HCV treatment challenges: Cirrhotic patients/CUPIC study

2nd Latin American Meeting on Treatment of Viral Hepatitis

Sao Paulo – 25th May 2013

Stefan ZeuzemUniversity Hospital,Frankfurt, Germany

0 1 2 3 4 5 6 7 8 9 100

10

20

30

p<0.001

SVR

non-SVR

Time - in years

LR-M

orta

lity

(%)

SVR and Mortality Among Patients With Chronic Hepatitis C and Advanced Fibrosis

A.J. van der Meer; JAMA 2012;308:2584-2593

Lens S, et al. EASL 2013, Amsterdam, #210

SVR decreases portal pressure gradient and prevents clinical decompensation in patients with HCV-cirrhosis

HVPG significantly reduced after SVR (11.3 ± 4.2 to 9.8 ± 4.6 mmHg; p=0.014) Not reduced if no SVR (12.7 ± 4.6 to 12.4 ± 5.7 mmHg; p=0.46)

Decompensation-free survival at 5 years higher among SVR (90%) than in non-SVR patients (70%, p<0.03)

Transplant-free survival higher in SVR group 95% vs 80% non-SVR, p=0.07

By multivariate analysis, final HVPG only predictor of decompensation (p=0.001) and of transplant-free survival (p=0.006)

Clinical decompensation according to SVR and final HVPG (mmHg)

50

60

70

80

90

100

Sur

viva

l (%

)

Months after end of treatment0 12 24 36 48 60 72 84 96

p=0.0052

SVR and HVPG ≥10No SVR and HVPG <10SVR and HVPG ≥10No SVR and HVPG ≥10

van der Meer AJP, et al. EASL 2013, Amsterdam, #504

Improvement of IFN-based therapy substantially reduced

NNT to prevent HCC among G1-infected cirrhotics

NNT to prevent HCC or death in 1 patient with chronic HCV G1 infection and cirrhosis

0

50

100

150

200N

NT

to p

reve

nt H

CC

or d

eath

in 1

pat

ient

5 10 15 20 25 30 35 40 45 50

SVR rate (%)

NNT95% CI

in 5 years

NNT=23(95% CI: 21–33)

in 10 years

NNT=33 (95% CI: 30–47)

NNT=10 (95% CI: 8–14)

NNT=7(95% CI: 6–10)

26% diagnosed >10 y after IFN (median 7.4 y) 54.9% moderate fibrosis (F3/4) 80% received curative treatment 5-y survival rate 83% Poor with inadequate follow-up

Development of HCC in chronic HCV patients who achieve SVR to IFN therapy

Yamashita N, et al. EASL 2013, Amsterdam, #510

Determinants of hepatocarcinogenesis Hazard ratio

Advanced fibrosis stage(F0–1 vs F2–4) 10.7 (p<0.001)

Advanced age(<50 vs ≥50 y) 4.1 (p<0.01)

Habitual drinking 3.9 (p<0.01)AFP (<8 vs ≥8 ng/mL) 2.6 (p<0.05)

Age at initiation of IFN inversely correlated with interval time from treatment until HCC

41.9% F2 fibrosis Median f/u 4.8 y (1–20.5) Majority of individuals were screened

N=562SVR

N=31 (5.5%) HCC

94.5%No HCC

Overall cumulative rate of HCC in 562 SVR patients

0

10

20

30

40

Cum

ulat

ive

inci

denc

e of

HC

C (%

)

5 10 15 20Follow-up (y)

0

266 100 58 5562No. at riskRelationship between age at start of IFN therapy

and interval from completion of therapy until development of HCC

35

45

6065

75

Age

at t

he s

tart

of

IFN

ther

apy

(yea

rs)

5 10 15 20Interval of time to carcinogenesis

from end of IFN therapy (y)

0

5550

40

70 r = –0.4294p<0.05

Boceprevir in Genotype 1 Patients 800 mg (four 200-mg capsules) q8hr with meal or light snack

All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks EMA label recommends fixed-duration therapy for all tx-expd patients: LI + 32 wks triple + 12 wks PR

BOC + PR

PRPR

BOC + PR

Boceprevir [package insert]. May 2011. EMA. Boceprevir [package insert] 2011.

Treatment Naive

Previous Relapsers or Partial RespondersBOC + PR

Wks480 28124

PRPR

8 36

BOC + PR

24

Time Point Criterion Stopping RuleWk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapyWk 24 Detectable HCV RNA Discontinue all therapyAny Discontinuation of PR for any reason Discontinue BOC

Early response; stop at Wk 28

Early response; stop at Wk 36

• 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is >20 g, eg, 1/2-cup nuts or 2-oz cheddar cheese)

• Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additional 36 wks of pegIFN + RBV (ie, to Wk 48)

No eRVR; PR

Telaprevir in Genotype 1 Patients

TVR + PReRVR; stop at Wk 24

PR

Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.

