Slide set 2 BMS Confidential – For Internal Use Only

Acute viral hepatitis

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Introduction

• Viral hepatitis is caused by one of the specific

hepatotropic viruses A, B, C, D, E and G
• Hepatitis caused by other viruses only accounts
for about 1% of cases
• All these viruses cause diseases which are
clinically similar

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Viral hepatitis

I. The viruses
II. Viral hepatitis

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 BMS Confidential – For Internal Use Only

The viruses

A. Basic virology
B. Viral infections
C. Diagnosis of viral infections
D. Antiviral treatments

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 BMS Confidential – For Internal Use Only

Basic virology

• What is a virus?
– An extremely small organism (nanometres scale)
– Genetic material (or genome) consisting of nucleic
acid: DNA or RNA
– Viruses invade living cells and reproduce, using the
host cell's own mechanisms for synthesis

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Basic virology

• Structure of a virus
– A virus consists of:
• Genome: nucleic acid (DNA or RNA: consisting of
nucleotides)
• Polymerase (enzyme)
• Capsid
• Envelope (‘naked’ viruses are not enveloped)

Polymerase (enzyme)
Nucleic acid
Capsid

Envelope

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Basic virology

• Genomes
– Each nucleotide consists of: Adenine
Thymine
• One molecule of phosphoric acid Guanine
Cytosine
• One sugar Uracil

– Deoxyribose in DNA
– Ribose in RNA
• One base

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Basic virology

• Genomes
– Bases are:
Bases DNA RNA

Purine bases

Adenine YES YES

Guanine YES YES

Pyrimidine bases

Cytosine YES YES

Thymine YES NO

Uracil NO YES

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Basic virology

• Capsid
– Consists of protein molecules or capsomers
– Naked viruses have a strong capsid to protect the genome from
the environment
– Examples of naked viruses
• Poliomyelitis viruses
Nucleic acid
• Rhinoviruses
Capsomere Nucleic acid
• Adenoviruses
• Hepatitis A Virus (HAV)
• Hepatitis E Virus (HEV) Capsid
Capsid

Capsomere

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Basic virology

• The viral envelope

– Consists of:
• Double lipid layer (bilayer)
– Carries glycoprotein viral determinants
– Generally comes from the host cell membrane
• Nuclear
• Cytoplasmic Icosahedral Helical
• Endoplasmic reticulum nucleocapsid ribonucleocapsid

Lipid bilayer

Structural protein

Glycoprotein

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Basic virology

• Key point…
– Hepatitis B, C and D viruses are enveloped viruses

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Basic virology

• Differences between viruses and bacteria

Characteristics Bacteria Virus

Unicellular organism YES NO

Passes through biological filters NO YES

Independent metabolic activity YES NO

Survives outside the host YES NO*

Multiplies outside the host YES NO

Sensitive to antibiotics YES NO

* Note – some viruses (e.g. HBV) can remain infectious for short periods outside the host

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Basic virology

• Viral classification or taxonomy

– According to genomic characteristics:
• RNA or DNA
• Characteristics of viral nucleic acid
• Method of replication
– According to morphological characteristics:
• Naked virus or enveloped virus
– According to pathogenicity or epidemiology

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Basic virology Adsorption

Penetration
Decapsidation (plus viral
genome enters the nucleus
as shown opposite)
Infecting virus Viral genome replication
Translation
DNA virus Virion assembly
replication Cellular Virion release

DNA

Viral envelope proteins

Viral structural proteins

Cell
nucleus
New
viruses
Cytoplasmic
membrane

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Murray PR, et al. Medical Microbiology. 4th ed. St. Louis, MO: Mosby; 2002.
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Basic virology

• Transcription errors
– Mutations
• Key mechanism for hepatitis B
– Recombination
– Capture of genetic material

No virus has a genome

absolutely identical to that of
another virus, even if it
belongs to the same family

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Basic virology

• Transcription errors
– Mutations
• Transcription errors occur during DNA or RNA replication
• Mutations in a gene coding for a viral protein targeted by an
antiviral drug  evolution of genotypic resistance

Mutation:
Transcription errors At least 10 errors
per replication

Viral polymerase

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Basic virology

• Key points …
– Viral genotype analysis (nucleotide sequencing) is used to
detect mutations
– Phenotypic analysis (characteristics of a viral isolate) is
used to evaluate the isolate's sensitivity to different
antiviral drugs
– Phenotypic resistance is a reduction in sensitivity to
antiviral drugs (in vitro)

