Clinicaloptions.com/hepatitis Seizing the Opportunity Management of Chronic Hepatitis C in 2013 John M. Vierling, M.D., F.A.C.P. Professor of Medicine.

clinicaloptions.com/hepatitis

Seizing the Opportunity

Management of Chronic Hepatitis C in 2013

John M. Vierling, M.D., F.A.C.P.

Professor of Medicine and Surgery

Chief of Hepatology

Director of Advanced Liver Therapies

Baylor College of Medicine

St. Luke’s Medical Center

Houston, Texas




I would rather donate all of my organs right now than hear another talk about currently approved therapies for chronic hepatitis C.

A. True

B. False

HCV Infection a Global Problem: 170 M PersonsHepatitis C Death Rates Per 100,000

www.worldlifeexpectancy.com



Chronic Hepatitis C: A Treatable Disease

HCV infection Chronic in 70-85% and progressive in substantial proportion

Complications increasingly common[1,2]

Decompensated cirrhosis

Hepatic failure

HCC 3-7% per year in cirrhotics

Treatment resulting in SVR Eradication of HCV infection (cure)

Results in histologic improvement and regression of fibrosis[3]

Reduces risk of hepatic failure and HCC

Improves survival[4,5]

1. Kanwal F, et al. Gastroenterology. 2011;140:1182-1188. 2. Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5:365-370. 3. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 4. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 5. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.



Cirrhosis: Treat Before Decompensation!

Fattovich G, et al. Gastroenterology. 1997;112:463-472.

Compensated

After first major complication

Survival Probability

100

Pat

ien

ts (

%)

80

60

40

20

01200 12 24 36 48 60 72 84 96 108

Mos

384 65

Pts at Risk, n 376 39

34221

28811

2367

1654

1264

793

523

392

251



No SVR

SVR100

Pat

ien

ts W

ith

Liv

er

Co

mp

licat

ion

s (%

) 80

60

40

20

01680 24 48 72 96 120 144

Mos

759 124

702119

634116

527108

34570

20741

3412

Liver-Related Complications Decrease Following SVR in Cirrhotic Patients

Bruno S, et al. Hepatology. 2007;45:579-587.

Pts at Risk, n

Compensated Cirrhosis: HVPG 10 mmHg is the strongest predictor of

decompensation

Compensated Cirrhosis: HVPG 10 mmHg is the strongest predictor of

decompensation

Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:481-488. Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:481-488.

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

Pro

bab

ilit

y o

f d

eco

mp

ensa

tio

n

(asc

ites

, V

H,

HE

)P

rob

abil

ity

of

dec

om

pen

sati

on

(a

scit

es,

VH

, H

E)

00 80802020 1001004040 6060MonthsMonths

Baseline HVPG ≥10mmHgBaseline HVPG ≥10mmHg

Baseline HVPG <10mmHg Baseline HVPG <10mmHg

Log rank test: p<0.01Log rank test: p<0.01

HR 3.95 (2.29–6.83)HR 3.95 (2.29–6.83)

HCV Antiviral Therapy Decreases HVPG in Patients with Advanced Fibrosis or Cirrhosis

with Portal Hypertension (n=20)

Rincon et al. Am J Gastroenterol 2006;101:2269–2274.Rincon et al. Am J Gastroenterol 2006;101:2269–2274.

9/11 patients with HVPG ≥ 12 mmHg had a reduction >20% or to <12 mmHg

HVPG reduction superior in virological and biochemical

responders at EOT

*

* Almost immediately after completing AVT

121200 60602424 7272

HVPG > 10% HVPG > 10%

HVPG 10% HVPG 10%

% F

ree

of

var

ice

s%

Fre

e o

f v

aric

es

MonthsMonths

100100

8080

6060

4040

2020

003636 4848

p=0.014p=0.014

Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353:2254-2261.Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353:2254-2261.

