Viral Hepatitis

Susanne Burger, M.D.

Jacobi Medical Center

North Central Bronx Hospital

Viral Hepatitis - Overview

A B C D EIncubation Period

15-50 days (mean 28)

60-180 days

(mean 120)

15-180 days (mean 42)

15-60 days 15-60 days (mean 42)

Tansmission fecal-oral Bloodborne

Sexual

Bloodborne

Sexual

Bloodborne

Sexual

fecal-oral

Progression to chronicity

no yes yes yes rarely

Comments Vaccine available

Vaccine available

Occurs only as co-infection with HBV or as superinfection of chronic HBV

Vaccine under develop ment

Type of Hepatitis

Case 1

A 21 y/o female college student has a 1-week h/o malaise,anorexia, nausea, and vomiting. Three weeks ago, she returned from Guatemala, where she had engaged in missionary work.PE: T 101, mild jaundice and a palpable, tender liver.Labs: HCT 48%WBC 9000/μlINR 1.0Alk Phos 110 U/LAST 1100 U/LALT 1700 U/LTotal Bili 3.0 mg/dl

(A) Ab to hepatitis B surface antigen (anti-HBs)

(B) Ab to hepatitis C virus (anti-HCV)(C) Indirect hemagglutination test for

Entamoeba histolytica(D) IgM antibody to hepatitis A virus

(IgM anti-HAV)(E) Ebstein-Barr virus DNA

Which of the following laboratory tests is most likely to establish the diagnosis?

Hepatitis A Virus

RNA picorna virus, incubation period ~ 30 days Transmission: close personal contact, contaminated

food or water Jaundice by age group: <6 years <10%

6-14 yrs 40-50% >14 yrs 70-80%

Rare complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis

Chronic sequilae: None Treatment: symptomatic

Geographic Distribution OfHepatitis A Virus Infection

Reported Cases Of Hepatitis A,United States, 1952-2002

Hepatitis A Vaccine

Events in Hepatitis A Virus Infection

Hepatitis A vaccine

Highly immunogenic 97-100% have protective levels of antibody within 1

month of receiving first dose; essentially 100% have protective levels after second dose

Post vaccination testing NOT recommended Commercially available assay not sensitive

enough to detect lower (protective) levels of vaccine-induced antibody

Provides protection even when administered following exposure to the virus – now preferred approach in between 1 – 40 years of age

Case 2

A 25 y/o woman is brought to the ER by her husband for yellowing of the eyes and increasing confusion and somnolence. The pt is 30 wks pregnant and just returned from visiting her parents in Africa. She has been previously healthy and only takes prenatal vitamins. She has been a social drinker until her pregnancy. PE: T 99.0 ºF, BP 90/40, HR 100, BMI 20Exam reveals a gravid uterus and asterixis.

Laboratory Studies

Hb 14g/dl HAV IgM neg

WBC 15,000/µl HBV SAg neg

PLT 450K HBV DNA neg

INR 4.7 HCV Ab neg

Bili (total) 12.0 mg/dL ANA neg

Bili (direct) 9.0 mg/dl Anti smooth neg

AST 3000 U/L Antimitochondrial Ab neg

ALT 2870 U/L Alcohol neg

Alk phos 400 U/L Herpes simplex virus (PCR)

Alb 2.3 g/dl neg

Ammonia 120 µg/dL

What is the most likely cause of this patient’s fulminant hepatic failure?

What is the most likely cause of this patient’s fulminant hepatic failure? HEV

Single most important cause of acute hepatitis in Central/S Asia and second only to HBV in Middle East and N Africa.

Transmission by fecal-oral exposure to contaminated water

In developed countries HEV related to international travel

5 domestic US cases, likely zoonotic spread

Hepatitis E

NEJM 2004,351;23

Case 3

A 30 y/o man comes to the emergency department because of a 1-week h/o of N/V, arthralgias, and dark urine. The pt has a h/o multiple sexually transmitted diseases. He drinks ~ 2 glasses of wine/d and denies the use of illicit drugs and over-the-counter prescription medications. PE reveals jaundice and a tender, enlarged liver. There are no other stigmata of chronic liver disease.

