HCV Treatment of Patients With Cirrhosis 2014 Singapore

Singapore Viral Hepatitis Meeting

June 2014

HCV: management of the patient with Cirrhosis: a focus on treatment

HCV and Cirrhosis

Robert G Gish MD

Professor Consultant– Stanford University

Vice Chair: – Executive Committee National Viral Hepatitis

Roundtable

Senior Medical Director – St Josephs Hospital and Medical Center– Phoenix Arizona

Disclosures

Dr Gish receives consulting fees from

BMS Gilead Merck Idenix AbbVie Genentech

All income is then expensed or donated to research and education

What is cirrhosis?

MELD over 6 CPT 7 and above Liver biopsy Elastography kPa value over 8-11 Spleen over 12 cm Portal vein over 12 mm Varices on EGD or abdominal imaging Large left lobe with physical finding of portal

hypertension Imaging with characteristic changes of liver

morphology and or portal hypertension

HCV Incremental All-Cause Health Care Costs by Liver Disease Severity (USD 2009)

Difference between HCV and non-HCV matched controls.Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.

McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546.

Incr

emen

tal A

ll-C

ause

Co

sts

(per

-pat

ien

t-p

er-y

ear)

5879(157) 5330

(491)

27,845(965)

810(49)

974(194)

15,464(710)

1721(123) 1081

(275)

5818(292)

641(37) 93

(130)

4526(213)

2659(41)

3102(157) 1893

(123)

No liver disease (n=26,977)

Compensated cirrhosis (n=1521)

Decompensated cirrhosis (n=4249)

InpatientTotal HealthCare Costs

Outpatient PhysicianServices

PharmacyCostsPlace of Service

HCV Incremental All Cause Health Care Costs by Liver Disease Severity (USD 2009)

Difference between HCV and non-HCV matched controls.Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.

McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546.

43,671(2588)

93,609(4482)

27,845(965)

60,143(3612)

17,197(194)15,464

(710)

5818(292)

Decompensated cirrhosis (n=4249)

Hepatocellular carcinoma (n=959)

Liver transplantation (n=891)

12,307(1069)

12,915(829)

4526(213)

9423(1188)

11,697(646)

1893(123)

4632(587)

8736(363)

Incr

emen

tal A

ll-C

ause

Co

sts

(per

-pat

ien

t-p

er-y

ear)

InpatientTotal HealthCare Costs

Outpatient PhysicianServices

PharmacyCostsPlace of Service

0

1000

2000

3000

4000

5000

6000

NCD CC ESLD NCD CC ESLD NCD CC ESLD

Treated

Untreated

1370

2389

1007

543591

3634

885

4656

3186

119312241023

729

5137

3547

1802

1369

P<0.001 P<0.001P<0.057P<0.001P<0.001P<0.826

Pre

dict

ed

cost

(20

10$U

SP

PP

M)

HCV-related costs Medical costs Total costs

225

P<0.001 P<0.001P<0.001

Mean follow-up per patient per month (PPPM) by treatment history and liver disease severity

35% lower

24% lower

31% lower

HCV Therapy Is Associated with Lower Healthcare Costs in Non-Cirrhotic and ESLD Patients

PPPM=per-patient-per-month; NCD=non-cirrhotic disease; CC=compensated cirrhosis; ESLD=end-stage liver diseaseCovariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities, and baseline treatment for HCVGordon S.C., et al. Aliment Pharmacol Ther. 2013; 38:784-793.

REALIZE: SVR by Baseline Fibrosis Stage and Prior Response

Prior relapsers

Prior partial responders

Prior null responders

No, minimal or portal fibrosis

CirrhosisStage

Pooled T12/PR48

Pbo/PR48

Pat

ien

ts w

ith

SV

R (

%)

Bridgingfibrosis


CirrhosisBridgingfibrosis


CirrhosisBridgingfibrosis

2/15

n/N= 53/62

145/167

12/38

0/5

10/18

36/47

3/17

0/9

16/38

11/32

1/5

1/15

48/57

24/59

1/18

7/50

1/10

Presented at AASLD – November 6th, 2011

Telaprevir

Category, n (%)Cirrhotics (F4)

