Gastrolearning V lezione Inibitori delle proteasi di I generazione: sono una reale innovazione? - Prof. A. Craxì (Università di Palermo) www.gastrolearning.it

1. 18 Dicembre 2012
Inibitori delle proteasi di HCV
di I generazione: sono una
reale innovazione?
Antonio Craxì
Gastroenterologia & Epatologia,
Di.Bi.M.I.S.
Università di Palermo
antonio.craxi@unipa.it

2. Epidemiology of Hepatitis C in Europe
Time trends incidence
• 9 million chronic carriers
• 27,000 to 29,000 newly
diagnosed cases per year
• 86,000 deaths per year
• Most affected age group: 25-
44 year, followed by 15-24
year
• Clustered to sub-populations
Van de Laar, Hepatitis Summit Conference, Brussels 2010

3. Map of estimated anti-HCV seroprevalence
by GBD region, 2005
Hanafiah et al, Hepatology in press

4. Treatment of Hepatitis C: Evidence for
Effectiveness in SVR Patients
1. Durable HCV-RNA eradication achievable
2. Histological reversal of cirrhosis documented
3. Reduced rates of decompensation and HCC
4. Reduced rates of liver-related mortality

5. Accessibility to Peg-IFN antiviral therapy in
different European countries
4 16
HCV prevalence
HCV prevalence rate (%)
Treatment levels 14
Patients treated per 100
3 12
prevalent cases
10
2 8
6
1 4
2
0 0
Belgium France Germany Italy Spain UK
There are substantial differences between European countries in
terms of HCV prevalence and access to antiviral therapy
Peg-IFN/RBV: peginterferon plus ribavirin Deuffic-Burban S, et al. Gastroenterology 2012;[ePub ahead of print]

6. Effect of treatment strategy* according to fibrosis
stage on HCV-related cirrhosis and deaths†
Cumulative HCV-related cirrhosis and deaths (95% CI)
Treatment scenario Cirrhosis Deaths
With treatment 330,700 282,300
(baseline scenario) (313,200–342,000) (268,600–294,200)
Never treating patients 359,300 295,000
with F0/F1 (339,900–372,200) (280,700–307,700)
Not treating F0/F1 332,200 282,700
until F2 is reached (314,600–343,600) (269,000–294,600)
Not treating F0/F1 342,400 285,900
until F3 is reached (324,100–354,300) (272,100–298,000)
• In comparison to the baseline scenario, delaying treatment in patients with
F0/F1 is associated with an increase in HCV-related cirrhosis and deaths,
regardless of the scenario
• Delaying treatment until F2 is reached appears to be efficient in terms of
mortality but will necessitate efficient diagnostic testing of fibrosis to detect
progression from F0/F1 to F2
*With Peg-IFN + RBV; †All genotypes Deuffic-Burban S, et al. Gastroenterology 2012 [Epub ahead of print]

7. Milestones in Therapy of Genotype 1 HCV
Direct-acting
antivirals
100
2011
Peginterferon
80 Ribavirin 2001
Standard 70+
interferon 1998
60
SVR (%)
55
1991
42
39
40 34
20 16
6
0
IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/
RBV RBV/
6 mos 12 mos 6 mos 12 mos 12 mos 12 mos DAA
Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.

8. Naive patients
Increased SVR compared to Peg-IFN/RBV
Boceprevir Telaprevir
SVR increases from 38% to SVR increases from 44% to
63/66% 72/75%
( + 25-28%) (+ 28-31%)
Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.
Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.

9. Treatment-experienced patients
Increased SVR compared to Peg-IFN/RBV
Boceprevir Telaprevir
Relapsers Relapsers
SVR increases from 29% to 75% SVR increases from 24% to 83/88%
Partial-Responders Partial-responders
SVR increases from 7% to 52% SVR increases from 15% to 54-59%
Null-responders
SVR increases from 5% to 29/33%
Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3

10. Chance for Cure in HCV 1. The Impact of Triple Therapy
A Systematic Review
Patients Dual Triple ∆
Pts # SVR Pts # SVR
Previously untreated 1545 39% 1634 <2-fold
68.5%
Relapsers/Partial
539 26% 719 73% 3-fold
Resp.
Nonresponders 255 7.5% 386 44% 6-fold
Jurchis AR et al. EASL 2012, Poster 1123 (S442)

11. Number of Patients Ever Treated With PEG IFNs
per 100 Prevalent HCV Cases until End of 2005
Patients ever treated with Peg-IFNs
per 100 prevalent cases
Lettmeier B et al, J Hepatol 2008;49:528-536

12. Treatment of HCV genotype 1 in Italy:
the current situation
∀ ∼ 7000 patients HCV Gt 1 patients treated each year (2008-
2011) with a 10% yearly trend to decrease (2010-2011):
– Spontaneous change due to disease epidemiology
– Warehousing effect (triple therapy  IFN-free)
∀ ∼ ¼ of Gt 1 patients treated yearly (2008-2010) were re-
treatments. This figure has decreased markedly in 2011
(warehousing for triple therapy)
• Yearly expenditure (2011) for P/R: 165,000,000 Euros
• Aging population of naives (mean age at tx 48 years) with 25-
30% of F3/F4 fibrosis
• At least 20,000 patients with previous P/R failures (usually
unclassified) with a mean age > 55 years and at least 40% of
F3/F4 fibrosis

13. HCV-AIFA Italian study: RVR and SRV to P/R in
genotype 1 patients according to baseline factors
Variables N. of patients RVR SVR
No favorable factors 21/179 (11.7%) 1/19 (5.2%) 3/21 (14.3%)
1 favorable factor 82/179 (45.8%) 17/80 (21.2%) 25/82 (30.5%)
MALES 2 favorable factors 62/179 (34.6%) 25/58 (43.1%) 37/62 (59.6%)
3 favorable factors 14/179 (7.8%) 9/14 (64.3%) 12/14 (85.7%)
Favorable factors:
 HCV-RNA < 400,000 UI/ml
C/C genotype of rs12979860 SNP
No visceral obesity (VOB)
Variables N. of patients RVR SVR
No favorable factors 58/152 (38.1%) 8/57 (14.1%) 16/58 (27.6%)
1 favorable factor 75/152 (49.4%) 20/70 (28.6%) 26/75 (48.0%)
FEMALES
2 favorable factors 19/152 (12.5%) 12/17 (70.1%) 16/19 (84.2%)
Favorable factors:
 Age < 50 years
C/C genotype of rs12979860 SNP

