Shaping the Future.Clinicians and Faculty Define - Strategies for the Next Era of HCV Therapy.2014

Shaping the Future: Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy

This program is supported by educational grants from

clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy

Program Director

Mark S. Sulkowski, MD Professor of MedicineMedical Director, Viral Hepatitis CenterDivisions of Infectious Diseases and Gastroenterology/HepatologyJohns Hopkins University School of MedicineBaltimore, Maryland


Faculty

Jordan J. Feld, MD, MPHAssistant Professor of MedicineUniversity of TorontoHepatologistToronto Western Hospital Liver CentreMcLaughlin-Rotman Centre for Global HealthToronto, Ontario, Canada

Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Marys University of LondonLondon, United Kingdom

Michael W. Fried, MDProfessor of MedicineDirector, UNC Liver CenterUniversity of North Carolina at Chapel HillChapel Hill, North Carolina

Alessandra Mangia, MDLiver Unit Hospital ‘Casa Sollievo della Sofferenza’Istituto di Ricovero e Cura a Carattere ScientificoSan Giovanni Rotondo, Italy

Fred Poordad, MDVice President, Academic and Clinical AffairsThe Texas Liver InstituteProfessor of MedicineUniversity of Texas Health Science CenterSan Antonio, Texas

Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine I JW Goethe University Hospital Frankfurt, Germany


New Standard of Care for HCV in 2013/2014

Standard Interferon

Interferon + Ribavirin

Peginterferon/ Ribavirin

1991 1998 2001

2005

Boceprevir or Telaprevir +

P/R

GT1

GT2/3

2011 2013

2013

Simeprevir or Sofosbuvir +

P/R

Sofosbuvir + Ribavirin


Key Questions That Define the Future of Hepatitis C Virus Therapy How do we determine the best regimen for genotype 1 going forward?

Jordan J. Feld, MD, MPH

Why does genotype 3 do poorly and how can we do better?Stefan Zeuzem, MD

Is one-size-fits-all treatment a possibility and how would that change management?Alessandra Mangia, MD

How will we manage patients who fail direct-acting antiviral therapies?Graham R. Foster, FRCP, PhD

Why do cirrhotics do poorly and how can we do better?Fred Poordad, MD

How will high-risk patients be managed going forward?Michael W. Fried, MD

Jordan J. Feld, MD, MPHAssistant Professor of MedicineUniversity of TorontoHepatologistToronto Western HospitalLiver CentreMcLaughlin-Rotman Centre for Global HealthToronto, Ontario, Canada

How Do We Determine the Best Regimen for Genotype 1 Going Forward?


Summary of New Agents for GT1 in 2013

Sofosbuvir + P/R

– Sofosbuvir is oral, once daily

– 12 wks with P/R

– SVR rate 89% in naives

– Low impact of baseline factors

Simeprevir + P/R

– Simeprevir is oral, once daily

– 12 wks with P/R + 12-36 wks with P/R

– SVR rate 80% in naives

– Q80K testing will be needed in GT 1a

Baseline Factor SVR12, % (n/N)

BlackNon-Black

86 (43/50)90 (218/242)

Genotype 1aGenotype 1b

92 (206/225)82 (54/66)

Cirrhosis*No cirrhosis*

80 (43/54)92 (252/273)

*Represents GT 1/4/5/6.

Sofosbuvir FDA hearing. October 25, 2013. Simeprevir FDA hearing. October 24, 2013.

Baseline Factor SVR12, % (n/N)

BlackNon-Black

67 (29/43)81 (378/464)

GT1a with Q80KGT 1a, no Q80KGT 1b

58 (49/84)84 (138/165)85 (228/267)

F3-F4*F0-F2*

68 (89/130)84 (317/378)


Priorities

SVR trumps all

But SVR is a necessity—assuming SVR > 90%, what is next?

Considerations

– Several new P/R-based regimens completing phase III

– Faldaprevir + P/R

– Daclatasvir + P/R

– But with 89% SVR with 12-wk SOF + P/R, will there be a clinical role for longer-duration P/R-based regimens?

– An all-oral future for GT1: multiple studies of 12- to 16-wk regimens


Over-treatmentof some

Tailoredregimen for each

population

Priorities

Cost

Fewestdrugs

Shortestduration

SimplicityOne size

fits all


2/12

One Size Fits All or Simpler Regimen for Genotype 1b Only? Genotype 1, naive

10% had cirrhosis

Dufour J-F, et al. AASLD 2013. Abstract 1102.