N=139Non-cirrhotics (F0–3)

N=391

Patients without SVR 73 (53) 107 (27)

On-treatment virologic failure*Prior relapsersPrior partial and null responders

44 (32)1 (1)

43 (31)

52 (13)2 (1)

50 (13)

Relapse‡

Prior relapsersPrior partial and null responders

17 (12)3 (2)

14 (10)

20 (5)5 (1)15 (4)

Other§

Prior relapsersPrior partial and null responders

12 (9)5 (4)7 (5)

35 (9)24 (6)11 (3)

REALIZE: Reasons for not Achieving an SVR in TVR-treated Patients

*Includes patients with viral breakthrough and/or patients who discontinued due to a virologic stopping rule‡Relapse rate calculated relative to total number of patients

§Includes patients with detectable HCV RNA at the end of treatment (for reasons other than virologic stopping rules) without viral breakthrough, or who had undetectable HCV RNA at the end of treatment but were subsequently lost to follow up before Week 72

Presented at AASLD – November 6th, 2011

REALIZE: AEs in ≥25% of TVR-treated Patients during Any Treatment Phase*

AE, n (%)Cirrhotics (F4)

N=139Non-cirrhotics (F0–3)

N=391

Rash SSC 93 (67) 206 (53)

Pruritus SSC 82 (59) 205 (52)

Fatigue 62 (45) 214 (55)

Headache 54 (39) 167 (43)

Anemia SSC† 59 (42) 134 (34)

Nausea 52 (37) 129 (33)

Influenza-like illness 55 (40) 124 (32)

Insomnia 39 (28) 113 (29)

Anorectal symptoms‡ 33 (24) 101 (26)

Diarrhea 33 (24) 102 (26)

Pyrexia 34 (25) 97 (25)

*Grouped special search category (SSC); †Anemia reported by the investigator as an adverse event; ‡ Grouped term including several different AEs in the anorectal area; AE = adverse event

CUPIC: French EAP: Baseline Demographics and 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)

Hb 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)


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%

CUPIC: SVR12 According to Prior Treatment Response


61/116 43/135 8/28

Relapsers Partial responders

Null responders

53%

32% 29%

P=0.004

P=0.001

P=0.03

TELAPREVIRTELAPREVIR

0

10

20

30

40

50

60

70

80

90

100

0

10

20

30

40

50

60

70

80

90

100

3119043/85 32/80 1/9

P=0.003

51%

40%

11%

BOCEPREVIR

Relapsers Partial responders

Null responders


CUPIC: Virological Failure

Non response

0102030405060708090

100

Vir

olo

gic

al

fail

ure

(

Per

cen

tag

e)

33/177 25/177*47/177

Premature discontinuationRelapse Breakthrough

19% 14%27%

72/177

41%

TELAPREVIR

01020304050607080

90100

Vir

olo

gic

al

fail

ure

(

Per

cen

tag

e)

40/111 12**/11130/111

Premature discontinuationRelapse Breakthrough

36%

11%

27%

29/111

26%

Non response

BOCEPREVIR*22 without failure

**10 without failure

CUPIC: SVR 12 According to HCV 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

31190 6/16

P=0.03

31%

51%

37%

49/9624/77

BOCEPREVIR

SV

R 1

2 (I

TT

) (

Pe

rcen

tag

e)

CUPIC: SVR12 According to Initial Viremia


< 800000 IU/mL ≥ 800000 IU/mL

48/108 68/182

45%37%

TELAPREVIR

0

10

20

30

40

50

60

70

80

90

100

SV

R 1

2 (I

TT

) (

Pe

rcen

tag

e)

< 800000 IU/mL ≥ 800000 IU/mL0

10

20

30

40

50

60

70

80

90

100

51/122

41% 42%

BOCEPREVIR

27/65

SV

R 1

2 (I

TT

) (

Pe

rcen

tag

e)

CUPIC: SVR12 Safety Findings

Patients, 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%)


