HCV-TARGET Hepatitis C Therapeutic Registry and...

Levels of Evidence Should Guide

Treatment Decisions for HCV

Systematic Reviews

Randomized Controlled Trials

Cohort Studies

Case-control Studies

Case Series

Expert Opinion

Cochrane Analysis

Examples Available for DAAs

No

Phase 3

No

Phase 2

Phase 4

Real world

Yes, limited

(no comparison

across regimens)

Yes, limited

Yes, too many!

Comparative Effectiveness Trials

Gaps in Evidence

Need for Real-world Data

• Gaps in evidence

– Major evidence gaps around effectiveness of HCV therapies

eg, SOF + SMV enters guidelines and recent FDA approval based

on 167 patients from phase 2

Patient populations: women, blacks, older, comorbidities,

cirrhosis, active substance abuse or mental illness, prior DAA

failure, HIV, transplant, ESRD

Treatment harms/benefits (short-term and long-term), side effects

Impact of adherence and out-of-pocket costs

– Need to understand real-world effects of antiviral regimens

in a broader spectrum of patients

Real-world data often very different than predicted by phase 3

studies

The Benefits of Phase 4

• The benefits gained from postmarketing data

– We learn how drugs “behave” in the real world

Patients are more heterogeneous

Prescribers are more heterogeneous

Patients are not as carefully screened

Treatment is not as carefully monitored

– We broaden our knowledge of short- and long-term

benefits and risks

Trials are short; real life has no time limit

• Mission: to maintain an international registry of patients undergoing treatment with new therapies for HCV at both academic and community practices

• Study design: longitudinal, observational study

– Inclusion criteria: adult patients (≥18 years) prescribed any HCV treatment

• Specific aims

– Improve information of populations underrepresented in phase 3 trials

– Evaluate regimens used in clinical practice (approved and unapproved)

– Identify and remediate educational gaps and adverse event management

– Serve as a core for collaborative, translational studies

• Highlights

– Partnership: academia + industry + FDA

– >4700 patients enrolled to date

http://www.hcvtarget.org/

HCV-TARGET

HCV-TARGET: An International Consortium

HI

Canada

PR

EU

IsraelSA

Academic Sites- 38

Community Sites- 15

Participating Institutions

Acknowledgements

Center Investigator

Univ of Florida Nelson/Morelli

UNC Fried

Saint Louis University Di Bisceglie

Scripps Pockros

University of Colorado Everson

University of Cincinnati Sherman

University of Chicago Reau/Jensen

Harvard Afdhal

Indiana University Kwo

Puerto Rico Rodriquez-Torres

Duke Muir

University of Massachusetts Szabo

Virginia Commonwealth Sterling

University of Miami Schiff

Johns Hopkins Sulkowski

Yale Lim

AshevilleGastro Harlan

Cornell Jacobson

University of Pennsylvania Reddy

UCSD Kuo

Henry Ford Health System Gordon

Emory University Spivey

University of Michigan LOK

Toronto Western Hospital Liver Center Feld

Columbia Medical Center Brown

Goethe University Hospital, Frankfurt Zeuzem

RWTH University Hospital, Aachen Trautwein

Liver Wellness Center Arkansas Williams/Frazier

Center Investigator

Atlanta Med Center Pearlman

The Methodist Hospital, Houston, Texas Galati

Mayo- Rochester Watt

Mayo- AZ Vargas

Orlando Immunology Center Hinestrosa

Virginia Mason Bredfeldt

Wilmington Gastro Meyer

HRH Care Kerr

University of Minnesota Hassan

Minnesota Gasto Coleman Smith

Lake Shore Gastro- Chicago community O'Riordan

UCSF Terrault

Liver Institute of Virginia/Bon Secours Shiffman

Hannover Medical School Manns

Dartmouth Dickson

Baylor O’Leary

University of Nebraska Malliard

Mountainview Medical Center Ramani

Massachusetts General Chung

Austin Hepatitis Center Alam

Baptist Medical Center Elbeshbeshy

Northwestern Levitsky

Southwest Care Center Hawkins

Thomas Jefferson University Fenkel

Sponsors: AbbVie, Bristol Myers Squibb, Genentech, Gilead, GSK, Janssen, Kadmon, Merck, Vertex

HCV-TARGET is an investigator-initiated study jointly sponsored by University

of Florida (PI: Nelson), and University of North Carolina at Chapel Hill (PI: Fried).

HCV-TARGET: Real-world

Data Promising Real-world

Solutions

Mark Sulkowski, MD

Professor of Medicine

Johns Hopkins University School of Medicine

Medical Director, Viral Hepatitis Center

Divisions of Infectious Diseases and

Gastroenterology/Hepatology

Baltimore, Maryland USA

Efficacy in Cirrhotics

Clinical Trials vs Real World

Study Naïve Relapsers Partial

Responders

Null

Responders

Telaprevir phase

3 studies1-2

71%

(F4)

59% (F3-F4)

84%

(F4)

34%

(F4)

14%

(F4)

CUPIC real life

telaprevir6

_ 71%

(SVR 12)

29%

(SVR12)

_

Boceprevir phase

3 studies3-5

42% 83%

(F3-F4)

46%

(F3-F4)

1/2

CUPIC real life

boceprevir6

_ 52%

(SVR 12)

31%

(SVR 12)

_

1. Marcellin P, et al. J Hepatol. 2011;54(Suppl 1):S183.

2. Pol S, et al. Hepatology. 2011;54(Suppl. S1):374A.

3. Buti M. AASLD 2012.

4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

5. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

6. Vierling J, et al. AASLD 2011. Hezode C, et al. J Hepatol. 2013;59:434-441.

49

38

0

10

20

30

40

50

60

French real-worldP

ati

en

ts w

ith

se

rio

us

AE

s (

%)

912 12 12

79

5 5

0

10

20

30

40

50

60

ADVANCE SPRINT-2 REALIZE RESPOND-2

Pa

tie

nts

wit

h s

eri

ou

s A

Es

(%

)

n=530 n=323n=734n=727 n=159n=296

SAEs in Clinical Trials

(including cirrhotics)

SAEs in Real World

(cirrhotics only)

Treatment naïve Treatment experienced Treatment experienced

Telaprevir

Boceprevir

n=132 n=80n=363n=361

PEG/RBV

Safety in Cirrhotics:

Clinical Trials vs Real World

Hezode C, et al. J Hepatol. 2013;59:434-441.