Compensated Cirrhosis:

Reduction in HVPG >10% at one-year prevents development of varices

clinicaloptions.com/hepatitisUse of Boceprevir and Telaprevir for the Treatment of Hepatitis C

SVR is Meaningful Clinical Endpoint

SVR= endpoint of successful HCV treatment

– Defined as undetectable serum HCV RNA levels 24 wks after end of treatment

– Represents a cure

SVR associated with significant reductions of HCV-associated complications and mortality[1,2]

1. Morgan TR, et al. Hepatology. 2010;52:833-844. 2. 2. Backus L, et al. 2010 AASLD. Abstract 213.

SVR better No SVR better

Genotype 1

Genotype 2

Genotype 3

P < .0001

P = .004

P < .0001

All-Cause Mortality HR (95% CI)

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0




SVR after antiviral therapy for HCV infection:

A. Represents a cure

B. Reduces liver-related mortality

C. Reduces all-cause mortality

D. Needs to be better understood by Dr. Goss

E. All of the above


Seizing the OpportunityFor HCV Genotype 2 or 3, PegIFN/RBV Current Standard of Care

Higher SVR rates than genotype 1

24 wks of therapy recommended[1,2]

Patients with RVR and low baseline HCV RNA can be treated for 16 wks

Relapse rates may be higher[2]

Future regimens may offer further improvements, such as

Shorter durations

All-oral therapy

Fewer adverse events

1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264.


Seizing the OpportunityAddition of BOC or TVR to Peg-IFN/RBV Improved 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

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.

0

20

40

60

80

100

SV

R (

%)

Relapsers[3,4] Partial Responders[3,4]

PegIFN + RBV

NullResponders[4,5]

BOC/TVR + pegIFN* + RBV

24-29

7-15

29-40

5

69-83

40-59

63-75

38-44

Treatment Naive[1,2]

*BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.



TVR

– Substrate of CYP3A

– Inhibitor of CYP3A

– Substrate and inhibitor of P-gp

BOC and TVR Potential for Multiple Drug–Drug Interactions

BOC

Strong inhibitor of CYP3A4/5

Partly metabolized by CYP3A4/5

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)


Seizing the OpportunitySPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC/PR

1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

BOC + pegIFN-α2b/RBV RGTBOC + pegIFN-α2b/RBV 48 wks

93/133

89/134

100

0

50

1b 1aGenotype[1]

70 66

≤ 800,000 > 800,000 HCV RNA (IU/mL)[1]

85

76

F0-2 F3/F4Fibrosis[1]

6767

SV

R (

%)

75

25

41/54

45/53

213/319

211/313

n/N =

63 5963 61

41

52

118/187

106/179

14/34

22/42

192/314

197/313

44/55

82/115

26/44

CC CT TT

80

71

59

IL28B[2]



1b 1aGenotype[1]

< 800,000 ≥ 800,000HCV RNA (IU/mL)[1]

F0-2 F3/F4Fibrosis[1]

ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR

Data from TVR12 + pegIFN-α2a/RBV arm only

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

CC CT TT

IL28B*[2]

152/213

118/149

100

0

50

7971

7874

62

78

SV

R (

%)

75

25

207/281

64/82

45/73

226/290

n/N =

45/50

48/68

16/22

90

71 73

*IL28B testing was in whites only.



Challenging Patients with Suboptimal Current Treatment Options

Cirrhosis (all genotypes)

Decompensated cirrhosis

Null responders

Pre-transplantation

Post-transplantation

Chronic Renal failure

Impaired renal function

Dialysis

Renal transplantation recipients

Injection-drug users

Methadone substitution

Thalassemics

Children

IFN contraindicated

IFN intolerant

Those with poor social support

Psychiatric comorbidities

HCV AntiviralsNew Studies Using Current Therapies

clinicaloptions.com/hepatitisHCV Phase III Studies and Approved Agents

CONCISE: Telaprevir + P/R for Patients with HCV GT 1 and IL28B CC

Interim analysis of ongoing, multicenter, randomized, active-controlled, exploratory phase IIIb study

Treatment-naive patients or previous relapsers with GT 1

HCV, IL28B CC genotype,

and no cirrhosis(N = 239)

T12/PR24Continue P/R alone

(n = 52)

2:1 randomization*

Wk 12 Wk 24

T12/PR12Stop all treatment

(n = 107)

*Patients with RVR randomly assigned 2:1 to T12/PR12 or T12/PR24.

