The document provides information on viral hepatitis treatment strategies. It discusses: 1. Hepatitis C virus (HCV) structure, life cycle, and natural history, with the majority of cases resulting in chronic infection that can lead to cirrhosis or liver cancer. 2. Treatment for HCV has evolved from interferon-based regimens to all-oral, interferon-free direct acting antiviral drug combinations, which achieve very high cure rates. 3. Hepatitis B virus (HBV) transmission, clinical signs of acute and chronic infection, and treatment involving pegylated interferon or long-term nucleotide analogue therapy to suppress viral replication indefinitely.

1. Viral hepatitis (HCV &
HBV) treatment strategies
Nehal M. Ramadan
Lecturer of clinical pharmacology

2. � Mode of transmission � primarily as a result of exposure
to infected blood.
� Incubation period �15 to 150 days.
� Clinical signs of the acute stage of infection 🡪
◦ Subclinical in 70-90% of people.
◦ 10-30% of individuals manifest non-specific symptoms such as
appetite loss, flu-like symptoms or musculoskeletal pain.
� Natural history �
◦ Spontaneous HCV elimination is observed in 20% of cases
◦ Chronic HCV infection develops in 80% of cases � can lead to
a range of liver diseases from mild inflammation to extensive liver
fibrosis and cirrhosis � Hepatocellular carcinoma is a serious
complication of HCV-related cirrhosis.
Hepatitis C Virus (HCV)

3. The hepatitis C virus structure
� It is an enveloped single-
stranded RNA (ssRNA)
virus.
� It consists of
◦ (1) a nucleocapsid, which
contains the RNA genome
surrounded by a protective
shell of proteins
◦ (2) a lipid bilayer envelope,
where two envelope
glycoproteins, E1 and E2, are
embeded.

4. � It is made up of a single RNA strand� translated by host
machinery to a single polyprotein product � further
cleaved to smaller 10 mature viral proteins.
◦ 3 structural proteins (core C proteins, envelope E1 and E2
proteins),
◦ a small protein p7 ion channel
◦ six non-structural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A
and NS5B).
The genome of HCV

5. The HCV life-cycle

6. � Of particular importance � the NS3/4A complex,
NS5A, and NS5B proteins.
◦ The NS3/4A serine protease complex � mediates
cleavage of the polyprotein into structural and NS mature
viral proteins.
◦ NS5B � RNA-dependent RNA polymerase activity �
viral replication.
◦ NS5A � has a number of roles
1. Aids in viral replication
2. Assembly of mature viral particles.

7. 1. Up to 2011, a combination of pegylated interferon
alpha (PEG INF α) + ribavirin (RBV) for a period of
24 or 48 weeks was the standard of care for chronic
HCV infection.
1. The poor outcomes and high incidence of side
effects amongst chronic HCV patients drove the
need for newer, more effective and tolerable
treatments for chronic HCV infection � direct
acting antivirals (DAAs).
1. The addition of DAAs to PEG-IFN+RBV (triple
therapy) � improved outcomes and shortened
treatment durations.
Treatment strategy for HCV

8. 4. However, triple therapy still involved INF � unpleasant side
effects and weekly injections � This led to the development of
new INF-free regimens 🡪 combination of various DAAs±RBV.
4. INF-free regimens are now the cornerstone of chronic HCV
infection, and vary depending on HCV genotype.
4. Almost all patients on INF-free regimens achieve undetectable
HCV RNA level 4 w following start of therapy.
7. The goal of therapy in chronic HCV patients is attainment of a
(sustained viral response), SVR, an undetectable HCV RNA
level 12 w following completion of therapy = cure.
7. All patients with serologic evidence of chronic HCV should be
considered for treatment.

9. Interferon α (INF α)
INFs �
naturally
occurring
proteins � two
types � INF I
(α and β) & INF
II (γ).
Viral infection
is the stimulus
for secretion of
INF I

10. MOA:
� INF I � secreted by cell (1) in response to viral
infection � binds to a specific receptor on cell (2) �
Induces transcription of several genes � increases
production of antiviral proteins � block viral entry &
replication.
� Polyethylene glycol chains are attached to
molecules of INFα � INFα 2a & 2b �
◦ Prevent rapid degradation of INF α � prolong its duration of
action.
◦ Reduce its immunogenicity.
INF α