AASLD/IDSA Recommendations for HCV Genotype 1 Treatment Naïve

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating

hepatitis C. www.hcvguidelines.org, accessed 4/24/2014

Genotype 1

treatment naïve

Sofosbuvir 400 mg/d

PEG + RBV x 12 weeks

Sofosbuvir 400 mg/d

Simeprevir 150 mg/d

+/- RBV

x 12 weeks

IFN eligible?Yes No

Simeprevir 150 mg/day x 12 weeks

+ PEG + RBV x 24 weeks

• GT 1b

• GT 1a Q80K negative

Sofosbuvir 400 mg/day

+ RBV x 24 weeks

Alternative regimens

Ribavirin dose =

1000-1200 mg/day

HCV Treatment Regimens Used in ~ 2000 HCV

Infected Patients in the US: HCV-TARGET

N=1994

SOF/SMV 53.1%

Genotype 2 Genotype 3

SOF/PEG/RBV

0.9%

SOF/RBV

99.1%

SOF/PEG/RBV

8.5%

SOF/RBV

91.5%

Genotype 1

SOF/SMV/RBV

14.9%SOF/PEG/RBV

23.1%

SOF/RBV

8.8%

Jensen DM, et al. Presented at AASLD: The Liver Meeting.

November 7-11, 2014. Boston, Massachusetts. Abstract 45.

HCV-TARGET: Patient Characteristics and

DemographicsSOF-

PEG-RBV

SOF-

RBV

SOF-SMV SOF-SMV-

RBV

Total*

n(%) (N=384) (N=667) (N=784) (N=228) (N=2063)

MALE 253 (66.2) 422 (63.6) 478 (62.0) 147 (65.3) 1300 (63.7)

MEAN Age, y (range) 53.9 (23 - 79) 56.9 (21 - 82) 59.5 (20 - 83) 58.8 (29 - 80) 57.6 (20 - 83)

Age 65+ 31 (8.1) 131 (19.7) 190 (24.6) 40 (17.8) 392 (19.2)

CAUCASIAN 270 (70.3) 539 (80.8) 584 (74.5) 177 (77.6) 1570 (76.1)

BLACK 68 (17.8) 37 (5.6) 96 (12.5) 33 (14.7) 234 (11.5)

HISPANIC 15 (3.9) 54 (8.1) 53 (6.8) 15 (6.6) 137 (6.6)

NAIVE 211 (54.9) 371 (55.6) 318 (40.6) 82 (36.0) 982 (47.6)

TREATMENT

EXPERIENCED 172 (44.8) 296 (44.4) 465 (59.3) 144 (63.2) 1077 (52.2)

TVR/BOC FAILURE 47 (12.2) 25 (3.7) 76 (9.7) 45 (19.7) 193 (9.4)

CIRRHOSIS 120 (31.3) 302 (45.3) 440 (56.1) 137 (60.1) 999 (48.4)

Hx Decompensation 12 (11.4) 136 (49.5) 167 (44.8) 60 (50.8) 375 (43.1)

MELD >10 18 (17.1) 120 (43.6) 122 (32.7) 34 (28.8) 294 (33.8)

LIVER CANCER 25 (6.5) 66 (9.9) 88 (11.2) 32 (14.0) 211 (10.2)

LIVER TRANSPLANT 27 (7.0) 57 (8.5) 111 (14.2) 32 (14.0) 227 (11.0)

HIV 14 (3.6) 18 (2.7) 8 (1.0) 7 (3.1) 47 (2.3)

*Total, patients who started therapy Jensen DM, et al. Presented at AASLD: The Liver Meeting.


Treatment Status by Regimen



N=68

Will not start treatment

N=35

Pending data transfer

Intent to Treat

SOF/SMV

Intent to Treat

SOF/SMV/RBV


Genotype 1

treatment naïve




Simeprevir 150 mg/day

+/- RBV

x 12 weeks

IFN eligible?

Yes No

Ribavirin dose =

1000-1200 mg/dayAASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating


NEUTRINO Study: PEG-IFN/RBV + Sofosbuvir for

12 Weeks in Patients with HCV Genotype 1 Infection

Error bars represent 95% CI.

Lawitz E, et al. Presented at: 48th Annual Meeting of the European Association for

the Study of Liver; April 24‐28, 2013; Amsterdam, Netherlands. Abstract 1411.

9193

99 96 100 10092

80

0

20

40

60

80

100

No cirrhosis Cirrhosis

Posttreatment On treatment

Pa

tie

nts

with

HC

V R

NA

<LL

OQ

(%

)

50/54 52/54 53/53

Week 2 Week 4 Week 12 Week 12

43/54249/273 269/271 267/267 252/273

SOF + PEG + RBV

N=209

Latest Available HCV RNA BLOQ

88% (177/200)Latest Available HCV RNA Quantified

12% (23/200)

Cohort of patients with treatment start on or before

4/15/14 ; BLOQ=Below Level of Quantitation

HCV RNA Outcomes for Sofosbuvir + PEG-RBV: G1

VB

0%

(0/164)

Relapse

13%

(21/164)

SVR4+

164/200

SVR4+ 85%

140/164

Non-Response

1.2%

(2/164)

SVR4+

No cirrhosis: 90% (114/127)

Cirrhosis: 70% (26/37)

Lost to f/u

0.6%

(1/164)




Genotype 1

treatment naïve




Simeprevir 150 mg/day

+/- RBV

x 12 weeks

IFN eligible?

Yes No

Ribavirin dose =

1000-1200 mg/dayAASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating


Guideline panel did not require

baseline Q80K testing

COSMOS: Simeprevir + Sofosbuvir ± RBV in

HCV G1: Phase 2a Study Design

• Cohort 1: Prior null responders (METAVIR F0-F2)

• Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4)

• SMV 150 mg QD + SOF 400 mg QD +/- RBV 1000/1200 mg/day

Jacobson I, et al. AASLD 2013. Abstract LB-3. Lawitz, et al. EASL 2014. Abstract 165.