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Basic virology

• Key points …
– Resistance mutations generally cause resistance to one
antiviral drug within a class of drugs
– Cross-resistance can occur if they cause resistance to
several drugs in a single class
– In the presence of a drug, resistant virus may replicate
faster than wild-type virus and become the dominant
species (selection pressure)
– In naïve patients, use of a potent drug minimises the
chance of resistance mutations occurring

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The viruses

A. Basic virology
B. Viral infections
C. Diagnosis of viral infections
D. Antiviral treatments

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Viral infections

• A viral infection may be acute or chronic

– Acute viral infection
• Occurs after a specific, relatively short incubation period
• Can be symptomatic or asymptomatic

Death may occur if immune responses

and/or medical treatments fail

Period of illness Period of decline

microorganisms
Number of

Prodomal period Mild signs or symptoms Period of

Incubation period No signs or symptoms convalescence
Time

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Tortora GJ, et al. Microbiology. An Introduction. 8th Ed. San Francisco, CA: Pearson Benjamin Cummings; 2003.
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Viral infections

• A viral infection may be acute or chronic

– Chronic viral infection
• Follows an acute infection; symptoms may differ from those
of an acute infection
• Reflects the immune system's inability to eliminate the virus:
– Immature immune response
– Immune system deficiency caused by the virus
– Presence of a virus where an immune response is
inappropriate

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Viral infections

• Defence systems
– To cope with pathogenic agents, the body has two
defence systems:

• Non-specific immunity – innate immunity

• Specific immunity – mediated by the immune system

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Viral infections

• Non-specific – innate immunity

Defence Description
Skin intact, mucosa and their secretions,
Physical and chemical barrier
commensal bacterial flora
Increases activation of T lymphocytes and
Fever
intensifies the antiviral action of interferons
These cells migrate to infected regions,
Phagocytes adhere to foreign particles and then digest
them
Characterised by redness, heat, swelling
and pain. It prevents the propagation of
Inflammation pathogenic agents into the surrounding
tissues, eliminates cell debris and starts
tissue repair
Antiseptic substances Secreted by the body, e.g. nitric oxide

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Viral infections

• Specific immunity
– Two mechanisms:
• Humoral response
• Cellular response

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 BMS Confidential – For Internal Use Only

Viral infections
1
Extracellular
antigen

• Specific immunity
1 B lymphocytes bind to
B lymphocyte antigens according to their
Humoral specificity

Response
2 2 B lymphocytes differentiate into
plasmocytes

Plasmocyte

3 Plasmocytes synthesise antigen-

3
specific antibodies
Antibody

4 4 The antibodies bind to free

Antigen antigens to form the antibody-
antigen complex

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Viral infections

• Specific immunity
3 A T-helper cell binds to the antigen
Cellular Antigen and actively expresses the T-helper
cell
Response

1 Macrophage

1 The antigen is Portion of

phagocytosed by a
antigen
macrophage
2 3

2 One part is expressed on the Cytotoxic

surface of the macrophage
T-cell
4 (destroys
infected cells)
4 The activated T-helper cell
synthesises cytokines which
provoke differentiation of the
T cells into cytotoxic T cells

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 BMS Confidential – For Internal Use Only

The viruses

A. Basic virology
B. Viral infections
C. Diagnosis of viral infections
D. Antiviral treatments

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Diagnosis of viral infections

• Two different but complementary approaches

– Indirect diagnosis
• Searching for the body's humoral immune response by
detecting the production of circulating antibodies specific to
the virus
– Direct diagnosis
• Aims to identify the virus itself and/or its constituents
(antigen, DNA, RNA) from clinical samples

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Diagnosis of viral infections

• Indirect diagnosis: Serology

– Principle of the enzyme-linked immunosorbent assay
(ELISA) technique
• Viral antigens are fixed to solid medium
• Serum or plasma antibodies are captured on antigen
• After incubation and washing, the immune complex is
revealed by the addition of anti-human immunoglobulin which
is coupled to an enzyme detection system
• The signal obtained can be quantified

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Diagnosis of viral infections

• Direct diagnosis:
– Detection of viral antigens
• Immunofluorescence (IF)
– Utilises antibodies linked to fluorescent tag e.g. fluorescein
• ELISA (see previous slide)

– Detection of the viral genome (RNA or DNA) using

molecular biology techniques:
• Signal amplification (branched DNA technique)
• Gene amplification (PCR technique)

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Diagnosis of viral infections

• Direct diagnosis
– Detection of the viral genome by signal amplification
(branched DNA technique)
• Applied to quantifying HBV DNA and HCV RNA

