Dr-MOHAMMED EMAM
Zagazig university-2014
“We're all really excited that for
the first time we have curative
therapies for hepatitis C which are
much more effective than what we
had before and much easier to
tolerate,“
“We think the move away from
interferon and toward a high
probability of success is remarkably
encouraging for all of us....
Suddenly, it's true to think that we can
cure most patients with hepatitis C,"
WHERE WE ARE NOW?
"
"
"
Sofosbuvir is a game-changer
and will allow high cure rates with
just 12-week regimens,"
sofosbuvir holds numerous advantages
over current therapy because of its:
-Efficacy profile,
-Safety,
-Tolerability across many different
patient populations and HCV
genotypes,
-Dosing simplicity.
-
-
INDICATIONS AND USAGE :
SOVALDI is Indicated for :
-Treatment
of chronic hepatitis C
(CHC) infection as a part of a
combination antiviral treatment
regimen.
Sofosbuvir and Ribavirin in HCV Genotype 4
Egyptian Ancestry Trial: Study Features
Egyptian Ancestry Genotype 4 Trial: Features
 Design: Randomized, open-label, phase 2 study of sofosbuvir + ribavirin in
treatment-naïve and treatment-experienced patients with HCV GT 4
 Setting: single study center in United States
 Entry Criteria
- HCV Genotype 4
- First generation Egyptian
- Treatment naïve or treatment experienced
- Age 18 or older
- Not co-infected with HIV
- Patients with compensated cirrhosis allowed
 Primary End-Points: Efficacy (SVR12) and safety
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.
Sofosbuvir and Ribavirin in HCV Genotype 4
Egyptian Ancestry Trial: Baseline Characteristics
Chronic HCV GT4: Treatment with Sofosbuvir + Ribavirin
Treatment Naive
Baseline Characteristic
Treatment Experienced
12-Week
(n=14)
24-Week
(n=14)
12-Week
(n=17)
24-Week
(n=15)
53 (26-69)
52 (27-75)
54 (32-72)
57 (38-68)
8 (57%)
5 (36%)
14 (82%)
14 (93%)
29.2
30.9
28.1
29.6
Cirrhosis, n %
3 (21%)
3 (21%)
4 (24%)
4 (27%)
IL28B non-CC, n (%)
11 (79%)
8 (57%)
16 (94%)
15 (100%)
Prior schistosomiasis, n (%)
8 (57%)
3 (21%)
6 (35%)
8 (53%)
5.7
5.9
6.2
6.1
Mean Age, y (range)
Male, n %
Mean BMI kg/m2
HCV RNA, mean baseline log10 IU/ml
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.
Sofosbuvir and Ribavirin in HCV Genotype 4
Egyptian Ancestry Trial: Design
Week
GT 4
Naïve
or
Experienced
0
12
Sofosbuvir + RBV
(n = 32)
24
36
SVR12
Sofosbuvir + RBV
(n = 28)
SVR12
Drug Dosing
Sofosbuvir: 400 mg once daily
Weight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.
Sofosbuvir and Ribavirin in HCV Genotype 4
Egyptian Ancestry Trial: Results
SVR 12 by Regimen Duration and Treatment Experience
Patients with SVR 12 (%)
100
100
87
80
79
60
59
40
20
0
11/14
14/14
10/17
13/15
SOF + RBV
x 12 weeks
SOF + RBV
x 24 weeks
SOF + RBV
x 12 weeks
SOF + RBV
x 24 weeks
Treatment Naive
Treatment Experienced
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.
Phase III NEUTRINO study: 96% SVR12
rate in patients with genotype4 HCV
treated with sofosbuvir plus
pegIFN/RBV for 12 weeks
Current pilot study evaluating
sofosbuvir plus RBV in immigrants of
full Egyptian ancestry in the US
infected with genotype 4 HCV
"
HCV FREE WORLD
NO DREAMS WITHOUT
PROBLEMS
Guidelines for low and middle
income countries
Most of the existing guidelines for the treatment of
hepatitis C have been developed by specialist medical
organizations and relate to the treatment of persons
with different genotypes and living in high-income
countries.
There are no evidence-based treatment
guidelines that focus on persons living
in low- and middle-income countries.
The suggestive objective of these
guidelines
These guidelines will provide a framework
for the development or strengthening of
hepatitis C treatment programmers' in lowand middle-income countries(especially in
Egypt) according to evidence-based
recommendations on screening for HCV
infection, and the care and treatment of
persons with HCV infection aiming to
achieve a mass treatment in our locality
Price of medicines
HCV treatment is expensive. Prices range from US$ 5 000 in Egypt
for 48-weeks of PEG/IFN RBV to as much as US$84 000 in the US
for a single 12-week course of sofosbuvir.