Nelson DR, et al. EASL 2013. Abstract 881.

Telaprevir + P/R


0

CONCISE: Virologic ResponsesTVR12/PR12 vs. TVR12/PR24 after eRVR

Relapse in 8% of patients in TVR12/PR12 arm vs 0% in T12/PR24 arm

Safety profile consistent with that observed in previous TVR studies

eRVR: undetectable HCV RNA at Wks 4 and 12. Nelson DR, et al. EASL 2013. Abstract 881. Reproduced with permission.

n/N =105/106

51/52

93/104

38/38

74/85

29/30

100

80

60

40

20Pat

ien

ts (

%)

99 9889

10087

97

eRVR SVR4 SVR12

T12/PR12 T12/PR24


TARGET-C: TVR With Reduced RBV + Peg-IFN in HCV-Infected Hemodialysis Patients

Increased incidence of select AEs in TVR arms vs P/R

Anemia (54% vs 33%)

Neutropenia (50% vs 33%)

Thrombocytopenia (37% vs 25%)

Rash (42% vs 17%)

Anorectal dysfunction (33% vs 0%)

Dysgeusia (42% vs 17%)Basu P, et al. EASL 2013. Abstract 67.

n/N =

8/12

6/12

3/12

7/12

6/12

3/12

80

60

40

20

0

HC

V R

NA

U

nd

etec

tab

le (

%)

EOT SVR

67

50

25

63

50

25

TVR + PegIFN/RBV 200 mg

Wk 12

Pts with GT 1 HCV; on hemodialysis

(N = 36)

PegIFN/RBV 400 mg

TVR + PegIFN + Placebo PegIFN/RBV 400 mg

Placebo + PegIFN/RBV 400 mg

Wk 24 Wk 36 Wk 48

n = 12

n = 12

n = 12

100 PegIFN alfa-2a dosed at 135 µg/wk

HCV Antiviral Therapyfor Genotype 1 Cirrhotics


HCV-TARGET: TVR or BOC + P/R in a Diverse Patient Populations

Interim analysis of longitudinal observational study of sequentially enrolled patients in academic and community medical centers in North America

Fried MW, et al. EASL 2013. Abstract 818.

Patient Disposition, n (%) DAA + P/R(N = 1919)

Patients in current analysis 1457

Patients with cirrhosis 550

Still on treatment, < 16 wks 139 (6)

Still on treatment, > 16 wks 664 (46)

Completed full course 319 (22)

Patient Disposition DAA + P/R(N = 1457)

Early discontinuation, n (%) 335 (23)

Lack of efficacy 8

Adverse event 9

Other reasons 5

Multiple reasons 2


HCV-TARGET: Baseline Characteristics


Patient Characteristic Cirrhotic(n = 550)

Noncirrhotic(n = 787)

40-64 yrs of age, % 84 80

Male, % 69 55

White, % 78 70

Genotype, % 1a 1b Not otherwise specified

581919

582213

Treatment naive, % 41 52

Mean hemoglobin > 12 g/dL 94 84

Mean platelets, cells/mm3 126,000 203,000

Mean total bilirubin, mg/dL (range) 1.0 (0.2-5.0) 0.63 (0.2-2.5)

Mean albumin, g/dL (range) 3.9 (1.4-5.0) 4.2 (1.9-5.4)

Mean Meld score (range) 8 (6-22) N/A

Presence of varices, % 33 1


HCV-TARGET: Virologic Response by Previous Treatment Category

In interim analysis, on-treatment efficacy of telaprevir and boceprevir in real-world setting comparable to registration trials

