1. Towards an End to HCV Epidemic in Egypt
New Treatment for HCV G4
Towards an End to HCV Epidemic in Egypt
Now let us move on to talk about the epidemiology of hepatitis C.

2. Several potential innovative drug targets in HCV
IFN-lambda
A type III interferon with a restricted distribution of receptors contributing to a favourable adverse event profile7
BMS
Cyclophilin A
Host protein involved in HCV replication through interaction with NS5A and the HCV polymerase
Alisporivir5,*
SCY-6351 c
NS2
NS3
NS5A
NS5B E1 E2
NS3/4A
NS5A
NS5B
A serine protease, essential for post-translational processing of HCV polyproteins
Multifunctional membrane- associated phosphoprotein, essential component of the HCV-RNA replication complex
An HCV-specific, RNA-dependent RNA polymerase
Boceprevir1
Telaprevir1
ABT-450/r2
Sovaprevir3
Asunaprevir11
Simeprevir9
Faldaprevir12
Danoprevir12 GS MK
ACH-806/GS-91321
Daclatasvir4
Ledipasvir4 ABT-2672
PPI-6686
AZ-6894
BMS
PPI-4614
Nucleos(t)ide analogue
Sofosbuvir10
Mericitabine15
VX-13520
Non-nucleoside analogue BI
ABT-3332
ABT-07217
BMS
Tegobuvir12
Setrobuvir12
VX-22219
Filibuvir12
*On clinical hold, Novartis press release
1. Rehman S, et al. Genet Vaccines Ther 2011;9: Gish R & Meanwell NA. Clin Liver Dis 2011;15:627– Coelmont L, et al. PLoS One 2010;5:e Miller DM, et al. Ann N Y Acad Sci 2009;1182: Poordad F, et al. AASLD 2012, abstract Gane E, et al. EASL 2012, poster Delang L, et al. Viruses 2010;2:826– ct2/show/NCT Wedemeyer H, et al. Hepatology 2013 January 24. [Epub ahead of print]. doi: /hep [Accessed April 10, 2013].

3. Characteristics of DAA
PI 1st generation
PI 2nd generation
NS5A Inh. 1st generation
NS5A Inh. 2nd generation
NS5B
nucleos(t)ide inh.
NS5B non nucleos(t)ide inh.
Efficacy
Resistance profile
Pangenotypic efficacy
Adverse events
Drug-drug interaction
Good profile
Average profile
Least favorable profile
Schinazi, et al. Liver Int 2014;34 Suppl 1:69-78

4. In different patient types
Many studies have looked at different ways of combining these compounds
Alfa
RBV
NS5A
In different patient types
NS5A
Alfa
RBV
NS3/4A
Different genotypes
Treatment-naive
Null-responders to prior therapy
Intolerant to previous therapy
RBV
Alfa
NS3/4A
Lambda
RBV
Lambda
RBV
NS5A
NS5A
NS3/4A
NS5B
(non-nuc inhibitor)
NS5B
(nuc inhibitor)
RBV
NS5A
NS3/4A
NS3/4A
Lambda
RBV
Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin
This slide represents just a small selection of studies and regimens in current clinical development – other combinations are therefore possible

5. Sofo+RBV Response Duration Regimen Patients Study SVR 24
Non cirrhotic: 90%
Wight based RBV: 68%
Low dose RBV: 48%
12 weeks
A: 10 non cirrhotic
B: 50 All stages of fibrosis:
25 (weight based RBV)
25 (low dose RBV: 600)
No: 60
treatment-naive patients
genotype 1
with bad predictors: (African-American, high BMI, low frequency of
IL28B CC, viral load and advanced fibrosis)
Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics
Osinusi (2013)
JAMA
12 weeks SVR %
24 weeks SVR %:
Or 24 weeks
Sofosbuvir + RBV
60 patients
Egyptians G4
Treatment naive and -experienced
Sofosbuvir plus ribavirin in the treatment of chronic HCV genotype 4 infection in Egyptian patients
Ruane (2013)
Hepatology
12 weeks SVR %
24 weeks SVR %
G patients
Egyptian study

6. Sofo+IFN+RBV Response Duration Regimen Patients Study SVR 24 A: 89%
C: 87%
12 w
24 weeks
24 weeks (12 +12)
A (N:52): sofosbuvir +P+R
B (N: 109, with 11 of them genotype 4): sofosbuvir +P+R
C (N: 155): 12 weeks of sofosbuvir +P+R followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir +R
316 naïve
genotype-1
ATOMIC
Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre
phase 2 trial
Kowdley et al (2013)
Lancet
Total 90% (295/327)
G1a 92% (206/225)
G1b 82% (54/66)
G4 96% (27/28)
G5/6 100% (7/7)
Cirrhosis 80% (43/54)
12 weeks
Sofosbuvir + PegIFN
+ RBV
G1, 4, 5, 6
Naïve
n = 327
(G1 79%)
NEUTRINO
Sofosbuvir for previously untreated chronic hepatitis C infection
Lawitz (2013)
NEJM

