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Viral Hepatitis Clinical Correlation September 2006 Byron E. Kolts MD Professor of Medicine Division of Gastroenterology University of Florida Shands Jacksonville Campus


Jaundice and

Cholestasis

Drug Metabolism

LIVER DISEASE CATEGORIES

Hepatocellular

Biosynthetic

Necrosis

Capacity


Biochemical Effects

Acute

Hepatocellula r Necrosis

Alanine Aminotransferase (ALT) & Aspartate Aminotransferase (AST)

Chronic

Serum Albumin Prothrombin Time


Clinical Stages Incubation Period - the time from exposure to the onset of symptoms, virus shedding may precede symptoms Prodromal Period - symptoms preceding hepatitis signs such as jaundice Icteric Phase - clinically evident signs of variable duration, may recur Post-icteric Phase - clinical and biochemical recovery of variable duration


Clinical Spectrum Subclinical Infection – serologic and biochemical evidence of infection but asymptomatic. Clinical Infection – signs and symptoms of hepatitis, Acute fulminant – massive necrosis Acute self-limited – complete recovery Chronic carrier – usually non-progressive Chronic active – progressive damage +/- symptoms Cirrhosis and liver failure Hepatocellular carcinoma


Human Hepatitis Viruses

Human Hepatitis Viruses Virus

Genome

HAV

RNA

7.5

-

Picornaviridae hepatovirus

HBV

DNA

3.2

+

Hepadnaviridae

HCV

RNA

9.6

+

Flaviviridae hepacivirus

HDV

RNA positive sense, single stranded, linear RNA positive sense, single stranded, linear

1.7

+

Unclassified

7.5

-

Unclassified,

HEV

positive sense, single stranded, linear partially double stranded, circular positive sense, single stranded, linear

Genome Envelope size (kb)

Family / genus

(viroid), delta virus togavirus and alpha virus-like


Hepatitis C


Hepatitis C Virus: Morphology and Characteristics

Hepatitis C Virus • Nucleic Acid: 9.6 kb ssRNA • Classification: Flaviviridae, Hepacivirus 40-60 nm

• Genotypes: 1 to 6 • Enveloped • In vitro model: primary hepatocyte and T cell cultures; replicon system • In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates


Prevalence

HCV - Epidemiology

Prevalence Worldwide

170 million ( 3%)

United States Anti-HCV positive HCV RNA positive

3.9 million (1.8%) 2.7 million (1.4%)

Alter MJ et al., New Engl J Med 1999; 341:556 Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.) Hepatitis C. New York: Academic Press, 2000:185


Current Likelihood of Transmission

HCV - Epidemiology

Current Likelihood of Transmission Transfusion

~ 1 in 1,000,000

Maternal-Infant • Mother HIV-negative

~ 5%

• Mother HIV-positive

Heterosexual partner

15 - 20%

~1 in 1,000 per yr

Needlestick injury

• HCV-positive source • HCV status unknown

Terrault NA, Hepatology 2002 ;36(Suppl 1):S99 Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106

~ 5% ~ 1%


Outcome Following Hepatitis C Infection

HCV - Natural History

Outcome Following Hepatitis C Infection Acute hepatitis C 55 - 85%

Chronic infection 70%

Chronic hepatitis 20%

1 - 4%/yr

HCC

Cirrhosis Time (yr)

4 - 5%/yr 10

20

Decompensation 30


Diagnostic Tests

HCV - Diagnosis

Diagnostic Tests • Hepatitis C antibody tests • Qualitative HCV RNA tests • Quantitative HCV RNA tests • Genotyping


Acute hepatitis C infection

HCV - Diagnosis

Acute HCV Infection

1000

HCV RNA positive 800

Anti-HCV ALT

600

(IU/L)

Symptoms

400 200 0

0

2

4

6

8

Weeks

10

12

24

1

2

3

Time After Exposure

Hoofnagle JH, Hepatology 1997; 26:15S

4

5

Months

6

Normal ALT

7


Antibody tests for hepatitis C

HCV - Diagnosis

HCV Antibody Test • Indicates past or present infection • Inexpensive, sensitive and specific • Poor positive predictive value in low prevalence populations • Low sensitivity in immunosuppressed patients