Luminescent probes

Branched probes: Branched DNA

Viral RNA or DNA to be quantified

Capture probes adsorbed onto

the medium

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Diagnosis of viral infections

• Direct diagnosis
– Detection of the viral genome by target amplification
(PCR technique)
• Qualitative and quantitative research into hepatitis B and C
viruses as well as HIV
• Method involves generating a large number of identical copies
(amplicons) from the target DNA, which will then be easier to
detect and analyse
• For RNA viruses, RT-PCR is performed – RNA is converted to
DNA by an initial reverse transcription stage

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 BMS Confidential – For Internal Use Only

Diagnosis of viral infections

• Detection range and sensitivity varies between HBV
DNA assays
Digene Corp.
HBV Digene Hybrid Capture I
HBV Digene Hybrid Capture II
Ultra-Sensitive Digene Hybrid Capture II
Bayer Corp.
Versant HBV DNA 1.0
Versant HBV DNA 3.0
Roche Molecular Systems
Amplicor HBV Monitor
COBAS Amplicor HBV Monitor
Cobas Taqman 48 HBV
Artus Biotech
Real Art HBV PCR Assay

0 2 4 6 8 10
HBV DNA concentration in log IU/mL

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Hoofnagle JH, et al. Hepatology. 2007;45:1056-1075.
 BMS Confidential – For Internal Use Only

Diagnosis of viral infections

• Key point …
– Molecular biology techniques can also be used to:
• Determine viral nucleotide sequences
• Identify mutations linked to HBV antiviral drug resistance
(compared with sequences from wild-type strains available in
genome sequence databases)

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 BMS Confidential – For Internal Use Only

The viruses

A. Basic virology
B. Viral infections
C. Diagnosis of viral infections
D. Antiviral treatments

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 BMS Confidential – For Internal Use Only

Antiviral treatments

• Anti-influenza agents
• Nucleoside analogues
• Nucleotide analogues
• Non-nucleoside reverse transcriptase inhibitors
(NNRTI)
• Protease inhibitors
• Fusion / entry inhibitors
• Integrase inhibitors

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Antiviral treatments
• Anti-influenza agents
Amantadine Zanamivir Oseltamivir
(Relenza®) (Tamiflu®)

Activity Influenza A Influenza A & B

against
Mechanism of Prevention and/or slowing of Inhibition of virus release
action nucleic acid release in the host from cells
cell  reduction of new virion
formation and prevention of
spread to other cells
Administration Must be administered as early May shorten the duration of
as possible after infection the disease if taken within the
first 48 hours of infection

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 BMS Confidential – For Internal Use Only

Antiviral treatments

• Nucleoside analogues
– To be active they must be phosphorylated in the infected
cell

– Different mechanisms of action

• Inhibition of priming
• Competitive inhibition of target enzyme
• Chain termination

– All prevent elongation of viral DNA/RNA chains

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Antiviral treatments

• Nucleoside analogues – drugs in this class

– Treatment of HIV infection (NRTI)
• Zidovudine, lamivudine, didanosine…
– Treatment of herpes virus infections
• Aciclovir, ganciclovir…
– Treatment of chronic hepatitis B
• Lamivudine, entecavir, telbivudine

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Antiviral treatments

• Nucleotide analogues
– Have undergone the first of three phosphorylation
steps required for activity
– Mechanism of action
• Comparable to that of nucleoside analogues

– Drugs in this class

• Adefovir dipivoxil and tenofovir disoproxil

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 BMS Confidential – For Internal Use Only

Antiviral treatments

• Non-nucleoside reverse transcriptase inhibitors

(NNRTI)
– Mechanism of action
• Inhibit HIV-1 reverse transcriptase by binding directly to the
enzyme, causing it to become deformed and blocking its
activity
– Drugs in this class
• Efavirenz
• Nevirapine
• Etravirine

41
Murray PR, et al. Manual of Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003.
 BMS Confidential – For Internal Use Only

Antiviral treatments

• Protease inhibitors
– Mechanism of action
• Inhibit the viral protease preventing the cleavage of viral
protein precursors and the maturation of new viral particles
– Drugs in this class
• Atazanavir
• Saquinavir
• Lopinavir
• Fosamprenavir
• Darunavir

42
Murray PR, et al. Manual of Clinical Microbiology. 8th ed. Washington, DC: ASM Press; 2003.
 BMS Confidential – For Internal Use Only

Antiviral treatments

• Fusion / entry inhibitors

– Mechanism of action
• Prevent fusion between the viral envelope and the cell
membrane
– Drugs in this class
• Enfuvirtide (HIV gp41 inhibitor)
• Maraviroc (CCR5 inhibitor)