SAEs in patientsSCAR: severe cutaneous adverse reaction

CUPIC:Predictors of Severe Anemia <8 g/dl

Predictors OR 95%CI p-value

Gender: Female 2.19 1.11-4.33 0.023

No lead-in phase 2.25 1.15-4.39 0.018

Age ≥65 years 3.04 1.54-6.02 0.0014

Hemoglobin level≤12 g/dL for female

≤13 g/dL for male

5.30 2.49-11.25 <0.0001

Multivariate analysis: baseline factors related to anaemia <8g/dl or blood transfusion

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

FactorsPlatelets count

>100,000/mm3

Platelets count

≤100,000/mm3

Albumin 35 g/L3.4 %

(10/298)

4.3 %

(3/69)

Albumin <35 g/L7.1 %

(2/28)

44.1 %

(15/34)

8%

CUPIC: Risk of Occurrence of Death or Severe Complications

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

French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1)

Prospective cohort, HCV genotype 1, compensated cirrhosis– Relapse or prior partial responders to PR– No HBV or HIV

SVR12– Telaprevir: 40% (range: 29%-53%)– Boceprevir: 41% (range: 11%-51%)– SVR12 predictors: partial responders, 1b

Discontinuations: 47% Serious adverse events: 40%

– Early treatment discontinuation: 21.3%– Death: 2.0%– Anemia (<9.0 g/dL): 29.4%– Hepatic decompensation: 2.4%

Fontaine H, et al. J Hepatol. 2013;58(suppl 1):S27. Abstract 60.Hezode C, et al. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.Hezode C, et al. J Hepatology. 2013;59:434-441.

AdjustedOdds Ratio

Platelet <100,000/mm3 3.1 (P=0.0105)

Serum albumin <35 g/dL 6.33 (P=0.0001)

Factors Associated WithDeath and Severe Complications (n=62)

Platelets (/mm3)

>100,000 <100,000

Albumin (g/dL) >35 (n=298/69) 3.4 4.3

<35 (n=28/34) 7.1 44.1

Risk of Death or Severe Complications (%)

Triple Therapy for HCV in Patients with Compensated Liver Cirrhosis: Real-World Experience

n=48 cirrhotic pts, 31% naïve, platelets 144 50% anemia <10 g/dl, 27<8.5 g/dl, dose reduction in 50% TVR 33 (69%), BOC 15 (31%)

Group APlatelets <110/nl

andChild-Pugh Score >5

n=7

Group BPlatelets <110/nl

orChild-Pugh Score >5

n=16

Group CPlatelets ≥110/nl

andChild-Pugh Score 5

n=20#

Treatment Failure 100% (n=7/7) 69% (n=11/16) 30% (n=6/14)

SAE 57% (n=4/7) 63% (n=10/16) 25% (n=5/20)

Either SAE or Treatment Failure 100% 94% 50%

Almost every patient (96%; n=22/23) with a Child-Pugh Score >5 and/or baseline platelets <110/nl (Group A/B) experienced either a treatment failure and or at least one SAE until EOT

Massoumy B, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 857.

Triple Therapy for HCV GT1 Difficult to Treat Patients: Real Word Experience

High rates of serious adverse events: 64% (BOC) and 53% (TVR)

Severe anemia (<9g/dl) occurred in 65%, blood tx 38% All pts >60 yrs and all cirrhotic patients received blood tx Discontinuation rate 33% (BOC) and 31% (TVR)

Baseline characteristics n = 143

Median age 55yrs30% > 60a

male 67%

Caucasian 90%

Genotype 1a / 1b 39% / 60%

Advanced fibrosis >F3 48%

F4 and platelets < 120/nl 23%

Tx naïve / pretreated 26% / 74%Non responder 50%Tx BOC / TVR 69 / 74

Patients at risk for development of SAE and treatment failure n = 83

Platelets <100.000 /ul and albumin <40g/l n=17

100% treatment failure and 100% SAE

Petersen J, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 891.