11. � Side effects:
◦ The most common � chronic fatigue, muscle/joint pain,
fever, headache
◦ Blood � anemia, neutropenia, thrombocytopenia,
hyperuricemia.
◦ Psychic anomalies � sleeplessness & depression � CI
in patients with depression or psychosis.
◦ Xeromucosa & dry skin.
◦ Allergies.
Interferon α 2a or 2b

12. MOA:
RBV is a prodrug � a guanosine analogue � resembles guanine
ribo-nucleoside � phosphorylated to mono- � di- � tri-phosphate
(RBV triphosphate).
� RBV triphosphate � competes with natural GTP for the catalytic
site of HCV RNA polymerase � Incorporated into the newly
formed viral RNA chain 🡪 chain termination.
� Mutagenic activity � increases the frequency of mutations in viral
RNA � Lethal to HCV.
� RBV monophosphate � competitive inhibition of IMPDH (inosine
monophosphate dehydrogenase) enzyme, involved in the de novo
synthesis of guanine nucleotides � depletion of GTP.
� Immunomodulation � induces T helper cell-mediated immune
response
Ribavirin (RBV)

13. Ribavirin (RBV)

14. � Side effects:
◦ GIT disturbances
◦ Hemolytic anemia.
◦ CNS disturbances � sleep problems & depression.
◦ Blood � hyperuricemia
◦ Bronchospasm � CI in asthma
◦ Allergy � rash
◦ Hyperbilirubinemia, increased iron concentration
◦ Teratogenic.
Ribavirin (RBV)

15. Direct acting antiviral (DAAs) drugs
(classification & MOA)
Def: Drugs that target specific
NS proteins of the HCV virus
and results in disruption of
viral replication and infection
Nucleotide
polymerase
inhibitors
NPIs
Non-
Nucleotide
polymerase
inhibitors
NNPIs

16. Direct acting antiviral (DAAs) drugs
(classification & MOA)

17. � First generation � boceprevir and telaprevir � bind
covalently to the catalytic site of NS3� both withdrawn
from the market (why??)
◦ SE � anemia, dysgeusia & rash.
◦ Complex dosing regimens � taken with fatty meals/8 hours.
◦ High incidence of drug interactions.
◦ High incidence of resistance (low barrier to resistance).
� Second generation � Simeprevir � competitive,
reversible, non covalent inhibitor � better affinity and
selectivity for protein targets.
� Third generation � Glecaprevir, grazoprevir,
paritaprevir and voxilaprevir.
1. NS3/4A protease inhibitor
(-previr)

18. Pharmacokinetics:
� Hepatic elimination � not used in patients with
moderate to severe hepatic impairment.
SE:
� Rash & photosensitivity.
� Mild transient elevation in bilirubin, pruritus and
nausea
Drug interactions:
Simeprevir is metabolized by CYP3A4, so
� Inducers of CYP3A4 as rifampin, phenytoin� ↓
simeprevir conc.
� Inhibitors of CYP3A4 as azole antifungals,
clarithromycin � ↑ simeprevir conc.
Simeprevir

19. 2. NS5A inhibitors (-asvir)
Daclatasvir, elbasvir, ledipasvir, ombitasvir,
velpatasvir.
� Daclatasvir
SE:
◦ Headache, fatigue, and nausea
Drug interactions:
metabolized by CYP3A4, so
◦ Inducers of CYP3A4 as rifampin, phenytoin� ↓ daclatasvir
conc.
◦ Inhibitors of CYP3A4 as azole antifungals, clarithromycin � ↑
daclatasvir conc.
Inhibits P-glycoprotein transporter � ↑ digoxin conc.

20. 1. Nucleoside/nucleotide polymerase inhibitors (NPIs) �
Sofosbuvir � a prodrug (analogue of uridine nucleotide) �
converted to an active sofosbuvir tri-phosphate form � competes
with natural UTP for the catalytic site of HCV RNA polymerase �
Incorporated into the newly formed viral RNA chain 🡪 chain
termination.
Pangenotypic �
the catalytic site of NS5B is
similar across all HCV
genotypes � giving NPIs
efficacy against all six genotypes
2. Non-nucleotide inhibitors (NNPIs) � Dasabuvir 🡪 binds to
NS5B at other sites rather than the catalytic sides � allosteric
inhibitors
3. NS5B RNA-dependent RNA
polymerase inhibitors (-buvir)

21. Pharmacokinetics:
� Renal elimination � however, safe � no need for dose
adjustment in patients with severe renal impairment.
SE:
� Fatigue, headache, nausea, insomnia, and anemia
� Rare cases of symptomatic bradycardia in patients
treated with the anti-arrhythmic amiodarone � CI with
amiodarone
Sofosbuvir

22. Example 1 of fixed dose DAAs
combinations
� Harvoni � Combination of NS5B
inhibitor sofosbuvir + NS5A
inhibitor ledibasvir �
recommended for use in Genotype
1 and 4–6 patients.
� Duration of treatment � 12 w
� Addition of RBV � for patients with
cirrhosis, or those who have
failed previous treatment.