16-Wk Regimen: Faldaprevir (PI) 120 mg QD + Deleobuvir (NNI) 600 mg BID + RBV

(N = 32)

Simple regimen for genotype 1b only?What if it were very cheap?

EOT SVR12

Un

det

ecta

ble

HC

V

RN

A (

IU/m

L)

100

80

60

40

20

0

58

100

17

95

7/12 20/20 19/20

Genotype 1a, IL28B CCGenotype 1b


One Size Fits All or Simpler Regimen for GT1b? Various Ways to Look at the Same Data

82

0

20

40

60

80

100

SV

R12

(%

)

100 100 100 100 100

79

100

29 12

85

100

52 27

8396

52 25

96 100

54 25

81

100

26 18

89100

28 17

Observed data (above bar)

ITT (within bar)

n =

81

988888

10089

1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b

ABT-450

ABT-333RBV

ABT-450ABT-267

RBV

ABT-450ABT-267ABT-333


RBV

ABT-450ABT-267

RBV


RBV

Treatment-Naive Patients Null Responders

Kowdley KV, et al. AASLD 2012. Abstract LB-1.

ABT-450/RTV (PI) ± ABT-333 (NNI) +ABT-267 (NS5A) ± RBV x 12 Wks

One size fits all OR “simpler regimen” for GT1b?


What Is the Role of Ribavirin for Genotype 1 Going Forward? Still an enigma

Prevents/delays resistance

– Important for genotype 1a

– Important with NNI, PI, and NS5A

– Not relevant with NI-based combination

Reduces relapse

– May be relevant with shorter durations

– Limited data to date but does not look critical for most NI-based combination regimens


Same Duration for All or Shorter for Naive, Longer for Previous Failures?

12 wks for all or 8 for naive and 12 for failures? What about RBV? A third DAA for 6 wks?

SV

R12

(%

)

0

20

40

60

80

100

19/20

SOFLDV

SOFLDVRBV

SOFLDV

95100

21/21

95

18/19

95

SOFLDV

100

18/19

21/21

8 Wks 12 Wks 12 Wks

SOFLDVRBV

NaivePI failure

n/N =

Lawitz E, et al. AASLD 2013. Abstract 215.


Are We Moving to Primary Care?

Project ECHO

One size fits all may be critical

Project ECHO Web site.


Conclusions

Research continues for GT1 HCV

– More tailored approach in the near future

– Longer duration or additional agents for difficult-to-treat populations?

One-size-fits-all approach ideal for inexperienced providers

Rising demand for treatment anticipated

– Increased screening

– Availability of IFN-free regimens

Stefan Zeuzem, MDProfessor of MedicineChief, Department of MedicineJW Goethe University HospitalFrankfurt, Germany

Why Does Genotype 3 Do Poorly and How Can We Do Better?


Standard Treatment for GT2/3 HCVBefore treatment

(HCV RNA quantification)

16 wkstherapy

HCV RNA < 12-15 IU/mL

Pre-tx< 8 x 105 IU/mL*

48 wkstherapy‡

HCV RNA ≥ 2 log decline†

Wk 4HCV RNA quantification

Wk 12HCV RNA

quantification

24 wkstherapy

HCV RNA < 12-15 IU/mL

*No treatment shortening in patients with advanced fibrosis, cirrhosis, metabolic syndrome, insulin resistance, HIV/HCV coinfection, etc. No data for patients with persistently normal ALT levels. †Detectable HCV RNA at Wk 24: discontinuation of treatment.‡Treatment duration of 36, 48, 72 wks in slow responders is currently investigated in prospective trials.

Tx discontinued

< 2 log decline

EASL Practice Guidelines.


