1. How to Optimize Treatment of non G1 Patients
Luncheons PHC Paris January 31, 2012
How to Optimize Treatment of non G1 Patients
Alessandra Mangia
S. Giovanni Rotondo
ITALY

2. March 14, 2011 49 years old man, BMI: 28 HCV diagnosed in 1998
- previous iv drug and alcohol user
- genotype 3, HCVRNA: IU/ml
- liver biopsy: stage 2/3 fibrosis (Metavir)
Combination treatment with standard IFN and RBV offered declined
Presents in 2011 to be treated with Peg-IFN/RBV new liver biospy offered  declined

3. Pt understanding of treatment
Double combination treatment with Peg-IFN and RBV 800 mg
Duration24 weeks
SVR rate75%

4. Counseling What is the response rate with Peg-IFN/RBV?
Is treatment recommended now?
Can the patient wait? How long?
Would a liver biospy guide the treatment making decision process?
How do we prepare this patient in light of comorbidities?
Is there any way to increase the response rate?
What might be the response rate with the coming treatment regimens?

5. What to do in this pts? Treat now Wait for next therapeutical options
Perfom fibrosis evaluation

6. Which is the likelihood of SVR with the current SOC?
SVR is achieved in 65-82% of pts infected with HCV 2 and 3
treated with Peg-IFN alpha plus Ribavirin at approved doses
EASL Clinical practice guidelines. J Hepatol 2011

7. PROPHESYS STUDY: Virological response over time in HCV 2 and 3 patients
wk wk EOT SVR
APASL 2012

8. Metanalisi di Jordan feld
Duarte-Rojo A et al J Hepatol 2011

9. Possible negative predictors

11. Cirrhosis reduces the response rate
Bruno S, Hepatology 2010

12. Peg-IFN α2a plus RBV in HCV pts with advanced fibrosis and cirrhosis
on treatment virologic response
N=629
N=189
S.Bruno, Hepatology 2010

13. Predictors of relapse in 67/476 EOT HCV 2/3 pts with RVR receiving 12 wks of Peg/RBV
OR; 95% CI
Age >45 years
0.004 -
BMI >30 kg / m2
0.0001
2.5;
1.49 – 4.20*
Platelet counts < m3
1.7;
1.03 – 2.70*
Peg INF α2b (1.5 μg/kg) + RBV ( mg)
EOT: 96%; SVR: 82%, Relapse: 14%
Mangia et al, Hepatology 2009
*independently associated

14. Which is the expected tx duration in this pt? 1. 12 2. 24 3. 48

15. Even if RVR+ve... treat for 24 weeks

16. Which is the most appropriate RBV dose ?
AASLD guidelines advise 24 wks course of Peg-IFN and fixed doses of RBV(800 mg)
European guidelines recommend 15 mg/kg in HCV 2 and 3 patients with unfavourable baseline predictors

17. Response rates in GT2 and GT3
100 94 90 84 81 85 82 79 80 80
EOT
SVR 60
REL
Patients (%) 40 20 11 10 6 4
24 Weeks- LD
24 Weeks- SD
48 Weeks- LD
48 Weeks- SD
Hadziyannis S, et al. Ann Intern Med. 2004;140: 17

18. SVR rates according to RBV dosage in 673 pts with HCV G2 and 3
wk – 4 R n = 473
wk – 4 NR n = 200 % %
269/356
19/22
110/169
23/30
mg/kg
mg/kg
Mangia et al EASL 2009

19. RG Peg-IFN plus RBV tx duration in chronic HCV: meta-analyses of RCT and implications for the future
Flat RBV or wks course
Flat RBV
WB-RBV or 16 wks course
Di Martino V et al Hepatology 2011

20. Is it possible to increase SVR extending tx duration?

21. Sustained Virologic Response
Variable Duration
Standard Duration
Mangia et al, AASLD 2009

22. Does IL28B matter?

23. IL28B is associated with increased SVR in non-RVR pts treated for 24 wks
Virological response on treatment in HCV G2-3 patients on the basis of IL-28B type.
Mangia A Gastroenterology 2010