14. The balance of triple therapy with
boceprevir and telaprevir
Advantages Disadvantages
 Not sufficiently tested in difficult
 First-generation protease inhibitors patients (cirrhosis)
increase SVR rates in naive and  Modest potency with development
treatment-experienced patients1,2 of resistance2,3
and may reduce liver-related
morbidity and mortality in the long-  Genotype 1 restricted
term1,2
 Complex regimens, with risk of
 Potential for shorter poor adherence2
treatment duration1,2
 Increased adverse reactions and
toxicity burden2
 Increased risk of DDIs2
 Costs
1. Ghany MG, et al. Hepatology 2011; 54: 1433–44
2. Ferenci P & Reddy KR. Antivir Ther 2011; 16: 1187–1201
3. Pawlotsky J-M. Hepatology 2011; 53: 1742–51

15. Addition of BOC or TVR to PegIFN/RBV
Improves SVR in Genotype 1 Patients
 BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV
patients who are previously untreated or who have failed previous therapy
100
69-83 PegIFN + RBV
80 BOC/TVR + pegIFN* + RBV
63-75
40-59
SVR (%)
60
38-44 29-40
40
24-29
20 7-15
5
0
Treatment Relapsers[3,4] Partial Null
Naive[1,2] Responders[3,4] Responders[4,5]
*BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
5. Bronowicki JP, et al. EASL 2012. Abstract 11.

16. Response-Guided Therapy

17. RGT Paradigm With BOC + PegIFN/RBV in
Tx-Naive Patients
 Indicated for all noncirrhotic treatment-naive patients
HCV RNA
Undetectable < 100 IU/mL Undetectable
PegIFN/
BOC + PegIFN/RBV Early response stop at Wk 28; f/u 24 wks
RBV
0 4 8 12 24 28 36 48
HCV RNA
Detectable < 100 IU/mL Undetectable
Slow response extend triple therapy
to Wk 36; PR to Wk 48; f/u 24 wks
PegIFN/
BOC + PegIFN/RBV PegIFN/RBV
RBV
0 4 8 12 24 28 36 48
Boceprevir [US package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Boceprevir [EU package insert]. July 2012.

18. Response-Guided Therapy Paradigm With
BOC + PegIFN/RBV in Tx-Exp Patients
 Indicated for noncirrhotic previous relapsers or partial responders* [1,2]
HCV RNA
Undetectable < 100 IU/mL Undetectable
PegIFN/
BOC + PegIFN/RBV Early response stop
RBV at Wk 36; f/u 24 wks
0 4 8 12 24 28 36 48
HCV RNA
Detectable < 100 IU/mL Undetectable Slow response
PR to Wk 48; f/u 24
wks
PegIFN/ BOC + PegIFN/RBV PegIFN/RBV
RBV
0 4 8 12 24 28 36 48
*RGT for this group indicated in US only; European prescribing information indicates that noncirrhotic previous relapsers or
partial responders should receive 4 wks of pegIFN/RBV followed by 32 wks of BOC + pegIFN/RBV and then 12 wks of
pegIFN/RBV, regardless of early response. [3]
1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Boceprevir [EU package insert]. July 2012.

19. RGT With TVR + PegIFN/RBV in Tx-Naive
Patients and Previous Relapsers
 Indicated for all noncirrhotic treatment-naive pts and previous relapsers*[1,3]
HCV RNA
Undetectable Undetectable Undetectable
TVR + PegIFN/RBV PegIFN/RBV eRVR stop at Wk 24, f/u 24 wks
0 4 12 24 48
HCV RNA
Detectable Undetectable or
(≤ 1000 IU/mL) Undetectable
detectable (≤ 1000 IU/mL)
No eRVR extend pegIFN/
RBV to Wk 48; f/u 24 wks
TVR + PegIFN/RBV PegIFN/RBV
0 4 12 24 48
*AASLD guidelines say RGT “may be considered” for previous partial responders but package inserts recommend
[2]
48 wks of therapy.[1,3]
1. Telaprevir [US package insert]. October 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Telaprevir [EU package insert]. March 2012.

20. Futility Rules for BOC or TVR +
PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts
 All therapy should be discontinued in patients with the following:
Boceprevir[1,2]
Time Point Criteria* Action
Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue all therapy
Telaprevir[2,3]
Time Point Criteria* Action
Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue pegIFN/RBV
*Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA
detection of approximately 10-15 IU/mL.
1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Telaprevir [US package insert]. October 2012.

21. Use of HCV RNA Assays in Managing
Patients Receiving BOC or TVR
 A quantitative assay with an LLOQ of ≤ 25 IU/mL and an
LLOD of approximately 10-15 IU/mL must be used
 HCV RNA undetectable* (“target not detected”) required to
qualify for RGT
– Detectable but < LLOQ is not equivalent to undetectable
– Carefully read HCV RNA assay report to ensure HCV RNA
was undetected or “target not detected” before truncating
therapy
*An assay with a LLOD of approximately 10-15 IU/mL must be used.

22. Adverse Events

23. BOC Plus PegIFN alfa-2b/RBV: Adverse
Events
 Higher rates of anemia, neutropenia, and dysgeusia in
BOC arms vs control
Adverse Event, % PR48 BOC + PR RGT/48*
(n = 467) (n = 1225)
Anemia* 30 50
Neutropenia 19 25
Dysgeusia 16 35
*Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24%
of PR).
Boceprevir [US package insert]. July 2012.

24. TVR Plus PegIFN alfa-2a/RBV: Adverse
Events
 Higher rates of rash, anemia, and anorectal signs and
symptoms in TVR arms vs control
Adverse Event, % PR48 TVR + PR RGT/48*
(n = 493) (n = 1797)
Rash 34 56
Anemia‡ 17 36
Anorectal events 7 29
*Pooled results from TVR arms.
†
Anemia was managed with RBV dose modification; epoetin alfa was not permitted.
 In most subjects, rash was mild to moderate
– Severe rash in 4%; discontinuation due to rash in 6% of
subjects
Telaprevir [US package insert]. October 2012.