FISSION: Poorer Response to SOF/RBV in GT3 vs GT2 Naives, Especially Cirrhotics

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

SV

R12

(%

)

All Patients Patients With Cirrhosis

n/N =10/11

13/38

8/13

11/37

100

80

60

40

20

0

97

56

78

63

91

34

62

30

68/70

52/67

102/183

110/176

GT2 GT3

SOF/RBV 12 WksPegIFN/RBV 24 Wks

GT2 GT3


FUSION: Impact of Cirrhosis and Duration on SVR Rates

Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

6/10 5/26

SV

R12

(%

)

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

No Cirrhosis

Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks

No CirrhosisCirrhosis Cirrhosis

Genotype 2 Genotype 3

19

6163

37

n/N =

100

80

60

40

20

0

96100

60

78

100

80

60

40

20

0

SV

R12

(%

)

n/N =


Wk 0 Wk 24 SVR4, SVR12, SVR24

Placebo*(n = 85)

Sofosbuvir + Ribavirin(n = 84)*

*Protocol amended to eliminate placebo arm. 12-wk arm predominantly GT2 patients (N = 73); 11 GT3 patients completed 12 wks of SOF + RBV prior to amendment to extend treatment duration.

Zeuzem S, et al. AASLD 2013. Abstract 1085.

VALENCE: Evaluating Impact of Duration on SVR With SOF/RBV

Wk 12

Tx-naive or -experienced

GT2 or GT3 pts


Overall Treatment Naive Treatment Experienced

SV

R4

(%)

n/N =2/2

30/33

12/13

87/100

100

80

60

40

20

0

9397

8594

1009192

87

68/73

212/250

29/30

86/92

No Cirrhosis Cirrhosis

7/8

27/45

88

60

No Cirrhosis CirrhosisOverall12 wks of SOF + RBV in GT224 wks of SOF + RBV in GT3

Zeuzem S, et al. AASLD 2013. Abstract 1085. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

VALENCE Efficacy Summary: SVR12

Phase III GT3 SVR12 data summary:

– TN noncirrhotics, 12 wks: 61% (FISSION)

– TN cirrhotics, 12 wks: 34% (FISSION)

– TE noncirrhotics, 16 wks: 63% (FUSION)

– TE cirrhotics, 16 wks: 61% (FUSION)


Conclusions

Most GT3 patients will be able to be treated with 24 wks of SOF/RBV

GT3, treatment-experienced, cirrhotic patients most challenging group to treat with all-oral regimens

– Experts recommend 12 wks of SOF + pegIFN/RBV in short term

Alessandra Mangia, MDLiver Unit Hospital 'Casa Sollievo della Sofferenza'Istituto di Ricovero e Cura a Carattere Scientifico San Giovanni Rotondo, Italy

Is One-Size-Fits-All Treatment a Possibility and How Would That Change Management?


How Far Are We?

One Size . . . . . . Fits All?

Same treatment regardless of fibrosis level, previous treatment

experience, or HCV genotype?


AVIATOR: Less Impact of Traditional Negative Predictors on SVR Rates

Comparable high SVR rates among 247 patients administered 12 or 24 wks of treatment

All enrolled patients were noncirrhoticKowdley KV, et al. EASL 2013. Abstract 3.

Treatment Naive Null Responders

100

80

60

40

20

0

Mal

eFe

mal

e 1a 1b≥

7 lo

g

F0-F

1

< 7

log

F2-F

3N

on-C

CC

C

SV

R24

(%

)

SV

R24

(%

)

n =

92 94 9198

8994 94 91 95

89

78 81 108 50 35 124 113 42 115 44

100

80

60

40

20

0

Mal

eFe

mal

e 1a 1b≥

7 lo

g

F0-F

1

< 7

log

F2-F

3N

on-C

CC

C

n =

9397 93 97

9196 95 93 94

100

55 33 55 33 22 66 41 45 85 3


GT1 HCV Tx Naive: SVR Rates With 12 Wks of IFN-Free Tx in Phase II Studies

Few or no cirrhotic patients included in above studies

Corresponding rates for 24-wk regimens showed SVR12/24 of 52% (QUANTUM[1]), 95% to 100% (AI-444040[6]), 93% (AVIATOR[5]), 94% (A1443-014[8])

1. Lalezari LP, et al. EASL 2013. Abstract 845. 2. Gane E, et al. EASL 2013. Abstract 14. 3. Lawitz E, et al. AASLD 2013. Abstract 215. 4. Sulkowski MS, et al. AASLD 2012. Abstract LB-2. 5. Kowdley K, et al. EASL 2013. Abstract 3. 6. Everson G, et al. AASLD 2013. Abstract LB-1. 7. Lawitz E, et al. AASLD 2013. Abstract 76. 8. Sulkowski M, et al. EASL 2013. Abstract 1423.