Lawitz E, et al. Lancet. 2014;6736:61036-61039.

QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response; SVR4, sustained virologic response 4 weeks after

planned treatment end; SVR12, sustained virologic response 12 weeks after planned treatment end.

SMV + SOF + RBV Posttreatment follow-up

0 4 12 24 36 48

Arm 1

Week

SMV + SOF

SMV + SOF

+ RBV

SMV + SOF

Posttreatment follow-up



Arm 2

Arm 3

Arm 4

Enrolment ratio

2:1:2:1

COSMOS Cohort 1: Baseline Demographics

and Disease Characteristics

Characteristic

SMV/SOF

+ RBV

24 wks

(N=24)

SMV/SOF

24 wks

(N=15)

SMV/SOF

+ RBV

12 wks

(N=27)

SMV/SOF

12 wks

(N=14)

Total

(N=80)

Male, n (%) 15 (63) 6 (40) 20 (74) 8 (57) 49 (61)

Race: White, n (%)

Black-African American, n (%)

18 (75)

6 (25)

9 (60)

6 (40)

19 (70)

8 (30)

11 (79)

3 (21)

57 (71)

23 (29)

Ethnicity, Hispanic or Latino, n (%) 10 (42) 4 (27) 4 (15) 2 (14) 20 (25)

Median age, years (range) 56 (27–70) 56 (27–61) 55 (28–67) 56 (35–68) 56 (27–70)

Median BMI, kg/m2 27 30 27 28 28

Median HCV RNA, log10 IU/mL 6.8 6.8 6.8 6.8 6.8

HCV GT 1a, n (%) 20 (83) 11 (73) 21 (78) 10 (71) 62 (78)

HCV GT 1a with Q80K, n (%) 12 (50) 4 (27) 9 (33) 6 (43) 31 (39)

IL28B non-CC, n (%) 23 (100)* 13 (87) 24 (89) 14 (100) 74 (94)

METAVIR score F2†, n (%) 13 (54) 12 (80) 16 (59) 6 (43) 47 (59)

*For one patient no IL28B genotype was defined;†Determined by biopsy


100 100 100 100 100100 100 100 100 100

89

100

89

83

89

0

20

40

60

80

100

GT1b GT1a without Q80K GT1a with Q80K

SMV/SOF±RBV

SV

R1

2 (

%)

SMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF

24 weeks 12 weeks Overall

4/4 7/7 8/9 3/3 7/7 3/3 6/6 12/12 8/9 4/4 4/4 5/6 17/1730/3024/27

Excluding patients who discontinued for non-virologic reasons

COSMOS Cohort 1: SVR12 by HCV GT1 Subtype

and Baseline NS3 Q80K Polymorphism


COSMOS Cohort 2: Baseline Demographics

and Disease Characteristics

Characteristic

SMV/SOF

+ RBV

24 wks

(N=30)

SMV/SOF

24 wks

(N=16)

SMV/SOF

+ RBV

12 wks

(N=27)

SMV/SOF

12 wks

(N=14)

Total

(N=87)

Male, % 70 44 74 71 67

Race: White/Black-African American, % 97/3 81/19 93/7 86/14 91/9

Ethnicity, Hispanic or Latino, % 10 31 19 14 17

Median age, years (range) 58 (28–70) 58 (49–63) 57 (36–68) 58 (47–64) 58 (28–70)

Median BMI, kg/m2 28 29 27 32 28

Median HCV RNA, log10 IU/mL 6 7 7 7 7

HCV genotype 1a, % 77 75 82 79 78

1a with Q80K, % 37 31 30 21 31

Treatment history: null, % 57 50 56 50 54

Cirrhosis, % 43 62 41 50 47

IL28B genotype: non-CC, % 73 87 85 71 79


GT 1b

COSMOS Cohort 2: SVR12 by HCV GT 1 Subtype and Baseline NS3 Q80K Polymorphism

0

20

40

60

80

100

SMV/SOF±RBVSMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF


Lawitz E, et al. 49th EASL; London, England; April 9-13, 2014. Abst. O165.

SV

R1

2 (

Pe

rce

nta

ge

)

GT 1a without Q80K

100 100

93

88

95

GT 1a with Q80K

100 100

88

10096

6/6 11/11 11/11 4/4 7/7 4/4 5/5 13/14 7/8 3/3 7/8 3/3 18/18 38/40 25/26

100 100 100 100 100

Excluding patients who discontinued for non-virologic reasons

Baseline Clinical Characteristics of Patients Treated

with Simeprevir/Sofosbuvir in HCV-TARGET

Sulkowski MS, et al. Presented at AASLD: The Liver Meeting. November 7-11,

2014. Boston, Massachusetts. Poster 955.

Total SOF-SMVSOF-SMV-

RBV

(N=989) (N=772) (N=217)

Male 618 (62.5%) 479 (62.0%) 139 (64.1%)

Age 65+ 225 (22.8%) 188 (24.4%) 37 (17.1%)

Black or African

American130 (13.1%) 98 (12.7%) 32 (14.7%)

Genotype 1a 600 (60.7%) 445 (57.6%) 155 (71.4%)

Q80K present 29 (3.8%) 18 (8.3%) 47 (4.8%)

Not done 697 (90.3%) 192 (88.5%) 889 (89.9%)

Prior HCV

Treatment Experience594 (60.1%) 458 (59.3%) 136 (62.7%)

TVR/BOC Failures 119 (12%) 76 (9.8%) 43 (19.8%)

Cirrhosis 567 (57.3%) 435 (56.3%) 132 (60.8%)

Liver Transplant 142 (14.4%) 110 (14.2%) 32 (14.7%)

SOF + SMV ± RBV

N=378

On/Post Tx HCV RNA BLOQ

91% (335/369)On/Post Tx HCV RNA Quantified

9% (34/369)

VB

0.33%

(1/303)

Relapse

8.9%

(27/303)