25. Cirrhotic Patients

26. Treatment regimen
Interim analysis
Peg-IFN
+ RBV BOC + Peg-IFN α-2b + RBV Follow-up
BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day
TVR + Peg-IFN α-2a +
RBV Peg-IFN α-2a + RBV Follow-up
TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day
0 4 8 12 16 36 48 72
Weeks
SVR assessment
http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf
http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf

27. Telaprevir: baseline characteristics
Telaprevir
n=292
Male, n (%) 197 (68)
Mean age, range (years) 57.2 (27-83) 54
Mean BMI, SD (kg/m2) 26.5 (4.1)
Genotype 1b / 1a / other (%) 54 / 34 / 12
HCV RNA >800,000 IU/mL, n (%) 181 (62)
Mean Neutrophils, range (109/mm3) 3.3 (0.8-9.7)
Mean Hemoglobin, range (g/dl) 14.6 (9.0-19.7) 15,6
Mean Platelets, range (/mm3) 152,000 (18,000-604,000) 167000

28. Telaprevir: baseline characteristics
Telaprevir
n=292
Mean Prothrombin Time, range (ratio) 86.3 (27-100)
Mean Total Bilirubin, range (µmol/L) 15.4 (4.0-73.5)
Mean Albumin, range (g/dL) 40.1 (20.7-52.0)
Child-Pugh A / B (%) 98 / 2
Mean MELD score, SD 8.1 (2.8)
MELD score <10 / 10 - <13 / ≥13 (%) 81 / 13 / 6
Esophageal varices (%) 33
Realize / Respond-2 exclusion criteria (%) 33 / 46

29. Telaprevir: week 16 safety findings
Patients, n (% patients with at least one event) Telaprevir
n=292
Serious adverse events (SAEs)* 132 (45.2%)
Premature discontinuation 66 (22.6%)
Due to SAEs 43 (14.7%)
Death 5 (2.6%)
Septicemia, Septic shock, Pneumopathy, Endocarditis,
Oesophageal varices Bleeding,
Infection (Grade 3/4) 19 (6.5%)
Hepatic decompensation (Grade 3/4) 6 (2.0%)
Asthenia (Grade 3/4) 16 (5.5%)
Rash
Grade 3/SCAR 14 (4.8%)
Renal failure 5 (1.7%)
*334 SAEs in 132 patients; SCAR: severe cutaneous adverse reaction

30. Telaprevir: week 16 safety findings
Patients, n (% patients with at least one event) Telaprevir
n=292
Anemia
Grade 2 (8.0 – <9.0 g/dL?) 55 (18.8%)
Grade 3/4 (<8,0 g/dL) 34 (11.6%)
EPO use 157 (53.8%)
Blood transfusion 47 (16.1%)
RBV dose reduction 38 (13.0%)
Neutropenia
Grade 3 (500 – <750/mm3) 6 (2.0%)
Grade 4 (<500/mm3) 2 (0.7%)
G-CSF use 7 (2.4%)
Thrombopenia
Grade 3 (20 000 – <50 000/mm3) 28 (9.6%)
Grade 4 (<20 000/mm3) 9 (3.1%)
Thrombopoïetin Use 4 (1.4%)
EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor

31. Boceprevir: baseline characteristics
Boceprevir
n=205
Male, n (%) 140 (68)
Mean age, range (years) 56.9 (34-81)
Mean BMI, SD (kg/m2) 26.2 (4.1)
Genotype 1b / 1a / other (%) 50 / 40 / 10
HCV RNA >800,000 IU/mL, n (%) 131 (64)
Mean Neutrophils, range (109/mm3) 3.3 (0.5-8.5)
Mean Hemoglobin, range (g/dl) 14.8 (9.7-18.4)
Mean Platelets, range (/mm3) 146,000 (33,900-346,000)

32. Boceprevir: baseline characteristics
Boceprevir
n=205
Mean Prothrombin Time, range (ratio) 87.3 (23-100)
Mean Total Bilirubin, range (µmol/L) 15.0 (4.0-78.0)
Mean Albumin, range (g/dL) 40.4 (27.0-50.3)
Child-Pugh A / B (%) 99 / 1
Mean MELD score, SD 8.1 (3.0)
MELD score <10 / 10 - <13 / ≥13 (%) 83 / 12 / 5
Esophageal varices (%) 40
Realize / Respond-2 exclusion criteria (%) 29 / 40

33. Boceprevir: week 16 safety findings
Patients, n (% patients with at least one event) Boceprevir
n=205
Serious adverse events (SAEs)* 67 (32.7%)
Premature discontinuation 54 (26.3%)
Due to SAEs 15 (7.3%)
Death 1 (0.5%)
Pneumopathy
Infection (Grade 3/4) 5 (2.4%)
Hepatic decompensation (Grade 3/4) 6 (2.9%)
Asthenia (Grade 3/4) 12 (5.8%)
Rash
Grade 3/SCAR 0
Renal failure 0
*159 SAEs in 67 patients; SCAR: severe cutaneous adverse reaction

34. Boceprevir: week 16 safety findings
Patients, n (% patients with at least one event) Boceprevir
n=205
Anemia
Grade 2 (8.0 – <9.0 g/dL) 48 (23.4%)
Grade 3/4 (<8,0 g/dL) 9 (4.4%)
EPO use 95 (46.3%)
Blood transfusion 13 (6.3%)
RBV dose reduction 22 (10.7%)
Neutropenia
Grade 3 (500 – <750/mm3) 2 (1.0%)
Grade 4 (<500/mm3) 7 (3.4%)
G-CSF use 9 (4.4%)
Thrombopenia
Grade 3 (20 000 – <50 000/mm3) 10 (4.9%)
Grade 4 (<20 000/mm3) 3 (1.5%)
Thrombopoïetin Use 2 (1.0%)
EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor

35. Multivariate analysis: baseline predictors
of severe complications*
Predictors OR 95%CI p-value
Prothrombin Time 1.03 1.01-1.06 0.038
(per unit decrease)
Age 1.05 1.01-1.11 0.025
(per year increase)
Platelet count 3.19 1.32-7.73 0.0098
≤100,000/ mm3
Albumin level 4.95 2.04-12.01 0.0004
<35 g/L
* Death, severe infection and hepatic decompensation, n=32

36. Multivariate analysis: predictors of
anemia <8g/dL or blood transfusion *
Predictors OR 95%CI p-value
Age 1.06 1.026-1.09 0.0003
(per year increase)
Gender 2.32 1.10-4.35 0.023
(Female)
No lead-in phase 2.33 1.22-4.35 0.01
Hemoglobin level 5.85 2.83-12.08 <0.0001
≤12 g/dL for female
≤13 g/dL for male
* n=71

37. Telaprevir: week 16 efficacy data
Per protocol
ITT
100
92% 93% 92%
90
Patients with undetectable HCV RNA (%)
80 80% 79%
70 67%
60 58%
55%
50
40
30
20
10
161/276 161/292 236/257 236/292 230/247 230/292 196/212 196/292
0
Week 4 Week 8 Week 12 Week 16

38. Telaprevir: Week 16 efficacy according
to prior treatment response (ITT)
80 75%
Patients with undetectable HCV RNA (%)
P=0.005
70 66%
60
50 46%
40
30
20
10
11/24 90/136 92/123
0
Null Partial Relapse
Response Response

39. Boceprevir: week 16 efficacy data
Per protocol
90 ITT
Patients with undetectable HCV RNA (%)
80 77%
70
64%
60 58%
55%
50
42%
40 38%
30
20
10
3% 2%
0 5/194 5/205 77/181 77/205 112/174 112/205 118/154 118/205
Week 4 Week 8 Week 12 Week 16

40. Boceprevir: Week 16 efficacy according
to prior treatment response (ITT)
80
P=0.001 69%
70
60
50%
50
40
30
22%
20
10
2/9 45/90 69/100
0
Null Partial Relapse
Response Response

41. Rationale for Prompt Treatment of HCV
 HCV is a progressive disease, associated with persistence
of viral replication and ongoing necroinflammation and
fibrosis
 Remission (SVR) is associated with loss of active viral
replication and improvement in hepatic fibrosis
 Important questions
– Does that equate to a need to treat all patients?
– Can we avoid losing time for patients destined to progress?
– How do we avoid unnecessary or detrimental treatment
when there are improved treatments pending?