Regimen N Study SVR 4/12, %

SOF (NS5B) + RBV 25 QUANTUM[1] 56

SOF (NS5B) + RBV 25 ELECTRON[2] 84

SOF (NS5B) + LDV (NS5A) 19 LONESTAR[3] 95

SOF (NS5B) + DCV (NS5A) ± RBV 82 AI-444040[4] 98-100

ABT-450 (PI) + ABT-267 (NS5A) + ABT-333 (NS5B) ± RBV

158 AVIATOR[5] 94

DCV (NS5A) + ASV (PI) + BMS-791325 (NS5B) 161 A1443-014[6] 92

MK-5172 (PI) + MK-8742 (NS5A) ± RBV 65 C-WORTHY[7] 96-100


Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV

ION-1*: GT1 Tx-Naive Pts (16% Cirrhotic): SOF/LDV

FDC ± RBV for 12 Wks

Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

*24-wk arms not yet reported.

ION-3: GT1 Tx-Naive Pts: SOF/LDV FDC ± RBV

for 8 or 12 Wks

SOF/LDV FDC SOF/LDV FDC + RBV

n/N =209/214

211/217

SV

R12

(%

)

12 Wks

98 97100

90

60

40

20

08 Wks 12 Wks

202/215

206/216

201/216

94 93 95


12-Wk Treatment in Previous Null Responders?

ABT-450/RTV + ABT-267 + ABT-333 + RBV

12 Wks

SV

R12

(%

)

Naive

n/N =42/45

F0-F2 fibrosis

SV

R4/

12 (

%)

n/N =

SMV + SOF + RBV 12 Wks

SMV + SOF12 Wks

*No F4

COSMOS[1,2]

Caveat: small numbers, few patients with cirrhosis

1. Jacobson IM, et al. AASLD 2013. Abstract LB-3. 2. Lawitz E, et al. CROI 2013. Abstract 155LB. 3. Kowdley K, et al. EASL 2013. Abstract 3.

26/27

13/14

96 93

76/79

14/15

7/7

93100

F3/4 fibrosis

96 93

AVIATOR[3]

100

80

60

40

20

0

Null*

100

80

60

40

20

0


SAPPHIRE Phase III Studies: PI Backbone + 2 Other DAAs

SAPPHIRE-1: GT1 Tx-Naive Noncirrhotic Pts:

ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 12 Wks


n/N =455/473

307/322

148/151

SAPPHIRE-2: GT1 Tx-Experienced Noncirrhotic Pts (49% Null Responders):

ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 12 Wks

100

80

60

40

20

0

SV

R12

(%

)

96 95 98

Overall GT1a GT1b

n/N =286/297

166/173

119/123

100

80

60

40

20

0

SV

R12

(%

)

96 96 97

Overall GT1a GT1b


SOF-Based IFN-Free DAA Treatment in GT1 Treatment-Experienced Patients

SOF + LDV + RBV x 12 wks(prior null, noncirrhotic)

100

80

60

40

20

0

SV

R 4

/12

(%)

100[1]

2 DAAs + RBV

SOF + LDV x 12 wks (prior PI failures, 50% cirrhotic)

2 DAAs, No RBV

7/10

70[2]

9/9

100[2]

SOF + LDV + RBV x 12 wks (TE with cirrhosis)

SOF + LDV x 12 wks (TE with cirrhosis)

95[3]

1. Gane EJ, et al. CROI 2013. Abstract 41LB. 2. Gane EJ, et al. AASLD 2013. Abstract 73. 3. Lawitz E, et al. AASLD 2013. Abstract 215.

18/199/9n/N =


Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV


SOF/LDV FDC SOF/LDV FDC + RBV

ION-2: GT1 Treatment-Experienced Pts (20% Cirrhotic): SOF/LDV FDC ± RBV for 12 or 24 Wks

n/N =

SV

R12

(%

)

100

90

60

40

20

012 Wks 24 Wks

102/109

107/111

108/109

110/111

94 96 99 99


Challenging Patient Groups

Patients with cirrhosis

HCV genotype 3 infection

Patients nonresponsive to DAA regimens

HIV coinfection


Conclusions

Future role for specialists in HCV

– Treating more complex cases

– Determining indication for starting treatment

– Surveillance of cirrhotic patients following successful therapy

Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Marys University of LondonLondon, United Kingdom

How Will We Manage Patients Who Fail Direct-Acting Antiviral Therapies?