SVR4+

303/369

SVR4+ 89%

269/303

Non-Response

2%

6/303

SVR4+


Cirrhosis: 87% (156/180)

G1a: 86% (154/180)

G1b: 95% (88/93)

Lost to f/u

0%

0/303

HCV RNA Outcomes for SOF/SMV+/-RBV

for 12 Weeks: G1



SOF + SMV ± RBV

N=72


86% (59/69)Latest Available HCV RNA Quantified

14% (10/69)

VBT

0%

(0/54)

Relapse

19%

(10/54)

SVR4+

54/69

SVR4+ 81%44/54

Non-Response

0%

(0/54)

SVR4+


Cirrhosis: 79% (27/34)

Lost to f/u

0%

(0/303)



HCV RNA Outcomes for SOF/SMV±RBV

for 12 Weeks: G1 Prior PI Failures

To compare SVR rates, logistic regression models with inverse probability weights

(IPW) were constructed to adjust for potential selection bias.

Adjusted SVR4: SOF/SMV±RBV for

12 Weeks

Sulkowski MS, et al. Presented at AASLD: The Liver Meeting.

November 7-11, 2014. Boston, Massachusetts. Poster 955.



Adjusted SVR4: SOF/SMV±RBV

for 12 Weeks Impact of Cirrhosis

Predictors of SVR4:

SOF/SMV±RBV for 12 Weeks



Adverse Events (>10%) By Regimen

Impact of PEG and RBV

*Total, patients with EOT date

Preferred Term,

n (%)

SOF PEG

RBV

(N=343)

SOF RBV

(N=462)

SOF SMV

(N=683)

SOF SMV RBV

(N=196)

Total*

(N=1684)

ANY AE 306 (89) 389 (84) 516 (76) 173 (88) 1384 (82)

Fatigue 144 (42) 177 (38) 168 (25) 74 (38) 563 (33)

Headache 55 (16) 74 (16) 108 (16) 46 (23) 283 (17)

Nausea 75 (22) 77 (17) 81 (12) 34 (17) 267 (16)

Anemia 95 (28) 98 (21) 7 (1) 58 (30) 258 (15)

Flu like Sx 93 (27) 58 (13) 72 (11) 24 (12) 247 (15)

Insomnia 54 (16) 66 (14) 58 (9) 35 (18) 213 (13)

Rash 62 (18) 50 (11) 57 (8) 28 (14) 197 (12)

Pruritus 34 (9) 39 (8) 56 (8) 28 (14) 157 (9)

Infections (ANY) 29 (9) 40 (9) 56 (8) 20 (10) 145 (9)

Dyspnea 54 (16) 43 (9) 28 (4) 12 (6) 137 (8)

Irritability 55 (16) 32 (7) 19 (3) 15 (8) 121 (7)

Depression 33 (10) 27 (6) 16 (2) 13 (7) 89 (5)

Neutropenia 28 (8) 0 (0) 3 (0) 0 (0) 31 (2)



Anemia by Treatment Regimen

Regimen

PEG/SOF/RBV

SOF/RBV

SOF/SMV

SOF/SMV/RBV

Hgb <8.5

4%

5%

3%

5%

Growth factor use

5%

3%

0%

3%

Hgb <10

19%

14%

6%

17%

Nelson DR. Real World Experience with DAA regimens. AASLD/EASL Special Conference on Hepatitis C.

September 13, 2014. New York, New York.

Of patients who

started treatment did

the patient experience

SAE (Serious Adverse

Event)?

SOF

PEG

RBV

SOF

RBV

SOF

SIM

SOF

SIM

RBV

All

N=384 N=667 N=784 N=228 N=2063

YES 11 (2.9%) 53 (7.9%) 36 (4.6%) 17 (7.5%) 117 (5.7%)

NO 373 (97.1%)614

(92.1%)

748

(95.4%)211 (92.5%)

1946

(94.3%)

Cause of Death (n=12)

SOF PEG RBV: Sepsis

SOF RBV: Multi organ failure, Cardiac arrest (2)

SOF SMV: Ischemic stroke, Hepatic failure (2), Renal & Hepatic failure#, Aspiration pneumonia#,

Vascular shock

SOF SMV RBV: cause unknown, Suicide (accomplished)#

* As reported in clinic notes, telephone records, or lab tests on ALL patients to date

# non-cirrhotic patients

SAEs* to Date By

Treatment Regimen



Safety and Tolerability

SOF/SMV ± RBV



AASLD/IDSA Recommendations for

HCV Genotype 2


hepatitis C. http://www.hcvguidelines.org, accessed 4/24/2014

• Consider Sofosbuvir/RBV for 16 weeks in treatment-

experienced patients with cirrhosis

Population Recommended Regimen Duration

Treatment naive & previous

relapsers, genotype 2

Sofosbuvir (400 mg) +

RBV (1000-1200 mg/d)

12 weeks*

98

82

91

62

0

20

40

60

80

100

SOF + RBV Peg-IFN + RBV

SV

R12 (

Perc

en

tag

e)


FISSION: Genotype 212 weeks of Sofosbuvir + RBV ± PEG-IFN

58/59 44/54 10/11 8/13

Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abstract 5.

Error bars represent 95% confidence intervals.

FUSION: SOF + RBV for 12 vs 16 Weeks: SVR12 in Prior Relapsers or Nonresponders

90

60

92

78

0

10

20

30

40

50

60

70

80

90

100

No Cirrhosis Cirrhosis

SV

R1

2 (

%)

Genotype 2 Sofosbuvir + RBV 12 wks

Sofosbuvir + RBV 16 wks

6/1026/29 7/924/26

Lawitz et al., N Engl J Med 2013, 368: 1878-1887.

Distribution of HCV Regimens in

Genotype 2

SOF/RBV99%

SOF/PEG/RBV1%

HCV G2n=325

Nelson DR. Real World Experience with DAA regimens. AASLD/EASL Special

Conference on Hepatitis C. September 13, 2014. New York, New York.