42. Indications for Treatment of Chronic
HCV Infection
 All patients, regardless of the degree of fibrosis, are
potential candidates for treatment
 IFN-based therapy is current standard of care
 Patients with mild disease may not require immediate
treatment
 For those who require treatment
– Patients should be fit for the regimen
– Patients should have the ability to adhere to treatment goals
and monitoring
 There is a complex ongoing debate regarding opportune
timing for treatment given the therapeutic landscape

43. Who Should Be Treated Now?
Pts Who Want Tx Pts Who Are Pts Who Are
Want to be cured of Eligible for Tx Motivated and
disease Eligible for pegIFN/ RBV
Understand . . .
Personal or social Fit for regimen Likelihood of response
reasons
No contraindications Risks/benefits of
Plans for pregnancy treatment
Disease stage
Social support Risk of resistance
Eligible for Possibility of shortened
reimbursement now therapy
What is “coming down
the line” for their
genotype

44. Severity of Disease Increases Need for
HCV Therapy but Also Impairs Response
 May not need immediate
treatment  Greater need for treatment
 BUT  BUT
 Easier to treat  Response may be impaired
 High likelihood of  Perhaps more effective options in
response future, but efficacy of some
investigational agents may be unclear
due to trial eligibility criteria
Mild disease Advanced disease/
cirrhosis

45. What Are the Chances of Being Cured With
Current Therapy?
 Black
 Cirrhosis
 Genotype 1
 White
 No fibrosis
(1a worse than 1b)
 IFN nonresponsive
 Genotype 2/3
 IFN responsive (eg,
 IL28B TT
RVR/EVR or response
to lead-in)
 Previous relapser
 IL28B CC
Less favorable Favorable
prognostic factors prognostic factors

46. Limitations of Current Regimens and
Prospects for Future Regimens
Current Future
Must be eligible for pegIFN/ RBV Perhaps IFN free
Large pill burden, TID dosing of Lower pill burden, less than TID
PIs (at present); parenteral IFN dosing; perhaps all oral
Challenging adverse events May be better tolerated
High likelihood of resistance with May not generate resistance
treatment failure
Pangenotypic or at least more
Current PIs only effective for
genotype 1 Higher barrier to resistance with
some classes
Possibility of resistance with poor
adherence

47. Challenging Patients for Whom Treatment
With Current Options Less Than Optimal
 Cirrhosis (all genotypes)  Injection-drug users
 Decompensated cirrhosis – Methadone substitution
 Null responders  Thalassemics
 Pretransplantation  Children
 Posttransplantation  IFN contraindicated
 Renal failure  IFN intolerant
– Impaired renal function  Those on “edge” of society
– Dialysis  Psychiatric comorbidity
– Renal transplantation
recipients

48. Cumulative Incidence of Liver-Related
Complications Following SVR in Cirrhosis
No SVR
100 SVR
80
Patients With Liver
Complications (%)
60
40
20
0
0 24 48 72 96 120 144 168
Mos
Pts at Risk, n 759 702 634 527 345 207 34
124 119 116 108 70 41 12
Bruno S, et al. Hepatology. 2007;45:579-587.

49. SVR to Telaprevir in Treatment-Naive Pts
With GT1 HCV and Compensated
Cirrhosis
ADVANCE ILLUMINATE All
100
92 92 Cirrhosis
90
79
80 74
71
66
61
60
SVR (%)
50 51
46
40 38
20
n/N= 285/ 15/ 166/ 8/ 149/ 11/ 144/ 11/ 78/ 6/ 398/ 31/
363 21 361 21 162 18 160 12 118 12 540 61
0
T12PR PR48 T12PR24 T12PR48 T12PR48 T12PR
eRVR+* eRVR-* Overall
*eRVR+ randomized: 60% (322/540); eRVR-: 22% (118/540).
Kauffman RS, et al. HepDart 2011. Abstract 52.

50. CUPIC: Efficacy of TVR in Cirrhotics
 ~ 80% of patients treated with TVR-based therapy had
undetectable HCV RNA at end of 16 wks of triple therapy
100
Per protocol
85 86 86 ITT
79
Undetectable HCV RNA (%)
78
80
71
60 53
51
40
20
n/N = 145/ 145/ 224/ 224/ 219/ 219/ 177/ 177/
276 285 265 282 254 281 205 251
0
Wk 4 Wk 8 Wk 12 Wk 16
Hezode C, et al. AASLD 2012. Abstract 51.

51. CUPIC: Efficacy of Boceprevir in
Cirrhotics
 ~ 60% of patients treated with BOC-based therapy had
undetectable HCV RNA at Wk 16 of ongoing therapy
100
Per protocol
ITT
Undetectable HCV RNA (%)
80
71
61 58 61
60
40 37 37
20 1 1
n/N = 2/ 2/ 55/ 55/ 88/ 88/ 89/ 89/
155 155 149 150 144 151 126 146
0
Wk 4 Wk 8 Wk 12 Wk 16
Hezode C, et al. AASLD 2012. Abstract 51.