DAA Failures: The Principles

In other viral infections, “failure” can be resolved by complementary drugs

– eg, in HBV, lamivudine failures respond to adefovir or tenofovir

Will the same hold true for HCV?


High SVR Rates With 24 Wks of All-Oral Therapy in GT1 Patients With PI Failure

Sulkowski MS, et al. EASL 2013. Abstract 1417.

*1 patient in daclatasvir/sofosbuvir/RBV arm had missing data at Wk 12 posttreatment; this patient had undetectable HCV RNA at Wk 4 and Wk 24 posttreatment.

SVR4 SVR12

24 wks of daclatasvir + sofosbuvir24 wks of daclatasvir + sofosbuvir + RBV

100 100 10095*100

80

60

40

20

0

Pat

ien

ts (

%)

n/N =21/21

20/20

21/21

19/20


LONESTAR: High SVR Rates With 12 Wks of Therapy in GT1 Patients With PI Failure

Lawitz E, et al. AASLD 2013. Abstract 215.

12 wks of SOF/LDV FDC12 wks of SOF/LDV FDC + RBV

95100

100

80

60

40

20

0

SV

R12

(%

)

n/N =18/19

21/21


Complementary Regimens:Drug Classes for the Future Nucleotide polymerase inhibitors (eg, sofosbuvir)

NS5A inhibitors (eg, daclatasvir, ledipasvir)

Protease inhibitors (eg, simeprevir, faldaprevir)

Non-nucleotide polymerase inhibitors (3 different classes)

Host-targeting drugs (cyclophilins, microRNAs RIG-I activators)

Which will work best together?


Conclusions

Second-line therapy and beyond

– New challenges with increased treatment options

– Continued treatment failures anticipated with more difficult-to-treat populations

Managing treatment failures

– Determine cause

– Risk factors – modifiable?

– Adherence with all-oral regimens

– Patient education and adherence management key

Fred Poordad, MDVice President Academic and Clinical AffairsThe Texas Liver InstituteProfessor of MedicineUniversity of Texas Health Science CenterSan Antonio, Texas

Why Do Cirrhotics Do Poorly and How Can We Do Better?


CUPIC: Telaprevir or Boceprevir + P/R in GT1 Treatment-Experienced Cirrhotics

Fontaine H, et al. EASL 2013. Abstract 60. Hezode C, et al. J Hepatol. 2013;59:434-441.

n/N =118/295

79/190

61/116

43/85

43/135

32/80

8/28 1/9

100

80

60

40

20

0

SV

R12

(%

)

Overall Relapsers PRs NRs

40 41

53 51

3240

29

11

Telaprevir + P/RBoceprevir + P/R

Risk of Death or Severe Complications, % (n/N)

Platelet Count > 100,000 cells/mm3

Platelet Count ≤ 100,000 cells/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)


Impact of Cirrhosis on SVR12 With Next-Generation PI + P/R

Jacobson I, et al. EASL 2013. Abstract 1425. Ferenci P, et al. EASL 2013. Abstract 1416.

18/31n/N =

5/17

188/229

60/113

82

53 58

29

Simeprevir + P/RP/R

100

80

60

40

20

0

SV

R12

(%

)


QUEST-1: Simeprevir + P/R

Treatment-Naive GT1

172/212

30/45

9/16

100

80

60

40

20

0

81

6756

< F3 ≥ F3 F4

STARTVerso1: Faldaprevir + P/R

Treatment-Naive GT1

Faldaprevir + P/R


Impact of Cirrhosis on SVR12 With Sofosbuvir-Based Therapy in Tx-Naive Pts

Lawitz E, et al. EASL 2013. Abstract 1411. Zeuzem S, et al. AASLD 2013. Abstract 1085.

