Hepatitis C in The US: Therapy Decision Making

Fred Poordad, MD Professor of Medicine

Texas Liver Institute/University of Texas Health Science Center

Case 1

Case: Genotype 1

• 55 yo African-American male having recently found to be anti-HCV positive with birth cohort screening at his PCP’s office

• Additional preliminary testing: – HCV RNA 4.5 million IU/mL – Genotype 1A – ALT 60 IU/mL. Prior records show ALT 42 IU/mL 5

years ago

Additional History and Exam • Source of HCV acquisition unknown: No history of IDU, blood

transfusions, etc. Served in military but no combat. • Rare alcohol use (

Additional Work-Up • CBC: WBC 4.5, Hgb 12.2, Plts 142K; INR: 1.2 • AST 55, ALT 43, ALP 112, TB 0.7, Alb 3.3, TP 7.4, BUN 11,

creatinine 1.1 • Hgb A1C 6.4, triglycerides 245, LDL/HDL cholesterol normal • Iron studies normal, HAV and HBV immune • Fib4 score is 0.53

• APRI = 0.49

• Fibroscan: 8.0

Fibroscan Score

8.0 kPa

2.5 7.5 9.5 12.5

2.5-7.4 9.5-12.4 12.5+ 7.5-9.4

F0/F1 NO, OR MILD

FIBROSIS Indicates no or minimal

liver fibrosis and no evidence of progressive

liver disease

F2 MODERATE FIBROSIS

Indicates significant liver fibrosis

and evidence of progressive liver disease

F3 SEVERE

FIBROSIS Indicates severe liver fibrosis and

high risk progression to cirrhosis

F4 CIRRHOSIS

Indicates extensive liver fibrosis

consistent with cirrhosis

Next Steps….

• Treatment candidate? – Insurance type?

• Additional testing needed?

– Based on insurance – Labs within 30 days – Drug testing, alcohol testing

• Counseling messages?

– PPI use?

Highest Priority

• Advanced fibrosis or compensated cirrhosis

• Organ transplant

• Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (eg, vasculitis)

• Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis AASLD Guidelines 2015

Highest priority • Fibrosis (Metavir F2)

• HIV-1 or HBV coinfection • Other coexistent liver disease (eg, [NASH])

• Debilitating fatigue

• Type 2 Diabetes mellitus (insulin resistant)

• Porphyria cutanea tarda

AASLD Guidelines 2015

Treatment Options

1. Ledipasvir/Sofosbuvir x 12 weeks

2. Paritaprevir/r/ombitasvir + dasabuvir + ribavirin x 12 weeks

3. Daclatasvir + sofosbuvir X 12 weeks

4. Simeprevir + sofosbuvir x 12 weeks

5. Sofosbuvir + ribavirin X 24 weeks

What if: • Genotype 1B?

– 3D without RBV?

• Albumin 2.7, total bilirubin 2.1, creatinine 1.2? – Can you use any protease inhibitor?

• Prior treatment failure with telaprevir/P/R? – Data supporting which regimens?

Case 2

72 Year Old Woman with Compensated Cirrhosis

• HCV genotype 1b

• Probably acquired 40 years ago when transfused for postpartum hemorrhage

• Cirrhosis (Metavir F4) on biopsy in 2011

• Had virologic breakthrough during course of PEG/RBV and telaprevir in 2011

• Complains of chronic fatigue

• Physical examination: palpable spleen tip

• Labs: ALT 58 U/L, AST 71 U/L, albumin 3.5 g/dL, platelets 90,000 cells/mm3, hemoglobin 11.8 g/dL, AFP 13 ng/mL

• MRI nodular liver contour, no focal liver lesions, spleen 16 cm

Treatment-Experienced GT1 Cirrhotic

Would you do anything else to assess hepatic fibrosis? • Fibroscan 24 kPa Any other measures while arranging treatment? • EGD: Grade 1 varices, too small for banding • Would you start beta blockers?

Question • How would you treat this patient?