SOF + RBV GT2

N=235


91% (204/223)

On/ Post Tx HCV RNA Quantified

9% (19/223)


4/15/14; BLOQ=Below Level of Quantitation;

VB

0.5%

(1/187)

Relapse

8%

(14/187)

SVR4+

187/223

SVR4+

90% (168/187)

Non-Response

1.1%

(2/187)

SVR4

Non-cirrhotic: 91% (116/128)

Cirrhotic: 88% (52/59)

Lost to f/u

1.1%

(2/187)

HCV RNA Outcomes for

Sofosbuvir + RBV Genotype 2

Jensen DM, et al. Presented at AASLD:

The Liver Meeting. November 7-11, 2014.

Boston, Massachusetts. Abstract 45.

HCV-TARGET

What Have We Learned So Far?

• HCV-TARGET is an ongoing study characterizing the use of

DAAs across a broad spectrum of clinical practices in North

America and Europe

• High percentage of “off-label” use of sofosbuvir and simeprevir

• Efficacy– Real-world data for new DAA regimens consistent with phase 2-3 trial

data to date…. Patients treated with SOF/Ledipasvir are currently being enrolled

• Viral issues:– Very low viral breakthrough rates

– Resistance testing is rarely obtained in clinical care

• Safety– Very low discontinuation and SAE rates

– AEs of all oral regimens much lower than those with PEG Lowest in RBV-free regimens



Real-World Outcomes:

Special Populations and

Management Issues

Nancy Reau, MD

Associate Professor of Medicine

University of Chicago School of Medicine

Chicago, IL

Objectives

• Evaluate efficacy in G1 populations

underrepresented in phase 3 clinical trials

– Cirrhosis

– African Americans

– Older age >65 years

– Posttransplant

HCV-Target: Populations of Special Interest



Age >6519%

Black 12%

Hispanic 7%Cirrhotic 48.4%

Liver Transplant11%

HIV2%

N=2063

Underrepresented Populations

• Cirrhosis

• African Americans

• Age >65

• Transplant

AASLD/IDSA HCV Guidance

Genotype 1

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C.http://www.hcvguidelines.org. Accessed September 25, 2014

Population Recommended

Treatment-naïve and Prior PegIFN + RBV Relapser (± Compensated Cirrhosis)

IFN Eligible SOF + PegIFN + RBV x 12 weeks, regardless of subtype (1, A)

IFN Ineligible SOF + SMV ± RBV x 12 weeks, regardless of subtype (1, B)

Prior PegIFN + RBV Failure (partial or null response to treatment with PegIFN + RBV)

SOF + SMV ± RBV x 12 weeks (IIa, B)

Prior PI + PegIFN + RBV Failure

(partial or null response to treatment with TVR or BOC + PegIFN + RBV)

GT 1a SOF x 12 weeks + PegIFN + RBV x 12-24 weeks (IIb, C)

GT 1b SOF x 12 weeks + PegIFN + RBV x 12-24 weeks (IIb, C)

Real-world Treatment in 2014: Distribution of HCV

Regimens in Genotype 1 Infection in HCV TARGET

SOF/RBV32%

SOF/PEG/RBV 19%

SOF/SMV38%

SOF/SMV/RBV 11%

SOF/RBV30%

SOF/PEG/RBV12%

SOF/SMV44%

SOF/SMV/RBV13%

Patients with CirrhosisAll Patients

n=999 Cirrhosisn=2063



NEUTRINO (PEG+RBV+SOF for 12 weeks):

HCV G1/4 SVR Rates in Selected Subgroups

Lawitz E, et al. N Engl J Med. 2013,368:1878-1887.

9287

71

80

91

0

20

40

60

80

100

Multiple Factors*

SV

R12 (

%)

252/

273

47/

54

248/

27337/

52

43/

54

COSMOS (SMV+SOF) Cohort 2:

SVR12 by METAVIR Score

Lawitz E, et al. Presented at: EASL 2014. London, April 9-13, 2014.


100 10094

100 98100 100

9186

95

0

20

40

60

80

100

SMV/SOF±RBV

SV

R1

2 (

%)

SMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF


16/16 12/12 6/6 9/9 15/16 10/11 7/7 6/7 44/45 37/39

F3 F4

HCV-TARGET Data:

Demographics of Cirrhotic Patients

SOF

PEG-RBVSOF-RBV SOF-SMV

SOF-SMV

RBV

Total

enrolled*

n=117 n=291 n=377 n=122 n=907

Male 70.5% 67.3% 66.4% 73.9% 68.2%

Age >65 10% 20% 22% 16% 19%

Race/ethnicity

White 74% 80% 78% 84% 79%

Black 15% 6% 9% 7% 9%

MELD 10-15 24% 46% 33% 36% 37%

MELD >15 5% 12% 7% 10% 9%

Prior

decompensation12% 51% 55% 52% 43%

Prior therapy

Naïve 31% 40% 39% 37% 38%

Experienced 68% 60% 61% 63% 62%

• DAA failure 29% 10% 11% 23% 16%

*Total started therapy

Nelson DR. Real World Experience with DAA regimens. AASLD/EASL Special Conference on Hepatitis C.

September 13, 2014. New York, New York.

HCV-TARGET Data: Genotype 1

Cirrhotic Patients SVR4*

66

55

87 8591

SOF/PEG-RBV SOF-RBV SOF-SMV +/-RBV

SOF-SMV SOF-SMV-RBV



SV

R4 (

%)

23/35 6/11 156/180 113/133 43/47

*Crude SVR4 data.

Non-randomized; non-comparable


• Cirrhosis


• Age >65

• Transplant

NEUTRINO: SVR Rates in

Selected Subgroups

Lawitz E, et al. N Engl J Med. 2013,368:1878-1887.

9287

71

80

91

0

20

40

60

80

100

Multiple Factors

SV

R12 (

%)

252/

273

47/

54

248/

273

37/

52

43/

54


Black SVR4*



SV

R4 (

%)

BlackNon-Black BlackNon-Black

88 89

SOF/PEG-RBV SOF-SMV +/- RBV

75

119/136 21/28 238/268 31/35

*Crude SVR4 data.