Patients, n (% patients with at least one event) Telaprevir n = 295

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

Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%)

Death 7 (2.4 %)

Infection (Grade 3/4) (3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection)

27 (9.1 %)

Hepatic decompensation (Grade 3/4) 15 (5.1 %)

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

Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9 %)

EPO use / blood transfusion 168 (57 %) / 53 (18 %)

GCSF use 8 (2.7 %)

TPO use 6 (2 %)* SAEs in patients; SCAR: severe cutaneous adverse reaction

Telaprevir : SVR12 safety findings

Patients, n (% patients with at least one event) Boceprevir n = 190

Serious adverse events (SAEs)* 321 in 97 patients (51.0%)

Premature discontinuation / due to SAEs 80 (42.1%) / 27 (14.2%)

Death (1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia) 3 (1.6 %)

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

Hepatic decompensation (Grade 3/4) 9 (4.7 %)

Rash (grade 3/SCAR) 2 (1.0 %)

Anemia (Grade 3/4: Hb < 8 g/dL) 19 (10.0 %)

EPO use / blood transfusion 119 (62.6 %) / 26 (13.7 %)

GCSF use 13 (6.8 %)

TPO use 3 (1.6 %)

* SAEs in patients; SCAR: severe cutaneous adverse reaction

Boceprevir : SVR12 safety findings

Evaluation of the true direct cost of treatment with PI+PR in unselected sequential population of patients (n=200) treated at a tertiary care center (BIDMC, Boston) for HCV

GT1

Real World Cost per SVR of HCV Triple Therapy with PIs

The mean cost per SVR was $172,889SVR rate of 49%

Yesn=82

No n=118

TNn=57

Rn=61

P/NRn=82

Yesn=109

No n=91

Yesn=33

Non=167

Yesn=39

No n=161

Prior Response Cirrhosis Anemia Thrombocytopenia Hospitalization

Sethi N, et al. AASLD 2013. Washington, DC. #1847TN: Treatment-naïve; R: Relapsers; P/NR: Partial or null responders

‡

PR + telaprevir or boceprevir or simeprevir Monotherapy with pegIFN, RBV, or a DAA Do not treat decompensated cirrhosis with pegIFN or simeprevir

AASLD and IDSA HCV Regimens: Failed Previous PR + Telaprevir or Boceprevir

Sofosbuvir 12 weeks + PR 24 weeks

PR: pegIFN + RBV.

AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.

Genotype 1a

Sofosbuvir 12 weeks + PR 12-48 weeksGenotype 1b

Preferred Regimens

Sofosbuvir + RBV 24 weeksGenotype 1a

Sofosbuvir + RBV 24 weeksGenotype 1b

Alternative Regimens

Genotypes 1a or 1b

Regimens Not Recommended

HCV Treatment Considerationsfor Transplant Candidates

Achieving sustained virologic response– Possible in some well-selected patients with HCV and decompensated

cirrhosis Post-transplantation recurrence of HCV may be prevented if SVR is

achieved pretransplant Potential benefits of HCV therapy need to be balanced against the

risk of sepsis, hepatic failure, and death Child’s C cirrhotics

– Risks usually outweigh benefits Transplantation evaluation

– Complete before initiating HCV treatment begins (in case patient should decompensate)

Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Antiviral Therapy Before Liver Transplantation for HCV-Infected Recipients With Advanced Fibrosis and Cirrhosis

Lower SVR rates in cirrhotics– Child-Pugh class A versus C: 40% to 50% versus 7% to 26%

Suboptimal SVR rates by genotype 1/4 versus 2/3 – Advanced fibrosis: 51% versus 61%– Cirrhosis: 33% versus 57%

Marked step-wise reduction in SVR by fibrosis stage in genotype 1– No fibrosis verus cirrhosis: 70% verus 10% (P<0.0001)

RVR is the strongest on-treatment predictor of SVR, regardless of genotype

Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Fried MW, et al. N Engl J Med. 2002;347:975-982.Manns MP, et al. Lancet. 2001;358:958-965.Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.Bruno S, et al. Hepatology. 2010;51:388-397.

Antiviral Therapy Before Liver Transplantation for HCV-Infected Recipients With Advanced Fibrosis and Cirrhosis

Challenges– Poor tolerance– Increased adverse events

• Risk of hepatic decompensation– Suboptimal SVR rates

HCV treatment in this patient population requires significant oversight and input in an experienced practice

Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Fried MW, et al. N Engl J Med. 2002;347:975-982.Manns MP, et al. Lancet. 2001;358:958-965.Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.Bruno S, et al. Hepatology. 2010;51:388-397.