7. Sofo and other DAA combination trials
Study
Patients
Regimen
Duration
Response
Electron (1)
Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin G1
prior null responders with compensated cirrhosis
and in naive, noncirrhotic patients
Sofosbuvir+ ledipasvir
With or without RBV
12 weeks
Cirrhotic TTT failure:
With RBV: 100% SVR12
Without RBV: 70% SVR 12
Non cirrhotic naïve:
6 weeks ttt: 68% SVR 12
8 weeks ttt; 100% SVR 12
LONESTAR (2)
Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial
G 1
treatment-naive, noncirrhotic
8 weeks
8 weeks with RBV: 100%
8 weeks without RBV: 95%
12 without RBV: 95%
COSMOS (3)
SVR results of a oncedaily
regimen of simeprevir (TM435) plus sofosbuvir (GS-7977) with of without ribavirin in cirrhotic and noncirrhotic HCV genotype 1 treatment naıve and prior null responder patients
Noncirrhotic and cirrhotic,
treatment-naıve and prior null responder
Sofosbuvir+simeprevir
with or without RBV
for 12 or
24 weeks
SVR12 in prior null responders with F0-F2 fibrosis were 93% (in both 12 and 24 weeks).
In cirrhotics: SVR 4: 100% (in both null responders and naïve) 24 weeks.
Gane (2013), Hepatology 2) Lawitz (2013), Lance, 3) Jacobson (2013), Hepatology

8. Treatment experienced
SOF + RBV: In genotype 4
This study done on 60 Egyptians (G4) living in USA
20% of them are cirrhotics.
SVR12 (%)
11/14
14/14
10/17
13/15
21/31
27/29
12 Week SOF + RBV
24 Week SOF + RBV
12 Week SOF + RBV
24 Week SOF + RBV
12 Week SOF + RBV
24 Week SOF + RBV
Treatment naïve
Treatment experienced
All
Ruane PJ, et al. EASL P1243
Ruane PJ, et al. EASL P1243
Ruane PJ, et al. AASLD Abstract 1090

9. Sofosbuvir+ Ribavirin in G4 (Egypt)
100 patients (20% C, 3 centers)
Arm 1 (12 wks)
Arm 2 (24 wks)
(Esmat, et al AASLD.2014)

10. In 51 patients GT4, received SOF + RBV for 12 weeks, SVR in 39 (77%)
Pts who were treatment naïve, Fibrosis stage<F3, and baseline viremia <600,000 IU were 9 pts. All showed SVR (100%)
Pts who were either treatment experienced, and/or fibrosis stage >F2 and viremia level >600,000 IU showed SVR (71%) (12 pts of whom 8 were treatment experienced)
P value 0.01 (S)

11. 0= naïve, Fibrosis <F3, viremial<600,000 IU
1= treatment experienced, and/or fibrosis ≥F3, viremial >600,000 IU

12. SOF STUDIES EGYPTIAN 1. Lawitz et al. DDW 2013.
2. Ruane et al. EAS L2014. Poster 1242.
3. Esmat et al,AASLD. 2014
EGYPTIAN

13. Non invasive detection of hepatic fibrosis
Fib-4 Formula

14. Non invasive detection of hepatic fibrosis
Fibroscan

15. Non invasive diagnosis of Advanced hepatic fibrosis(>F2)
AUC
No of patients
Best cutoff
sensitivity
specificity
PPV
NPV
accuracy
LR+
LR-
*Fib-4
0.71
36841
1.45
0.69
0.63
0.28
0.90
1.9
0.49
♠Fibroscan
0.82
231
9.5
0.87
0.68
0.93
0.86
6.52
0.20
Fib-4
Fibroscan
>1.45
≤1.45
Wait or Do liver biopsy
Do not treat
≤9.5
Treat
>9.5
*National Committee for control of viral hepatitis, NNTC data , Jan 2014
♠ Esmat et al, Arab Journal of Gastroenterology 14 (2013) 109–112

16. PEARL 1 INTERFERON-FREE REGIMENS OF ABT-450/R + ABT-267 WITH OR WITHOUT RIBAVIRIN In 135 Ch HCV GENOTYPE 4 Patients
Treatment-naive and Peginterferon/RBV-experienced patients with chronic HCV GT4 infection were enrolled. Treatment-naive patients received ABT-450/r (150/100mg QD) + ABT-267 (25mg QD) ± weight-based RBV for 12 weeks. Experienced patients received the RBV-containing regimen for 12 weeks.
Hezode EASL 2014 Ab 58

19. ABT-450/r + Ombitasvir +RBV*4
Current and future regimens containing the new DAAs for genotype 4 patients
Phase III
Phase IIb
Naive
Naive
Experienced
Naive
Experienced
Naive
Experienced
Naive
Experienced
Naive
100
100
Experienced
No data for
DCV/PR
SVR (%)
27/28
11/14
10/17
14/14
13/15
29/35
42/42
37/37
12/12
12/12
41/72
SOF/PR1 NEUTRINO
SOF/RBV2
12 wk
SOF/RBV2
24 wk
SMV/PR*3 RESTORE
ABT-450/r + Ombitasvir +RBV*4
PEARL-I
(SVR4 only in experienced)
DCV 60 mg/PR*5 COMMAND-1
1. Lawitz et al. DDW 2013.
2. Ruane et al. EAS L2014. Poster 1242.
3. Moreno et al. EASL Poster 1319.
4.Hézode et al.EASL2014.
4. Hézode et al. AASLD Poster 755.