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Antiviral treatments

• Integrase inhibitors
– Mechanism of action
• Inhibit the HIV integrase protein preventing the insertion of
the viral DNA into the host genome
– Drugs in this class
• Raltegravir

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Viral hepatitis

I. The viruses
II. Viral hepatitis

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 BMS Confidential – For Internal Use Only

Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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Hepatitis A

• Hepatitis A virus (HAV)

– Enterovirus (picornavirus)
• RNA genome
• Replicates in the liver
• Excreted in the faeces via the bile duct.
– Transmission
• Mainly faecal-oral route
– Commonly spread by poor hygiene
– Average incubation period: 28 days

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Hepatitis A

• Clinical symptoms
– Mild fever
– Muscular and joint pain
– Headaches
– Generally feeling ill
– Anorexia
– Abdominal pain
– Jaundice (icterus)

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Hepatitis A

• Diagnosis
– Detection of anti-HAV IgM during acute phase
– The IgM response is of short duration compared with
the IgG response which persists for a long time

• Key point…
– Hepatitis A does not
cause chronic infection

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Hepatitis A

• Hepatitis A markers
Incubation Acute phase Convalescence Cure
Time
15–45 days 0–14 days 3–6 months years

Jaundice

Total anti-HAV
ALT/AST

Virus shed in faeces

Anti-HAV IgM

Contact

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Hepatitis A

• Prognosis
– Excellent
• Fulminant hepatitis occurs rarely
• The severity of hepatitis A infection increases with age
• No specific treatment
• Vaccines available
– Alone or in combination with other disease agents
e.g. hepatitis B or typhoid

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Hepatitis A

• Vaccination recommended for subjects at risk

– Travellers in areas where hepatitis A is endemic
– People working in nurseries and nursing homes
– Medical and paramedical personnel
– Employees in the food sector and wastewater
treatment networks
– Homosexuals and drug addicts

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 BMS Confidential – For Internal Use Only

Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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Hepatitis B

• Hepatitis B virus (HBV)

– The only hepatotropic virus to have a DNA genome
– Capsid and envelope are highly immunogenic
– Endemic throughout the world
– Human reservoir (blood, secretions)
– Transmitted via blood, sexual contact or during early
childhood (in endemic areas)

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Hepatitis B

• Acute hepatitis B
– Symptomatic in around 30% of adult cases
– Fulminant hepatitis occurs in <1% of cases
• Chronic hepatitis B
– 5–10% of acute cases develop into chronic infection
– Prevalence varies in Europe
• North-western Europe: <1%
• Mediterranean: 1–8%

Aggarwal R, et al. Br Med J 2004; 329: 1080–1086. 55

The EASL Jury. J Hepatol 2003; 39:S3–S25.
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Hepatitis B
• Vaccines available
• Treatment of chronic hepatitis B
– Interferons
– Nucleoside analogues: Lamivudine, Entecavir, Telbivudine
– Nucleotide analogues: Adefovir, Tenofovir

• Key point …
– Entecavir is a nucleoside analogue indicated
for the treatment of hepatitis B

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 BMS Confidential – For Internal Use Only

Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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Hepatitis C

• Hepatitis C virus (HCV)

– Flavivirus – RNA genome
– Mode of transmission
• Mainly through intravenous drug use or unscreened blood
transfusion/products
• Low socio-economic status has been linked with increased
transmission
• Rarely sexual or perinatal

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Hepatitis C

• Acute hepatitis C
– Variable incubation period: 2 months on average
– Asymptomatic in many cases
– Fulminant hepatitis is rare
• Chronic infection develops in 75–85% of cases
– Progression to cirrhosis in approximately 25% of
chronic cases
– Cirrhosis is a source of hepatocellular carcinoma in 1–
4% of cases

Hoofnagle JH, Hepatology 2002; 36:S21–S29 59

Flamm SL, JAMA 2003; 289:2413–2417
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Hepatitis C

• Diagnosis
– Detection of anti-HCV antibodies – confirmed by
detection of viral RNA by PCR
• Prevention
– Systematic screening and education of ‘at-risk’
population (e.g. IVDU)
– No vaccine is available at present
• Highly variable virus

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Flamm SL, JAMA 2003; 289:2413–2417
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Hepatitis C

• Treatment of chronic hepatitis C

– Combination therapy: Pegylated interferon alpha and
ribavirin (nucleoside analogue) for 24–48 weeks
• Sustained response rates of 54–56% can be expected
(normalisation of ALT levels and undetectable HCV RNA)
• Response rates vary depending on HCV genotype
– Numerous small molecule inhibitors are in
development for HCV