24. IL28B in HCV G3 Pts number SVR SVR if RVR+ve RVR-ve Scherzer TM CC CT71 53
57 (80%) 14 CC
27 (38%)
19 (70%)
18/25 (72%)
1/2 (50%) CT
39 (54%)
31 (79%)
26/29 (89%)
5/10 (50%) TT
5 (7%)
3 (60%)
3/3 (100%)
0/2
Moghaddam
281
226
201 (71%) 81
129 (46%)
99 (77%)
87/108 (81%)
22/22 (100%)
105 (81%)
77/80 (96%)
28/49 (57%)
23 (8%)
22 (96%)
13/13 (100%)
9/10 (90%)

25. IL 28B: clinical implications in G2 and G3
RVR (+) No
role for IL28B
24 wks
If IL28B CC
RVR (-)
48 wks?
DAA?
If unfavourable IL28B

26. What if the patients is tx experienced?

27. Re-treatment of relapser pts after an initial short course
Study
Schedule
SVR (%)
HCV G1
Berg C, 2006
Pegα2a+
RBV >1000 mg/daily
18/35 (51%)
HCV G2/3
Mangia A,2009
RBV mg/daily
30/43
(70%)

29. Wait for new therapeutical options?

30. What else is in our therapeutic
armamentarium?
Agents directly targeting viral functions (DAAs)
NS3/4 protease inhibitors
NS5B polymerase inhibitors
Nucleoside
Nonnucleoside
NS5A inhibitors
Other viral targets
Alternative interferons
Agents targeting host cofactors
Cyclophillin antagonists
miRNA inhibitors

31. DAAs as components of new treatment paradigm for hepatitis CPR
Prospect of
shorter
treatment
duration
for a greater
proportion of
patients
1 x DAA + PR
IFN-based
2 x DAAs + PR
Slide 6. DAAs as components of new treatment paradigm for hepatitis C
IFN-free?
IFN-free?
2009
~2012
2016
Time
DAA = direct-acting antiviral; IFN = interferon; PR = pegylated interferon (Peg-IFN) plus ribavirin (RBV) 31

32. Is the tx safe? Risk/benefit analysis with comorbidities How do we prepare the patient in light of comorbidities?

33. Safety profile of HCV therapy
Contraindications
Decompensated cirrhosis
Renal insufficiency
Advanced cardiac/pulmonary disease
Active depression
Severe mental illness
Anemia, neutropenia, throbocytopenia
Lack of compliance

34. AEs More Frequent in Experimental Arm vs PR
Agent
AEs More Frequent in Experimental Arm vs PR
Discontinuations due to AEs, % (Wk)
Boceprevir[1]
Anemia, dysgeusia
14 (48)
Telaprevir[2]
Rash, anemia, pruritus, nausea
10 (48)
ANA598[3]
Rash incidence and severity increased with 400-mg dose
2 (12)
BI [4]
Gastrointestinal events, jaundice, and rash*
5 (12)
BMS [5]
None reported
8 (12)
Danoprevir[6]
ALT elevation, neutropenia, nausea diarrhea
4 (12)
Filibuvir[7]
0 (4)
RG7128[8]
TMC435[9]
Mild bilirubin increases in first 2 wks of therapy
7 (24)
Vaniprevir[10]
Vomiting with 600-mg dose
0 (6)

35. Pros Peg/RBV tx Cons Peg/RBV tx Risk of liver disease progression
IFN free tx available not earlier than 2017
Possible additional SAE of future Tx
Cons Peg/RBV tx
Risk of low response rate
IFN and RBV related SAE

36. Conclusions
This pt can be treated now with Peg-IFN and weight based RBV for not less than 24 wks
Fibrosis re-evaluation is needed
IL28B evaluation useful
In case of non response….

37. Thank you

38. Biomarkers for significant fibrosis and cirrhosis
Adjusted AUROC (n=382)
Biomarker
Significant fibrosis
Cirrhosis
Fibrometer
0.86
0.90
Fibrotest
0.84
0.87
Forns’ score
0.81 –
APRI
0.80
Hepascore
0.89
FIB4
Fibroscan
0.93
Significant fibrosis: AUROCs range from 0.80 to 0.86 with no significant difference between Fibrometer, Fibrotest, Hepascore and Fibroscan
Cirrhosis: AUROCs are higher (range 0.87–0.93) with no significant difference
Zarski JP, et al. J Hepatol 2011; in press

39. RG Peg-IFN plus RBV tx duration in chronic HCV: meta-analyses of RCT and implications for the future
Flat RBV
Weight-based RBV
Di Martino V et al Hepatology 2011