52. The First-Generation Protease Inhibitors:
Where Are We Now?
 Telaprevir and boceprevir are harbingers of important treatment
advance
 Improved SVR rates in both naive and experienced patients
 Certain patients (advanced disease) require therapy imminently and
should be treated now
 Others may be motivated to be treated now—opportunities for cure,
candidates for shortened therapy, and/or personal reasons
 For many, the choice is not clear
 The advent of triple therapy changes the way treatment discussed
with patients
– Clinicians must educate and advocate for patients to choose the correct
course of treatment

53. Factors That Influence
Outcomes With HCV Therapy

54. SPRINT-2: Influence of Baseline Patient
and Virus Factors on SVR With BOC
BOC + pegIFN-α2b/RBV 48 wks
BOC + pegIFN-α2b/RBV RGT
100
85
80
76
75 70 71
66 67 67
63 63 61
59 59
SVR (%)
52
50
41
25
n/ 93/ 89/ 118/ 106/ 45/ 41/ 197/ 192/ 211/ 213/ 22/ 14/ 44/ 82/ 26/
N = 133 134 187 179 53 54 313 314 313 319 42 34 55 115 44
0
1b 1a ≤ 800,000 > 800,000 F0-2 F3/F4 CC CT TT
Genotype [1]
HCV RNA (IU/mL)[1] Fibrosis[1] IL28B[2]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

55. ADVANCE: Influence of Baseline Patient
and Virus Factors on SVR With TVR
 Data from TVR12 + pegIFN-α2a/RBV arm only
100 90
79 78 78
71 74 71 73
75
62
SVR (%)
50
25
n/ 118/ 152/ 64/ 207/ 226/ 45/ 45/ 48/ 16/
N = 149 213 82 281 290 73 50 68 22
0
1b 1a < 800,000 ≥ 800,000 F0-2 F3/F4 CC CT TT
Genotype[1] HCV RNA (IU/mL)[1] Fibrosis[1] IL28B*[2]
*IL28B testing was in whites only.
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

56. IL28B Genotype Predicts Likelihood of
Eligibility for Shortened Therapy
SPRINT-2: BOC + ADVANCE: T12 +
PegIFN-α2b/RBV [1] PegIFN-α2a/RBV *[2]
100 100
89
78
80 80
60 60 57
52
45
40 40
20 20
% T GRr o y ili b gl E
% T GRr o y ili b gl E
n/ 117/ 158/ n/ 39/ 39/ 10/
N= 132 304 N= 50 68 22
f t i i
f t i i
0 0
CC CT/TT CC CT TT
*IL28B testing in ADVANCE was in whites only.
1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract
1369.
(
(

57. IL28B Genotype Should Not Be Used to
Exclude Patients From Therapy
 If patients have favorable CC genotype
– Likelihood of SVR is high with pegIFN/RBV alone, but triple therapy may
allow shorter therapy and, in one TVR study, higher SVR rates[1]
 If patients have unfavorable CT/TT genotype
– Likelihood of SVR is higher with triple therapy than with pegIFN/RBV
– 59% to 71% in SPRINT-2[2]
– 71% to 73% in ADVANCE*[1]
 Limited value of IL28B genotyping in treatment-experienced patients
– Most have unfavorable TT or CT genotype
*IL28B testing in ADVANCE was in white Americans only.
1. Jacobson IM, et al. EASL 2011. Abstract 1369. 2. Poordad F, et al. Gastroenterology. 2012;143:608-
618.

58. Lead-in Strategies

59. Lead-in Strategy Can Help Determine
Whom to Treat
 4 wks of pegIFN/RBV lead-in before BOC (or TVR)
– Lowers HCV RNA burden
– May identify rapid responders who may not need DAA
– Allows assessment of IFN responsiveness
– Provides useful information regarding likelihood of SVR with
addition of DAA
– Provides insight into tolerability of pegIFN/RBV backbone
– Elucidates hematologic response to pegIFN/RBV, especially
in “marginal” patients; make needed dose adjustments
before addition of DAA

60. Early IFN Response (Lead-in) Further
Defines Likelihood of SVR for Non-CC Pts
PegIFN-α2b/RBV*
 A > 1 log10 decrease in HCV RNA at Wk 4 of therapy is the strongest
BOC + pegIFN-α2b/RBV
predictor of SVR RGT*
SPRINT-2 and RESPOND-2 Combined BOC + pegIFN-α2b/RBV
100
48 wks*
81 81 82 82
80 75 75 76
67
60
SVR (%)
50 50
44
40
40 37
32
24
20 4 5
1/ 1/
n/N= 0/ 2/ 2/ 56/ 83/ 58/ 27 19/ 20/ 37/ 83/ 109/ 20 6/ 10/ 13/ 23/ 26/
2 3 4 75 102 72 51 45 117 111 133 25 25 26 28 34
0
< 1 log ≥ 1 log < 1 log ≥ 1 log < 1 log ≥ 1 log
CC CT TT
*BOC was administered with pegIFN-α2b in these trials.
Poordad F, et al. Gastroenterology. 2012;143:608-618.

61. Preparing for Treatment:
Possibilities of
Drug–Drug Interactions

62. Both BOC and TVR Have Potential for
Many Drug–Drug Interactions
 BOC  TVR
– Strong inhibitor of – Substrate of CYP3A
CYP3A4/5
– Inhibitor of CYP3A
– Partly metabolized by
CYP3A4/5 – Substrate and inhibitor of
P-gp
– Potential inhibitor of and
substrate for P-gp
 Most drug–drug interactions can be overcome by
careful survey of the patient’s medications and
judicious substitutions during HCV therapy (or just
during the period of PI-based triple therapy)

63. Medicines That Are Contraindicated With
BOC and TVR
Drug Class* Contraindicated With BOC[1] Contraindicated With TVR[2]
Alpha 1-adrenoreceptor Alfuzosin Alfuzosin
antagonist
Anticonvulsants Carbamazepine, phenobarbital, N/A
phenytoin
Antimycobacterials Rifampin Rifampin
Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV
Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine,
ergotamine, methylergonovine ergotamine, methylergonovine
GI motility agents Cisapride Cisapride
Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum
HMG CoA reductase Lovastatin, simvastatin Lovastatin, simvastatin
inhibitors
Oral contraceptives Drospirenone N/A
Neuroleptic Pimozide Pimozide
PDE5 inhibitor Sildenafil or tadalafil when used for Sildenafil or tadalafil when used for
treatment of pulmonary arterial HTN treatment of pulmonary arterial HTN
Sedatives/hypnotics Triazolam; orally administered Orally administered midazolam,
midazolam triazolam
*Studies of drug–drug interactions incomplete.
1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.

64. Preparing for Treatment:
Management of Adverse Events

65. Adverse Effect Management: Anemia
 Recommendation: anemia should be managed initially by
reducing the RBV dose[1]
 Do not dose reduce DAA or stop and then restart
 Do not discontinue pegIFN/RBV and continue DAA
 Monitor closely if Hb falls < 10 g/dL
 ESA agents are unlabeled for HCV anemia
– May be effective as a secondary anemia management
strategy
1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

66. EPO and RBV Dose Reduction for Anemia
Lead to Similar SVR Rates in BOC Patients
 Nested study within randomized trial of genotype 1 HCV therapy-naive patients
receiving 4 wks of lead-in with pegIFN-α2b/RBV and then either 44 wks of triple therapy
or RGT (24-44 wks)
100 ∆ -0.7%
(95% CI: -8.6 to 7.2)*
80
71 71
SVR (%)
60
40
20
n/N = 178/249 178/251
0
RBV DR EPO
*Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.
 82% of RBV dose reduction group vs 62% in EPO group did not require secondary
anemia intervention
Poordad F, et al. EASL 2012. Abstract 1419.