Qualitative tests for HCV RNA

HCV - Diagnosis

Qualitative HCV RNA (PCR) • Confirms diagnosis of HCV infection • Useful in the early diagnosis of acute hepatitis C • Demonstrates the presence of active infection • “Gold standard” for documenting response to treatment


Clinical Features of Hepatitis C Transmission Oral Percutaneous Sexual Perinatal Incubation period Clinical Illness at presentation

No Common Yes, rare Yes, low frequency 14 – 160 (days) 5 - 10%


Clinical Features of Hepatitis C Jaundice Fulminant Diagnostic tests Acute infection Chronic infection >6 months Immunity Case-fatality rate Chronic infection

5 – 10% Rare HCV RNA (anti-HCV) HCV RNA (anti-HCV), Unknown 1 – 2% 60 – 85%


Hepatitis B


Hepatitis B Virus: Morphology and Characteristics

Hepatitis B Virus • Nucleic Acid: 3.2 kb DNA • Classification: Hepadnaviridae • Multiple serotypes and genotypes A-F

42 nm

• Enveloped

22 nm

• In vitro model: primary hepatocyte culture and transfection of cloned HBV DNA

HBsAg

42 nm

HBcAg

HBV DNA

• In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte and other tissues, human and other primates 4


Epidemiology of Hepatitis B

HBV - Epidemiology

Prevalence of HBsAg Carrier State

>8% 2-8% <2%

WHO


Risk factors for hepatitis B infection

HBV - Epidemiology

Risk Factors for Infection Percutaneous • Injection drug use • Transfusion or transplant • Occupational exposure • Parenteral practices Permucosal • Perinatal • Sexual • Household contact


Clinical Outcome of Acute Hepatitis B

HBV - Natural History

Outcome of Acute HBV Infection Recovery

Subclinical Hepatitis

Acute Hepatitis

Acute Infection Chronic Infection

Fulminant Hepatitis

Deat h


Risk of chronic infection

HBV - Epidemiology

Risk of Chronic Infection 100 80

%

60

Risk 40 20 0

Neonates

Infants

Children

Age at Infection

Adults


Clinical Outcome of Chronic Hepatitis B

HBV - Natural History

Outcome of Chronic HBV Infection Chronic HBV Infection

Inactive Carrier State

Chronic Hepatitis Cirrhosis HCC


Hepatitis B Virus: The Functions of Gene Products

Hepatitis B Virus

Gene Products and Functions Polymerase

Terminal protein (priming) Reverse transcriptase, RNAse H

Surface

Envelope proteins Receptor binding, Regulation of cccDNA, viral assembly Viral assembly, fusion sequence

Pre - S1 Pre - S2 S

Core

HBeAg Core

HBX

Primary structural component, major antigenic determinants Secreted, immunomodulatory function Nucleocapsid component Pleiotropic effects


Serological Markers of Acute HBV Infection

HBV - Diagnosis

Acute Infection HBV DNA HBeAg

Anti-HBe Anti-HBs

Anti-HBc

HBsAg

0

Anti-HBc IgM

2 Months

4

6

Years


HBV - Diagnosis

Serological Markers of Chronic HBV Infection

Chronic Infection HBV DNA HBeAg

Anti-HBe HBsAg Anti-HBc IgG

Anti-HBc IgM

Months

Years


Clinical Significance of Serological Markers for HBV Infection

HBV - Diagnosis

Serological Markers

Clinical Significance

HBsAg

Acute/Chronic infection

Anti-HBc IgM

Acute infection

HBeAg

High infectivity

Anti-HBe

Low infectivity

Anti-HBs

Immunity

Anti-HBc IgG and HBsAg

Chronic infection

Anti-HBc IgG and anti-HBs

Resolved infection


Clinical Features of Hepatitis B Transmission Oral Percutaneous Sexual Perinatal Incubation period Clinical Illness at presentation

Not likely Common Common Common 60-180 (days) 10 - 15%


Clinical Features of Hepatitis B Jaundice Fulminant Diagnostic tests Acute infection Chronic infection Immunity Case-fatality rate Chronic infection

5 –20% <1% HBsAg, IgM anti-HBc HBsAg, IgG anti-HBc IgG anti-HBc, anti-HBs 1 – 3% >90% infants <5% adults


Hepatitis D


Hepatitis D Virus: Morphology and Characteristics

Hepatitis D Virus • Nucleic Acid: 1.7 kb ssRNA • Classification: unclassified, related to viroids; deltavirus • HBV envelope 35-37nm