At these prices, these treatments will remain unaffordable for most
persons who need treatment. A concerted effort is needed to
reduce the price of HCV medicines.
The experience with HIV, where the price of antiretrovirals was
reduced by nearly a hundred fold through the introduction of
generic drugs, has shown that the key to achieving low prices
for medicines is to use a multipronged approach..
key to achieving low prices for medicines
This can include:
1- Voluntary licensing (where the patent owner licenses
the medicine to generics-producing companies or a patent pool),
2- Tiered pricing (where the manufacturer sets different prices for different
countries based on their income level and disease burden),
3- compulsory licensing (where a national government grants a license
to companies producing generic drugs or importing the product
4-National governments, international agencies, donors,
civil-society organizations, and the pharmaceutical industry will need to work
together to help assure that hepatitis C treatment is affordable and accessible
for all those who need treatment.
The primary goal of HCV therapy is to cure the infection.
A sustained virological response (SVR) is defined as
undetectable HCV RNA 12 weeks (SVR12) or 24 weeks
(SVR24) after treatment completion.
The infection is cured in more than 99% of patients who
achieve an SVR.
The SVR is generally associated with resolution of liver
disease in patients without cirrhosis.
Patients with cirrhosis remain at risk of lifethreatening complications; however hepatic
fibrosis may regress and the risk of
complications such as hepatic failure and portal
hypertension is reduced.
More data is required to ascertain the lifetime
residual risk of hepatocellular carcinoma after
viral infection has been eradicated
.
In addition to pegylated IFN-α and ribavirin, three new HCV
DAAs licensed in the first half of 2014, for use as part Of
combination therapies for HCV infection.
1-Sofosbuvir, a nucleotide analogue inhibitor of HCV RNAdependent RNA polymerase, has been approved in
January 2014.
2-Simeprevir, a second-wave, first generation NS3/4A
protease inhibitor approved in May 2014.
3-Daclatasvir, an NS5A inhibitor, is likely to be approved in
August or September 2014.
Other drugs may be approved later in 2014 or in 2015.
Who should be treated?
All treatment-naïve and -experienced patients with
compensated disease due to HCV should be
considered for therapy (Recommendation A1)
• Treatment should be prioritized for patients with
significant fibrosis (METAVIR score F3 to F4)
(Recommendation A1)
• Treatment is justified in patients with moderate
fibrosis (METAVIR score F2) (Recommendation A2)
• In
patients with no or mild disease
(METAVIR score F0-F1), the indication for
and timing of therapy can be
individualized.
• Patients with decompensated cirrhosis
who are on the transplant list should be
considered for IFN-free, ideally ribavirinfree therapy
Available drugs (approved by
before the end of 2014
Pegylated IFN-α2a should be used at the dose of
180 μg/week,
whereas pegylated IFN-α2b should be used at the
weight-based dose of 1.5 μg/kg/week. Ribavirin
dose should be 1000 or 1200 mg/ day, based on
body weight (<75 kg or ≥75 kg, respectively).
Sofosbuvir should be administered at the dose of
400 mg (one tablet).
Sofosbuvir should be administered at the
dose of 400 mg (one tablet) Once per day.,
No dose recommendation can be given for
patients with severe renal impairment (estimated
glomerular filtration rate <30 ml/min/1.73m2) or
with end-stage renal disease due to higher
exposures (up to 20-fold) of the predominant
sofosbuvir metabolite.
.
Sofosbuvir.
Sofosbuvir is well tolerated over 12 to 24 weeks of
administration.
The most common adverse events (≥20%)
observed in combination with ribavirin were
fatigue and headache. The most common
adverse events (≥20%) observed in combination
with pegylated IFN-α and ribavirin were fatigue
,headache, nausea, insomnia, and anaemia.
Simeprevir should be administered at the
dose of 150 mg (one capsule) once per day.
No dose recommendation can be Given for
patients with Child-Pugh Class B or C
cirrhosis, due to Higher simeprevir
exposures (particularly in Child-Pugh C
patients) that may be associated with
increased frequency of adverse reactions.
.
Simeprevir. is well tolerated. Adverse
reactions With at least 3%higher frequency in
patients receiving simeprevir in Combination
with pegylated IFN-α and ribavirin were
rash(including photosensitivity), pruritus
and nausea.
Because simeprevir is an inhibitor of the
transporters ( MRP2,) mild, transient Hyper
bilirubinaemia not accompanied by changes in
other liver parameters was observed in 10% of
cases.
Daclatasvir should be administered at the
dose of 60 mg (one tablet) once per day. It is
overall well tolerated.
