will ‘difficult-to-treat patients remain ‘difficult- to-treat’ with the … · 2016. 5....

Will ‘difficult-to-treat patients remain ‘difficult-

to-treat’ with the new generation of treatments?

Jordan J Feld MD MPH

Toronto Centre for Liver DiseaseSandra Rotman Centre for Global Health

University of Toronto

Disclosures – Dr. J. Feld

Consulting or speaker fees: AbbVie, Achillion, BI, BMS, Gilead, Idenix,

Janssen, Merck, Roche, Vertex

What does Difficult-to-Treat mean?

Difficult-to-Treat ≠ Difficult-to-Cure Some overlap but not always the same With HCV – both groups exist Factors: Host

VirusTreatment

‘Difficult-to-Treat’ vs ‘Difficult-to-Cure’

Difficult-to-Treat Host

Cirrhosis Age Co-morbidities

Renal failure, autoimmunity, Hemoglobinopathy, Psych, transplant

Social factors

Virus None

Treatment Injections, Pill burden Side effects

Difficult-to-Cure Host

Cirrhosis Age Co-morbidities

Renal failure, Transplant HIV/HCV

Past non-responder Genetics – ethnicity, IL28B

Virus Genotype (1a, 3) Viral load

Treatment None

0%

20%

40%

60%

80%

100%

IFN IFN IFN/R IFN/R PegIFN PegIFN/R

Sust

aine

d Vi

rolo

gica

l Res

pons

e

16%

55%

6%

Difficult defined by IFN-use

34%42% 39%

6 mo 12 mo 6 mo 12 mo 12 mo

19911995

1998

20022001

Ribavirin

Peginterferon

Standard Interferon

6-12 mo

75%

2011DAA+PR

PegIFN/R/S-C12 mo

Courtesy of Jay Hoofnagle

Therapy got a lot harder…

Additional side effects

Other issues with PI-based therapy

BOC = 18/d TVR = 12/d

Pill Burden Food Requirement

CYP3A4PI Metabolites

Drug-Drug Interactions

Resistance

First generation PIs?

Actually made it more ‘Difficult-to-Treat’ Increased side effects Pill burden Drug-interactions …and add good ol’ Peg/RBV to all that

What about ‘Difficult-to-Cure’ Greatest improvement actually in ‘Easy-to-Cure’ PIs augment a good IFN-response PIs minimal ability to overcome a poor IFN response

What about first generation PIs?

Prior relapsers

Prior partial responders

Prior null responders

2/15n/N= 53/62144/167 12/38 0/510/1834/47 3/17 0/915/3811/32 1/5

No, minimal or portal fibrosis

CirrhosisStage

Pooled T12/PR48

Pbo/PR48

SVR

(%)

2/1548/57 24/59 1/18 7/50 1/10

Bridgingfibrosis


CirrhosisBridgingfibrosis


CirrhosisBridgingfibrosis

Zeuzem EASL 2011

Room for improvement…

But we all know what’s coming…~100%SVRNo AEs

IFN-free

1 pill OD

RBV-free

Minimal/No Resistance

No DDIs ShortDuration

Priorities for ‘Difficult-to-Cure’

Non-responders Cirrhosis

Decompensated cirrhosis Co-morbidities

Renal disease HIV co-infection

Post-transplant Genotypes

1a 3

Second Wave DAAs for G1

100

80

60

40

20

0

SVR

12 (%

)

80

50

211/264

65/130

84

208/257

50

67/134

QUEST 1 QUEST 2

100

80

60

40

20

0

SVR

12 (%

)

79

36

206/260

48/133

PROMISE

Treatment Naïve Prior

Relapsers

Manns M, et al. EASL 2013. Abst. 1413.Jacobson I, et al. EASL 2013. Abst. 1425.

PRPR + SMV Simeprevir + PR

x 24 weeks

100

80

60

40

20

0

SVR

12 (%

)

89

261/292

NEUTRINO

Sofosbuvir + PRX 12 weeks

Lawitz E, et al. NEJM 2013

What about in the ‘Harder-to-Cure’?