• One serotype, three genotypes • In-vitro model: primary hepatocyte culture and transfection of cloned HDV DNA • In-vivo replication: in nucleus, requires HBV for assembly and infection


Transmission of hepatitis D virus (HDV)

HDV

Epidemiologic Patterns Pattern

Distribution

Modes of transmission

Endemic

Mediterranean Middle East Central & South America Africa

Intra-familial Sexual

Non-endemic North America Northern Europe

Injection drug use Transfusion of clotting factor concentrates


Modes of HDV infection

HDV

Coinfection

B

D Superinfection

B D


HDV Co-infection

HDV

HDV - Coinfection ALT HDV RNA IgM anti-HDV

IgG anti-HDV

HDAg IgM anti-HBc HBsAg

IgG anti-HBc anti-HBs

Months


HDV Superinfection

HDV

HDV - Superinfection ALT HDV RNA IgM antiHDV HDAg

IgG anti-HDV

HBV DNA HBsAg, IgG anti-HBc Years


Clinical sequelae of HDV infection

HDV

Clinical Sequelae Coinfection

Superinfection

Acute hepatitis

Acute exacerbation

Uneventful recovery

Fulminant hepatitis

Chronic hepatitis

Cirrhosis and HCC


Clinical Features of Hepatitis D Transmission Oral Percutaneous Sexual Perinatal Incubation period Clinical Illness at presentation

No Common Yes, rare No 21 â&#x20AC;&#x201C; 45 (days) 10%, higher with superinfection


Clinical Features of Hepatitis D

Jaundice Fulminant Diagnostic tests Acute infection Chronic infection Immunity Case-fatality rate Chronic infection

Unknown 2 – 7.5% IgM anti-HDV IgG anti-HDV, HBsAg + Not applicable 1 – 2% Superinfection – 80% Coinfection < 5%


Hepatitis A


Hepatitis A Virus: Morphology and Characteristics

Hepatitis A Virus • Nucleic Acid: 7.5 kb ssRNA 27 nm

• Classification: Picornaviridae, Hepatovirus • One serotype and multiple genotypes • Nonenveloped, acid and heat stable • In vitro model: monkey and human cell cultures • In vivo replication: in cytoplasm of hepatocyte; human and other higher primates


Global Prevalence of Hepatitis A

HAV - Epidemiology

Global Prevalence of Hepatitis A Infection

HAV Prevalence High Intermediate Low Very Low


Prevalence of Hepatitis A in the United States

Prevalence of Hepatitis A in the United States

<5 5 - 10 10 - 20 >20 cases per 100,000 population CDC


Routes of Hepatitis A Transmission

Hepatitis A Transmission • Close personal contact Household or sexual contact Daycare centers

• Fecal-oral contamination of food or water Food handlers Raw shellfish Travel to endemic areas

• Blood-borne (rare)

Injecting drug users


Serological Course of Acute Hepatitis A

HAV

Typical Serologic Course of Acute Hepatitis A Virus Infection Symptoms

ALT

Total anti-HAV

Fecal HAV

0

1

IgM anti-HAV

2

3

4

5

6

Months after exposure

12

24


Age-specific Incidence of Hepatitis A

Clinical Variants of Hepatitis A Infection • Asymptomatic (anicteric) disease Children under 6 years of age, > 90% Children from 6-14 years old, 40-50%

• Symptomatic (icteric) disease Adults and children over 14, 70-80%


Hepatitis A Prevention: Immune Globulin

HAV

Hepatitis A Prevention - Immune Globulin Preexposure – Travelers to high HAV-prevalence regions

Postexposure (within 14 days) – Routine • Household and other intimate contacts

– Selected situations • Institutions (e.g. daycare centers) • Common source exposure (e.g. food prepared by infected food handler)


Hepatitis A Vaccination: Preexposure Vaccination

HAV

Hepatitis A: Pre-exposure Vaccination Persons at increased risk or danger of infection – Travelers to intermediate and high HAV prevalence areas – Men having sex with men – Injecting drug users – Persons with chronic liver disease

Communities with high rates of hepatitis A (e.g., Alaskan Natives, Native-Americans)

Routine pre-school childhood vaccination ACIP Recommendations MMWR 1999; 48(RR12):1