Pre-Transplant Antiviral Treatment Strategies for HCV-Infected Liver Transplant Recipients

Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Pract Res Clin Gastroenterol. 2012;26:531-548; Roche B, et al. Liver Int. 2011;32(suppl 1):120-128.

Standard Duration

Antiviral Treatment(24 to 48 weeks) Post-Transplant Follow-Up

Transplantation

Follow-Up

HCV Goal:SVR

Candidates: Compensated cirrhosis Mild decompensated cirrhosis (MELD <18)

Projected HCV outcome: Prevents HCV recurrence in 100% if SVR achieved pre-transplant

Short Duration

Antiviral Treatment(12 to 16 weeks)

Post-Transplant Follow-Up

Transplantation

HCV Goal:Undetectable

HCV RNAOn-Treatment

Candidates: Compensated cirrhosis Mild decompensated cirrhosis (MELD <18)

Projected HCV outcome: Prevents HCV recurrence in 30% if HCV RNA negative at time of transplantation; 50% if HCV RNA negative >16 weeks pre-transplant

HCV Treatment Before Liver Transplantationin Patients With Decompensated Cirrhosis

G1 (%)

Child-Pugh(%) Treatment

EOTRG1/non-G1 (%)

SVRG1/non-G1 (%)

HCV RNA Negative Post Transplant (%)

Crippin 2002(pilot study; n=15)

73 11.9 IFN + RBV 33(overall)

NA 0

Thomas 2003(single cohort; n=20)

67 10.0 IFN 60(overall)

NA 20

Everson 2005(single cohort; n=124)

70 7.4 IFN + RBV(LADR)

30/82 13/50 26

Forns 2003(single cohort; n=30)

70 A (50%);B (43%); C (7%)

IFN + RBV 30(overall)

NA 20

Carrion 2009(case controlled; n=51)

80 A (45%); B (43%); C (4%)

PR 20/100 NA 20

Everson 2013(randomized, controlled; n=79)

56 7.0 PR(LADR)

41/53 NA 25

Crippin JS, et al. Liver Transpl. 2002;8:350-355; Thomas RM, et al. Liver Transpl. 2003;9:905-915;Everson GT, et al. Hepatology. 2005;42:255-262; Forns X, et al. J Hepatol. 2003;39:389-396;Carrion JA, et al. J Hepatol. 2009;50:719-728; Everson GT, et al. Hepatology. 2013;57:1752-1762.

G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen.

Adult-to-Adult Living DonorLiver Transplant Cohort Study (A2ALL)

First, randomized, controlled trial of pre-transplant PR (LADR) to prevent recurrent HCV post-transplant– HCC, MELD waiting list upgrade, stable

clinical status, MELD <20– >12 weeks to transplantation

Exclusion criteria– Prior null responders– Creatinine (>2.2 mg/dL); Hb (<10 g/dL); ANC

(<750/µL); platelets (<35K/µL) Randomized to either pegIFN + RBV

(LADR) or control (untreated) Primary endpoint

– Post-transplant HCV RNA undetectable at week 12

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

PR: pegIFN + RBV; LADR: low accelerating dose regimen.

Treatment(n=63)

Control(n=16)

Male (%) 73 81

Age (years) 56 56

Genotype (%) 1/4 or 6 2/3

47/424/25

88/120/0

HCV RNA (log10 IU/mL) 5.7 5.7

HCC upgrade (%) 54 94

MELD 12.0 12.0

CPT score 7.0 6.3

Hemoglobin (g/dL) 13.1 13.5

ANC (/µL) 794 531

Platelets (x103/µL) 92 93

Previous IFN treatment (%)

92 93

Baseline Characteristics

A2ALL Study:Virologic Response With PR

Trea

ted

Pat

ien

ts (

%)

Overall(n=44)

59%

25% 22%

2, 3(n=21)

Virologic Responseby Genotype

52%

HCV RNA Undetectable

At liver transplantation

Week 12 post-transplant


29%

67%

1, 4, 6(n=23)

HCV Genotype

Per protocol analysis. PR: pegIFN + RBV.