Fried MW, et al. EASL 2013. Abstract 818. Reproduced with permission.

n = 400 247 101 79 133 92 28 25 119 74 21 16 149 76 37 32

100

80

60

40

20

0

TVR Wk 4TVR Wk 12

BOC Wk 8BOC Wk 12

Treatment Naive

Previous Relapser

Previous Partial or Null Response

UnknownResponse

54

86

61

78

54

78

25

48 43

73

15

44 45

80

43

63

Un

det

ecta

ble

HC

V R

NA

(%

)

clinicaloptions.com/hepatitisHCV Phase III Studies and Approved AgentsHCV-TARGET: Safety Assessment

in Patients With Cirrhosis


Event, % Cirrhotic(n = 550)

Noncirrhotic(n = 787)

SAE 8 8

Death, n 2 1

Early discontinuation Due to adverse event Due to lack of efficacy

264431

213338

Decompensation 11 1

Infection 21 24

Severe rash (grade 3/SCAR) 2 1

Hemoglobin < 8.5 g/dL 20 14

RBV dose reduction 42 31

EPO 10 10

Transfusion 11 5

CUPICBoceprevir and Telaprevir Treatment Regimens

Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.

Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBV Follow-up

484 160 128Weeks

72SVR12

BOC + Peg-IFN α-2b + RBV Follow-upPeg-IFN + RBV

36

BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day

TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day

SVR24

CUPIC Baseline Demographics and Disease Characteristics

CharacteristicTelaprevir

N=295Boceprevir

N=190

Child-Pugh score A/B, n (%)* 280 (95) / 6 (2) 177 (93) /1 (1)

MELD score, mean (range) 8.1 (6-22) 8.1 (6-28)

Prothrombin time ratio, mean % (range) 86 (27–100) 87 (23–100)

Serum albumin g/L, mean (range) 40.0 (20.7–53.2) 40.7 (27.0–50.3)

Total bilirubin μmol/L, mean (range) 15.5 (4.0–73.0) 15.2 (4.0–78.0)

Hgb level g/dL, mean (range) 14.5 (9.0–19.7) 14.8 (10.8–18.4)

Neutrophils, mean (range) (109/mm3) 3.3 (0.8-8.5) 3.2 (0.5-8.5)

Platelet count, mean (range) (103/mm3) 151(18–604)

144(34–346)

Esophageal varices, n (%) 51/145 (35.2) 37/97 (38.1)

Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

* Missing data : 21

CUPIC Virological Response (ITT): SVR12


TELAPREVIR BOCEPREVIR

0

10

20

30

40

50

60

70

80

90

100

49%

Pat

ien

ts w

ith

un

det

ecta

ble

HC

V R

NA

(P

erce

nta

ge

)

79% 81%

56%

W4 W8 W12 W24 W48 W60W16

77 %

68 %

146295

234295

239295

227295

200295

165295

118295

0

10

20

30

40

50

60

70

80

90

100

16%

51%

62%65%

67%

W4 W8 W12 W16 W24 W48 W60

31190

97190

118190

124190

128190

108190

57%

79190

40% 41%

CUPICSVR12 According to HCV G1 Subtype


Genotype 1a

Genotype 1b

Undeterminedgenotype 1

33/98 75/162 9/33

34%46%

27%

P=0.004

0

10

20

30

40

50

60

70

80

90

100

SV

R 1

2 (I

TT

) (

Pe

rcen

tag

e)

TELAPREVIR

Genotype 1a

Genotype 1b

Undeterminedgenotype 1

0

10

20

30

40

50

60

70

80

90

100

6/16

P=0.03

31%

51%

37%

49/9624/77

BOCEPREVIR

SV

R 1

2 (I

TT

) (

Pe

rcen

tag

e)

CUPIC: SVR12 Safety FindingsPatients, n

(% patients with at least one event) Telaprevir n=295 Boceprevir n=190

Serious adverse events (SAEs)* 535 in 160 patients (54.2%)