Labs:HCT 49% ALT 1550 U/LWBC 11,000/μL Total Bili 6.5 mg/dLINR 1.1Alk Phos 90 U/LAST 850 U/L

(A)IgM antibody to hepatitis B core antigen (HBV cor Ab IgM)

(B)IgG antibody to cytomegalovirus (CMV Ab IgG)

(C)Antibody to hepatitis B surface antigen (HBV S Ab)

(D)Antibody to hepatitis B e antigen (HBV e Ab)(E)IgG antibody to hepatitis A virus (HAV IgG

Ab)

Which of the following laboratory studies is most likely to establish the correct diagnosis?

Hepatitis B

5% of the world’s population is chronically infected with hepatitis B (~350 million cases)

Hepatitis B is the 10th leading course of death globally leading to more than 600,000 premature deaths annually

Half of all deaths are attributed to HCC

Age of Infection Modes of Transmission

Risk of Developing chronic HBV Infection

Birth Perinatal 90%

0-5 years Horizontal: person to person; interfamilial via open cuts and scratches

Unsafe injections

25 – 30 %

> 5 years Horizontal: person to person; interfamilial via open cuts and scratches

Unsafe injections

Sexual Transmission

Injection-drug use

5 – 7%

Routes of Transmission of HBV and Risk of Chronic Infection by Age

Prevalence

HBV vaccine efficacy

12.812

9.38.2

6.25.4

4.1

2.20.9

8.8

0

14.76

0.030.80.8

1.40.8

1.90.9

3

0.51.4

0

2

4

6

8

10

12

14

16

South Africa Gambia Taiw an Alaska Indonesia Thailand Singapore Egypt Japan Urban China Rural China

Pre

va

len

ce

of

HB

SA

g

Preimmunization Postimmunization

Acute Hepatitis B Virus Infection with Recovery - Typical Serologic Course

Progression to Chronic Hepatitis B Virus Infection - Typical Serologic Course

Natural Course of Hepatitis B

Stages of chronic hepatitis B: Summary

HbeAg HbeAb HBV-DNA

ALT Histology

Immune tolerant chronic HBV

Chronic hepatitis B

1) HbeAg pos HBV

2) HbeAg neg HBV

Inactive HbSAg carrier state

Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87

Stages of chronic hepatitis B: Summary

HbeAg HbeAb HBV-DNA

ALT Histology

Immune tolerant chronic HBV

+ - (>105)

nl nl

Chronic hepatitis B

1) HbeAg pos HBV

2) HbeAg neg HBV

Inactive HbSAg carrier state

Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87

Stages of chronic hepatitis B: Summary

HbeAg HbeAb HBV-DNA

ALT Histology

Immune tolerant chronic HBV

+ - (>105)

nl nl

Chronic hepatitis B

1) HbeAg pos HBV + - (>105)

Chronic hepatitis

2) HbeAg neg HBV

Inactive HbSAg carrier state

Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87

Stages of chronic hepatitis B: Summary

HbeAg HbeAb HBV-DNA

ALT Histology

Immune tolerant chronic HBV

+ - (>105)

nl nl

Chronic hepatitis B

1) HbeAg pos HBV + - (>105)

Chronic hepatitis

2) HbeAg neg HBV - + (>104)

Chronic hepatitis

Inactive HbSAg carrier state

Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87

Stages of chronic hepatitis B: Summary

HbeAg HbeAb HBV-DNA

ALT Histology

Immune tolerant chronic HBV

+ - (>105)

nl nl

Chronic hepatitis B

1) HbeAg pos HBV + - (>105)

Chronic hepatitis

2) HbeAg neg HBV - + (>104)

Chronic hepatitis

Inactive HbSAg carrier state

- + (<104)

nl Various degree of fibrosis

Adapted from Lok AS, Hepatology. 2001;34:1225; Keeffe EB, Clin Gastroenterol Hepatol. 2004; 2;87

Replication cycle of Hepatitis B

HBV Disease Progression

Chronic infection

Acuteinfection Cirrhosis

Liver failure

(decompensation)

Liver cancer (HCC)