Dose adjustments are not needed in patients with
Child B or C disease.
The most frequently reported side effects with
daclatasvir were fatigue, headache, and nausea.
Little information has been released on daclatasvir
drug-drug interactions.
2014
Treatment of chronic
hepatitis C -G4
Broad choice of drug combinations
2014
Genotype 4 ,
6 Options
Genotype 4 , Option 1
weekly pegylated IFN-α, daily weight-based
ribavirin (1000 or 1200 mg in patients<75 kg
or ≥75 kg, respectively), and daily
sofosbuvir (400 mg) 12 weeks
Whether longer treatment duration
would be needed in the most difficultto-treat population is unknown
NO STOPPING RULES
IS RECOMMENDED
Genotype 4 , Option 1
Comments:
This combination has been evaluated in the NEUTRINO
Phase III trial in treatment-naïve patients The SVR
rate in genotype 4 patients was 96% .
Whether longer treatment duration would be needed
in the most difficult-to-treat population is unknown
Genotype 4 , Option 2
weekly pegylated IFN-α, daily weight-based
ribavirin (1000 or 1200 mg in patients<75 kg
or ≥75 kg, respectively), and daily
semiprevir (150 mg) 12 weeks
Semipervir should be continued alone for
an in naïve and relapser12 weeks(total
duration 24 weeks)An additional 36 weeks
(total treatment duration 48 weeks) in prior
partial and null responders, including
cirrhotics
HCV RNA levels should be monitored on
treatment. Treatment should be stopped if
HCV RNA level is ≥25 IU/ml at treatment
week 4, week 12 or week 24
Genotype 4 , Option 2
Comments:
Indeed, SVR was achieved in 89%
(31/35) of treatment-naïve patients,
86% (19/22) of prior relapsers,
100% (10/10) of prior partial
responders, and 75%, (30/40) of
prior null responders.
Genotype 4 , Option 3
weekly pegylated IFN-α, daily weight-based
ribavirin (1000 or 1200 mg in patients<75 kg
or ≥75 kg, respectively), and daily
daclatasvir (60 mg) 12 weeks
patients who do not achieve an HCV RNA level <25
IU/ml at week 4 and undetectable at week 10
Daclatasvir should be continued in combination
with pegylated IFN-α and ribavirin an additional 12
weeks(total duration 24 weeks)
patients who achieve an HCV RNA level <25 IU/ml at
week 4 and undetectable at week 10
Pegylated IFN-α and ribavirin should be continued
alone between week 12 and 24 (total duration 24
weeks)
Genotype 4 , Option 3
Comments:
Although this combination is
theoretically effective, few
data is available. The SVR
rate was 100% (12/12) in the
COMMAND-1 trial
Genotype 4 , Option 4
Patients infected with HCV
genotype 4 who are IFN
intolerant or -ineligible
Daily weight based ribavirin (1000 or
1200 mg in patients <75 kg or≥75 kg,
respectively), and daily sofosbuvir
(400 mg) 24 weeks
No available trials with
simeprevir or dalactaasvir
Genotype 4 , Option 4
Comment:
Only preliminary data is available (SVR at week 4
post-treatment) in a small number of American patients of
Egyptian ancestry
The preliminary SVR rates were 79% (11/14) and
100% (14/14) after 12 and 24 weeks of treatment,
respectively, in treatment-naïve patients, and 59%
(10/17) and 93% (14/15) after 12 and 24 weeks,
respectively, in treatment-experienced patients
Genotype 4 , Option 5
Patients infected with HCV genotype 4 can
be treated of daily sofosbuvir (400 mg) and
daily simeprevir (150 mg) 12 weeks
There is no data on the impact of
adding ribavirin to this regimen
Ribavirin should be considered in patients
with predictors of poor response to antiHCV therapy, especially prior nonresponders and/or patients with cirrhosis
Genotype 4 , Option 5
Comments:
There is no data with this combination in patients
infected with HCV genotype 4. Nevertheless,
given the antiviral effectiveness of both
sofosbuvir and simeprevir against this
genotype, it is likely that the results of the
COSMOS trial in patients infected with genotype
1 can be extrapolated
Genotype 4 , Option 6
interferon-free combination of daily
sofosbuvir (400 mg) and daily daclatasvir (60
mg) 12 weeks in treatment-naïve patients or
24 weeks in treatment-experienced
There is no data on the impact of
adding ribavirin to this regimen
Ribavirin should be considered in patients with
predictors of poor response to anti-HCV therapy,
especially prior non-responders and/or patients with
cirrhosis
Genotype 4 , Option 6
Comments:
There is no data with this combination in
patients infected with HCV genotype 4.
