Viral Hepatitis

Carla S. Coffin, MSc, MD, FRCPC

Liver Unit
Division of Gastroenterology
University of Calgary

Objectives: Viral Hepatitis

Review epidemiology
Recognize clinical presentation
Interpret serologic testing
Know available treatments
Cases

Viral Hepatitis
Infectious
Viral
hepatitis
Serum

A E
Non A-E

B C

Enterically
transmitted
CMV, EBV
HSV, others
Parenterally
transmitted

Acute Viral Hepatitis: Presentation

Symptoms

Signs/Labs

Adults >> infants, children

Jaundice (mild to severe)

Typically within 1-2 weeks

of prodrome

Hepatomegaly: mild

Fatigue, anorexia, nausea,

vomiting, fever, headache,
arthralgia, myalgia,
diarrhea, RUQ or epigastric
discomfort

AST, ALT >500U/L typically

and often >1000 U/L. Initially
levels fall rapidly -- then more
slowly

Splenomegaly: mild if at all

Jaundice: Scleral icterus

dark urine, pale stool,
pruritus

Bilirubin levels peak later than

ALT. Normalization within 3
mos in 85% cases

Duration: typically 2-4wks

INR >1.5 should raise concern

about incipient fulminant
failure

Hepatitis A Virus

Factors Associated With Reported

Hepatitis A in USA 1990-2000
Sexual or
Household
Contact 14%

Unknown
46%

Other Contact
8%

International
travel 5%
Men who have
sex with men
10%
Injection drug
use 6%

Day-care contact
child/employee 6%

Food- or
waterborne
outbreak 4%

Child
employee in
day-care 2%

CDC Data

Hepatitis A: Diagnosis
Incubation
period:1549d, avg 25d

Clinical illness

ALT
IgM anti-HAV

Infection

Levels

IgG anti-HAV
Viremia
HAV in stool

Titers of IgM fall to

undetectable levels
between 6-12 mos

Week

10

11

12

13

Notable Clinical Features of HAV

No chronic hepatitis
High attack rate ~90% exposed ->infected
Prodrome usually leads to jaundice within 1-2 wks
Can cause ALF, older adults, immune
compromised, pts with CLD at risk
Atypical Patterns of Infection
Relapsing -- occurs in up to 10%
Recurrent transaminitis and HAV in stool/serum 1-3
mos after initial resolution

Prolonged Cholestasis
Jaundice > 12 wks, pruritus, constitutional symptoms
Short steroid taper may help

Prevention and Treatment HAV

General
Hygiene (e.g., hand
washing)
Sanitation (e.g., clean
water sources)

Specific
Hepatitis A vaccination
(pre-exposure)
Immune globulin (pre- and
post-exposure)
Pre-exposure --> travelers to

intermediate and high HAVendemic regions

Post-exposure - within 14 d

Recommendations For Adult

HAV Vaccination

Men who have sex with men

Illicit drug users
International travelers
People with clotting factor
disorders
Patients with chronic liver
disease

Treatment Hepatitis A:

Supportive
LTx referral if fulminant hepatitis develops

HAV Infection in Persons with Chronic Liver

Disease
Vento, N Engl J Med, 1998

Prospective study of 595 patients with chronic

hepatitis C (432) or B (163)
HAV superinfection in 10 pts with hepatitis B and 17
pts with hepatitis C
Fulminant hepatic failure in 1 patient with hepatitis B
and 7 patients with hepatitis C (6/7 pts. died)

Message: HAV vaccination

Hepatitis E Virus

HEV Epidemiology: 2 Patterns

Endemic Areas

Non-Endemic Areas

Epidemics and Sporadic cases

Sporadic cases

Fecal-oral transmission via

contaminated water supplies;
worse during heavy rain
season
Fatality rate 0.5-4%.
Higher fatality rate during
pregnancy (->30%),
Primarily in African, Indian
subcontinent and Central
America

Travelers returning from

endemic areas
Domestic cases rare

Hepatitis E - Notable Clinical

Features

No chronic hepatitis; long-lasting

immunity after exposure
Low rate of illness among household
contacts
Peak ALT corresponds with onset of
jaundice
Fulminant courses and case fatalities
occur more frequently in pregnancy