321 in 97 patients(51.0%)

Premature discontinuation / due to SAEs

139 (47.1%) / 63 (21.3%)

80 (42.1%)/27 (14.2%)

Death 7 (2.4 %) 3 (1.6%)

Infection (Grade 3/4) 27 (9.1 %) 8 (4.2%)

Hepatic decompensation (Grade ¾ ) 15 (5.1 %) 9 (4.7%)

Anemia (Grade ¾ : Hb < 8 g/dL) 38 (12.9 %) 19 (10%)

Rash (grade 3/SCAR) 16 (5.4 %)/ 2 (0.6 %) 2 (1.0%)/

EPO use / blood transfusion

168 (57 %) / 53 (18 %)

119 (62.6%) /26 (13.7%)

GCSF use 8 (2.7 %) 13 (6.8%)

TPO use 6 (2 %) 3 (1.6%)


CUPICPredictors of Death or Severe Complications

Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.

PredictiveFactors

Platelets count >100,000/mm3

Platelets count ≤100,000/mm3

Albumin 35 g/L 3.4 %(10/298)

4.3 %(3/69)

Albumin <35 g/L 7.1 %(2/28)

44.1 %

(15/34)

Meta-Analysis: Five Boceprevir Phase 3 Trials

• A pooled analysis of 5 BOC phase III clinical trials in patients with HCV genotype 1 infection

– Cirrhosis defined as METAVIR F4 score – Central reading of all liver biopsies

BOC = boceprevir; P/R = peginterferon and ribavirin; RGT = response-guided therapy

Study PatientsP/R, n (%)

BOC/P/R 48 weeks,

n (%)

BOC P/RRGT, n (%)

All, n (%)

Cirrhotic Patients,

n (%)

SPRINT-2 Previously untreated 363 (33) 366 (33) 368 (34) 1097 (100) 53 (5)

Anemia Management study

Previously untreated — 111 (16) 576 (84) 687 (100) 60 (9)

RESPOND-2 Previous treatment failure 80 (20) 161 (40) 162 (40) 403 (100) 49 (12)

PEG2a Previous treatment failure 67 (33) 134 (67) — 201 (100) 33 (16)

PROVIDE Previous treatment failure — 134 (100) — 134 (100) 17 (13)

Total 510 (20) 906 (36) 1106 (44) 2522 (100) 212 (8)

Vierling JM, et al. EASL 2013. Abstract 1430.

Patient CharacteristicsP/R BOC/P/R

F0-2(n = 436)

F3(n = 22)

F4(n = 32)

F0-2(n = 1638)

F3(n = 107)

F4(n = 180)

Age, mean (SD), y 49.5 (9.6) 51.6 (10.2) 54.7 (6.8) 49.7 (9.4) 52.7 (7.3) 53.2 (6.7)Male, n (%) 252 (58) 20 (91) 23 (72) 860 (53) 73 (68) 112 (62)Viral load

Log10 Geometric Mean* 6.54 6.54 6.22 6.49 6.47 6.39>800,000 IU/mL, n (%) 372 (85) 19 (86) 20 (63) 1371 (84) 91 (85) 144 (80)

Genotype subtype, n (%) 1a 208 (48) 10 (45) 17 (53) 811 (50) 60 (56) 92 (51)1b 160 (37) 11 (50) 12 (38) 622 (38) 37 (35) 65 (36)1 (other) 68 (16) 1 (5) 3 (9) 204 (12) 10 (9) 23 (13)Missing 0 0 0 1 (<1) 0 0

Platelets Mean (SD) × 109/L 252.9 (69.3) 188.5 (64.5) 183.1 (73.4) 249.8 (70.9)† 198.4 (64.7) 165.8 (57.4)<150 × 109 cells/L, n (%) 26 (6) 8 (36) 10 (31) 99 (6) 27 (25) 78 (43)

