This document provides an overview and update on treatments for Hepatitis C genotype 4. It discusses direct-acting antiviral (DAA) medications including NS3/4A protease inhibitors, NS5A inhibitors, NS5B polymerase inhibitors, and specific medications from each class. It covers dosing, mechanisms of action, drug interactions and side effects for medications like sofosbuvir, simeprevir, daclatasvir, and paritaprevir/ombitasvir. Guidelines from EASL and AASLD are summarized for genotype 4 treatment and special populations like renal impairment, HIV co-infection, and treatment failure.

1. By
Dr. Mohammed Abd Ellatif
Update on Hepatitis C
genotype 4 Treatment

2. Introduction
About 170 million or more are chronically infected
with HCV worldwide.
Chronic HCV infection may progress to cirrhosis,
liver decompensation, HCC and ultimately death.
The current concept of HCV treatment is to achieve
SVR as it is associated with permanent eradication of
the virus and diminished long term risks of HCV
especially HCC.
PegINF/RBV was the SOC for HCV treatment with
50-60% SVR.

3. HCV life cycle

6. Categories of the new HCV treatment

8. Mechanism of action of DAAs
 [NS3/4A] Protease Inhibitors “…previr”:
NS3 has a proteolytic activity.
NS4 is a co-factor.
NS3/4A PIs disrupt post-translation processing
and replication of HCV.
Members: Telaprevir, boceprevir, simprevir,
paritaprevir.

9.  CYP3A4 and PIs:
Telaprevir, boceprevir, paritaprevir are
metabolized
by liver CYP3A4.
Simprevir is metabolized by liver and intestine
CYP3A4.
Inhibitors of CYP3A4 affect these drugs.

10.  NS5A Inhibitors “….asvir”:
Unknown mechanism of action.
Is used in regulating replication, and in the
assembly of the viral particle released from the host
cell.
Members: Ledipasvir, ombitasvir, daclatasvir.

11.  NS5B Non-nucleoside Polymerase Inhibitors
“…buvir”:
NS5B is an RNA-dependent RNA polymerase
essential for viral replication.
Genotype specific.
Metabolized by CYP2C8
Members: Dasabuvir.

12.  NS5B Nucleoside Polymerase Inhibitors:
NS5B NPIs target the catalytic site and result in
chain termination during RNA replication of the viral
genome.
Members: sofosbuvir.

13. Sofosbuvir
 Sofosbuvir should be administered at the dose of
400 mg (one tablet per day).
 Approximately 80% of sofosbuvir is renally
excreted,whereas15% is excreted in faeces.
 No sofosbuvir dose recommendation can be
given for patients with sever renal impairment
(eGFR< 30 ml/min)

14.  The most common adverse events observed in
combination with ribavirin were fatigue and
headache.
 The most common adverse events in combination
with PegIFN-a and ribavirin headache, nausea,
insomnia and anaemia.

15.  Sofosbuvir is not metabolised by cytochrome
P450 but is transported by P-glycoprotein (P-gp).
Drug that are potent inducers significantly
decrease sofosbuvir plasma concentration so
reduce theraputic effects.
 Thus sofosbuvir should not be administered with
other known inducers of P-gp, such as rifampin,
carbamazepine, phenytoin.

16. Simeprevir
 Simeprevir should be administered at the dose of
150 mg (one capsule) once per day. Simeprevir is
extensively bound to plasma proteins (>99.9%),
primarily to albumin. Simeprevir primarily
undergoes oxidative metabolism by the hepatic
CYP3A system. Elimination occurs via biliary
excretion, where as renal excretion is negligible.

17.  Adverse reactions with at least 3% higher
frequency in patients receiving simeprevir
incombination with PegIFN-a and ribavirin
were rash (including photosensitivity), pruritus
and nausea. Because simeprevir is an
inhibitor of the hepatic transporters, mild,
transient hyperbilirubinaemia occur.

18. Daclatasvir
 Daclatasvir should be administered at the dose of
60mg , or 30mg (one tablet) when a reduced
dose is needed approximately 90% of daclatasvir
is elimined in feaces and less than 10% is
execreted in urine.
 The most frequently reported side effects are
fatigue, headache and nausea.
 Daclatasvir is a substrate of CYP3A4, and a
substrate and inhibitor of f P-gp.

19. paritaprevir, ombitasvir
 Ritonavir-boosted paritaprevir, ombitasvir and
dasabuvir.
 Paritaprevir is an NS3- 4A protease inhibitor
which is metabolised Primarily by CYP3A4 and is
given with a low dose of the CYP3A inhibitor
ritonavir as apharmacokinetic enhancer. This
enables once daily dose.
 Ombitasvir is an NS5A inhibitor given in a fixed-
dose combination with paritaprevir/ ritonavir.

20.  The recommended dose of this combination is
two tablets of ritonavir/ paritaprevir/ ombitasvir
 (50mg/75mg/12.5 mg per tablet) taken orally
once daily with food.
 Dasabuvir is a non-nucleoside Inhibitor of
HCVRNA- dependent RNA polymerase in 250 mg
tablets administered twice daily in combination
with ritonavir/ paritaprevir/ ombitasvir in genotype
1 patients.