67. Predictive Value of Anemia for SVR With
BOC or TVR
 In phase III trials, anemia positive predictor of SVR with BOC[1] but not TVR[2]
 EOTR, relapse, and SVR comparable between RBV DR and EPO arms in
treatment-naive patients who developed anemia during BOC/PR therapy[1]
SPRINT-2*[1] ADVANCE and ILLUMINATE†[2]
100 100
Hb ≥ 10 g/dL
Hb < 10 g/dL
80 72 80 73 74
58
SVR (%)
60 60
40 40
20 20
0 n/N = 212/363 263/363
0 n/N = 384/524 267/361
*Data from BOC/48 and BOC RGT arms. †
Data from T12/PR arm only.
1. Sulkowski MS, et al. Hepatology. 2012;[Epub ahead of print]. 2. Poordad F, et al. DDW 2011. Abstract 626.

68. Adverse Effect Management:
Rash and Anorectal Symptoms
 Rash management
– Mild to moderate rash can be treated with oral antihistamines,
topical steroids
– Systemic steroids are not recommended
– For severe rash, many practitioners will stop TVR alone and follow
for 1 wk to see if the rash improves
– If not, stop all 3 drugs
– Important to have “go-to” dermatologist; vigilance with rash is key
 Anorectal symptom management
– Fiber, loperamide, hydrocortisone, pramoxine topical cream,
topical lidocaine

69. Managing Major Adverse Effects of
PegIFN
 Depression
– Assess mood, sleep, suicidal thoughts
– Consider SSRI to treat baseline or new depression
– Refer to mental health services to follow high-risk patients during
treatment
 Influenzalike symptoms
– Acetaminophen, hydration
– Reduce dose of IFN if necessary
 Neutropenia, thrombocytopenia: monitor CBC frequently
 Others: GI upset, hair loss, insomnia, injection-site reactions

70. Helping Patients Adhere to Complex
Regimens
 PegIFN/RBV + BOC or TVR = very complex regimen
– BOC 800 mg TID: 12 pills/day with food
– TVR 750 mg TID: 6 pills/day with high-fat meal
– RBV (2-6 pills/day) and weekly pegIFN injection
 Adherence enhanced by a combination of
– Patient education and motivation
– Reducing pill burden when possible
– Shortening therapy when appropriate
– Prompt adverse effect management

71. Optimizing Current HCV Therapy
With PIs Plus PegIFN/RBV

72. Strategies to Enhance Current Therapy
With PegIFN/RBV Plus PI for GT1 Pts
 Shorter therapy may be possible for certain patients
– Investigational T12/PR12 regimens for IL28B CC patients
 PR alone for IL28B CC patients?
– Being evaluated in phase III trial vs BOC + pegIFN-α2a/RBV
 Potential for BID dosing of TVR
– OPTIMIZE[1]: TVR 1125 mg BID noninferior to TVR 750 mg every 8
hrs (both with pegIFN-α2a/RBV) in treatment-naive GT1 patients
– SVR12 in 74% vs 72% of patients, respectively
– No increase in adverse events
1. Buti M, et al. AASLD 2012. Abstract LB-8.

73. NAIVES: RESULTS (SVR)
Universal treatment SVR % ICER ( €)
• BOC-RGT 67.0 85,000
• TVR-RGT 74.5 118,000
Selective treatment
• BOC-RVR 72.1 56,000
• TVR-IL28 79.0 74,000

74. NAIVES: RESULTS (LYG)
Universal treatment LYG (yrs) ICER ( €)
• BOC-RGT 3.75 13,400
• TVR-RGT 4.18 19,200
Selective treatment
• BOC-RVR 4.04 8,300
• TVR-IL28 4.42 11,400

75. ICER/LYG different clinical settings
ICER = < 12.000 € triple therapy for naives
ICER = 15.000 € Heart transplantation
ICER = 60.000 € erlotinib pancreatic cancer
ICER = 74.000 € sorafenib HCC

76. Naives: key points
Triple therapy with first-generation PIs in naïve Gt 1 CHC patients:
• improves survival by about 4 years
• is cost-effective, with an ICER per LYG below € 12,000
• is strongly influenced by the IL28B CC prevalence and the
ensuing likelihood of RVR and SVR, but also by the pricing of
BOC and TVR
• is optimised by allocating patients according to IL28B
and/or RVR based strategies
- An individualized treatment strategy can avoid triple
therapy in 25-33% of naive HCV G1 patients

77. Re-treatment with P/R of treatment-experienced
patients
FULL PAPERS
Overall SVR rate after retreatment: 16.1% (CI 6-33%)
EASL and AASLD Guidelines recommend that G1
HCV patients failing to eradicate HCV on P/R
ABSTRACTS
should not be retreated with P/R alone
Cammà C, et al. J Hepatol. 2009 Oct;51(4):675-81.

78. Re-treatment with P/R plus a 1 st
generation PI
of treatment-experienced patients
Phase 3 RCTs (BOC: RESPOND-2, PROVIDE: TVR:
REALIZE) show that TT achieves SVR in about 30%-75% of
experienced G1 CHC patients, with SVR rates progressively
decreasing from :
• Relapse (RR)
• Partial responders (PAR) (HCV-RNA drop >2 log at week
12, but never not detectable)
• Null responders (NR) (HCV-RNA drop < 2 log at week 12).

79. Cost-effectiveness of Boceprevir or
Telaprevir for previously treated patients
with Gt 1 CHC
Competing strategies
Response to Response
Strategy
previous P/R to lead-in
• RR • BOC LEAD IN • BOC-POOR§
• PAR • TVR LEAD IN • BOC-GOOD*
• NR • TVR NO LEAD IN • TVR-POOR §
• TVR-GOOD*
*>1Log drop at week 4 of DT
§<1Log drop at week 4 of DT
Cammà C, et al. J Hepatol, in press

80. ICERs According to Profile of Previous
Response and Severity of Liver Fibrosis
20000
18000
16000 TVR
14000 BOC
12000
ICER for LYG
10000
8000
6000
4000
2000
0
F3-F4 F3-F4 F3-F4 CHC CHC CHC CHC CHC
RR PAR NR RR GOOD PAR POOR NR
Cammà C, et al. J Hepatol, in press

81. CAVEATS
• Efficacy data from registration trials
• Inconclusive data on cirrhosis
• Aggregate rather than individual patient data
• Analysis limited to direct medical costs
• Time horizon = 20 years