– Ledipasvir/sofosbuvir 24 weeks – Ledipasvir/sofosbuvir + RBV 12 weeks – Paritaprevir/ritonavir/ombitasvir + dasabuvir 12

weeks – Simeprevir plus sofosbuvir 24 weeks – Daclatasvir plus sofosbuvir 24 weeks

• Would your decision be different if she had

failed PEG/RBV without a protease inhibitor?

ION-2: Ledipasvir + Sofosbuvir ± RBV

86 82

100 100

0

20

40

60

80

100

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

SVR1

2 (%

)

19/22 22/22

Genotype 1 Treatment Experienced Patients With Cirrhosis

Afdhal N et al, N Engl J Med 370;1483-93

12 weeks 24 weeks

18/22 22/22

P=0.007 12 vs 24 wk

Integrated Analysis of Cirrhotic Patients From the Ledipasvir/Sofosbuvir Development Program

• 513 patients with HCV GT 1, compensated cirrhosis • Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies

– LONESTAR, ELECTRON, ELECTRON-2, 337-0113, ION-1, ION-2, SIRIUS • Primary efficacy endpoint: SVR12

Bourliere M et al, AASLD 2014

Wk 0 Wk 12 Wk 36 Wk 24

SVR12 LDV/SOF

SVR12 LDV/SOF + RBV

SVR12 LDV/SOF + RBV

SVR12 LDV/SOF

n=118

n=204

n=133

n=58

Integrated Analysis: SVR12 by Treatment Regimen

Total Treatment

Naïve Treatment

Experienced Overall SVR12 96% 98% 95%

Duration 12 wk 95% 97% 94%

24 wk 98% 99% 98%

Regimen LDV/SOF 95% 96% 95%

LDV/SOF + RBV 97% 99% 96%

Duration/± RBV

LDV/SOF 12 wk 92% 96% 90% LDV/SOF + RBV 12 wk 96% 98% 96%

LDV/SOF 24 wk 98% 97% 98% LDV/SOF + RBV 24 wk 100% 100% 100%

SVR12, % Bourliere M et al, AASLD 2014

Chart1

96.11.52.1

94.72.23

98.41.32.9

95.22.33.4

96.91.82.8

92.44.16.4

96.12.23.7

97.71.84.2

10006.2

0��

9

8

7

6

5

4

3

2

1

Forest Plot

Total: SVR12CI lowerCI upperRateCI lowerCI upperlowerupper

Overall996.19497.62.11.5

Duration 12894.791.796.932.2

Duration 24wk798.495.599.72.91.3

Regimen LDV/SOF695.291.897.53.42.3

Regimen LDV/SOF + RBV596.994.198.72.81.8

Duration 12wk492.48696.56.44.1

w/ RBV 12wk396.192.498.33.72.2

24wk297.793.599.54.21.8

w/ RBV 24wk110093.81006.20

0

Forest Plot

96.991.7

99.795.5

97.591.8

98.794.1

96.586

98.392.4

99.593.5

10093.8

��

Plan1

This work is licensed under a Creative Common license Attribution 3.0 Unported (CC BY 3.0).

More information at http://creativecommons.org/licenses/by/3.0/

Permission to use program if source is cited. Neyeloff J, Fuchs S, Moreira L. Meta-analyses and forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.

More information at http://creativecommons.org/licenses/by/3.0/

Chart1

97.51.83.7

96.72.65.9

98.61.46.4

96.32.96.9

98.81.25.5

95.73.810.2

97.82.19.6

972.912.8

10009.7

0��

9

8

7

6

5

4

3

2

1

Forest Plot

Treatment Naïve: SVR12CI lowerCI upperRateCI lowerCI upperlowerupper

Overall997.593.899.33.71.8

Duration 12896.790.899.35.92.6

Duration 24wk798.692.21006.41.4

Regimen LDV/SOF696.389.499.26.92.9

Regimen LDV/SOF + RBV598.893.31005.51.2

Duration 12wk495.785.599.510.23.8

w/ RBV 12wk397.888.299.99.62.1

24wk29784.299.912.82.9

w/ RBV 24wk110090.31009.70

0

Forest Plot

99.390.8

10092.2

99.289.4

10093.3

99.585.5

99.988.2

99.984.2

10090.3

��

Plan1

This work is licensed under a Creative Common license Attribution 3.0 Unported (CC BY 3.0).