Trea

ted

Pat

ien

ts (

%)

<8(n=8)

25%

0%

18%

>16(n=14)

Virologic Responseby Treatment Duration

68%


At liver transplantation

Week 12 post-transplant

50%

64%

8 to 16(n=22)

PegIFN + RBV Duration (Weeks)

A2ALL Study:Predictors of Response and Safety

Predictors of undetectable HCV RNA 12 weeks post-transplant– Increased duration of treatment (P<0.01)– Nonsignificant trend

• Genotype 2 or 3, lower baseline HCV RNA, growth factors during treatment, achieved target doses of antiviral therapy

Serious adverse events– Similar incidence between treated and controls (68% versus 55%)– Higher number per patient in treated versus controls (2.7 versus 1.3; P=0.003)– No association with MELD score

Death– Pretransplant HCV treatment not associated with increased risk of death versus

controls (15% versus 10%)– Transplant recipients versus no transplant (7.0% versus 31.8%)


AASLD and IDSA Recommendations:HCV-Related Cirrhosis

Patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C)– Should be referred to a medical practitioner with expertise in that

condition (ideally in a liver transplant center)

AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.

Preferred Regimen Sofosbuvir + RBV for up to 48 weeks

(consider creatinine clearance and hemoglobin)Any Genotype

Any IFN-based therapy Monotherapy with pegIFN, RBV, or a DAA Telaprevir-, boceprevir-, or simeprevir-based regimens

Any Genotype

Regimens Not Recommended

Mangia A, et al. AASLD 2013. Washington, DC. #1115.

No Cirrhosis vs Cirrhosis: SVR12 Rates

No cirrhosis Cirrhosis

9892 96 100

91 94

60

78

FISSION POSITRON FUSION 12 FUSION 16

58/59 85/92 25/26 23/23

10/11 16/17 6/10 7/9

6168

37

63

34

21 19

61

FISSION POSITRON FUSION 12 FUSION 16

13/38 3/14 5/26 14/23

89/145 57/84 14/38 25/40252/273

43/54

GT 2 GT 3GT 1, 4, 5, 6

92

80

NEUTRINO0

20

40

60

80

100

SV

R12

(%

)Virologic Response: CirrhosisSOF Phase 3 Analysis in Patients with TraditionalNegative Factors

40/40 40/40 29/40 28/40 28/40

Virologic Response

Post-Liver Transplant Study (SOF+RBV)

Samuel D, EASL, 2014, P1232

LLOQ, lower limit of quantification (25 IU/mL)

Twenty-four weeks of SOF+RBV resulted in high SVR rates in this difficult-to-treat post-transplant population, including many cirrhotics and treatment-experienced patients

Relapse was not influenced by RBV dose or exposure SOF + RBV in patients with recurrent HCV after liver transplantation was safe and well

tolerated No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC

dosing due to improved liver function

Pre-Liver Transplant Sofosbuvir + RBV:Prevention of Recurrent HCV

Open-label, phase 2 study conducted at 16 sites (n=61)– Deceased donor liver transplantation

candidates with HCV– HCC meeting MILAN criteria– MELD exception for HCC– CPT <7– Exclusion: decompensated cirrhosis, prior

solid organ transplantation, HBV or HIV coinfection, renal impairment

Up to 48 weeks of sofosbuvir 400 mg + RBV (1000-1200 mg) pre-transplant

Post-transplant, immunosuppressive regimen: tacrolimus + prednisone + mycophenolate mofetil.

Primary endpoint: SVR12 post-liver transplant

Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.

