASL/JGH JGH 2000 15825841
• Indications for treatment
• Those with normal ALT should not be treated
• Patients with ALT gt2 x ULN should be considered
  for treatment
• Liver biopsy is recommended prior to antiviral
  therapy (especially if ALT 12 x ULN)

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Asia-Pacific Guidelines

• APASL/JGH JGH 2000 15825841
• Patients with ALT gt5 x ULN should be treated with
  lamivudine
• Patients with ALT 25 x ULN can be treated with
  lamivudine or interferon inform patients about
  adverse effects, treatment duration, possible
  emergence of drug-resistant HBV
• No firm recommendation on ALT 12 x ULN consider
  severity, HBeAg monitor if dont treat

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Implications of HBeAg Seroconversion

• Usually (gt80) permanent suppression of HBV
  replication (HBV DNA not detectable in serum)
• Loss of HBsAg possible (1030 with IFN)
• Normalisation ALT reduced necroinflammatory
  change
• Functional improvement abolishes risk of liver
  failure or transplantation
• Effect on HCC risk less clearcut 50 reduction

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HBeAg Seroconversion Over 4 Years Treatment in
Patients with Elevated ALT Seroconversion
HBeAg-ve and anti-HBeve
80
73
65
70
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Patients ()
60
49
50
42
38
37
40
27
30
20
10
0
1
2
3
4
Duration of therapy (years)
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HBVSummary

• Most commonly diagnosed in patients with early
  acquisition
• HBsAg to diagnose infection, HBeAg and HBV DNA to
  assess replication
• IgM anti-HBc is absent in chronic infection

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HBVSummary

• Therapy indicated for chronically infected
  patients with elevated ALT
• Lamivudine limited by viral resistance, adevofir
  has recently received FDA approval

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Hepatitis C Transmission Factors

• Recipients of clotting factors made before 1987
  (85 transmission rate)
• Injection drug use/intranasal drug use (80
  transmission rate)
• Long term hemodialysis patients (10 - 20
  transmission rate)
• Persons with multiple sex partners (5
  transmission rate)
• Recipients of blood transfusions prior to July
  1992 ( 5 transmission rate)

Carithers RL. Am J Med. 199910790S-94S.
Alter MJ, Kruszon-Moran D, Nainan O, et al. The
prevalence of hepatitis C virus in the United
States, 1988-1994. New Engl Jour of Med.1999
341556-562. Ohto H, Terazawa S, Sasaki N, et
al. Transmission of hepatitis C from mothers to
infants. New Engl Jour of Med. 1994 330744-750.
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HCV InfectionUtility of Diagnostic Tests
Centers for Disease Control and Prevention. MMWR.
19984711.
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HCV Genotypes

• Genotypes are viral sequences
• Utilized for estimating potential for response to
  treatment not used to determine eligibility for
  treatment
• Genotype 1 4 least responsive to therapy
• Genotype 2 3 more responsive to therapy

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Factors Influencing HCV Progression

• Heavy alcohol intake
• Male gender
• Obesity
• Coinfection with HIV
• Coinfection with HBV
• Iron in the liver, as detected via liver biopsy
• gt40 years of age at time of infection,
  particularly if contracted via blood transfusion

Note HCV progression has NOT been demonstrated
to be influenced by viral load, serum ALT, or
mode of transmission.
Thomas DL, Astemborski J, Rai RM. et al The
national history of hepatitis C Virus Infection
Host, viral, and environmental factors. American
Journal of Medicine. 2000 284(4) 450-456.
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Role of Liver Biopsy
Diagnosis of HCV Role of Liver Biopsy
Assess severity of necro-inflammation

• Confirm clinical diagnosis

Evaluate possible concomitant disease processes
Assess therapeutic intervention
Assessfibrosis
Brunt EM. Hepatology. 200031241-246.
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Future Disease Burden Related to HCV 2008
Need for Liver Transplantation
528
Decompensation
279
Liver-related Deaths
223
HCC
68
Cirrhosis
61
0
100
200
300
400
500
600
Estimated Increase by the Year 2008
Davis GL. Hepatology. 199828(4 pt 2)390a.
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HCV Clinical Manifestations

• Present only 20 40 of time
• Frequently no symptoms until development of
  advanced liver disease
• Frequently nonspecific, mild, and intermittent
• Most common symptoms
• Malaise, weakness, anorexia (25 35 of cases)
• RUQ abdominal discomfort and pruritus
• Less common symptoms
• Jaundice
• Intermittent nausea
• Vomiting

Management of Hepatitis C. NIH Consensus
Statement, March 24-26, 199716(3) 1-41.
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HIV-HCV Coinfection in the USA
Coinfected
Mono-infected
40
30
X100,000
20
10
0
Hepatitis C
HIV
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1999 USPHS/IDSA Guidelines for the Prevention of
Opportunistic Infections

• HCV disease specific recommendations
• HIV-infected persons should be screened for HCV
  by EIA
• Patients should be advised on alcohol use
• Screen for HAV IgG. If negative, vaccinate
• Patients should be evaluated for liver disease
  and possible need for treatment
• Monitor liver enzymes after initiation of HAART

MMWR Vol. 48 / No. RR10 (http//www.cdc.gov)
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HCV and Healthcare WorkersTransmission Rate
after Needle Stick
Risk of Transmission by Single Needle Stick to
Susceptible Healthcare Workers
40
30
30
Percent
20
10
3
0.3
0
HBV
HCV
HIV
Alter MJ. N Engl J Med. 1999341556 (NHANES III,
19881994).
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HCVAntiviral therapy