Clinical Features of Hepatitis A Transmission Oral Percutaneous Sexual Perinatal Incubation period (average 25) Clinical Illness at

Common Rare No No 15 â&#x20AC;&#x201C; 49 days 5% Children

presentation 70-80% Adults


Clinical Features of Hepatitis A Jaundice Fulminant Diagnostic tests Acute infection Chronic infection Immunity Case-fatality rate Chronic infection

Adults-30% Children-<5% <1% IgM anti-HAV Not applicable IgG anti-HAV 0.1 â&#x20AC;&#x201C; 2.7% None


Hepatitis E


Hepatitis E Virus: Morphology and Characteristics

Hepatitis E Virus • Nucleic Acid: 7.5 kb ssRNA

32 nm

• Classification: unclassified, togavirus, and alphavirus-like • One serotype with genetic heterogeneity • Non-enveloped, acid stable • Invitro model, no cell culture system • Invivo replication: in cytoplasm of hepatocyte; human and other primates


Epidemiology

Hepatitis E

Epidemiology • Suspected from study of waterborne hepatitis in India in 1980 • Confirmed by transmission to chimp and human in 1983 • Probably accounts for many historical outbreaks of hepatitis • Endemic mainly in Asia, Middle East, North Africa


Epidemiology

Hepatitis E

Epidemiology • Fecal-oral transmission (human to human) • Contaminated water supplies in tropical or subtropical developing countries • Mainly young adults • Can infect primates, swine, sheep, rats • Swine may be reservoir of infection in North America (attenuated virus) • Maternal-infant transmission occurs and is often fatal


Clinical Characteristics

Hepatitis E

Clinical Characteristics • Similar to hepatitis A • Can cause severe acute hepatitis • Subclinical infection is common

• Attenuated virus from animal reservoirs • Low-dose infections often asymptomatic

• No chronic infection • Up to 20% mortality among pregnant women (esp. third trimester)


Course of Acute Infection

Hepatitis E

Course of Acute Infection Viral Replication IgM Antibody IgG Antibody ALT

Viremia

Symptoms Virus in Stool 0

10

20 30 40 50 Time After Infection (days)

60

1 2 (years)


Prevention

Hepatitis E

Prevention Passive (Immune serum globulin) • Does not prevent infection • May ameliorate hepatitis

Active (Vaccine) • Anti-ORF2 prevents infection in chimps and humans • Clinical trials in progress


Clinical Features of Hepatitis E Transmission Oral Percutaneous Sexual Perinatal Incubation period Clinical Illness at presentation Jaundice

Common Unknown No Yes, unknown frequency 15 – 60 (days) 70 – 80% in adults Common


Clinical Features of Hepatitis E Fulminant Diagnostic tests Acute infection Chronic infection Immunity Case-fatality rate Chronic infection

<1%, in pregnancy up to 30% IgG anti-HEV (seroconversion) Not applicable Not applicable 0.5 â&#x20AC;&#x201C; 4% 1.5 â&#x20AC;&#x201C; 21% in pregnant women None


Other Hepatitis Viruses


Additional Hepatitis Agents

Additional Hepatitis Agents • 12% of post transfusion hepatitis unrelated to A-E • 18% of acute hepatitis unrelated to A-E • Up to 40% of fulminant hepatitis no etiology is present • Cases of acute hepatitis followed by aplastic anemia Alter H, AASLD Postgraduate course syllabus. 2002; 68-75


Hepatitis A Vaccine Efficacy Studies

HAV

Hepatitis A Vaccine Efficacy Vaccine

Site/Age Group

N

HAVRIX  Thailand 38,157 1-16 yrs 2 doses 360 EL.U.

94%

VAQTA 

1,037

1 dose 25 units

New York 2-16 yrs

JAMA 1994; 271:1363; N Engl J Med 1992; 327:453

Vaccine Efficacy (95% CI) (79%-99%)

100% (85%-100%)