Liver transplantation

Death

90% of children< 5% of adults1

30%1

5 – 10%1,3

23% in 5 yrs2

Chronic HBV is the 5th leading cause of liver transplantationIn the US4

Torres J, Gastroenterology. 2000;118:83Fattovich G, Hepatology. 1995;21:77Moyer LA, Am J prev med. 1994;10:45Perillo R, Hepatology. 2001;33:424

Therapy for chronic HBV approved by the FDA

Interferon alfa-2b (1992) Lamivudine (1998) Adefovir dipivoxil (2002) Entecavir (2005) Peginterferon alfa-2a (2005) Talbivudine Viread

Treatment endpoints in chronic HBV

HBeAg loss or seroconversion

HBsAg clearance

Normal ALT

Decreased HAI and fibrosis

cccDNA clearance

Undetectable serum HBV DNA

Treatment endpoints

Cumulative Probability of LAM and ADV Resistance

0%

10%

20%

30%

40%

50%

60%

70%

80%

year 1 year 2 year 3 year 4

ADV(N236T orA181V)LAM(YMDD)

ENT

TFV

Case 4

A 34 y/o nurse reports a needle stick injury. After drawing blood from a pt, the nurse inadvertently stuck the needle into his own finger. The source pt is known to be HBsAg +. The nurse was vaccinated against HBV when he was hired 3 yrs ago. He completed the series of three injections but has never had a serologic confirmation of his response.

(A) Administer hepatitis B immune globuline immediately and restart his immunization sequence

(B) Check his antibody response to the hepatitis B vaccination; if antibodies are inadequate, administer hepatitis B immune globulin and restart his immunization sequence.

(C)Check his antibody response to the hepatitis B vaccination; if antibodies are adequate, administer only hepatitis B immune globulin

(D) As the nurse has completed his hepatitis B vaccination series, no intervention is necessary

Which of the following post-exposure options is mostappropriate for this health care worker?

Case 5

A 44 y/o male IDU has a 5 day h/o malaise, N/V, RUQ discomfort, and jaundice. He takes no medications and drinks ~ 6 cans of beer/d. He has not had any sexual contact for the past 18 months and has never traveled outside the United States. Review of his medical records shows normal serum aminotransferase values despite having repeated pos tests for HBsAg.

Labs 8 weeks ago:AST 24 U/LALT 28 U/LHBV DNA undetectableHBsAg positive

Current labs:CBC normalCoags normalAlk Phos 117 U/LAST 900 U/LALT 1050 U/LTotal bili 7.8 mg/dl

HBV DNA undetectableHBsAg positiveHBeAg negativeHbeAb positive

Physical examination today discloses jaundice. The liver is mildly tender; liver span is 15 cm.

(A)Hepatitis D virus infection(B)Hepatitis E virus infection(C)Acute Ebstein-Barr virus hepatitis (D)Granulomatous hepatitis (E)Alcoholic hepatitis

Which of the following is most likely the cause of this patient’s current clinical presentation?

Case 6

A 25 y/o female IDU comes to the ER because of a 10-day h/o progressive fatigue, anorexia, and abdominal discomfort. The pt uses daily heroin and drinks ~ 2-3 cans of beer/d.PE: jaundice, tender, enlarged liverLabs:CBC WNL HBsAg negativeINR 1.1 Hep A Ab IgM negativeAlk Phos 120 U/L Hep C Ab negativeAST 1250 U/L Hep B cor Ab IgM negativeALT 2120 U/LTotal bili 3.5 mg/dl

(A)Hep A Ab IgG(B)Hep B cor Ab IgG(C)HCV RNA(D)HBsAb(E)Antimitochondrial antibody titer

Which of the following tests is the most likely to establish the diagnosis?