40. SNP near IL28B predicts SVR with PR
p = 1.06 x 10–25
p = 2.06 x 10–3
p = 4.39 x 10–3
p = 1.37 x 10–28
SVR (%)
rs predicts SVR
-chromosome 19
-3kb upstream of IL28B
-P=1.37 x10-28 across
all population groups TT TC CC TT TC CC TT TC CC TT TC CC
n=102
n=433
n=336
n=70
n=91
n=30
n=14
n=35
n=26
n=186
n=559
n=392
Caucasian
African American
Hispanic
Combined
SVR
Non-SVR
Ge D, et al. Nature 2009; 461: 399–401

41. Original study protocol
Standard-24 (SD)
PegIFN + ribavirin for 24 weeks
n=68
Variable-12/24 (VD)
PegIFN + RBV for 12 or 24 weeks
n=200
Week 0
HCV-RNA -ve Treated for 12 weeks n=122
HCV-RNA +ve
Treated for 24 weeks n=78
Week 4
Drop out
n=2
Drop out
n=3
Week 12
Completed
n=120
Drop out
n=4
Drop out
n=1
Completed
n=64
Completed
n=74
Week 24
* 13 patients did not provide informed consent; genotyping failed in 2
Mangia EASL 2010

42. . Association of the IL28B genotypes with (A) sustained virologic response, (B) relapse, (C) non-response to (pegylated) interferon-alfa and ribavirin in HCV genotype 2/3 infected patients.
Sarrazin C et al. J Hepatol 2010 in press

43. On-treatment responses in a real-world setting
RVR
cEVR
pEVR
100 80 73 66 60
Patients (%) 40 31 31 27 25 21 17 16 20 11 11 7
G1 (n=3387)
G2 (n=740)
G3 (n=940)
G4 (n=225)
Ribavirin prescribed with either PEGASYS or Peg-IFN a-2b in accordance with local label
Ferenci P, et al. EASL 2010; poster 256

44. HCV RNA titre at week 2 G1 (n=887) G2 (n=138) G3 (n=199) G4 (n=45) 10090 80 70 60 54
Patients (%) 50 47 39 37 40 35
Missing:
G1, n=963 (51%); G2, n=140 (49.1%); G3, n=281 (57.7%); G4, n=74 (61.2%)
HCVRNA >15 IU/mL not quantifiable:
G1, n=38 (2%); G2, n=7 (2.5%); G3, n=7 (1.4%); G4, n=2 (1.7%) 31 33 30 24 21 22 20 20 10 9 10 5 6 7
<15 IU/mL
>2-log
>1-log to <2-log
<1-log
(Prophesys) 44 44

45. Genotypes 2 & 3 treatment duration: ≤ 16 vs 24 wks
SVR rates
Shiffman, 2007 Yu, Lagging, 2008
62 %, 94 %, 69%
70 %, 95 %, 78 %
≤ 16 weeks
24 weeks
NoRVR
Dalgard, Von Wagner, 2005
81 %, 82 %
91 %, 80 %
NoRVR
Mangia, 2005
Mecenate, 2008
77 %
76 %
noRVR = 64%
RVR = 85 % 4
≤ 16 24
Weeks 45 45 45 45

46. HCV 2 and 3 pts without RVR
Shiffman 2007; Lagging 2008

47. Genotype 1, high viral load Genotype 1, low viral load
Genotypes dictates dose & duration of Tx
800mg
x 24 wks
1.0 – 1.2g
x 48 wks
PegIFN -2a Plus RBV
100 80 60 40 20 16 41 78 51 26 35 53 73 77 61 46
SVR (%)
Genotype 1, high viral load
Genotype 1, low viral load
Genotype 2/3
Hadzyiannis et al, Ann Int Med 2004;140:

48. Re-treatment of HCV 2 and 3
HALT-C (only 12% of previous IFN/RBV failure)
Genotype % % %
EPIC C
Genotype 2/3 F3 54% F4 15%

49. PPV and NPV of RVR in these pts

50. SVR to PEG IFN+RBV in NRs to IFN+RBV by Genotype50
37% 40 30 20 % 10 0%
Genotype 1
Genotype 2-3
SVR
Moucari et al. J Hepatol 2007