Nevertheless, given the antiviral
effectiveness of both sofosbuvir and
daclatasvir against this genotype, it is
likely that the results in patients infected
with genotype 1 can be extrapolated.
Post-treatment follow-up of
patients who achieve an SVR
Non-cirrhotic patients who achieve an SVR should be retested
for HCV RNA at 48 weeks post-treatment.
If HCV RNA is still not detected, the infection can be
considered as definitely eradicated and HCV RNA need not
be retested.
As hypothyroidism may occur after stopping
IFN therapy, thyroxin and TSH levels should also be assessed
1and 2 years after treatment if the patient has received IFN.
Cirrhotic patients who achieve an SVR should
remain under surveillance for HCC every 6
months by ultrasound, and for oesophageal
varices by endoscopy if varices were present at
pretreatment endoscopy (though first variceal
bleed is seldom observed after SVR).
The presence of cofactors of liver disease, such
as history of alcohol drinking and/or type 2
diabetes may determine that additional
assessments are necessary
Perspective of new treatments
-A large number of other HCV drugs have reached late clinical
development.
Phase III data have been presented for the combination
of pegylated IFN-α, ribavirin and faldaprevir.
- Phase III data presented in April 2014 for the fixed-dose
combination of sofosbuvir and ledipasvir, and for the
three-drug combination of ritonavir, boosted ABT-450,
ombitasvir (formerly and dasabuvir.
A large number of additional Phase II data has been and will be
presented with other HCV drugs in development.
These recommendations
will be updated regularly,
following approval of
new drug regimens by
the European Medicines
Agency
New EGYPTIAN
guidelines
for management of HCV
‫اللجنة القومية لمكافحة الفيروسات الكبدية‬
1-Priority for treatment :will be directed towards
patients with F3 and F4.
2. No differentiation in treatment priority will be
established based on the previous treatment
experience.
.
3. Assessment of fibrosis stage: will be performed by
using a combination of both Fibro scan results and FIB
4 score. F3 & F4 stage will be considered if both Fibro
scan result is more than 9.5 and FIB4 score is more than
1.45. If both results are below these cut-off values,
patient will not be assigned as a treatment priority. If
one of these two methods is above the cut- off values
while the other is below, performing liver biopsy or reassessment after one year is recommended to rule out
the fibrosis stage of the patient.
.
.
5. Patients who are eligible to receive Interferon
(according to the currently used inclusion/
exclusion criteria for combined INF/RBV
treatment ) will be treated with: Daily sofosbuvir
(400 mg) and weight-based RBV (1000 mg [ <75
kg ] to 1200 mg [˃75 kg]) plus weekly PEG for 12
weeks.
6.Recommended regimen for patients
who are not eligible to receive
Interferon is : Daily sofosbuvir (400 mg)
and weight-based RBV (1000 mg [ <75
kg ] to 1200 mg [˃75 kg]) for 24 weeks.
Inclusion criteria for treatment: will be expanded to adapt for
more advanced liver fibrosis patients (who will be treated with
interferon free regimen ) as defined with the presence of all the
following
a-Child score up to 8
b) Total bilirubin < 3
c) Albumin ≥ 2.5
d) Platelet count ≥ 50.000
e) Prothrombin concentration ≥ 50%
f) Hemoglobin concentration ≥ 10 mg
Otherwise, waiting for new DAAs combination is advised .
7. Patients with more decompensated liver
disease: will be exluded from treatment until
enough data will be available and this will be
applied to:
a) Child C patients with scores ≥ 9
b) Presence of ascites (except after control )
c) Patients with HCC except after successful
radical curative intervention (4 months after
resection or successful local ablation )
d) Presence of large risky esophageal varices
(except after prophylactic management )
.
9. Governmental fund supports: will be issued on
2 bases; for the value of the interferon based
regimen (for interferon eligible patients ) and for
the value of interferon free regimen (for interferon
ineligible patients ) according to the
aforementioned inclusion / exclusion criteria. The
same rules will be applied for all patients
regardless the source of payment and there will
be on role for patients preferences in deciding the
treatment regimen.
8. Age limits
for treatment: legibility will be
above 18 years and below 70 years for all
patients while BMI will be accepted up to 35.
.
10-For special population groups: priority for
treatment will be awarded for post liver
transplantation, post kidney transplantation
patients and combined HCV/HBV infection
regardless the fibrosis stage.
Other groups, like pediatric age group and
kidney disease patients will be kept for
discussion after the availability of enough
data .
11- Patients with documents extra-hepatic
manifestations: will be prioritized for
treatment according to the same guidelines.
12. Treatment experienced patients: should not
start evaluation for new treatment regimens
except after 6 months from cessation of
interferon therapy .