82. Approval of triple therapy for reimbursement in Italy:
basic principles (presumably) followed by AIFA
• Local disease epidemiology and cost issues do not allow
universal use of triple therapy (TT) in Italy
• Patients with F3/F4 fibrosis deserve priority for TT
• Selected patients with F0/F2 fibrosis may benefit from TT
• Some non-responders should not be retreated with currently
available therapies
• Boceprevir and telaprevir are equally effective
• Only Centers who meet specific requirements are allowed to
prescribe TT
• HCV monoinfected and HCV/HIV coinfected patients should
both receive access to TT
• TT after OLT can only be used off-label (law 648/96)

83. Approval of triple therapy for reimbursement in Italy:
basic principles (presumably) followed by AIFA
• IL28b status and virological features (baseline viral load and
HCV subtype) are weak predictors at the individual level of
RVR and SVR and cannot be used to pre-assign to TT or P/R
• Response to a lead-in phase (P/R alone for 4 weeks>1 log
drop in HCV RNA from baseline) is the strongest predictor of
SVR*, and its absence of appearance of RAVs, hence a lead-in
period is enforced for both boceprevir and telaprevir to:
– Rule-in naïve patients in need of TT
– Rule-out treatment experienced patients with a low likelihood of
response to TT
* Proven for boceprevir, assumed for telaprevir

84. Approval of triple therapy for reimbursement in Italy:
AIFA criteria for naive Gt 1 patients
Fibrosis Triple therapy (P/R Dual therapy Comments
stage with Boc or Tpv) (P/R)
F0, F1, F2 RVR* negative RVR* positive
Lead-in not
needed for
F3, F4 All patients None telaprevir
* RVR: at least 1 log10 drop after 4 weeks of P/R

85. Approval of triple therapy for reimbursement in Italy:
AIFA criteria for treatment exp. Gt 1 patients
RR: relapsers; PR: partial responders; NR: null responders; UK: unknown pattern
Fibrosis stage Triple therapy (P/R with Dual Comments
Boc or Tpv) therapy
(P/R)
RR: all
PR: all
F0, F1, F2 NR: only if RVR* positive None
UK: only if RVR* positive
Lead-in not
F3, F4 All patients None needed for
telaprevir
* RVR: at least 1 log10 drop after 4 weeks of P/R

86. Approval of triple therapy for reimbursement in Italy:
potential critical issue
• AIFA criteria are partly hypothetical:
• Lead-in largely unproven for telaprevir
• No statements about indications for treatment (Do all patients
with F0/F2 fibrosis deserve therapy? What policy for informed
deferral)?
• Assimilating an unknown response to null response may
be unsound
• Unclear diagnostic criteria for fibrosis
• Efficacy in terms of cost reduction may be insufficient
• 20% of naïve patients
• 30-40% of treament experienced patients
• Selection of Centers for treatment is delegated to
regional Health Authorities, who are also empowered to
impose further restrictions

87. The Future of HCV Therapy

88. Investigational Agents for HCV
Antiviral Therapeutic Host
Interferons
agents vaccines target
miRNA-122 Cyclophilin
Entry Replication, polyprotein Cyp
processing and/or assembly inhibitors
NS5A
NS5B NS3
replication
polymerase protease
complex
inhibitors inhibitors
inhibitors

89. Drugs in the HCV pipeline (November 2012)
Phase 2 Phase 3 Approved
Mericitabine4
X IDX-184
Sovaprevir1 X INX-189 ABT-267 miR-122 a-s* Simeprevir Peg-IFNα-2a*
GS 9256
BI-207127 ALS 2200 BMS 824393 Silymarin (IV) * ABT-450/r Peg-IFNα-2B*
GS 9451 GS-5885 CT-011 mAb* Asunaprevir7
ABT 072 RBV
Danoprevir2 GSK 2336805 GS6624 mAb* Vaniprevir 8
BI 207127
IDX 719 Celgosivir Faldaprevir11 Boceprevir
Narlaprevir3
BMS 791325
GS-9620 TLR7 Sofosbuvir Telaprevir
Tegobuvir 5
GI-2005 ABT-333
GS-9669
Ad3NSmut*
Daclatasvir9
GS-9254
IDX-375 Peg-IFNλ-3 *
Alisporivir10 *
Setrobuvir6
VX-222
Protease Inh (PI)
Former IDs:
1 ACH-1625 2. RG7227 (ITMN-191) 3 SH9005182
Polym Inh (nuc)
4 RG-7128; RO5024048 5 GS-9190 6 RG7790 Polym Inh (nn)
7 BMS-0032 8 MK-7009 9 BMS 790052 10 Deb025 NS5A (RCI) Inh
11 BI-201335 Other (misc mechs)

90. Characteristics of HCV DAA classes
Characteristic Protease Nucleos(t)ide Non-nucleoside NS5a inhibitors
inhibitors polymerase polymerase
inhibitors inhibitors
Potency High, variable Moderate-high, Variable, variable High, multiple
among HCV consistent across across HCV genotypes
geno/subtypes geno/subtypes geno/subtypes
Barrier to Low High Very low Low
resistance 1a < 1b 1a = 1b 1a < 1b 1a < 1b
DDI potential High Low Variable Low-moderate
Toxicity Rash Mitochondrial Variable Variable
Anemia nucleos(t)ide
↑ Bilirubin interactions (ART,
RBV)
Pharmacokinetics Variable: QD to QD Variable: QD to QD
TID TID
Comments 2nd generation Pis: Single target Allosteric Multiple mode of
better barrier, active site inhibition, many action
pangenotypic targets

91. No cross resistance between classes:
a combination of DAAs can eliminate RAVs
Kieffer T, et al. J Antimicrob Chemother 2010;65:202–12
R: resistant (>4-fold increase in EC50) Gao M, et al. Nature 2010;465:96–100; Lagrace L, et al. Hepatology 2010;52(4 Suppl):1205A
S: susceptible (<4-fold change in EC50) Lenz O, et al. Hepatology 2010;52(4 Suppl):709A; Zeuzem S, et al. Hepatology 2010;52(4 Suppl):400A

92. HCV therapy: hopes and hypes….
• Interferon-free
• >90% SVR
• Once daily
• High tolerability with low adverse event
• Few drug-drug interactions
• Short, fixed duration (12-24 weeks)
• Pan-genotypic
• High barrier to resistance or lack of cross
resistance
• Affordable

93. IL28B genotype has been associated with
viral kinetics during IFN-free therapy
INFORM-1 : Mericitabine (NI) + danoprevir (PI), 14 days, n = 15
Chu, Gastro , 2012

94. Investigational HCV Regimens
in Phase III Clinical Trials
•Regimens With 1 DAA •Regimens With 2 DAAs
•IFN-Free Regimens
+ PegIFN alfa/RBV + PegIFN alfa/RBV
 Faldaprevir* (BI 201335, PI)  Daclatasvir + asunaprevir*  Sofosbuvir + RBV
 Daclatasvir* (BMS-790052,  Sofosbuvir + GS-5885
NS5A) (FDC) ± RBV
•New Interferons  Daclatasvir + asunaprevir
 Sofosbuvir* (GS-7977, NI)
 Simeprevir* (TMC435, PI)  PegIFN lambda-1a + RBV  ABT-450/RTV + ABT-267
± ABT-333 ± RBV
 Alisporivir* (CYP) On Hold  PegIFN lambda-1a +
 Vaniprevir (MK-7009, PI) daclatasvir + RBV
•Alternative Dosing
 TVR BID* (approved PI)
*Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.
ClinicalTrials.gov.