Baseline haemoglobin (g/dL), mean (SD) 14.7 (1.3) 15.7 (1.3) 15.2 (1.1) 14.6 (1.3) 15.1 (1.4) 14.6 (1.2)

Baseline serum albumin Mean (range), g/L 40.7 (32-49) 40.1 (34-46) 39.1 (34-44) 40.9 (30-51) 39.9 (30-49) 38.8 (31-49)<35 g/dL, n (%) 6 (<1) 1 (5) 3 (9) 38 (2) 5 (5) 21 (12)

*Baseline viral load is the geometric mean of all virology collections during screening and before the randomization date.†Baseline platelets for 1637 patients.

BOC = boceprevir; PR = peginterferon and ribavirin


F0-2 F3 F4METAVIR Fibrosis Score

0%

25%

50%

75%

100%

66%54% 55%

28% 26% 17%

Boceprevir + PR PR

SVR

(%, 9

5 CI

%)

Sustained Virologic Response

• SVR rates were substantially higher with BOC/P/R compared with P/R alone, regardless of fibrosis score

• In patients receiving BOC/P/R, SVR rates were similar in patients with bridging fibrosis (F3) and cirrhosis (F4)

*Treatment-naive patients and those with previous treatment failure combined. The analyses of the pooled studies were homogeneous for the SVR rates for F0-2 and F3 patients treated with BOC/P/R, and for F3 patients treated with P/R. Therefore, the fixed-effect estimates for the SVR rates were used for these patients. The analysis of the studies for the SVR rates was heterogeneous for F4 patients treated with BOC/P/R or P/R, and for F0-2 patients treated with P/R; therefore, the random-effect estimate for the SVR rate was used for these patientsBOC = boceprevir; CI = confidence interval; P/R = peginterferon and ribavirin; SVR = sustained virologic response.

n=1638 n=436 n=107 n=22 n=180 n=32



0%

25%

50%

75%

100%

77% 67% 66%40% 29% 21%

≥1 log HCV RNA decline at TW4 <1 log HCV RNA decline at TW 4

SVR

(%, 9

5% C

I)

SVR According to TW4 Virologic Response

• Regardless of METAVIR fibrosis score, SVR rates were higher in patients with ≥1 log10 decline in HCV RNA at TW4 than those with <1 log10 decline

• Among patients with ≥1 log10 decline in HCV RNA, SVR rates with BOC/P/R were similar in patients with METAVIR F3 and F4 fibrosis

• SVR rate was 21% in cirrhotic patients receiving BOC/P/R with <1 log10 decline in HCV RNA at TW4

*Treatment-naive patients and those with previous treatment failure combined (total treatment duration = 8 weeks).CI = confidence interval; HCV = hepatitis C virus; SVR = sustained virologic response; TW = treatment week.

895/1155 168/415 47/70 10/35 85/128 10/48



0%

25%

50%

75%

100%

86% 85% 89%

54%34% 35%

6%0% 0%

Undetectable ≥3 log HCV RNA decline and detectable <3 log HCV RNA decline and detectable

SVR

(%, 9

5% C

I)SVR According to TW8 Virologic Response

• SVR rates were high in all patients with undetectable HCV RNA at TW8, intermediate in those with >3 log10 decline at TW8, and low in those with <3 log10 decline at TW8, regardless of METAVIR fibrosis score

• Few F0-2 and no F3-4 patients with detectable HCV RNA and <3 log10 decline in HCV RNA at TW8 achieved SVR

*Treatment-naive patients and those with previous treatment failure combined. BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.

