Viral

Hepatitis A-E
Viruses
Prof. Sanaa Kamal

Hepatitis B Virus

Hepatitis B - Clinical
Features
Incubation period:

Average 60-90 days

Range 45-180 days
Clinical illness (jaundice):
<5 yrs, <10%
5 yrs, 30%-50%
Acute case-fatality rate:
0.5%-1%
Chronic infection:
<5 yrs, 30%-90%
5 yrs, 2%-10%
Premature mortality from
chronic liver disease:
15%-25%

Spectrum of Chronic
Hepatitis B Diseases
1.

Chronic Persistent
asymptomatic

Hepatitis

2. Chronic
Active
Hepatitis
symptomatic
exacerbations
hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma

of

Acute Hepatitis B Virus Infection

with Recovery
Symptoms
HBeAg

anti-HBe
Total anti-HBc

Titre
HBsAg

anti-HBs

IgM anti-HBc

12 16 20 24 28 32 36

Weeks after

52

100

Progression to Chronic Hepatitis B

Virus Infection
Titr
e

Acute
(6 months)

Chronic
(Years)
HBeAg

anti-HBe
HBsAg
Total anti-HBc

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36

52

Weeks after Exposure

Years

Concentration of Hepatitis B Virus

in Various Body Fluids

High

Moderate

blood
semen
serum
vaginal fluid
wound exudates
saliva

Low/Not
Detectable
urine
feces
sweat
tears
breastmilk

Hepatitis B Virus
Modes of Transmission
Parenteral - IVDA, Health Workers
are at increased risk
Sexual.
Perinatal - Mothers who are HBeAg
positive are much more likely to
transmit to their offspring than those
who are not. Perinatal transmission is
the main means of transmission in
high prevalence populations.

Chronic Hepatitis B
Therapy
Prof. Sanaa M. Kamal
Ain Shams University

What do we treat?

Vertical

Acute
Infection

Chronic
Infection

Compensated
cirrhosis

Decompensated
cirrhosis

Transplantation
Horizontal

HCC
Mortality

Ccc DNA:
covalently closed
circular DNA

Treatment goal
To prevent cirrhosis and
Hepatocarcinoma
How to meet it...
HBV DNA
suppression

HBeAg
seroconversion
ALT
normalization
Histologic
improvement

How to select/assess treatment

HBeAg

ALT

biopsy

HBV DNA
It is essential to have the quantitative determination
of HBV DNA in every patient.

How do we treat ?

Points of intervention for the

treatment of HBV infection
Hepatocyte
Regeneratio
n

Block the HBV

production and/or
Nonreinfection with
infected
antiviral therapy
hepatocyte
Infection

immune
response

HBV production

HBV-Infected
hepatocyte

Lysis of infected

Stimulate
immune response

Inflammation
and cell death hepatocytes and

suppression of vira
replication

Clinical Hepatitis

Drugs approved for treatment

Immunomodulators Nucleos(t)ide Analogues

Conventional IFN
alfa
PEG-IFN alfa-2a/b

Lamivudine
Adefovir
Entecavir
Telbivudine

Peginterferon alfa
Pros
Limited time of therapy.
Possibility of HBsAg seroconversion.

Cons
Responses are limited.
Injected.
Bad tolerance.
Cost.

Entecavir
Cyclopentyl guanine
nucleoside analog
Potent and selective
inhibitor of HBV replication
(EC50 = 4 nM)
Inhibits all 3 HBV
polymerase functions
Priming
DNA-dependent synthesis
Reverse transcription

Active against lamivudineresistant HBV

O
N NH
CH2 N N NH2

OH
O
H

BARACLUDE

Telbivudine (LdT)
Specific inhibitor of
HBV polymerase
Not active against HIV
or other viruses

Favorable toxicology
for long-term
treatment:
Once daily oral dosing
indicated by PK
Consistent
absorption, no food
effect

O
CH

HN
O

3
OH

OH
-L-2-deoxythymidine
(LdT, telbuvidine)

Initial treatment according to

patients characteristics ?
Interferon (Peg)

Nucleos(t)ides

Young and motivated

HBV DNA < 109 cp/ml

Any age
HBV DNA > 109 cp/ml

Baseline ALT level >

Any baseline ALT level

Any genotype

2-3 LSN
Genotype A or B
Without cirrhosis ?

Compensated or
decompensated
cirrhosis
Chemotherapy,
pregnancy

If you choose Nucleos(t)ides:

Resistance is a main issue !!!

Nucleos(t)ides Resistance:
Consequences

Increase of HBV DNA.

Increase of ALT.
Decreased HBeAg seroconversin.
Histological progression.
Possibility of clinical decompensation.
Transmission of resistant virus.
Possibility of multiresistance
development.