Hoofnagle JH, Hepatology 2002; 36:S21–S29 61

Flamm SL, JAMA 2003; 289:2413–2417
 BMS Confidential – For Internal Use Only

Hepatitis C

• Key point …
– Hepatitis C is the leading indication for liver
transplant, but re-infection of the transplanted organ is
common

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 BMS Confidential – For Internal Use Only

Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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Hepatitis D

• Hepatitis D or delta virus (HDV)

– Incomplete RNA virus (defective virus)
• Requires HBV co-infection to replicate
– Areas of increased incidence:
• Mediterranean, Middle East, Central Asia, West Africa, Amazon
Basin, and some South Pacific islands
– Mode of transmission (similar to HBV)
• Parenteral (drug addiction)
• Sexual
– Transmission by co-infection or superinfection

World Health Organization. Hepatitis Delta. WHO/CDS/CSR/NCS/2001.1. 64

Available at: [Link] (accessed 17 April 2009).
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Hepatitis D

• Clinical
– Symptoms indistinguishable from hepatitis B; biphasic
illness course more common with hepatitis D
– Chronic infection develops in up to 80% of cases
– Progression to cirrhosis is observed in 20–60% of
cases within 2–6 years and is more likely than in non-
HDV infection

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Polish LB, et al. Clin Microbiol Rev 1993; 6:211–229.
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Hepatitis D

• Diagnosis
– Detection of anti-delta antibodies in the serum
• No vaccine is available at present
• Treatment: difficult
– High doses of interferon over a prolonged period
• High rate of recurrence
– Combination of interferon/nucleoside analogue
• Apparently ineffective

Polish LB, et al. Clin Microbiol Rev 1993; 6:211–229

World Health Organization. Hepatitis Delta. WHO/CDS/CSR/NCS/2001.1. 66
Available at: [Link] (accessed 17 April 2009).
 BMS Confidential – For Internal Use Only

Hepatitis D

• Key point …
– Hepatitis D virus can only infect patients infected with
the hepatitis B virus
– Co-infection with HBV and HDV increases the risk of
fulminant hepatitis, chronic hepatitis and cirrhosis

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Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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Hepatitis E

• Hepatitis E virus (HEV)

– RNA calicivirus
– Prevalence:
• Endemic in Asia and Latin America
– Mode of transmission (similar to HAV)
• Faecal-oral route

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Hepatitis E

• Clinical
– Short incubation
– Can be fatal if contracted during the first 3 months of
pregnancy
• Does not develop chronic infection
• No vaccine available
• No specific treatment

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 BMS Confidential – For Internal Use Only

Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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Hepatitis G

• Hepatitis G virus (HGV)

– RNA, flaviviridae
– Mode of transmission similar to HCV
• Mainly parenteral (IV drug use, transfusion)
• Sometimes sexual or perinatal
– Prevalence
• 2–5% in the general population
• Persistent infection in 15–30% of adults

Hepatitis G Fact Sheet, Health Canada, 2003. Available at: 72

[Link] (accessed
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Hepatitis G

• Hepatitis G virus (HGV)

– Could influence the severity of chronic hepatitis B / C
– May play a role in some types of fulminant hepatitis
• Clinical
– Infection generally mild
– ALT levels often normal

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Hepatitis G

• Development of chronic infection:

– Limited data available
• No vaccine available
• Diagnosis
– PCR

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 BMS Confidential – For Internal Use Only

Viral hepatitis

A. Hepatitis A
B. Hepatitis B
C. Hepatitis C
D. Hepatitis D
E. Hepatitis E
F. Hepatitis G
G. Other types of viral hepatitis

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 BMS Confidential – For Internal Use Only

Other types of viral hepatitis

• Other viruses likely to cause hepatitis in rare

cases
– Herpes virus (HSV, CMV, EBV)
– Measles virus
– Rubella virus
– Yellow fever virus
– Dengue fever virus

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Viral hepatitis: Summary

Hepatitis Genome Transmission Vaccine Progression to chronic

virus status
A RNA Faecal-oral Yes No
Sexual, parenteral, Newborns: 90%
B DNA Yes
perinatal Adults: 5–10%
Mainly parenteral
C RNA No 75–85%
(sexual, perinatal rare)
Same as HBV, HBV HBV co-infection: 5–10%
D RNA No
co-infection required HBV secondary infection: 80%
E RNA Faecal-oral No No
Mainly parenteral
G RNA No Limited data
(sexual, perinatal rare)

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