766/889

293/544 40/47 16/47 65/73 28/79

0/170/55/78


Predictors of SVR in F3/F4 Patients Receiving BOC/PR

1 2 3 4 5 6 7 8

10.57 (5.23 – 21.36); P<0.0001

2.64 (1.33 – 5.21); P=0.0053

2.23 (1.18 – 4.24); P=0.0141

2.55 (1.05 – 6.20); P=0.0383

1.76 (0.90 – 3.44); P=0.0971

1.08 (0.43 – 2.72); P=0.8636

9 10Odds Ratio (95% CI)

TW8: undetectable vs. detectable HCV-RNA

TW4: ≥1log decline vs. <1 log decline

Male vs. female

Baseline viral load ≤800,000 IU/mL vs. >800,000 IU/mL

G1b vs. G1a

Non-black vs. black

CI = confidence interval; G = genotype; TW = treatment week.


SVR According to Treatment Duration in Patients with Undetectable HCV RNA at TW8 receiving BOC/PR*

*Treatment-naive patients and those with previous treatment failure combined. BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.

58/132 4/6279/306 15/18 78/84 6/6 8/916/183/7

351/367 17/18 38/39


Significant Medical EventsPatients with Potential Hepatic Decompensation or Sepsis

Patient ID(Study)

Baseline Data Event Treatment regimen (weeks of treatment)

Outcome

Cirrhotic Patients016301(PROVIDE)

Male, 64 yo; F4.History of ascitesPlatelets, 108KAlbumin, 3.7 g/L

Decompensated cirrhosis with ascites and encephalopathy (confusion)

BOC/P/R(TW6)

Discontinued treatment; events resolved

012072(RESPOND-2)

Female, 51 yo; F4Platelets, 170KAlbumin, 3.5 g/L

Bleeding esophageal varices and portal hypertension

P/R(TW2)

Discontinued treatment; events resolved

000603(PEG2a study)

Male, 48 yo; F4Diabetic, IVDUPlatelets, 135KAlbumin, 3.8 g/L

Multi-organ failure with total bilirubin peak 17.4 mg/dL(Staphylococcus pneumonia, resulting in multi-organ failure)

BOC/P/R(TW12)

Died of multi-organ failure

Non-Cirrhotic Patients000005(PEG2a study)

Male, 52 yo; F2Platelets, 280KAlbumin, 4.2 g/L

Possible urosepsis(negative blood and urine cultures)

P/R(TW3)

Discontinued treatment; event resolved

001868(SPRINT-2)

Male, 58 yo; F2Platelets, 192KAlbumin, 3.5 g/L

Ascites(Hospitalized with severe epiglottitis and neutropenia; developed acute renal failure; treatment discontinued; ascites and oedema noted 12 days later)

12 days after discontinuing BOC/P/R (TW12)

Discontinued treatment for other AEs; ascites resolved

BOC = boceprevir; IVDU = intravenous drug user; P/R = peginterferon and ribavirin; TW = treatment week; yo = years old.



Seizing the OpportunityLimitations of Current Regimens and Prospects for Future Regimens

Current

Must be eligible for pegIFN/ RBV

High pill burden, TID dosing of PIs (at present); parenteral IFN

Multiple adverse events

Selection of resistance –associtaed variants with treatment failure

Only effective for genotype 1

Risk of resistance with poor adherence

Future

Increasingly IFN free

Lower pill burden, daily dosing;

Better tolerated

Limited resistance-associated variants

Pangenotypic

Higher barrier to resistance with some classes



Investigational Agents for HCV in 2013

Interferons Antiviral agents

Therapeuticvaccines

Hosttarget

Replication, polyprotein processing and/or assembly

Entry

NS5Bpolymerase inhibitors

NS3/4Aprotease inhibitors

NS5Areplication complex inhibitors

miRNA-122 Cyclophilin

CypA

inhibitors




Regimens containing Peg-IFN are contraindicated for patients with cirrhosis who have all but one of the following:

A. Compensated cirrhosis

B. Decompensated cirrhosis

C. Albumin <3.5 mg/dL and Platelets <100,000 mm3

D. ESRD

Clinicaloptions.com/hepatitis Seizing the Opportunity Management of Chronic Hepatitis C in 2013 John M. Vierling, M.D., F.A.C.P. Professor of Medicine.

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