100

80

60

40

20

0

SVR

24 (%

)

85

37

45/53

10/27

70

32/46

9

2/23

Relapsers Partials

Treatment Experienced

45

15/33

193/16

Nulls

SMV + PR x 12 + PR x 36

FDA Analysis

100

80

60

40

20

0

SVR

12 (%

)

Sofosbuvir + PRX 12 weeks

78

Modeled Numbers

?Poor or no results in null responders

What about cirrhosis?

Jacobson I, et al. EASL 2013. Abst. 1425.

Post-treatment On treatment

Week 2 Week 4 Week 12 SVR 12

Sofosbuvir + PR x 12 wks

Lawitz E, et al. NEJM 2013

Improved results for Child’s A cirrhotics,particularly with sofosbuvir/PR

50/54

52/54

53/53

43/54

249/273

269/271

267/267

252/273

Options without interferon

RBV

Nuc PIHigh barrier to resistance

Modest barrier to resistance

NS5A NNILow barrier to resistance(esp to G1a)

PI

Nuc NS5A

Nuc

NNI

NS5API

Nuc NS5API

NNI

Nuc RBV

Medium:G1b, G3?

Hard:G1a, G3? RBV?PI NNI NS5A

Easy: G2, G3?

Curability

PI + NS5A in prior null responders

100

80

60

40

20

0

36

Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free)SV

R24

(%)

US [1]

90Japan [2]

9/104/11

• 2 drugs for 1b, 3 for 1a• Excellent results in NULL responders!

1. Lok et al NEJM 2012;366:216-24, 2. Chayama AASLD 2011 LB-4 3. Everson AASLD 2013 LB-1

US Study9/11 G1a

Japanese Study10/10 G1b

Daclatasvir (NS5A) + asunaprevir (PI) + BMS 791325 (NNI) x 12 wks

121/133

91

27/28

96

G1aG1b

SVR

12 (

%)

0

20

40

60

80

10082

12

88

24

98

251a 1b 1a 1b 1a 1b 1a 1b

450

333RBV

450267

RBV

450267333

450267333RBV

100

29

100

2752

88

100

2752

100

54

Treatment Naive100

18

89

281a 1b 1a 1b

450267333RBV

450267333RBV

1726

81

100

Prior Nulls

AVIATOR: PI/r + NS5A + NNI + RBV x 12 wks

Kowdley AASLD 20125 drugs (3 pills) BUT 12 wks, 1 size fits all

Post-AASLD: IFN-Free Phase 3 study

100

80

60

40

20

0

SVR

12 (%

)

95

307/322

G1a

98

148/151

ABT-450/r + ABT-267 + ABT-333 + RBV x 12 wks

96

455/473

All

Abbvie press release Nov 18 2013 and Dec 10 2013 to be presented at EASL 2014

G1b

100

80

60

40

20

0

SVR

12 (%

)

96

166/173

G1a

97

119/123

96

286/297

All G1b

Naive Treatment Failures (49% nulls)

Clear prior null response can be overcome

If nucs are good and PIs are good

How about nucs + PIs?

If only we could all get along…

SMV SOF

FDA

Nuc (SOF) + PI (SMV)Naïve & Prior Null Responders

Jacobson AASLD 2013

Sofosbuvir (Nuc) + Simeprevir (PI) +/- RBV x 12 wks F0-2

Major caveats: small n, no plan for Phase 3 trial

100

80

60

40

20

0

SVR

4 or

8 (%

)

96[1] 93[1]

S/S/R S/SF0-2

78% G1a50% Q80K94% non-CC

78% G1a40% Q80K79% non-CC47% F454% Null

Sofosbuvir (Nuc) + Simeprevir (PI) +/- RBV x 12 wks F3-4

96[2] 100[2]

S/SS/S/RF3-4

26/27 14/1426/27 13/14

Another option: Nuc + NS5A

Sulkowski M, et al. NEJM 2014

Sofosbuvir (Nuc) + Daclatasvir (NS5A) +/- RBV x 24 wks

Major caveats: small n, no plan for Phase 3 trial

100

80

60

40

20

0

SVR

4 or

12

(%)