23. Ritonavir-boosted paritaprevir and ombitasvir ±
dasabuvir
� This combination of NS3/4A inhibitor paritaprevir +
NS5A inhibitor ombitasvir ± NS5B inhibitor
dasabuvir � effective in treating Genotypes 1 & 4
infection.
� Ritonavir � an inhibitor of CYP P450 enzyme
CYP3A4 � acts as a pharmacological enhancer
(increase level) of paritaprevir � allowing for once-
daily dosing
� Duration of treatment � 12 w
Example 2 of fixed dose DAAs
combinations

24. Take a breath
I have only 5 slides left
plus a conclusion ☺

25. Hepatitis B virus (HBV)

26. � Mode of transmission � primarily as a result of
exposure to infected blood.
◦ Vertical transmission from mother to her baby during birth.
� Clinical signs of the acute stage of infection 🡪
◦ Subclinical and transient � 75% of cases.
◦ Acute hepatitis � 25% of cases
◦ Acute liver failure �1% of cases.
� Natural history �
◦ Spontaneous HBV elimination is observed in 95% of adults
and less than 5% progress to chronic HBV.
◦ Chronic HBV infection � lead to either chronic active
hepatitis or an asymptomatic carrier state 🡪 Both can
ultimately develop hepatocellular carcinoma.
Hepatitis B Virus (HBV)

27. The HBV life cycle
1
2 3 4
5
An enveloped
partially double-
stranded circular
DNA virus

28. Treatment strategies for chronic
HBV
Treatment with PEG IFNα-2a
Treatment with a nucleotide
analogue (NA)
(Reverse transcriptase inhibitors)
Classified into �
1. More potent NAs with low
rate of drug resistance
(high barrier to resistance) �
entecavir & tenofovir
1. NA with high rate of drug
resistance (low barrier to
resistance) � lamivudine,
telbivudine, adefovir
Currently, there are two main treatment options for chronic
hepatitis B

29. Nucleotide analogues (MOA)
1. NA � prodrugs �
converted to
triphosphate form �
Compete with natural
corresponding
nucleotide for HBV
reverse transcriptase�
Incorporated into the
newly formed viral DNA
chain 🡪 chain
termination.
Revise MAO of
action of
Ribavirin and
Sofosbuvir
Guanosine
analogue
Adenosine analogues
Cytidine analogues

30. Treatment strategies for HBV
Treatment with PEG IFN α
Treatment with a
nucleotide analogue (NA)
⮚ At least 4-5 y, maybe
indefinite duration
⮚ Risk of viral resistance
(minimal with tenofovir &
entecaver)
⮚ Inhibiting viral replication
⮚ Potent antiviral effect
⮚ Unknown long term safety
(maybe renal SE &
osteoprosis)
⮚ Oral administartion
⮚ Improved tolerability
⮚Finite duration (48 w)
⮚No viral resistance
⮚Induction of a long-term anti HBV
immunological response
⮚Moderate antiviral effect
⮚Risk of side effects
⮚Weekly s.c. injections
⮚Inferior tolerability

31. � For most patients regardless of the severity of liver disease �
monotherapy with a potent NA with low risk of drug resistance
(tenofovir or entecavir) is the treatment of choice
� PEG IFNα is CI in patients with severe liver disease including cirrhosis
� Only considered in patients with mild to moderate chronic HBV who
do not wish to be on long-term therapy.
� For pregnant females � Tenofovir disoproxil fumarate in the 3rd
semester.
� Combination therapy with two NAs is not recommended (vs.
HCV?!!!)
� Tenofovir, rather than entecavir, in patients failing therapy with one of
NAs with high risk of resistance (lamivudine, telbivudine, adefovir).
Pearls for treatment of chronic HBV
Choice of initial agent

32. Thank youuuuuuu