• Eradicate virus-negative PCR
• Arrest Progression of liver disease
• Improve Quality of Life

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Treatment Responses
Biochemical Virologic End of treatment
Normal ALT HCV RNA response (ETR)
negative Sustained virologic Normal ALT HCV
RNA response (SVR) negative
(6 mos post-treatment)
Lindsay KL. Hepatology. 199726(suppl 1)72S.
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Clinical Significance of Sustained Virologic
Response

• gt90 of those with 6 months post treatment SVR
  maintain response during 1-6 years of follow-up
• Liver histology improves or stabilizes

Lindsay KL. Hepatology. 199726(suppl 1)75S.
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Optimizing Interferon ? Kinetics
Pegylated IFN ?
Serum IFN ? Levels (U/mL)
Time
Higher-Dose IFN ?
1 week
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Pegylated IFNs

• PEG IFN alfa-2b
• Molecular weight 12 kDa
• Linear
• 1.0 ug/kg QW subcutaneous (SC) injection with
  monotherapy
• 1.5 ug/kg SC when given in combination with
  ribavirin

• PEG IFN alfa-2a
• Molecular weight 40 kDa, linear structure
• 180 ug QW subcutaneous
• injection

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Who Should Be Treated?

• Persistently elevated ALT levels
• Detectable HCV RNA levels
• Liver biopsy (not required) indicating portal or
  bridging fibrosis or at least moderate degrees of
  inflammation and necrosis
• No active autoimmune disease
• No hepatic encephalopathy, variceal bleeding,
  ascites, or other clinical decompensation
• Consider
• Co-morbid conditions
• Symptomatic cryoglobulinemia
• Continuing substance abuse

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Who Should Not Be Treated?

• Pregnant or nursing mothers
• Current substance abusers
• CDC recommends patient be alcohol/drug free for
  gt6 months prior to undergoing treatment

• Caution in patients with
• Decompensated cirrhosis
• Prior history of psychiatric disorders
• Persistent ALT elevations, with less severe
  histological changes
• Patients aged lt 18 or gt 60 years

Centers for Disease Control and Prevention, MMWR.
1998 4724
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IFN alfa-2b/RBV Summary of Predictive Factors
for a SVR
Increasing usefulnessin predictingsustained
response
6
6
20
40
80
Sustained Virologic Response
Adapted with permission from McHutchison JG et
al. Semin Liver Dis. 199919(suppl 1)63.
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PEG-IFN alfa-2b (12 kDa)/RBV vs. IFN alfa-2b/RBV
IFN/RBV 1000 -1200 mg/d (n505)
PEG (12 kDa) 0.5 qw /RBV 1000-1200 mg/d (n514)
PEG (12 kDa) 1.5 qw /RBV 800 mg/d (n511)
Sustainedviralresponse
80
82
End-of-treatment not reportedP0.01 vs
IFN/RBVNot approved dosing for PEG-IFN
alfa-2bP0.02 vs IFN/RBV
79
54
47
47
42
34
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Manns MP et al. Peginterferon alfa-2b plus
ribavirin compared with interferon alfa-2b plus
ribavirin for initial treatment of chronic
hepatitis C A randomised trial. The Lancet
(358) 958-965.
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SVR Genotype 1
60
51
50
41
40
40
29
SVR ()
30
20
10
n101
n118
n250
n271
0
PEG-IFN ?-2a (40 KD) 180 µg
RBV 800
RBV 1000/1200
RBV 800
RBV 1000/1200
48 weeks
24 weeks
Hadziyannis SJ et al., EASL. 2002.
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SVR Genotype Non-1
90
78
78
77
73
80
70
60
50
SVR ()
40
30
20
10
n106
n162
n111
n165
0
PEG-IFN ?-2a (40 KD) 180 µg
RBV 800
RBV 1000/1200
RBV 800
RBV 1000/1200
48 weeks
24 weeks
Hadziyannis SJ et al., EASL. 2002.
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HCV Genotype 1

• Commonest genotype
• Less responsive to therapy than genotype 2,3
• 80 of genotype 1 are high viral load
• 56 of all US patients are genotype1, high viral
  load

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SVR Genotype 1 Low Viral Load
61
53
51
41
SVR ()
n51
n71
n60
n85
PEG-IFN ?-2a (40 KD) 180 µg
RBV 800
RBV 1000/1200
RBV 800
RBV 1000/1200
48 weeks
24 weeks
Hadziyannis SJ et al., EASL. 2002.
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SVR Genotype 1 High Viral Load
46
50
45
35
40
35
26
30
SVR ()
25
16
20
15
10
5
n50
n47
n190
n186
0
PEG-IFN ?-2a (40 KD) 180 µg
RBV 800
RBV 1000/1200
RBV 800
RBV 1000/1200
48 weeks
24 weeks
Hadziyannis SJ et al., EASL. 2002.
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Viral Hepatitisinitial tests

• IgM anti-HAV
• HBsAg, IgM anti-HBc
• Anti-HCV

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Viral Hepatismanagement

• Vaccinate
• Educate (alcohol etc.,)
• Evaluate for therapy

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Hepatitis A - Clinical Features

• Incubation period Average 30 days
• Range 15-50 days
• Jaundice by lt6 yrs, lt10age
  group 6-14 yrs, 40-50 gt14 yrs,
  70-80
• Complications Fulminant hepatitis Choles
  tatic hepatitis Relapsing hepatitis
• Chronic sequelae None

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