95. Interferon Plus
DAA-Based Regimens

96. ASPIRE: Simeprevir (TMC435) 150 mg for
12, 24, 48 Wks + PR in Tx-Exp’d GT1 Pts
 SVR24 rates according to previous response category[1]
100 Placebo + pegIFN-α2a/RBV 48 wks
85
Simeprevir 150 mg* + pegIFN-α2a/RBV
80 76 48 wks
SVR24 (%)
*Pooled.
60 51
40 37
19
20 9
n/ 10/ 67/ 52/ 3/ 26/
N = 27 79 2/23 69 16 51
0
Relapsers Partial Null
Responders Responders
 High rates of efficacy in patients with METAVIR F3/F4 fibrosis[2]
1. Jacobson I, et al. IDSA 2012. Abstract 1287. 2. Poordad F, et al. AASLD 2012. Abstract 83.
̶ Relapsers: 65%; partial responders: 67%; null responders: 33%

97. ATOMIC: Sofosbuvir (GS-7977) Plus PR in
Treatment-Naive GT1 Patients
 Interim analysis of randomized, open-label phase II study
Wk 12 Wk 24
SVR12,%
Sofosbuvir +
PegIFN-α2a/RBV 90
(n = 52)
Treatment- 92 overall
naive, Sofosbuvir + PegIFN-α2a/RBV
noncirrhotic (n = 125) 82 GT4
patients*
(N = 332) 100 GT6
Sofosbuvir
Sofosbuvir + (n = 75)
PegIFN-α2a/RBV 91
(n = 155) Sofosbuvir + RBV
(n = 75)
*All infected with genotype 1 HCV, except for 16 patients with GT4 or 6 HCV who were eligible for 24-wk arm of sofosbuvir
plus PR.
Kowdley KV, et al. EASL 2012. Abstract 1. Hassanein T, et al. AASLD 2012. Abstract 230.

98. Interferon-Free Regimens

99. ELECTRON: Sofosbuvir and RBV in Naive
and Experienced GT1 Patients
Viral Response, %
Wk 8 Wk 12 SVR4 SVR12
Sofosbuvir + RBV 1000/1200 mg (GT1; naive) (n = 25)
84
Sofosbuvir + RBV 1000/1200 mg (GT1; null responders) (n = 10) 10
Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; naive) (n = 25)
100
Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; nulls) (n = 9) 100*
*Data reported for 3 pts only. Data collection ongoing.
Gane EJ, et al. AASLD 2012. Abstract 229.

100. NIH SPARE: Interim Data on Sofosbuvir
and RBV in Difficult-to-Treat GT1 Patients
 Patients with poor prognostic indicators: GT1a (70%), male (63%), black
(83%), IL28B CT/TT (80%), advanced liver disease (22%)
 Median BMI: 28; median HCV RNA: 6.4 logs
Viral Response, %
Wk 24
Part 1 (early-stage fibrosis) EOT SVR4 SVR12
Sofosbuvir + RBV 1000/1200 mg (n = 10) 90* 90* 90*
Part 2 (all stages of fibrosis)
Sofosbuvir + RBV 600 mg (n = 25) 88† 56†
Sofosbuvir + RBV 1000/1200 mg (n = 25) 96* 72*
*1 dropout at Wk 3.
†
3 dropouts by Wk 8.
Osinusi A, et al. AASLD 2012. Abstract LB-4.

101. Daclatasvir Plus Sofosbuvir ± RBV in
Treatment-Naive GT1 or 2/3 Patients
 No impact of RBV on viral response
SVR24, %
Wk 1 Wk 24 GT1 GT2/3
Sofosbuvir Daclatasvir + Sofosbuvir
Treatment-naive, 93 88
noncirrhotic
patients
GT1a or 1b Daclatasvir + Sofosbuvir
100 100
(n = 44)
GT2 or 3
(n = 44)
Daclatasvir + Sofosbuvir + RBV 100 93
Sobosbuvir dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for
GT1 patients (1000-1200 mg/day); 800 mg/day for GT2/3 patients.
Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

102. AVIATOR: IFN-Free Regimens With
ABT-450/RTV, ABT-267, ABT-333, and RBV
Phase II trial with 2 cohorts SVR12, %
ABT-450/RTV 150/100 mg +
ABT-267 + ABT-333 + RBV
(n = 80)
87.5
ABT-450/RTV 100/100 mg + ABT-267 +
Cohort 1: ABT-333 + RBV
Treatment-naive (n = 79) 97.5
ABT-450/RTV 150/100 mg + ABT-267 +
pts, GT1 HCV ABT-333 + RBV
ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV
(n = 80)
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
NR
ABT-450/RTV 100/100 mg + ABT-267 +
ABT-333 + RBV
Cohort 2:
(n = 45) 93.3
ABT-450/RTV 150/100 mg + ABT-267 +
Tx-exp’d pts, GT1 ABT-333 + RBV
HCV, with previous
null response ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV
(n = 43) NR
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
Wks 0 8 12 24
Kowdley KV, et al. AASLD 2012. Abstract LB-1.

103. Future Role of Interferon
 What role may interferon play in future regimens?
– Preventing resistance?
 For which sets of patients may IFN play a role?
– Patients with cirrhosis?
– Treatment-experienced patients?
– Patients with resistance to DAAs?
 Will newer IFNs replace currently available agents?
– EMERGE: IFN lambda may have comparable efficacy but fewer
hematologic AEs vs pegIFN alfa[1]
1. Muir AJ, et al. AASLD 2012. Abstract 214.

104. HCV: 2013-2020
0
PEG/RBV
10
20 PI+PEG+RBV
PI2+PEG+RBV
30
% of Patients
40
50
DAA1 + DAA2 + RBV (or)
DAA1 + DAA2 + DAA3 + RBV
60
70
80 QUAD: PE
G/RBV/DA
A1/DAA2
90 (???)
100
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