Baseline CharacteristicsTreatment

(n=61)

Male (%) 80

Age (years) 59

BMI <30 kg/m2 (%) 43

Genotype (%) 1a/1b 2/3 4

39/3413/12

4

HCV RNA >6 log10 IU/mL (%) 41

IL28 B non-CC (%) 78

MELD 8

CPT score 5-7 (%) 95%

Prior HCV treatment (%) 75

Pre-Liver Transplant Sofosbuvir + RBV:Virologic Response in HCV Genotypes 1-4

HCV recurrence prevented in 64% of patients HCV RNA <LLOQ at time of transplantation

On treatment HCV RNA suppression was rapid (1 week)

Factors associated with HCV recurrence (multivariate exact odds ratio)– Days continuously TND prior to

transplantation: 1.04 (1.01, 1.08; P=0.0007)

TND: target not detected.


Pat

ien

ts (

%)

Overall(n=44)

93%

Post-TransplantWeek 12

(n=39)


91%

64%

>12 WeeksTreatment

(n=33)

At Transplant

Pre-Liver Transplant Sofosbuvir + RBV:Target Not Detected and Safety in Genotypes 1-4

Median days TND– No HCV recurrence (n=28): 95 – HCV recurrence (n=10): 5.5

(P<0.001) Sofosbuvir + RBV was generally

well tolerated– Discontinuations due to adverse

events: 3% (none related to sofosbuvir)

– Selected adverse events• Fatigue: 38%• Anemia: 23%• Headache: 23%• Nausea: 16%• Rash: 15%


TND: target not detected.

Ind

ivid

ual

Pat

ien

t D

ata

Days Continuously TND Before Liver Transplant and Preventing HCV Recurrence

HCV RNA Continuously TND (Days)

>30 days TND

HCV recurrence (n=10)

No HCV recurrence (n=28)

Cost Per Cure of Sofosbuvir vs PIs: Treatment-Naïve With and Without Cirrhosis Genotype 1

-$10,708 (-10%)

-$18,039 (-16%)

-$17,153 (-13%)

-$31,472 (-24%)

Tota

l C

ost

per

Su

cce

ssfu

lly

Trea

ted

Pat

ien

t

BOC + PR TVR + PR SOF + PR BOC + PR TVR + PR SOF + PR

‡

AMCP Dossier Data on file, Gilead Sciences December 2013

Cost Per SVR of Sofosbuvir vs Simeprevir: Treatment Naïve With and Without Cirrhosis Genotype 1

Tota

l C

ost

per

Su

cce

ssfu

lly

Trea

ted

Pat

ien

t

-$6,730 (-6%)

Without Cirrhosis (F0-F3) With Cirrhosis (F4)

-$33,573 (-20%)

‡

Gordon SC, et al. Hepatology. 2012;56(5):1651-60.Lawitz E, et al. N Engl J Med. 2013 May;368(20):1878-87.Lenz O, et al. AASLD 2011. San Francisco, CA, USA. Poster #1329Jacobson I, et al. EASL 2013. Amsterdam, the Netherlands. Poster #1525

Manns M, et al. EASL 2013. Amsterdam, the Netherlands. Poster #1525McAdam-Marx C, et al. J Manag Care Pharm. 2011;17(7):531-46.Zein NN, et al. Clin Microbiol Rev. 2000 Apr;13(2):223-35.

Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic Fibrosis

Meta-analysis (n=1000)– 10 cohorts, individual patient data– SVR with IFN-based therapy– Bridging fibrosis or cirrhosis– No HIV or HBV coinfection

51 events of HCC over 5.1 years of follow-up

Patients with HCV-induced cirrhosis who achieve SVR remain at risk for HCC

Risk increased with age, severity of liver disease, and presence of diabetes mellitus

van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143.

Rat

e (%

)

Cumulative HCC by Age Group

0 1 2 3 4 5 6 7 8 Years After SVR

P=0.006

12.2%

2.6%

9.7%

Age Group <45 years 45 to 60 years >60 years

Conclusion

Patients with HCV cirrhosis globally remain an enigma as to timing of treatment– Cirrhosis: when present, are those patients most in

need of treatment today– Treat with INF based therapy down to albumin of 3.5

and platelets of 100,000

With the advent of new therapies, all oral regimens– Cirrhosis treatment will evolve to be simple and

expedient – Prices will need to be aligned with GDP and health

care allocations per country

HCV Treatment of Patients With Cirrhosis 2014 Singapore

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