Hepatitis E: Control and

Prevention
General

Avoid drinking water and ice of unknown purity

uncooked shellfish, vegetables and fruit
Improved sanitation

Specific

None available
Passive Ig - no proven efficacy
Vaccine under evaluation

Chronic Viral Hepatitis

Infectious
Viral
hepatitis
Serum

A E
Non A-E

B C
D

Enterically
transmitted
CMV, EBV
HSV, others
Parenterally
transmitted

Agents of Chronic Viral Hepatitis

HBV

Disease Burden
Chronic infections

1.25 mill

Chronic liver disease

deaths/year

5, 000

Percent Ever Infected 4.9%

HDV

HCV

70,000

2.7 mill

1,000

8,000 10,000

No data

1.8%

US: ~4 million with chronic viral infections

Canada: HBV & HCV ~450,000
Source: NHANES III and CDC, unpublished data

Chronic Viral Hepatitis Presentation

Symptoms
Most asymptomatic
If symptoms present -nonspecific
Fatigue most common
Jaundice uncommon until
cirrhosis
Extrahepatic manifestations
may predominant

Signs/Labs
Stigmata of CLD,
hepatomegaly uncommon
Splenomegaly, signs of
Portal hypertension if
cirrhosis
AST, ALT <500 U/L, usually
<250 U/L. Higher levels if
HBV flare
Liver function tests
abnormal (PT, bilirubin,
albumin) if cirrhosis

Hepatitis C

Risk Factors for Hepatitis C

Clotting Factor
Treatment Prior
to 1987
Long-Term
Hemodialysis

Multiple
Sexual Partners

Risk Factors
for Hepatitis C

Mass Injections
and Traditional
Practices

Blood
Transfusion
or Organ
Transplant
Prior to 1992
Injection
Drug Use

Birth from
Infected Mother

HCV Infection: Diagnosis

2000

100,000,000

HCV RNA + by day 12 avg

1800

10,000,000

1600
1400

No Symptoms

100,000

ALT

1200

10,000

1000
800

HCV RNA

1,000,000

1,000

600

HCV EIA + wk 10 avg

100

400

10

200
0

10

15

20

25

Weeks post-exposure

30

35

Anti-HCV after
3 mos.
HCV RNA PCR
after 1 mo.

Natural history

Marcellin, J Hepat 1999

Impact of Chronic HCV

Epidemic of new HCV cases is

declining
Complications of chronic HCV are
increasing
Simulation analysis: from 1998 2008
in Canada we should expect:

92% more cirrhosis cases

126% more liver failures
102% more HCC
Zou, Can J Gastro 2000

Chronic HCV: Treatment Goals

HCV Infection

Viral Eradication

Delay Disease
Progression

Definitions of Treatment
Responses in Hepatitis C

Early virological response (EVR): Decrease in

HCV RNA by >2 logs10 (or to < 50 IU/ml) after
12 weeks of therapy

End of treatment response (ETR): HCV RNA <

50 IU/ml at end of treatment

Sustained virological response (SVR): HCV

RNA < 50 IU/ml 6 months after completing
treatment

HCV Genotype Definition

Terminology

Definition

% Nucleotide
similarity

Example

Genotype

Sequence
heterogeneity
between
isolates

66-69%

G1, 2, 3

Subtype

Related isolates 77-80%

within a
genotype

G1a, 1b

Zein, Clin Microbiol Rev 2000;13:222-235

Hepatitis C Genotypes
G 1 = ~70% of HCV in NA
G2/3 = ~30% of HCV in NA
G4 = Middle East and Egypt
G5 =
G6 = Vietnam

Evolution of Therapy for Chronic

Hepatitis C
60
55
46

40
30
20
15
0

IFN 24wk IFN 48wk

PEG IFN

INF/R

PEGINF/R

HCV Therapy: lessons from

the past

Poor response to IFN alone

Better response by adding RBV

Concept of differential duration of therapy

and genotype targeted therapy

Current HCV Therapy:

Making IFNs more effective
Tailoring therapy by genotype
80:80 rule (80% dose RBV, 80%
time)
Implications of an SVR

Pegylated Interferons
PEG-IFN 2a

PEG-IFN 2b

PEGASYS

PEG-INTRON

Serum Levels

Optimizing IFN-Alfa

PEG- IFN

Standard IFN

Time

1 Week

Genotype Tailored Therapy

Need to measure genotype before starting

therapy to determine:

1) Duration of therapy
12 months for G 1 and 6 months for G 2/3

2) Dose of ribavirin
800 mg for G 2/3 vs 1000/1200 mg for G 1

Predictors of response to IFN plus

RIB therapy
Genotype 2 or 3
Genotype 1
Minimal Fibrosis
Advanced Fibrosis
Low HCV RNA
High HCV RNA
Age 40
Age > 40
Female
Male
Weight 75 kg
Weight > 75 kg

20

40

% SVR
Semin Liver Dis 1999;19(Suppl 1):57

60

80

What is an SVR??
SVR = no detectable HCV RNA
by RT-PCR when measured 6
months after stopping therapy

PEGIFN+ RBV:
SVR in Patients With Genotype 1
51
SVR (%)

50
40
30

41

40

n = 118

n = 250

29

20

10

n = 101
0

n = 271

PEG-IFN -2a 180 mg qw

RBV
RBV
800 mg/day 1000/1200 mg/day

24 Weeks

RBV
RBV
800 mg/day 1000/1200 mg/day

48 Weeks
Hadziyannis et al. Ann Int Med 2004; 140:346

PEGIFN-2a [40KD] + RBV: SVR in

Patients With HCV Genotype 2/3
90
80

78

78

73

77

n = 111

n = 165

SVR (%)

70
60

50
40
30
20
10

n = 106

n = 162

PEG-IFN -2a 180 mg qw

RBV
800
mg/day

RBV
1000/1200
mg/day

24 Weeks

RBV
800
mg/day

RBV
1000/1200
mg/day

48 Weeks
Hadziyannis et al. Ann Int Med 2004;140:346

Major adverse events reported

with IFN therapy

Flu-like symptoms

Injection-site reactions

Myalgia and arthralgia

Nausea, anorexia, weight loss

Neuropsychiatric side effects

Bone marrow suppression

Thyroid dysfunction

Exacerbation of underlying autoimmune

disease

Major side effects of Ribavirin

Teratogenic

Hemolytic anemia

Skin rash

Cough

Insomnia

Principles of Side Effect

Management

Some adverse effects may diminish

with continued therapy (tachyphylaxis)

Dose reduction or discontinuation may

be required

Patients and caregivers should be

informed about possible side effects

General Management of Flulike Symptoms

Acetaminophen / other analgesics
Bedtime / early evening
administration

Conserve energy

Drink plenty of fluids

Eat balanced meals/exercise

Focus on the positive

Management Psychiatric Issues

Occurs in up to 37% of patients

(higher in homeless?)

Conduct pre-therapy and routine clinical

assessments

Adjust interferon dose or discontinue therapy

according to severity

May warrant use of antidepressants such as

SSRIs

Summary HCV Therapy

HCV RNA and Genotype

12 wk HCV RNA Quantitative

< 2 Log drop

> 2 Log drop

STOP

24 wk G2/3

6 mo HCV RNA (SVR)

48 wk G1

End of Rx HCV RNA (ETR)

Hepatitis B

Worldwide Burden of HBV

>2 billion have been infected1

100 times more contagious than HIV2
4 million acute cases per year1
350 million chronic carriers1
Nearly 75% of chronic carriers are Asian3
25% of carriers die from chronic active hepatitis,
cirrhosis, or liver cancer1
1 million deaths per year1
Second only to tobacco as most important
carcinogen4
Causes ~60% of all primary liver cancer worldwide1
1. WHO. Hepatitis B. 2002. 2. CDC. MMWR. 2001;50:RR-11. 3. Maynard JE, et al. In: Viral Hepatitis and Liver Disease.
New York: Alan R. Liss, Inc; 1988. 4. CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. The Pink Book.
8th ed.

Natural History of Chronic HBV

HBeAg
Anti-HBe

HBV DNA
Treatment opportunity 1

Treatment opportunity 2

ALT
Immune
Tolerant
Normal or
minimal hepatitis

Immune
Clearance
Chronic
hepatitis

Immune
Inactive

Reactivation

Normal or
Progressive
inactive hepatitis
fibrosis

Cirrhosis
HCC

Liver
Histology

Adapted from Zakin & Boyer (eds). Hepatology: A Textbook of Liver Disease, 5th edition

Hepatitis B Serology

Anti-HBc exposure (IgM = acute)