89


• Cirrhosis


• Age >65

• Transplant


Age >65 SVR4*



87 88

71

91

SOF/PEG-RBV SOF-SMV +/- RBV

SV

R4 (

%)

130/150 10/14 200/227 69/76

≥65<65 ≥65<65

*Crude SVR4 data.



• Cirrhosis


• Age >65

• Transplant

HCV-TARGET: Distribution of HCV

Regimens for Post-liver Transplant

n=227 posttransplant

SOF/RBV25%

SOF/PEG/RBV12%

SOF/SMV49%

SOF/SMV/RBV14%



SOF + SMV ± RBV

N=131


91% (92/101)

Latest Available HCV RNA Quantified

9 %(9/101)

Cohort of patients with known treatment

start date; Excludes prior PI failures;

BLOQ=Below Level of Quantitation;

VBT=Viral Breakthrough

HCV RNA Outcomes for SOF/SMV ± RBV:

Genotype 1

VBT

1%

(1/68)

Relapse

6%

(4/68)

SVR4+ evaluable

68/101

SVR4+ 90%

61/68

Non-Response

3%

(2/68)

Lost to f/u

0%

(0/68)

SVR4+

G1a: 83% (30/36)

G1b: 95% (18/19)

Brown RS, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014.

Boston, Massachusetts. LB-4.

SVR4 Post-OLT

Brown RS, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014.

Boston, Massachusetts. LB-4.

Conclusions

• Most populations of special interest

received all-oral regimens

• Real-world data approximates clinical trial

data

• Special populations are no longer so

special

Treating Amid New

Guidelines and Options:

How to Decipher and

Apply to Practice

Ira M. Jacobson, MD

Weill Cornell Medical College

New York, New York USA

Many Considerations to Integrate

When Making Therapeutic Decisions

Clinical

judgmentGuidelines(“Guidance”)

Data

from

trials

Package

insert

CostThird

parties

Recommendations for HCV Genotype 1

AASLD/IDSA

• Treatment naïve (recommended)

– PEG-IFN/RBV/SOF (IFN eligible) (1A)

– SIM/SOF (IFN ineligible) (1B)

• Treatment naïve (alternative)

– PEG-IFN/RBV/SIM (except Q80K) (2a, A)

– SOF/RBV 24 weeks

(IFN ineligible) (2b, B)

• Treatment experienced (recommended)

– SIM/SOF (IFN eligible or ineligible)(non-PI)

– PEG IFN/RBV/SOF (IFN eligible)(PI)

• Treatment experienced (alternative)

– PEG-IFN/RBV 12-24 weeks/SOF 12 weeks

(IFN eligible) (2b,C)

– SOF/RBV 24 weeks (IFN ineligible) (2b,C)

EASL

• Option 1

– PEG IFN/RBV/SOF (1A)

• Option 2

– PEG IFN/RBV/SIM (except Q80K) (1A)

• Option 3

– PEG IFN/RBV/DCV (G1b only) (B1)

• Option 4

– SOF/RBV 24 weeks (IFN ineligible) (B2)

• Option 5

– SIM/SOF + RBV* 12 weeks (B1)

• Option 6

– DCV/SOF + RBV* 12 weeks (naïve) (B1)

– 24 weeks (experienced) (B1)

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and

treating hepatitis C. http://www.hcvguidelines.org. Accessed Oct 12, 2014.

EASL recommendations on treatment of HCV, April 2014

*Consider RBV for cirrhotics/nonresponders

Mostly

obsolete (November 2014)

Proposition

There is no longer a role for interferon in

the treatment of HCV genotype 1.

What about ribavirin?

ION-1: Sofosbuvir + Ledipasvir ± RBVHCV G1 Treatment Naïve, N=865

Cirrhosis in 16%

0

20

40

60

80

100

SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV

Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.

12 weeks 24 weeks

SVR12

(%)

209/214 211/217 212/217 215/217

99 97 98 99

ION-2: Ledipasvir + Sofosbuvir ± RBV

HCV G1 Treatment ExperiencedCirrhosis in 20%

0

20

40

60

80

100



12 weeks 24 weeks

SVR12

(%)

102/109 107/111 108/109 110/111

94 96 99 99

HCV-TARGET Study: SMV/SOFSVR4 Rates by Subgroups: No Impact of Ribavirin



Paritaprevir/r - Ombitasvir +

Dasabuvir ± RBV

HCV G1b Naïve, 12 Weeks

Noncirrhotic (PEARL-3)

0

20

40

60

80

100

RBV No RBV

HCV G1b Experienced, 12 Weeks

Noncirrhotic (PEARL-2)

0

20

40

60

80

100

RBV No RBV

Ferenci P, et al. N Engl J Med. 2014;370:1983-1992.

Andreone P, et al. Gastroenterology. 2014;147(2):359-365.

210 209 88 91

99 99 97 100

Conclusion: RBV not needed for HCV G1b

SVR12

(%)

Paritaprevir/r- Ombitasvir + Dasabuvir ± RBVHCV G1a, No Cirrhosis, Naïve, 12 Weeks (PEARL-4)

0

20

40

60

80

100

RBV No RBV

Ferenci P, et al. N Engl J Med. 2014;370:1983-1992.

100 205

9790

Implication: SVR difference is sufficient to warrant

ribavirin in HCV G1a patients

SVR12

(%)

How Short Can We Make

Therapy With the First-wave

Regimens?

ION-3: Ledipasvir + Sofosbuvir ± RBVHCV G1 Treatment Naïve

Noncirrhotic: 8 weeks vs 12 weeks

0

20

40

60

80

100

SOF/LDV SOF/LDV+RBV SOF/LDV

Kowdley K, et al. N Engl J Med. 2014:370:1879-1888.

8 weeks 12 weeks

SVR12

(%)

202/215 201/216

94 93 95

206/216

Does ION-3 Establish 8 Weeks as Standard

Duration for HCV G1 Noncirrhotics?

LDV/SOF 8 weeks LDV/SOF 12 weeks

SVR - overall 94% (202/215) 96% (208/216)

Relapse - overall 5% (11/215) 1% (3/216)

HCV RNA <6M 2% (2/123) 2% (2/131)

HCV RNA >6M 10% (9/92) 1% (1/85)

Ledipasvir and sofosbuvir (LDV/SOF) Prescribing Information. Gilead Sciences, Inc. October 2014. Jensen DM, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014. Boston, Massachusetts. Abstract 45.