100

14/14

100

15/15D/S/R D/S

24 wks

Sofosbuvir (Nuc) + Daclatasvir (NS5A) +/- RBV x 12 wks

40/41

98

39/41

95

D/SD/S/R12 wks

2 drugs, 1 pill

Naïve

100

80

60

40

20

0

SVR

4 or

12

(%)

95

19/20

100

21/21

S/L S/L/R8 wks

100

19/19

S/L/R

18/19

95

20/21

95

S/L/RS/L12 wks

PI Failures

12 wks

• No breakthrough, relapses all without RBV• 1 case of resistance – retreated w/ RBV x 24 wks…SVR

Lawitz AASLD 2013

LONESTAR: SOF (nuc) + LDV (NS5A) FDC +/- RBV

Just in…

Naïve

100

80

60

40

20

0

SVR

4 or

12

(%)

98

209/214

97

211/217

S/L S/L/R12 wks

Prior Trt (incl PI) Failures

94

102/109

S/L

107/111

96

S/L/R12 wks

ION 1, 2 & 3: SOF (nuc) + LDV (NS5A) FDC +/- RBV

108/109

99

S/L24 wks

110/111

99

S/L/R

94

202/215

93

201/216

95

8 wks 12 wksS/L S/L/R S/L

206/216

Gilead Press Release Dec 17 2013 to be presented at EASL 2014

Includes 15-20% cirrhosis, only 1 BT – non-compliant






1a 3

✓

6/10 5/26

FUSION: (Treatment Failures)SVR12 by HCV Genotype/Cirrhosis

SVR

12 (P

erce

ntag

e)

25/26 7/923/23 14/38 14/2325/40

No cirrhosis

SOF + RBV 12 weeks SOF + RBV 16 weeks

No cirrhosisCirrhosis Cirrhosis

GT 2 GT 3

• Cirrhosis clearly matters limited data G2• Convincing data for G3

Jacobson NEJM 2013

VALENCE

100

80

60

40

20

0

SVR

12 (%

)93

86/92

85

85/100

Naive Treatment Failures

SOF + RBV x 24 wks

• 24 weeks better for naives• Not ideal for cirrhotic treatment failures

Zeuzem AASLD 2013

92

12/13

60

27/45

No CirrhosisCirrhosis

61

14/23

16 wks

Do we still need IFN for G3?

100

80

60

40

20

0

SVR

12 (%

)100

9/9

83

10/12

G2 G3

93

13/14

No CirrhosisCirrhosis

LONESTAR 2: Peg + RBV + SOF x 12 wks

83

10/12

Lawitz AASLD 2013

• Small single centre study but looks promising…• IFN is not dead yet!

85% treatment failures

Treatment pre-transplant for HCC (low MELD)

Curry MP, et al. AASLD 2013. Abstract 213.

3300 30 60 90 120 150 180 210 240 270 300Days With HCV RNA Continuously TND Prior to Liver Transplant

> 30 days TND

No Recurrence (n = 28)Recurrence (n = 10) Median days undetectable

No recurrence: 95Recurrence: 5.5(P < .001)

Only 1 of 24 with HCV RNA neg > 30 days with recurrence

SOF + RBV x up to 48 wks

Cirrhosis

Cirrhosis is still an issue with current regimens ‘Simple’ IFN-free regimens sub-optimal in

cirrhosis (esp G3) Increased duration only partially overcomes this

More potent IFN free regimens seem to work equally well in compensated cirrhotics in G1 VERY limited data to date Possibly higher relapse rate

No data in decompensated cirrhosis Studies ongoing






1a 3

✓

✓ (?)

PHOTON-1: HCV/HIV co-infected

n/N =

Sulkowski M, et al. AASLD 2013. Abstract 212.

100

80

60

20

0

40

HC

V R

NA

< LL

OQ

(%)

Genotype 1 Genotype 2 Genotype 3SOF + RBV 24 Wks SOF + RBV 12 Wks

Wk 4EOTSVR12

10096

76

96 9688

100 98

67

110/114

103/103

87/114

25/26

22/23

23/26

41/41

39/40

28/42

ARVs: PI/NNRTIs/Integrase Inhibitors

Looking fairly similar to HCV mono-infected pop’n…






1a 3

✓

✓ (?)