21.  Paritaprevir is excreted predominantly into the
faeces.
 Ombitasvir shows linear kinetics, and is
predominantly eliminated in the faeces.
Dasabuvir is metabolised in the liver.
 no dose adjustment is required in mild hepatic
impairment (Child-Pugh A) and no dose
adjustment is expected to be required for patients
with moderate hepatic impairment (Child-Pugh B)
In contrast, this combination is contraindicated in
patients with severe hepatic impairment (Child-
Pugh C).

22. EASL Recommendations 2015
For HCV genotype 4

24. AASLD 2016 guidelines for
HCV genotype 4

26. Treatment failure

27. RAVs and Retreatment

28. EASL 2015 treatment failure
 Patients infected with HCV genotype 1 or 4 who
failed on a regimen combining PegIFN-α, ribavirin
and simeprevir should be retreated with a
combination of sofosbuvir with daclatasvir or
ledipasvir .

29.  Patients who failed on a regimen combining
PegIFN-α ribavirin and daclatasvir should be
retreated with a combination of sofosbuvir and
simeprevir (if they are infected with genotype 1 or
4).
 Patients infected with genotype 1 or 4 who failed
on regimen containing sofosbuvir and simeprevir
should be retreated with a combination of
sofosbuvir with daclatasvir or ledipasvir.

30.  Patients who failed on a regimen containing
sofosbuvir and daclatasvir or sofosbuvir and
ledipasvir should be retreated with a combination
of sofosbuvir and simeprevir (genotype 1 and 4).
 Patients infected with genotype 4 who failed on
the double combination of ritonavir-boosted
paritaprevir and ombitasvir should be retreated
with a sofosbuvir-based regimen, e.g. sofosbuvir
and simeprevir, sofosbuvir and daclatasvir or
sofosbuvir and ledipasvir.

31. Treatment of HCV in Special populations

32. AASLD “ Unique Patient Populations
 Decompensated liver disease
 Pre-transplant and/or Post-transplant
 HIV/HCV co-infected patients
 Renal Disease
 PEG-IFN and RBV intolerant patients
 Patients with prior DAA experience

33. EASL Recommendations on Treatment of
Special Populations 2015:
 HBV co-infection
 Immune complex-mediated manifestations of
chronic hepatitis C
 Haemodialysis patients
 Non-hepatic solid organ transplant recipients
 Active drug addicts and patients on stable
maintenance substitution
 Haemoglobinopathies
 Bleeding disorders

34. Patients With Renal Impairment:
Mild to moderate renal impairment (CrCl
rate >30-80 mL/min)
 No dose adjustment is required when using:
 1- Sofosbuvir
 2- Simeprevir
 3-Fixed-dose combination of ledipasvir (90 mg)/
sofosbuvir (400 mg)
 4-Fixed-dose combination of paritaprevir (150mg)/
ritonavir (100 mg)/ ombitasvir (25 mg) plus twice daily
dosed dasabuvir (250 mg) to treat or retreat HCV
infection in patients with appropriate genotypes.

35. CrCl rates <30 mL/min:
 Daily fixed-dose combination of [PrOD]
paritaprevir (150 mg)/ ritonavir (100 mg)/
ombitasvir (25 mg) plus twice-daily dosed
dasabuvir (250 mg) with or without RBV (200 mg)
once daily is recommended.
 RBV should only be given if the baseline
hemoglobin level is >10 g/dL.

36. HIV/HCV-coinfected persons:
Should be treated and retreated the same as
persons without HIV infection:
 1- Managing interactions with antiretroviral
medications.
 2- Antiretroviral treatment interruption to allow
HCV therapy is not recommended.
 3- Drug switches, when needed, should be done
in collaboration with the HIV practitioner.

37.  Ledipasvir
Ledipasvir increases tenofovir levels and should
be avoided in those with CrCl <60 mL/min.
 Ledipasvir/ Sofosbuvir
Fixed-dose combination of ledipasvir (90 mg)/
sofosbuvir (400 mg) should not be used with
cobicistat, tipranavir and elvitegravir, pending
further data.

38.  Simeprevir
Should not be used with any HIV protease inhibitor.
Should only be used with antiretroviral drugs which
does not have clinically significant interactions:
raltegravir (and probably dolutegravir), rilpivirine,
maraviroc, enfuvirtide, tenofovir, emtricitabine,
lamivudine,and abacavir.
 RBV
RBV should not be used with didanosine,
stavudine, or zidovudine.

39. HBV co-infection:
 Patients should be treated with the same
regimens, following the same rules as HCV mono
infected patients.
 If HBV replicates at significant levels before,
during or after HCV clearance, concurrent HBV
nucleoside/ nucleotide analogue therapy is
indicated.

40. Patients with hemophilia:-
 Studies investigating PEG-IFN/RBV in hemophilia
patients are limited and often include small
numbers of patients but data suggest that
treatment success of HCV-infected hemophiliacs
is similar to that achieved in the general HCV-
infected population with frequent need of blood
transfusion.

41. Patients with extrahepatic manifestations:-
 The primary goal of treatment is HCV eradication,
which is associated with improvement of clinical
symptoms, especially in patients with mixed
cryoglobulinemia.

48. Thank you