More information at http://creativecommons.org/licenses/by/3.0/

Permission to use program if source is cited. Neyeloff J, Fuchs S, Moreira L. Meta-analyses and forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.

More information at http://creativecommons.org/licenses/by/3.0/

Chart1

95.51.92.8

93.92.73.9

98.41.44.2

94.72.94.5

96.12.33.9

90.15.89.4

95.62.64.5

981.85

100015.4

0��

9

8

7

6

5

4

3

2

1

Forest Plot

Treatment Experienced: SVR12CI lowerCI upperRateCI lowerCI upperlowerupper

Overall995.592.797.42.81.9

Duration 12893.99096.63.92.7

Duration 24wk798.494.299.84.21.4

Regimen LDV/SOF694.790.297.64.52.9

Regimen LDV/SOF + RBV596.192.298.43.92.3

Duration 12wk490.180.795.99.45.8

w/ RBV 12wk395.691.198.24.52.6

24wk2989399.851.8

w/ RBV 24wk110084.610015.40

0

Forest Plot

96.690

99.894.2

97.690.2

98.492.2

95.980.7

98.291.1

99.893

10084.6

��

Plan1

This work is licensed under a Creative Common license Attribution 3.0 Unported (CC BY 3.0).

More information at http://creativecommons.org/licenses/by/3.0/

Permission to use program if source is cited. Neyeloff J, Fuchs S, Moreira L. Meta-analyses and forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes 2012;5:52.

More information at http://creativecommons.org/licenses/by/3.0/

TURQUOISE III: RBV-free 12 week option for G1b cirrhotics

Paritaprevir/r + ombitasvir + dasabuvir x 12 weeks WITHOUT RBV In G1b naïve/experienced cirrhotics

100

80

60

40

20

0

SVR

12 (%

)

100

60/ 60

62% Male 12% African American 55% Experienced Fibroscan med – 19 Kpa 22% Plt

Case 3

54 Year Old Woman with Compensated Cirrhosis and Small HCC

• HCV genotype 3A

• Cirrhosis (Metavir F4) on biopsy in 2010

• Prior treatment with PEG/RBV in 2011 with response but relapse

• Physical examination: palpable spleen tip

• Labs: ALT 58 U/L, AST 71 U/L, albumin 3.5 g/dL, platelets 80,000 cells/mm3, hemoglobin 11.8 g/dL, AFP 113 ng/mL

• MRI nodular liver contour, spleen 16 cmm 2.5 cm hypervascular lesion with washout in right lobe consistent with HCC

• She has been referred for consideration of liver transplantation

SVR and All-cause Mortality in CHC Patients with Advanced Fibrosis

Baseline factors significantly associated with all-cause

mortality:

– Older age – Genotype 3 (2-fold

increase in mortality and HCC)

– Higher Ishak fibrosis score

– Diabetes – Severe alcohol use

SVR patients Non-SVR patients

10-y

ear c

umul

ativ

e oc

curr

ence

rate

(%

)

8.9

26.0

1.9

27.4

5.1

21.8

2.1

29.9

25

20

15

10

5

0

30

All-cause mortality

Liver-related mortality or

liver transplant

HCC Liver failure

Van der Meer A, et al. JAMA 2012; 308:2584‒2593.