Algorithm management:
Responses Intra-treatment
Start treatment
Week 12: evaluate primary treatment failure

Week 24:
early predictors of efficacy

Full response

Negative HBV DNA

Partial response

60<2000 IU/mL or
300<10,000 copies/mL

Inadequate response
>2000 IU/mL or
10,000 copies/mL

Hepatitis C Virus
capsid envelo
pe
protei
c2
n
2

protease/heli
case
33
c

RNARNA
dependentpolymerase
c100

core E1

E2

hypervariable
region

NS
2

NS
3

NS
4

NS
5

Hepatitis C - Clinical
Features
Incubation period:

Average 6-7 wks

Range 2-26 wks

Clinical illness (jaundice):

30-40% (20-30%)

Chronic hepatitis:

70%

Persistent infection:
Immunity:

85-100%
No protective

antibody
response

Hepatitis C - Sources of
Infection
IVDU 60%

Sexual 15%
Transfusion 10%
Occupational 4%
Other 1%*
Unknown 10%

*Nosocomial; iatrogenic; perinatal

Hepatitis C Genotypes

Biochemical, Serological, and

Virological Profiles of Acute and
Chronic Hepatitis C
A

anti-HCV

anti-HCV

Symptoms +/-

HCV RNA

HCV RNA

Titre

Titre

Symptoms +/-

Core Ag

Core Ag

ALT

ALT

Normal

Normal
0 1 2 3 4 5 6 1 2 3 4
Months

Years

Time after Exposure

0 1 2 3 4 5 6 1 2 3 4
Months

Years

Time after Exposure

Years

Exposure
(Acute Phase)

20-40%

60-85%
Chronic

Resolved

20% (range 2-32%)

5-10

10-20 years

20-30

Cirrhosis

Stable

Slowly
Progressive

ESLD
HCC
Transplant
Death

Natural History of
HCV
29

Chronic HCV

30

Rational for Treatment

Achieve SVR
Alter the natural
history of HCV
infection by
halting the
progression of
fibrosis.
Reduce risk of
cirrhosis and
HCC.

No fibrosis

Portal fibrosis

Numerous septa

Few septa

Cirrhosis

Chronic Hepatic viral

infections
HCV

12

10 virions/day
Error prone viral
polymerase
Viral quasi-species
Eradication possible
(no known latency)
No overlapping
reading frames
Moderate infected
cell turnover

HBV
12-13

10
virions/day
Error prone viral
polymerase
Viral quasispecies
Eradication not
possible?
(cccDNA)

Overlapping
reading frames
Slow infected
cell turnover

HCV replication and antiviral

targets

CyPA

Moradpour D. Nat Rev Micro 2007.

Evolution of Therapies of Chronic

HCV

Interferon
and
Ribavirin
Interferon
Monotherapy

Peginterferon
and
Ribavirin

Evolution of Therapies of Chronic

HCV

Mechanism of Action:
Interferon
HCV

HCV virions
Interferon alfa
Assembly

IFN receptors
JAK

Viral RNA

HCV replicative
complex

PKR
STAT

IRF9

ADA

STAT1

ISG mRNA
ISGF3
ISRE

OAS

OAS: activates
antiviral RNAses
PKR: inactivates
viral ptn
translation
ADA: edits viral
RNA

Side Effects of
PegIFN/Ribavirin
Depression ranging

Interferon Man

from mild to
suicidality
Irritability, aggressive
behavior
Worsening of mania
Fatigue
Insomnia
Myalgias, fever, flulike symptoms
Hair loss
Cytopenias

Definition of Response to Therapy

Relapser

Nonresponder

Nonrespon
der

HCV RNA

Sustained
Responder

HCV RNA
negative
12

24

Time (wk)

48

72

Clinical Algorithm
Chronic Hepatitis C
PEG IFN/Ribavirin therapy
Quantitative HCV RNA
after 4 weeks
Quantitative HCV RNA
Week 12 of treatment
Minimal or no change in HCV RNA

2-log decline in HCV RNA

HCV RNA negative

HCV RNA positive

Continue full course of therapy

48 weeks

Retest HCV RNA at wk 24

HCV RNA neg

HCV RNA pos

Continue full cours

48 weeks

Stop therapy

Assess fibrosis/stop therapy

NS3 Protease Targets

Serine proteinase
catalytic site

NS3 Protease Inhibitors

Telaprevir
Boceprevir
Potent inhibition (34log)
PI/PEG/RBV =
SVR rates (6575%)
Low resistance barrier

Tolerability
Telaprevir
Pruritus, nausea, rash, anemia, and
diarrhea
Severe rash in 3-6% (1% PEG/RBV)
5-7% stop TVR; 1% stop treatment
Hgb <10g/dl: 35-45% vs. 14% [ESA use
not allowed]

Boceprevir
Anemia, dysgeusia
Hgb <10g/dl: 50% vs. 18%
Erythropoietin use: 43% vs. 24%
Jacobson I. AASLD 2010. Poordad F.

Protease Inhibitor
Resistance
Rapidly selected with monotherapy
10% during combination therapy
HCV subtype matters (1a vs 1b)

Kieffer T. AASLD 2010. Vierling J. AASLD 2010. Hezode C.