Hepatitis E vs. Hepatitis A

Hepatitis E

Hepatitis E vs. Hepatitis A HEV

HAV

Fecal-oral transmission

Yes

Yes

Transmission in family

No

Yes

Developing

Worldwide

Young adults

All

Subclinical infection

Yes

Yes

Chronic infection

No

No

Distribution countries Ages infected


Prevalence In Groups at Risk

HCV - Epidemiology

Prevalence In Groups at Risk Recipients of clotting factors before 1987

75 - 90%

Injection drug users

70 - 85%

Long-term hemodialysis patients

10%

Individuals with > 50 sexual partners

10%

Recipients of blood prior to 1990

5%

Infants born to infected mothers

5%

Long-term sexual partners of HCV positive

1 - 5%

Health workers after random needlesticks

1 - 2%

CDC, MMWR 1998;47(No. RR-19):1


Evolution of treatment for chronic hepatitis C

HCV - Treatment

Evolution of Treatment for Chronic Hepatitis C 60 55 46

40

SVR %

30 20 15 0

6

IFN 24wk

IFN 48wk

PEG IFN

INF/R

PEGINF/R


Vaccination of selected high-risk groups in adults

HBV - Vaccine

Indications in Adults • Sexual and household contacts of carriers • Sexually active individuals with multiple sex partners and men who have sex with men • Injection drug users • Hemodialysis patients • Recipients of clotting factor concentrates • Families of adoptees from endemic areas CDC and WHO


Indications for HBV vaccination

HBV

Vaccine Indications • HBIG and HB vaccine to infants of HBsAg+ mothers • Routine vaccination of infants and adolescents • Catch-up vaccination of children • Vaccination of adults at risk of infection


Vaccination of selected high-risk groups in adults

HBV - Vaccine

Indications in Adults (con’t.) • Health care and public safety workers with occupational risks • Persons in institutions for the developmentally disabled or in long-term correctional facilities • Travelers to countries endemic for hepatitis B who plan to stay > 6 months • Transplant candidates before transplantation • Patients with chronic liver disease CDC and WHO


Hepatitis B immune globulin for neonates born to HBsAg+ mothers

HBV - Vaccine

Neonates of HBsAg+ Mothers Vaccine HBIG 0 Birth

1

6

Months


Dose schedule of HBV vaccine

HBV - Vaccine

Dose Schedule Vaccine

Age Group

Dose

Volume

# Doses

Engerix-B

0-19 yr â&#x2030;Ľ 20 yr Adults on hemodialysis

10 20

0.5 1.0

3 (mo 0,1,6) 3 (mo 0,1,6)

40

2.0

4 (mo 0,1,2,6)

0-19 yr â&#x2030;Ľ 20 yr 11-15 yr Adults on hemodialysis

5 10 10

0.5 1.0 1.0

3 (mo 0,1,6) 3 (mo 0,1,6) 2 (mo 0, 4-6)

40

1.0*

3 (mo 0,1,6)

Recombivax HB (Optional 2-dose)

*Special Formulation

(ug)

(ml)


Combined hepatitis A and B vaccines

Combined HAV and HBV - Vaccine

Twinrix • Bivalent HAV and HBV vaccine • 1ml contains 720 ELISA Units of inactivated HAV and 20 ug of recombinant HBsAg protein • Dosage: 1 ml at 0, 1, 6 months • Recommended for all susceptible persons ≥ 18 years at risk of exposure to both HAV and HBV, including travelers to areas of high/intermediate endemicity for both viruses Knoll A, Vaccine 2000; 18:2029


Immunogenicity of Twinrix

Combined HAV and HBV - Vaccine

Immunogenicity of Twinrix 100 Anti-HAV Anti-HBs

75

Seroconversion 50 (%) 25 0

0

7

24

Months Twinrix vaccinations Thoelen S, Vaccine 1999; 26:1657

36

48


Management of non-responders

HBV - Vaccine

Management of Non-responders Primary series No response

5-10%

Repeat 3-dose series

Respons e 50% - 75% Immunocompetent adults

No response Test for HBsAg


Therapeutic agents for chronic hepatitis B

HBV - Therapy

Therapeutic Agents Immune Modulators

Nucleo(s)tide analog

Interferon

Lamivudine

Thymosin

Adefovir dipivoxil

Therapeutic vaccines

Emtricitabine Entecavir L-dT/ L-dC Clevudine Famciclovir


Treatment of chronic hepatitis D

HDV - Therapy

Treatment Indications Chronic infection

HBsAg+, anti-HDV for > 6 months

Replicative infection

Serum HDV RNA+

Active liver disease

Elevated ALT Chronic hepatitis Âą cirrhosis

Recommendations IFN 9 MU tiw for 12 months

13h فيروسات الكبد ممتاز  
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