SV

R12

(%

)

92

80

252/273 43/54

NEUTRINO: 12 Wks of SOF +

P/R GT1/4/5/6


58/59 10/11 89/145 13/38

100

80

60

40

20

0n/N =

9891

61

34

FISSION: 12 Wks of SOF + RBV

GT2/3

CirrhoticNoncirrhotic

94

86/92 12/13

92

VALENCE: 24 Wks of SOF +

RBV GT3

Genotype 1/4/5/6 Genotype 3

100

80

60

40

20

0

100

80

60

40

20

0


100

80

60

40

20

0

37

63

87

19

61 60


Impact of Duration, Addition of PegIFN on Efficacy of SOF in Tx-Experienced GT2/3

FUSION: 12 wks of SOF/RBVFUSION: 16 wks of SOF/RBVVALENCE: 24 wks of SOF/RBV

LONESTAR-2: 12 Wks of SOF + PegIFN/RBV

Sofosbuvir FDA hearing. October 25, 2013. Lawitz E, et al. AASLD 2013.

SV

R12

(%

)

14/38

25/40

87/100

5/26

14/23

27/45

Genotype 3

100

80

60

40

20

0

96 93100

83 83 83


SV

R12

(%

)

Overall Cirrhotic Noncirrhotic

n/N =22/23

13/14

9/9

20/24

10/12

10/12


Efficacy of IFN-Free DAA Combinations in Tx-Naive and Tx-Experienced Cirrhotics

COSMOS:12-Wk Regimens in GT1 HCV Cirrhotic Tx-Naive or Previous Null Responders

SV

R4/

12 (

%)

Jacobson IM, et al. AASLD 2013. Abstract LB-3. Lawitz E, et al. AASLD 2013. Abstract 215. Everson GT, et al. AASLD 2013. Abstract LB-1.

LONESTAR:12-Wk Regimens in GT1 HCV

PI Failures (55% Cirrhotic)

AI443-014:12-Wk Regimen in GT1

Tx-Naive Cirrhotics

100

80

60

40

20

0

91

100

10/11 7/7

Simeprevir + sofosbuvir + RBVSimeprevir + sofosbuvir

100

80

60

40

20

018/19 21/21

95100

Sofosbuvir/ledipasvir Sofosbuvir/ledipasvir + RBV

100

80

60

40

20

0

87

Daclatasvir + asunaprevir + BMS-791325

13/15n/N =


Conclusions

Eradication of HCV optimal before progression to cirrhosis

Poorer response of cirrhotic patients likely multifactorial

– Poor prior IFN response and GT3 most challenging

Treatment approaches

– GT3 experienced, cirrhotic: 12 wks of SOF + pegIFN/RBV

– GT3 naive, cirrhotic: 24 wks of SOF + RBV

Further improvements anticipated with DAA combinations

Michael W. Fried, MDProfessor of MedicineDirector, UNC Liver CenterUniversity of North Carolina at Chapel HillChapel Hill, North Carolina

How Will High-Risk Patients Be Managed Going Forward?


Goals of Antiviral Therapy

Decompensated cirrhosis

– Eradicate HCV to prevent further deterioration

– Eradicate HCV to prevent reinfection of graft

– Improve hepatic functional status

– Delay or obviate the need for transplantation

Posttransplantation

– Treat acute complications of HCV reinfection

– Prevent/arrest progression to cirrhosis

– Improve morbidity and mortality

– Liver related

– Extrahepatic effects on cardiovascular disease


HCV Management Issues Unique to Pre- and Posttransplantation Patients Pretransplantation

– Intolerance to peginterferon regimens

– Impaired hepatic metabolism

– Renal insufficiency

Posttransplantation

– High HCV RNA/impact of immunosuppression

– Fibrosing cholestatic hepatitis

– Drug–drug interactions

– Renal insufficiency

– Other medical comorbidities


PegIFN/RBV Before Transplantation to Minimize HCV Recurrence Post-LT

Everson GT, et al. Hepatology. 2013;57:1752-1762.