Sofosbuvir
Approval Status: FDA approved December 6, 2013
Indication for HCV Monoinfection and HCV-HIV Coinfection
- GT 1,4: Sofosbuvir + peginterferon + ribavirin (12 weeks)
- GT 2: Sofosbuvir + ribavirin (12 weeks)
- GT 3: Sofosbuvir + ribavirin (24 weeks)
Additional Indication for HCV Monoinfection
- GT 1 (interferon ineligible): Sofosbuvir + ribavirin (24 weeks)
- HCC and awaiting transplant: Sofosbuvir + ribavirin (up to 48
weeks)
Class & Mechanism
- Nucleotide analog inhibitor of NS5B polymerase enzyme
Dosing: 400 mg PO once daily with or without food
Adverse Effects (AE) attributable to Sofosbuvir
- Fatigue, headache
Wholesaler Acquisition Cost in United States
- 28 tablet bottle = $28,000; estimated 12-week cost = $84,000

Sofosbuvir
NS5B Polymerase Inhibitor
Ingestio
n of
Prodrug
Sofosbuvir

Predominant
Circulating
form
GS331007

Intracellular
Active
Triphosphate
GS461203

P P P

Hepatocyt
e

Sofosbuvir

Drug-Drug Interactions
Sofosbuvir not recommended for coadministration with*:
Anticonvulsants
- Carbamazepine
- Oxcarbazepine
- Phenobarbital
- Phenytoin
Antimycobacterials
- Rifabutin
- Rifampin
- Rifapentine
Herbal Supplements
- St. Johns wort
HIV Protease Inhibitors
*Not recommended because of potential marked decrease in sofosbuvir levels
- Tipranavir/ritonavir

Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6

NEUTRINO Trial: Results
NEUTRINO: HCV RNA <25 IU/ml by Study Timepoint
100

99 RNA < 25 IU/ml

Patients (%) with HCV

99
90

80
60
40
20
321/325

326/327

Week 4

Week 12 (End of Tx)

SVR = sustained virologic response

Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

295/327

SVR12

Ledipasvir-Sofosbuvir (Harvoni)
Approval Status: FDA approved October 10, 2014
Indications and Usage
- Indicated for the treatment of chronic HCV genotype 1 in adults
Class & Mechanism
- Ledipasvir: NS5A inhibitor
- Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor
Dosing: Ledipasvir-Sofosbuvir (fixed dose 90 mg/400 mg)
One tablet orally once daily with or without food
Adverse Effects (AE): Fatigue, headache

Ledipasvir-Sofosbuvir (Harvoni)

Indications and Usage

Genotype 1 Patient Populations

Treatment
Duration*

Treatment nave with or without

cirrhosis

12 weeks

Treatment experienced** without

cirrhosis

12 weeks

Treatment experienced** with

cirrhosis

24 weeks

*Consider treatment duration of 8 weeks in treatment-nave patients

without cirrhosis who have a pretreatment HCV RNA less than 6
million IU/mL
**Treatment-experienced patients who have failed treatment with either
(a) peginterferon alfa plus ribavirin or (b) HCV protease inhibitor plus

Ledipasvir-Sofosbuvir (Harvoni)

Estimated Cost of Therapy

Estimated Cost of Ledipasvir-Sofosbuvir Based on
Treatment Duration
Duration of Treatment

Estimated Cost*

8 Weeks

$63,000

12 Weeks

$94,500

24 Weeks

$189,000

*Estimated cost based on Wholesaler Acquisition Cost in United States

of $1125 per pill

Ledipasvir-Sofosbuvir (Harvoni)

Drug-Drug Interactions

Not recommended for coadministration with:

- P-gp inducers (eg. rifampin, St. Johns Wort)
Consult Prescribing Information Regarding Interactions
with:
- Acid reducing agents
- Antiarrhythmics
- Anticonvulsants
- Antimycobacterials
- HIV antiretrovirals

Ledipasvir-Sofosbuvir (Harvoni)

Adverse Effects
Adverse Effects with Ledipasvir-Sofosbuvir Reported in 5% of Subjects

Ledipasvir-Sofosbuvir
8 Weeks

12 Weeks

24 Weeks

N=215

N=539

N=326

Fatigue

16%

13%

18%

Headache

11%

14%

17%

Nausea

6%

7%

9%

Diarrhea

4%

3%

7%

Insomnia

3%

5%

6%

Source: Harvoni Prescribing Information. Gilead Sciences

Simeprevir (Olysio)
Approval Status: FDA approved December 6, 2013
Indication for HCV Monoinfection
- GT 1: Simeprevir (12 weeks) + peginterferon + ribavirin (12 or 36
weeks)
- Poor response to Simeprevir + Peginteferon + Ribavirin
with GT1a
Class & Mechanism
- NS3/4A protease inhibitor
- Activity against GT 1,2,4,5,6 (strongest activity against GT 1a, 1b)
Simeprevir Dosing
- 150 mg PO once daily with food
- In combination with peginterferon + ribavirin (triple therapy)
Adverse Effects (AE) attributable to Simeprevir
- Rash (including a photosensitivity reaction), pruritus, and nausea