Diagnostic approach to hepatitis C virus infection

Diagnostic approach to hepatitis C virus infection

Hepatitis C Elisa

positive negative

Diagnostic approach to hepatitis C virus infection

Hepatitis C Elisa

positive negative

Confirm chronic infection:Hep C PCR (qual/quant)

positive negative

Diagnostic approach to hepatitis C virus infection

Hepatitis C Elisa

positive negative

Confirm chronic infection:Hep C PCR (qual/quant)

positive negative

Chronic HCV

Vaccinate againstHBV, HAV

HCV cleared,but repeat PCR

once in 6 months

Diagnostic approach to hepatitis C virus infection

Hepatitis C Elisa

positive negative

No HCV unless pt severely

immunocompromisedor

high index of suspicionfor acute Hep C

Confirm chronic infection:Hep C PCR (qual/quant)

positive negative

Chronic HCV

Vaccinate againstHBV, HAV

HCV cleared,but repeat PCR

once in 6 months

Who should be tested?CDC Recommendations

• Test:– h/o IVDU

– Received clotting factors before 1987, blood/organs before 1992

– Chronic hemodialysis

– Evidence of liver disease

– Intranasal cocaine users

– h/o tattooing, body piercing

– h/o STDs or multiple sex partners

– Long-term steady sex partners of HCV-positive persons

• Do not test: – Healthcare workers

– Pregnant women

– Household (non-sexual) contacts of HCV-positive persons

– General population

Serologic Pattern of Acute HCV Infection with Progression of Chronic

infection

Natural Course of Hepatitis C

Treatment of chronic Hepatitis CEvolution of HCV therapy

18

25

38 40

54 56

63

0

10

20

30

40

50

60

70

Pat

ient

s w

ith

sust

aine

d vi

rolo

gica

l res

pons

e (%

)

IFN

Peginterferon alfa-2b

Peginterferon alfa-2a

IFN/RBV

Peginterferon alfa-2b/RBV(ITT)Peginterferon alfa-2a/RBV(ITT)Peginterferon alfa-2b/RBV(80/80/80)

Mc Hutchinson et al., Lindsay et al. Zeuzem et al. Manns et al. Fried et al.

20041990s

Response Patterns

Peginterferon/Ribavirin

0

1

2

3

4

5

6

7

8

-6 0 4 6 12 18 24 30 36 42 48 54 60 66 72

WEEKS

Lo

g H

CV

RN

A (

IU/m

l)

2-log decline

Limit of detectionSVR

Time to response and SVRGenotype 1

Week 4 15%Null

20%

Partial 15%

91

66

45

0102030405060708090

100

4 12 24

Week HCV RNA (-)

SV

R (

%)

Week 1235%

Week 2415%

P Ferrenci et al.J Hepatology 2005;43:453-471

Treatment of HCVImpact of STAT-C Drugs

0

1

2

3

4

5

6

7

8

-6 0 4 6 12 18 24 30 36 42 48 54 60 66 72

WEEKS

Lo

g H

CV

RN

A (

IU/m

l)

2-log decline

Limit of detectionSVR

Telaprevir – PROVE 1Study Design

PEGIFN+R+Telaprevir

PEGIFN+R+Telaprevir

PEGIFN+R+Telaprevir

PEGIFN+Ribavirin

0 12 48Weeks

JM McHutchinson et al.EASL 2008

24

PEGIFN+R

PEGIFN+R

All patients GT 1Treatment naive

11

59

80 81

45

7168

80

4135

6167

0

10

20

30

40

50

60

70

80

90

Control T+0 T+12 T+36

% o

f P

atie

nts

Week 4

Week 12

SVR

Telaprevir – PROVE 1Phase 2 Final Results

JM McHutchinson et al.EASL 2008

Boceprevir – SPRINT 1Boceprevir – SPRINT 1Study DesignStudy Design

PEGASYS + Ribavirin

0 48Weeks

P Kwo et al.EASL 2008

244

PEG-INTRON + RBV

PEG-INTRON + RBV + B

PEG-INTRON + RBV

PEG-INTRON + RBV + B

PEG-INTRON + RBV + B

PEG-INTRON + RBV + B

8

34

6056

62

74

0

10

20

30

40

50

60

70

80

RVR SVR

% H

CV

RN

A (

-)

PEG/RBV

PEG/RBV/Bo/24wks

PEG/RBV/Bo/48wks

Boceprevir – SPRINT 1Boceprevir – SPRINT 1Lead In Phase ResultsLead In Phase Results

P Kwo et al.EASL 2008