P = .6011

Tre

ated

LT

Pat

ien

ts (

%)

100

80

60

40

20

0Overall(n = 44)

GT1/4/6(n = 23)

GT2/3(n = 44)

59

25

52

22

67

29

HCV RNA negative at LTHCV RNA negative 12 wks of post-LT


Characteristic SOF + RBV(N = 61)

Median age, yrs (range) 59 (46-73)

HCV genotype, %

1a 39

1b 34

2 13

3a 12

4 2

Non-CC IL28B genotype, % 78

CTP score, %

5-7 96

8 5

Previous HCV treatment, % 75

Pretransplant Sofosbuvir + RBV to Prevent Posttransplant HCV Recurrence Study 025: single-arm, open-label,

phase II study from 16 LT sites

– Listed for LT due to HCC meeting Milan criteria

– MELD exception for HCC

– CTP score ≤ 7

Excluded decompensated cirrhosis, renal impairment, living donor LT

Pre-LT therapy: SOF 400 mg/day + RBV 1000-1200 mg/day for 48 wks or until time of LT

– Post-LT immunosuppression: ≥ 12 wks of tacrolimus + prednisone + MMF

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


Duration of Undetectable HCV RNA Before Transplant Predicted Lack of Recurrence

64% of pts HCV RNA negative 12 wks post-LT (93% at LT)

Continuous days TND pre-LT only factor predicting HCV recurrence in multivariate analysis

– Only 1/24 pts with > 30 days TND experienced recurrence

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 LT

> 30 days TND

No recurrence (n = 28)Recurrence (n = 10)

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


CRUSH C: PI + PegIFN/RBV in Liver Transplantation Recipients 112 patients: 30 were F4 or FCH

Treatment: TVR 88% or BOC 12%

– P/R lead-in 96%

Verna EC, et al. EASL 2013. Abstract 23.

HC

V R

NA

< L

OD

(%

)

100

80

60

40

20

0EOTR SVR4

67 65

n = 43

Adverse Effect All Patients(N = 112)

AE requiring treatment d/c, % 11

Dose reduction, %PegIFN/RBV 34/80

Transfusion, % 46

Erythropoietin, % 79

G-CSF 41

Hospitalization, %* 21

Renal functionCr increase > 0.5 mg/dL, %Max ↑ in Cr, mg/dL (range)

340.4 (0-2.5)

Rejection, %† 4

Death, % 6

*Significantly differed between groups (P = .02). †Any treated rejection during or after TT.


Daclatasvir 60 mg/day + Sofosbuvir 400 mg/day

Case Report: Sofosbuvir + Daclatasvir in Post-LT Fibrosing Cholestatic Hepatitis

Fontana RJ, et al. Am J Transplant. 2013;13:1601-1605.

8

7

6

5

4

3

2

1

0

Lo

g H

CV

RN

A (

IU/m

L)

Treatment Wk

400

350

300

250

200

150

100

50

0

AL

T (IU

/L)

Alk P

ho

s (IU/L

)

0 1 2 3 4 6 8 1012 14 1618 20 22 2425 2848 56 60

ALTAlk PhosHCV RNA


Sofosbuvir + RBV for Treatment of Post-LT HCV Recurrence Ongoing prospective,

multicenter, single-arm, open-label pilot study

– Median time since LT: 4.3 yrs (range: 1.02-10.6)

– CTP ≤ 7 and MELD ≤ 17

– 83% GT1, 33% IL28B CC, 40% with comp’d cirrhosis

SOF 400 mg/day + RBV 400-1200 mg/day for ≤ 24 wks

– RBV started at 400 mg/day and increased based on hemoglobin levels

Charlton MR, et al. AASLD 2013. Abstract LB-2. Reproduced with permission.

Virologic Response Rates

*1 patient still on treatment.†4 patients had not reached SVR4 visit.

Wk 4 EOT* SVR4

Res

po

nse

(%

)

100

80

60

40

20

0

100 100

77

40/40 39/39 27/35†


Other Studies Recruiting

Sofosbuvir/ledipasvir FDC + RBV for 12 or 24 wks in patients with advanced liver disease or posttransplantation recurrence[1]

Simeprevir + daclatasvir + RBV for 24 wks in genotype 1b patients with posttransplantation recurrence[2]

ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 24 wks in liver transplantation recipients[3]

1. ClinicalTrials.gov. NCT01938430. 2. ClinicalTrials.gov. NCT01938625. 3. ClinicalTrials.gov. NCT01782495.


Conclusions

Pre- and post-LT patients greatest challenge to eradication of HCV

– Recent data encouraging

– Significant challenges remain

Go Online for More From This Program!

CME-certified module that goes in-depth on each of the key questions addressed in this slideset

clinicaloptions.com/shaping

http://www.clinicaloptions.com/shaping

Health & Medicine

Shaping the Future.Clinicians and Faculty Define - Strategies for the Next Era of HCV Therapy.2014