HBsAg infection (carrier)
anti-HBs immunity
HBeAg Viral replication

Pre-core mutants cant make HBeAg

Anti-HBe seroconversion
HBV-DNA Viral replication

Chronic HBV:
A Dynamic Disease

Longitudinal follow-up of ALT and HBV

DNA levels to determine phase of
infection

HBeAg seroconversion may not be a

stable event

A single ALT or HBV DNA level is not enough

Reversion to HBeAg or evolution to HBeAgnegative active disease can occur

Long term monitoring required to

determine time to intervene with treatment

Indications for HBV Vaccination

Illicit Intravenous Drug Users
Men having sex with men (MSM)
Heterosexuals with multiple sexual partners or
recent STD
HCWs, including laboratory personnel
Staff/clients of correctional institutes and
institutes with mentally handicapped individuals
Recipients of pooled blood products
Infants of HBsAg+ mothers (plus HBIG)
All sexual and household contacts of HBsAg+
persons
Recommendation of the Immunization Practices Advisory Committee (ACIP)
Inactivated Hepatitis B Virus Vaccine, 1982 and 1985

Who is Recommended to
Undergo HCC Surveillance?
Cirrhosis Present
Hepatitis B and C
Alcoholic cirrhosis
Primary biliary cirrhosis
Genetic
hemochromatosis
Consider if*:
Alpha 1-antitrypsin
Non-alcoholic fatty liver
disease
Autoimmune hepatitis

No Cirrhosis,
Chronic Hepatitis B

* At increased risk, but lack of data to

determine if surveillance beneficial

Asian males 40 yrs

Asian females 50
years
Africans 20 yrs
All those with cirrhosis
Family history of liver
cancer

AASLD Practice Guidelines, 2005

Chronic HBV Infection

Who Should be Treated?
Treatment indicated in those with active disease

Activity defined by:

Elevated ALT, AST and/or
Necroinflammation on biopsy

Presence of sufficient virus

HBeAg+: 20,000 IU/ml
HBeAg-: 2000 IU/ml

Biopsy not required but can be helpful

Probably most useful in those with suspected concurrent
conditions (NAFLD) or CHB with normal ALT

If cirrhosis: all recommended to be receive

treatment
Keefe E, US Treatment Algorithm, Clin Gastroenterol Hepatol 2006

Approved HBV RX
Peg-IFN (Pegasys)
180 ug weekly

Lamivudine (Epivir)
100 mg daily for 12 mos

Entecavir (Baraclude)
0.5 mg daily for 12 mos (1.0 mg daily for lamivudineresistant HBV)

Adefovir dipivoxil (Heptovir)

10 mg daily for 12 mos; approved for wild-type and
lamivudine-resistant HBV

Interferon (Intron-A, Roferon A)

Duration differs for HBeAg+ versus HBeAg- CHB

Drugs for Treatment of CHB

IFN / PEG IFN

Nucleos(t)ide analogs

Applicability

Best candidates are

younger, few
comorbidities

HBeAg
seroconversion

~33%
HBsAg loss occurs

All groups, including

cirrhotics, pregnant,
immune compromised
Increases with
duration of therapy
(1245%)

Acceptability

Numerous adverse
effects
Finite

Duration of therapy
Resistance
Cost

(for HBeAg-negative
CHB, long-term
response less likely)

N/A
High initial cost

Well tolerated
Long-term treatment
possible and may be
required
Increased risk with
duration of therapy
Expense increases
with time on therapy

Keefe E, US Treatment Algorithm, Clin Gastroenterol Hepatol 2006

Drug Resistance
Resistance defined by:
Virological breakthrough = 2-log increase in HBV
DNA levels
Associated with increase in ALT levels
Biochemical breakthrough lags behind virological
breakthrough typically

Rule out non-compliance

Factors Associated with resistance
Baseline HBV DNA levels
Duration of time HBV DNA levels are detectable
Specific antiviral used

Incidence of Drug Resistance

Incidence of Resistance

Viral mutations conferring resistance less frequent & delayed

in onset with adefovir and entecavir versus lamivudine
80%

70%

70%
60%

53%

50%

Adefovir
(N236T+A181V)2

42%

Lamivudine1
(YMDD)

40%
30%

24%

20%
10%

6%

9%

11%

18%

ETV- Lam-R
(L180M +M204V)
Entecavir - Rx naive

2%

0%
year 1

year 2

year 3

year 4

1. Lai et al Clin Infect Dis (2003) 36:687

2. Westland et al. Hepatology July 200
3. Colonno et al. AASLD 2005. A962

Key Points in Treatment of

Chronic HBV
IFN, lamivudine and entecavir, adefovir are approved
as first-line agents: focus on patient selection
Expert panels are relegating lamivudine to 2nd line due to
resistance issues
HBV genotype associated with response (esp. with IFN)