20. EASL Guidelines: Treatment of HCV GT 4 infection
Treatment Options
Recommendation status: Regimen
Comments by authors
Option 1
B1: PR + SOF 12 wks
„appears the most efficacious and the easiest to use “
Evaluated in TN Neutrino SVR 96% 27/28
No data in TE
Option 2
B1: PR+ SMV 12 wks + additional PR for either 12 or 36 wks
(12 wks SMV + PR; 24 wks total duration for TN & relapsers including cirrhosis and 48 wks for Prior partials and nulls including those with cirrhosis)
TN: SVR 89% 31/35
Prior Relapsers: SVR 86% 19/22
Non Responders 57% 41/72
Option 3
B1: PR + DAC 60mg 24 wks
B2: 12 wks TT + additional PR for either 12 or 36 wks: (24 wks total duration for TN & relapsers including cirrhosis and 48 wks for Prior partials and nulls including those with cirrhosis)
Theoretically effective, few data available SVR 100% in 12/12 COMMAND 1 trial
Option 4
IFN intolerant or ineligible
C2:R + SOF 24 wks
„only preliminary data is available in Egyptian pts“
TN 12 wks treatment: SVR 79% 11/14
TN 24 wks treatment: SVR 100% 14/14
TE 12 wks treatment: SVR 59% 10/17
TE 24 wks treatment: SVR 93% 14/15
Option 5
B2: SOF+SMV 12 wks
Consider adding RBV in patients with predictors of poor response or in pts with cirrhosis
„no data with this combination- it is likely that data from Cosmos can be extrapolated“
Option 6
B2: SOF +DAC (60mg) 12 wks TN or 24wks TE
„no data with this combination- it is likely that data can be extrapolated“

22. COST EFFECTIVENESS CHART
120,000 L.E
SVR %
COST/PT
12,000 L.E
9600 L.E
12,600 L.E
6600 L.E
*NAÏVE, NON CIRRHOTIC, LOW VIREMIA,

23. Eradication of HCV in Egypt Overcoming the Barriers

24. Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

25. Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients

26. Overcome the Barriers
Ideal drug
Decrease incidence
Mass treatment

27. Ideal Drug
It is important for patients treatment but more important for control and eradication of any infectious disease

28. Decrease incidence Blood safety. Avoid unneeded injection.
Auto destructive syringes.
Infection control.
Media awareness.
Case detection and treatment by Ideal drug

29. HCV in EGYPT from Control to Eradication
To decrease HCV prevalence to< 2 % in Egypt
in 10 years(Mathematical modeling)
Effective treatment SVR > 90%
Annual treatment of to patients
Decrease incidence by prioritize treatment to most frequent injectors
J.viral hepatitis,2014

30. HCV Treatment guidelines (Draft)

31. Priority for treatment will be directed towards patients with F3 and F4.
No differentiation in treatment priority will be established based on the previous treatment experience.

32. Assessment of fibrosis stage will be performed by using a combination of both Fibroscan results and FIB 4 score. F3-4 stage will be considered if both Fibroscan result is more than 9.5 and FIB4 score is more than 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 value while the other is below, performing liver biopsy or re-assessment after one year is recommended to rule out the fibrosis stage of the patient.

33. Upper GI endoscopy is mandatory in the following circumstances:
a. Histological evidence of cirrhosis by liver biopsy
b. Fibroscan > 19.2 K.Pa
c. Platelet count < 100,000

34. Patients who are eligible to receive Interferon (according to the currently used inclusion/exclusion criteria for combined IFN/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.
Recommended regimen for patients who are not eligible to receive IFN is daily Sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks

35. Otherwise, waiting for new DAAs combination is advised.
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 one or more of the following;
Child score up to 8
Total bilirubin ≤ 3
Albumin ≥ 2.5
Platelet count ≥ 50,000
Prtothrombin concentration ≥ 50%
Hemoglobin concentration ≥ 10 mg
Otherwise, waiting for new DAAs combination is advised.

36. Patients with more decompensated liver disease will be excluded from treatment until enough data will be available and this will be applied to:
Child C patients with scores ≥ 9
Presence of ascites (except after control)
Patients with HCC except after successful radical curative intervention (4 months after resection or successful local ablation) evident by triphasic CT.
Presence of large risky esophageal varices (except after prophylactic management)

37. 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.
The same rules will be applied for all patients regardless the source of payment and there will be no role for patients' preferences in deciding the treatment regimen.

38. For special population groups; priority for treatment will be offered 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.

39. Patients with documented extra-hepatic manifestations will be prioritized for treatment according to the same guidelines.
Treatment experienced patients should not start evaluation for new treatment regimens except after 6 months from cessation of interferon therapy.

40. Gamal Esmat