~60% of patients had baseline HCV RNA <6M IU/mL*

• Relapse rates identical

• SVR12: 97% with LDV/SOF 8 weeks, 96% 12 weeks

SOF/LDV Label: Treatment-naïve, non-cirrhotics,

HCV RNA < 6 million IU may be treated for 8 weeks

*HCV-TARGET: 78% (253/323) of G1, non-cirrhotic, naïve had a baseline

HCV RNA <6 million IU/mL

How Long Should

Treatment-experienced

Cirrhotics Be Treated With the

First-wave DAA Regimens?

TURQUOISE-II:

Paritaprevir/r - Ombitasvir + Dasabuvir ± RBV

Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

0

20

40

60

80

100

12 Weeks 24 Weeks

9296

208 172

Relapse/viral breakthrough in 6% (12 weeks) and 2% (24 weeks)

P =.089

HCV G1 Patients with Compensated Cirrhosis

Treatment Naïve and Treatment Experienced

%

Arm A: 12-week regimen

Which Population Drove the Difference Between

12 and 24 Weeks in TURQUOISE-II?

Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

100 100

85.7

100

92.2 93.3

100

80

100 100 100 100

92.9

100 100

92.9

0

20

40

60

80

100

Naive Relapser Partial Null Naive Relapser Partial Null

SV

R12, %

Arm B: 24-week regimen

GT1b GT1a

n

N

22

22

18

18

14

14

10

10

6

7

3

3

25

25

20

20

59

64

52

56

14

15

13

13

11

11

10

10

40

50

39

42

Implication: HCV G1a null responders should receive 24 weeks of therapy

ION-2: Ledipasvir + Sofosbuvir ± RBV HCV G1 Treatment-experienced

Patients with Cirrhosis

0

20

40

60

80

100


Afdhal N, et al. N Engl J Med. 370;1483-1493.

12 weeks 24 weeks

SVR12

(%)

8682

100 100

19/22 18/22 22/22 22/22

P =.007

12 vs 24 weeks

Implication: Treatment-experienced cirrhotics should receive 24 weeks

GT 1b

0

20

40

60

80

100

SMV/SOF±RBVSMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF


SV

R1

2 (

%)

HCV G1a without Q80K

100 100

93

88

95

HCV G1a with Q80K

100 100

88

10096

6/6 11/11 11/11 4/4 7/7 4/4 5/5 13/14 7/8 3/3 7/8 3/3 18/18 38/40 25/26

100 100 100 100 100

COSMOS Cohort 2 (F3-4): 3/3 Relapsers

Received 12 Weeks of Treatment(Excludes Nonvirologic failures)

Adapted from:


0 relapsers 3 relapsers (2 cirrhotics,

1 treatment naïve)

HCV G1b

Q80K: Does It Matter When SMV

and SOF Are Used Together?

Is There an Impact of Q80K With Oral

Simeprevir-containing Regimens?

• 10-fold reduction in sensitivity to SMV

• Impact when SMV given with PEG-IFN/RBV

• Less to no impact when SMV given with SOF


0

20

40

60

80

100

G1b G1aQ80K-

G1aQ80K+

18/18 38/40 25/260

20

40

60

80

100

G1b G1aQ80K-

G1aQ80K+

COSMOS SVR12: Excludes nonvirologic failures

Cohort 1 (F0-2) Cohort 2 (F3-4)

17/17 30/30 24/28

100 95 96100 100

86

SVR12

(%)

Phase 3 data needed to further address this question

HCV-TARGET Study: SMV/SOFAdjusted SVR4 by RBV and G1 Subtype



Treatment of

Protease Inhibitor Failures

Treatment of Protease

Inhibitor Failures

• Population sequencing is commercially available

– Detection limit 20% of viral population

– Negative sequencing assay may not identify

levels of RAVs sufficient to impair efficacy of

PI-containing regimens

• Non-PI regimens may be superior for this

population

ION-2: Ledipasvir + Sofosbuvir ± RBV HCV G1 Treatment Experienced, Including Cirrhotics

0

20

40

60

80

100



12 weeks 24 weeks

SVR12

(%)

66 64 50 51

94 97 98 100

Protease Inhibitor Failures: No Impact of Baseline PI RAVs

LDV/SOF + RBV 12 Weeks

vs LDV/SOF 24 Weeks

Cirrhotic G1 Patients with PR/PI Failure

Bourliere M, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014. Boston, Massachusetts. LB-6

• Double-blind: LDV/SOF with RBV placebo for 24 wks or matching

placebo for 12 weeks followed by LDV/SOF + RBV for 12 wks

• 18% platelets <100,000 /uL, 13% albumin < 3.5 g/dL

LDV/SOF+RBV

12 weeks

(n=77)

LDV/SOF

24 weeks

(n=77)

Total

(n=154)

SVR12, n (%) 74 (96%) 75 (97%) 149 (97%)

Discontinuations on

active treatment, %

0 0 0

Relapse, n (%) 3 (4%) 2 (3%) 5 (3%)

SVR12 for Treatment Experienced,

Genotypes 1, Prior Regimen

Intent to Treat Per Protocol

Dieterich D, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014. Boston, Massachusetts. Abstract 46.

TRIO Cohort

SVR12, % Prior PEG

+ RBV + PI

Failure

Prior PEG

+ RBV

Failure

SOF +

PEG/RBV73 67

SMV + SOF ±

RBV82 80

SVR12, % Prior PEG

+ RBV +

PI Failure

Prior PEG

+ RBV

Failure

SOF +

PEG/RBV78 73

SMV + SOF

± RBV87 86

HCV-TARGET Study: SMV/SOFPredictors of Response



SVR 81%


AASLD/IDSA

• Treatment naïve

– SOF + RBV 12 weeks

Class I, Level A

• Treatment experienced


– “Patients with cirrhosis

may benefit from

extension of treatment

to 16 weeks”

Class I, Level A

EASL

• Option 1


Recommendation A1

– “Should be prolonged to

16-20 weeks in patients

with cirrhosis, especially

if treatment experienced”

Recommendation B1

• Option 2

– PEG-IFN + RBV + SOF

for cirrhosis and/or

treatment experienced

Recommendation B1


hepatitis C. http://www.hcvguidelines.org. Accessed Oct 12, 2014.