Treatment duration:
HBeAg+: until seroconversion +6-12 months
HBeAg-: unknown, generally years liver biopsy still has a
role in selecting patients for treatment

Resistance is bad
Results in resistance to other antiviral medications
Associated with flares, progression, and potentially death or
urgent liver transplant

Cases

Case #1
A 26 year old male, previously health, presents with
sudden onset of anorexia, right upper quadrant pain,
and dark urine
PMH: not contributory. No regular medications.
Heterosexual, one partner. Male housemate, not sick.
Travels within US related to work in sales.
Moderate alcohol and marijuana use, no IDU.
Exam: VSS, scleral icterus, few cervical nodes, mild
RUQ tenderness
Labs: WBC 3.2 (50 PMN, 32L, 5M, 4E), creat WNL, ALT
1604, AST 1204, total bilirubin 45, ALP 211

Case #1
If this acute viral hepatitis, what is the most
likely source of his infection?
A. Tick
B. Sexual partner
C. Food/beverage
D. Housemate

E. Occupational

Diagnostic Evaluation in
Suspected Acute Viral Hepatitis
Agent

First Order Testing

HAV

Anti-HAV IgM

HBV

Anti-HBc IgM, HBsAg

HCV

Anti-HCV

HDV

Anti-HDV IgM

HEV

Anti-HEV IgM

Case #1: Hepatitis A

The patients serum contains IgM anti-HAV; all
other viral markers negative, Repeat labs show:
AST- 900, ALT-1000, Tbili 50, INR 1.2
Which is the MOST appropriate next step in
management?

A. Admit to hospital for close monitoring

B. Vaccinate household & sexual contacts
C. Refer to liver transplant center as FHF is a
concern
D. Give patient HAV IG to reduce risk of liver
complications

Case #2
26 yo intern during her first night on call was
inserting an intravenous catheter when she
stuck her finger with a needle that had just been
removed from the patients vein. The wound
bled.
The source patient was:
HIV RNA 6000 copies/ml, CD4 50, on HAART
HCV RNA 3 million IU/mL
HBsAg negative
The intern is tested and found to be:
Anti-HCV negative, anti-HBs positive, anti-HIV
negative

What Do You Recommend?

A.
B.

C.
D.

E.

Check HCV antibody at 3 months - if negative, can

tell her that she is unlikely to be infected
Check ALT levels at 3 months - if negative, she is
unlikely to be infected.
Give immunoglobulin as this has been shown to
reduce rates of infection after HCV exposure
Start interferon and ribavirin (HCV treatment) since
it has been shown to be effective prophylaxis in
the setting of acute infection
She should not engage in any exposure prone
procedures, as she is at risk of transmitting the
virus to patients during the acute phase

Case #3: Chronic Hepatitis B

27 yo Taiwan-born heterosexual male
Testing has revealed: HBsAg+, total anti-HBc+,
HBeAg+, HBV DNA 107 IU/mL. HIV negative.
ALT 30 (N), AST 25 (N), normal total bilirubin,
prothrombin time and alkaline phosphatase
Sexually active, single partner. No other risk
factors.
PH unremarkable. No meds.
FH: No known family members with HBV infection,
cirrhosis or liver cancer.

What will be included in your

management plan for this patient?
A.

B.

C.

D.

E.

Monitoring of ALT, AST levels every 3-6

months
HBV genotype to determine likelihood of
responding to HBV treatment
Vaccinate sexual and household
members (if they are not HBV immune)
Ultrasound and alpha fetoprotein every 6
mos to screen for hepatoma
Initiate treatment with entecavir

Summary: Chronic HBV

Immune Tolerant Phase
27 yo male with CHB: HBeAg positive, HBV DNA 107 IU/mL, normal
AST and ALT. FH negative for HBV, liver cancer.

Monitor ALT, AST every 3-6 months

If elevation of ALT, AST - obtain HBV DNA, HBeAg
Treatment not indicated
Biopsy - if ALT were upper limits of normal or minimally
elevated, could be considered to assess for necroinflammation
Vaccinate sexual and household members
Vaccinate for HAV (if not immune)
HCC screening not recommended at this age without
positive FH

Thank you
Questions?