✓

No data – no RBV will help

Sofosbuvir + RBV ± PegIFN in Post-LT HCV with Severe Recurrence

69% of pts had SVR4; 56% had SVR12 Deaths and

posttreatment relapse accounted for nearly all cases of virologic failure

64% demonstrated improvement of decompensation events

11% showed stabilization of events

Forns X, et al. AASLD 2013. Abstract 1084.

Overall SOF + RBV SOF +PegIFN/RBV

SV

R4

(%)

100

80

60

40

20

0

SVR4 Outcomes

6974

56

25/36 20/27 5/9n/N =

FCH 45%Mean MELD 15

Not quite so sick post-OLTxSOF + RBV x 24 wks 24-48 wks post OLTx (n=40)

G1 n=30MELD<=17CPT<=7Cirrhosis n=16

Relapse 23%DC due to AEs n= 2

Charlton AASLD 2013 LB-2

Looking fairly similar to HCV non-OLTx pop’n…






1a 3

✓

✓ (?)

✓

No data – no RBV will help

✓

✓

✓ (?)

Priorities for ‘Difficult-to-Treat’

Cirrhosis Decompensated cirrhosis

Co-morbidities Renal disease Psychiatric disease Hemoglobinopathy

Social Factors People who inject drugs Incarcerated Access to specialists

✓

?

More drugs…shorter therapy

• IFN and RBV-free therapy for 6 wks or less possible• Will increase options for treating ‘difficult-to-treat’

Kohli AASLD 2013

SOF/LDV FDC

Weeks0 6 12

SOF/LDV FDC + NNI (GS-9669)

SOF/LDV FDC + PI (GS-9451)

SVR4

20/20

18/20

20/20

SVR12

20/20

NA

NA

Priorities for ‘Difficult-to-Treat’

Cirrhosis Decompensated cirrhosis

Co-morbidities Renal disease Psychiatric disease Hemoglobinopathy

Social Factors People who inject drugs Incarcerated Access to specialists

Few DDIs, Few AEs, No RBV

✓

?

Few DDIs, No IFNNo IFN, No RBV

No IFN, Few AEs, PCP treatNo IFN, Short DurationPCPs can treat

$$$$$$$$$$$

May become our biggest barrier to treatment…

Bottom Line ‘Difficult-to-Cure’ populations disappearing

Non-responders, compensated cirrhosis, HIV, post-transplant, co-morbidities likely to be non-issues

Decompensated cirrhosis…likely to remain a challenge ‘Difficult-to-Treat’ populations decreasing

Minimal toxicity will allow more to be treated Simple regimens will increase treaters increase access

‘Difficult-to-Reach’ populations Our new challenge

Paying for it all Everyone’s challenge!!

Please visit the CAG website at http://www.cag-acg.org/ to complete the session evaluation and to print

your certificate of attendance.

Thank you!

Evaluation and Certificate of Attendance

AccreditationThis event has been approved as an accredited (Section1) group learning activity as defined by the Maintenance of Certification program of the RCPSC. It has been produced under RCPSC guidelines for the development of co-developed educational activities between CAG and Vertex Pharmaceuticals.

2013 CDDW/CASL Winter Meeting

Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.)

Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.)

Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal patient care.)

Manager (as Managers, physicians are integral participants in healthcare organizations, organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.)

Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to advance the health and well-being of individual patients, communities, and populations.)

Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.)

Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.)

CanMEDS Roles Covered:

Learning ObjectivesAt the end of this session, participants will be able to:1. Describe the baseline laboratory and clinical

profile in the cirrhotic patient that contraindicates interferon-based treatment.

2. Describe clinical current experience and future protocols for treatment of patients with HCV after liver transplantation.

3. Discuss the newer therapies for HCV for relapsers and non-responders.

will ‘difficult-to-treat patients remain ‘difficult- to-treat’ with the … · 2016. 5....

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