Is Response to SOF+RBV Impaired in HCV G2

Treatment-experienced Cirrhotics?

0

20

40

60

80

100

FISSION POSITRON VALENCE0

20

40

60

80

100

FUSION FUSION VALENCE

Treatment experienced

12 weeks 12 weeks 12 weeks 12 weeks 16 weeks 12 weeks

60

78

98

91 92 94 97 100

9196

100

6/10 23/23 7/9 30/33 7/829/30 2/268/70 10/11

>80% naïve

101

109

16

17 35/26

88

No cirrhosis

Cirrhosis

Treatment naïve

No cirrhosis

CirrhosisSVR12 (%)SVR12 (%)

Lawitz E, et al. N Engl J Med. 2013;368(20):1878-87. Jacobson IM, et al. N Engl J

Med. 2013;368(20):1867-77. Zeuzem S, et al. N Engl J Med 2014; 370:1993-2001.

SOF + RBV 12 Weeks for Genotype 2

Per ProtocolDieterich D, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014. Boston, Massachusetts. Abstract 46.

TRIO Cohort

% All Treatment

Naïve

Treatment

Experienced

All 90 91 89

Non-cirrhotic 93 93 92

Cirrhotic 81 79 83

SOF + RBV GT2

N=235


91% (204/223)

On/ Post Tx HCV RNA Quantified

9% (19/223)


4/15/14 ; BLOQ=Below Level of Quantitation;

VB

0.5%

(1/187)

Relapse

8%

(14/187)

SVR4+

187/223

SVR4+

90% (168/187)

Non-Response

1.1%

(2/187)

SVR4

Non-cirrhotic: 91% (116/128)

Cirrhotic: 88% (52/59)

Lost to f/u

1.1%

(2/187)

HCV RNA Outcomes for Sofosbuvir

+ RBV Genotype 2

Jensen DM, et al. Presented at AASLD:

The Liver Meeting. November 7-11, 2014.

Boston, Massachusetts. Abstract 45.


AASLD/IDSA

• Treatment naïve


“Recommended”

Class I, Level B

– PEG-IFN + RBV + SOF 12 weeks

“Alternative” (IFN eligible)

Class IIa, Level A

• Treatment experienced


“Recommended”

Class IIa, Level A

– PEG-IFN + RBV + SOF 12 weeks

“Alternative” (IFN eligible)

Class IIa, Level B

EASL

• Option 1

– PEG IFN + RBV + SOF 12 weeks

Recommendation A2

• Option 2


Recommendation A2

– Suboptimal in treatment

experienced cirrhotics, who should

be offered an alternative regimen

• Option 3

– SOF + DCV 12 weeks in naïve

– SOF + DCV 24 weeks in

treatment-experienced

Recommendation B1

– Consider adding RBV in cirrhosis

and/or treatment experience (B1)AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating

hepatitis C. http://www.hcvguidelines.org. Accessed Oct 12, 2014.


Sofosbuvir + Ribavirin for

HCV G3

0

20

40

60

80

100

Naïve Experienced

No cirrhosis

Cirrhosis

Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.

VALENCE: 24 weeks, N=250

9592

87

62

86/92 2/13 87/100 28/45

Implication: SOF+RBV suboptimal for HCV G3

%

20

40

60

80

100


SV

R12 (

%)

83

10/12

83

10/12

SOF 400 mg QD + PEG-IFN + RBV 1000–1200 mg for 12 weeks

Sofosbuvir + PEG-IFN + RBV in

HCV G3 Treatment-experienced Patients

Lawitz E, et al. Presented at: AASLD; 2013; Washington, DC. Abstract #LB-4.

Retreatment of HCV G3

Sofosbuvir + RBV Failures

9388

74

47

0

20

40

60

80

100


PR + SOF 12 Wks SOF + RBV 24 Wks

Esteban R, et al. Presented at: EASL; 2014; London. Abstract O8.

SV

R12 (

%)

13/14 17/23 7/8 7/15

ALLY-3: DCV+SOF for 12 Weeks in

Genotype 3

96 97 94

63 58

69

0

20

40

60

80

100

SV

R12 (

%)

PresentAbsent PresentAbsent PresentAbsent

Treatment-

naïve

Treatment-

experiencedOverall

Cirrhosis

Nelson DR, et al. Presented at AASLD: The Liver Meeting. November 7-11, 2014. Boston,

Massachusetts. LB-3.

105/109 20/32 73/35 11/19 32/34 9/13

DCV= Daclatasvir

Ledipasvir/Sofosbuvir ± RBV for

Treatment-naïve HCV G3 Patients

0

20

40

60

80

100

LDV/SOF LDV/SOF/RBV

Gane EJ, et al. Presented at: EASL; 2014; London. Abstract O6.

65

16/25 26/26

SVR12

(%)

0

20

40

60

80

100

Overall Nocirrhosis

Cirrhosis

100

8289

73

LDV/SOF±RBV 12 weeks LDV/SOF+RBV 12 weeks

Treatment Experienced

41/50 25/28

Treatment-naïve noncirrhotic

Gane EJ, et al. Presented at AASLD: The Liver Meeting.

November 7-11, 2014. Boston, Massachusetts. LB-11.

16/22

Conclusions

• No more interferon for genotype 1, still a role for ribavirin

• Possible role for IFN as “placeholder” for genotype 3 pending

new DAAs to put into combination regimens

• Full disclosure to patients, e.g. risk of resistance if regimen fails

• Important considerations for treatment

– Correct regimen for patient’s genotype or subtype

– Appropriate duration of therapy (or unnecessarily prolonged)

– Need to assess degree of hepatic fibrosis pretreatment

– Education re: importance of compliance

– Attention to drug-drug interactions

– Monitoring during and after treatment especially for HCC in

patients with advanced fibrosis

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