530 patients followed for a median of 8.4 years

Question

• How would you treat this patient? – Sofosbuvir plus ribavirin for 24 weeks – Daclatasvir plus sofosbuvir 24 weeks – Daclatasvir plus sofosbuvir plus ribavirin for

12 weeks – Sofosbuvir plus peginterferon/ribavirin for 12

weeks – Something else

• Clear advantage to PEG/RBV/SOF – especially in cirrhosis • Only 1 trt-discontinuation – good safety

Treatment Naive Treatment Experienced

58/ 70

65/ 72

68/ 71

12/ 21

18/ 22

21/ 23

26/ 34

17/ 36

30/ 35

44/ 54

49/ 52

41/ 54

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

83 90 96

57

82 91

76 82

94

47

77 86 100

80

60

40

20

0

SVR

12 (%

)

SOF + RBV 16 wks SOF + RBV 24 wks SOF + PEG/RBV 12 wks

n/N =

Foster. EASL. 2015.

BOSON: SOF/RBV 16 vs 24 vs PEG/SOF/RBV x 12

Cirrhosis

SVR

12 (%

)

Yes No Yes No Yes No

Overall Tx-naive Tx-experienced

DCV/SOF for GT 3: SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3)

Nelson DR et al., Hepatology 2015; 61: 1127-1135.

Chart1

Cirrhosis (absent, present)Cirrhosis (absent, present)

Cirrhosis (absent, present) naiveCirrhosis (absent, present) naive

Cirrhosis (absent, present), experiencedCirrhosis (absent, present), experienced

Column1

Column2

96

96.3

62.5

97.3

57.9

94.1

69.2

Sheet1

SVR12Column1Column2LowerUpperLowerUpper

Cirrhosis (absent, present)96.362.55.42.718.816.4

Cirrhosis (absent, present) naive97.357.919.415.3

Cirrhosis (absent, present), experienced94.169.2

Ally 3+ SVR12: Patients with Cirrhosis ALLY-3+

ITT ANALYSIS

VBTa 0 0 0 Relapseb 4 2 2 Deathc 1 1 0

VBT 0 0 0 Relapse 4 2 2

OBSERVED ANALYSIS

0102030405060708090

10089 88 89

16 18

Overall 12 Weeks 16 Weeks HC

V RN

A <

LLO

QTD

/TN

D (%

)

31 35

15 17

0102030405060708090

100

15 18

16 18

86 83 89

Overall 12 Weeks 16 Weeks

HCV

RNA

< LL

OQ

TD/T

ND

(%)

31 36

26

a VBT (virologic breakthrough): confirmed HCV RNA ≥ 1 log10 IU/mL above nadir, or ≥ LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA ≥ LLOQ at any posttreatment visit following < LLOQTND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment; cirrhosis status diagnosed by liver biopsy (F4) n = 9; FibroScan ≥ 14.6, n = 27.

UK Compassionate Access Program, 66% CP-B, 34% CP-C

N=

p

Summary

• Geno 1a: SOF/LDV or 3D/RBV • Geno 2: SOF/DAC or SOF/RBV • Geno 3: SOF/DAC +/- RBV • Geno 4: 2D/Rbv or SOF/LDV/RBV

Hepatitis C in The US: �Therapy Decision MakingCase 1��Case: Genotype 1Additional History and ExamAdditional Work-UpFibroscan ScoreNext Steps….Highest PriorityHighest priorityTreatment OptionsWhat if: Case 272 Year Old Woman with Compensated CirrhosisTreatment-Experienced GT1 Cirrhotic QuestionION-2: Ledipasvir + Sofosbuvir ± RBVIntegrated Analysis of Cirrhotic Patients From the Ledipasvir/Sofosbuvir Development ProgramIntegrated Analysis: SVR12 by Treatment RegimenTURQUOISE III: RBV-free 12 week option for G1b cirrhoticsCase 354 Year Old Woman with Compensated Cirrhosis and Small HCCSVR and All-cause Mortality in CHC Patients with Advanced Fibrosis QuestionBOSON: SOF/RBV 16 vs 24 vs�PEG/SOF/RBV x 12DCV/SOF for GT 3: SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3)Ally 3+ SVR12: Patients with CirrhosisSOF Plus NS5A Therapy for 12 Weeks in Decompensated CirrhosisSummary