Time Point Criterion Stopping RuleWk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapyWk 24 Detectable HCV RNA Discontinue PRAny Discontinuation of PR for any reason Discontinue TVR

Treatment Naive and Previous Relapsers

Previous Partial or Null Responders

TVR + PR

480 24124

PR

wks

SVR ADVANCE (TVR) SPRINT-2 (BOC)PR + TVR PR PR + BOC PR

Lead-in < 1 log - - 28-38% 4%Lead-in ≥ 1 log - - 79-81% 51%eRVR1 achieved 83-89% 97% 96% 93%eRVR1 not achieved 50-54% 39% 72-75% 66%Caucasian, non-black 70-75% 46% 67-68% 40%African Amer., black 58-62% 25% 42-53% 23%Stage F0-2 73-78% 47% 67% 38%Stage F3-4 53-62% 33% 41-52% 38%IL28B CC 84-90% 64% 80-82% 78%IL28B CT/TT 57-73% 23-25% 55-71% 27-28%

SVR rates in treatment naive patients(no head-to-head data)

1 Different definitions of eEVR in ADVANCE and SPRINT-2Jacobson et al., AASLD 2010; EASL 2011Reddy et al., APASL 2011Poordad et al., NEJM 2011; EASL 2011

BOCEPREVIR inTX-experienced Patients

RESPOND-2: Phase 3 Trial in Tx-Experienced* HCV-1 Infected Patients

Bacon et al., NEJM 2011

Viro

logi

c re

spon

se ra

tes

(%)

Peginterferon alfa-2b 1.5 µg/kg qwRibavirin 600-1400 mg/dayLead-in phaseBoceprevir 800 mg q8h

* Only previous partial respondersand relapsers enrolled (N=403)

11

RESPOND-2: SVR in Patients With or Without F4 Cirrhosis

0

24

35

64

77

66

0

20

40

60

80

100

Cirrhosis No Cirrhosis

% o

f Pat

ient

s

PR48 BOC RGT BOC/PR48

N=10 N=17 N=22 N=66 N=132 N=128

12

RESPOND-2: SVR by Fibrosis Score and Historical Response

N=61

23/42

F0/1/2 F3/4

15/1811/222/106/133/100/558/7759/7912/3818/382/23

9 0

20

13

RESPOND-2: SVR in Early (Week 8 HCV RNA -) and Late (Week 8 HCV-RNA +)

Responders by Fibrosis Score

88

52

86

49

0

20

40

60

80

100

Early Responder

Late Responder

% o

f Pat

ient

s

F0/1/2 F3/4BOC RGT BOC/PR48

52/59 51/59 24/46 28/57 8/10 18/20 5/19 2/8

Safety and efficacy of BOC/PegIFN/RBV therapy for chronic G1 patients with compensated cirrhosis

Vierling JM, et al. EASL 2013, Amsterdam, #1430

Meta-analysis of 5 Phase 3 trials Patients were predominantly male

with G1a HCV infection andbaseline viral load >800,000 IU/mL Cirrhotic patients were slightly older

and had lower baseline plateletcounts compared with patients withF0–3 METAVIR fibrosis scores

Efficacy was high in cirrhotic patients achieving undetectable HCV RNA at TW8

Viral response at TW8 can be key in deciding to continue or discontinue treatment

Treatment% SVR, number of patientsF4 F3 F0–F2

BOC/P/R 55%n=180

54%n=107

66%n=1638

P/R 17%n=32

26%n=22

28%n=436

86% 85% 89%

54%

34% 35%

6% 0% 0%0

20

40

60

80

100

F0–2 F3 F4

Undetectable≥3 log HCV RNA decline and detectable<3 log HCV RNA decline and detectable

METAVIR fibrosis score

SV

R (%

)

SVR according to Week 8 virologicresponse in patients receiving BOC/P/R

Increased SVR rates with triple therapy

15

Adverse Experience (AE) Summary in Combined SPRINT-2 and RESPOND-2

BOC/PR Groups by Fibrosis ScoreMedian Treatment Duration 201 days

SPRINT-2 and RESPOND-2 BOC/PRF0/1/2N=868n (%)

F3/4N=139n (%)

Treatment-emergent AE 862 (99) 138 (99)Serious AE 99 (11) 21 (15)Discontinuation due to AE 116 (13) 17 (12)a

Dose modification due to AEb 301 (35) 57 (41)Death 3c (<1) 0

a 11/79 (14%) discontinuations due to AE in F4 group; 6/60 (10%) in F3.b Any study drugc All deaths were in F0/1/2 group and were suicides.

TELAPREVIR inTX-experienced Patients

REALIZE: SVR by Baseline Fibrosis Stage and Prior Response

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

No, minimal or portal fibrosis

CirrhosisBridgingfibrosis

No, minimal or portal fibrosis

CirrhosisBridgingfibrosis

REALIZE: AEs leading to study drug discontinuation (FAS, pooled TVR arms, n=530)

Cirrhotics (F4) n=139

Non-cirrhotics(F0–3) n=391

Totaln=530

Discontinuation of all study drugs during TVR treatment phase, n (%)

Any AERashAnemiaPruritusAnorectal signs and symptoms*

10 (7)1 (<1)

01 (<1)

0

17 (4)1 (<1)3 (<1)

02 (<1)

27 (5)2 (<1)3 (<1)1 (<1)2 (<1)

Discontinuation of TVR or Pbo during TVR treatment phase, n (%)

Any AERashAnemiaPruritusAnorectal signs and symptoms*

21 (15)4 (3)3 (2)2 (1)

1 (<1)

46 (12)6 (2)9 (2)

2 (<1)2 (<1)

67 (13)10 (2)12 (2)4 (<1)3 (<1)

*Grouped term including several different AEs in the anorectal area; Pbo: placebo; FAS: full analysis set Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

REALIZE (TVR): laboratory abnormalities

Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

n (%) Cirrhotics (F4) N=139

Non-cirrhotics (F0–3) N=391

Hemoglobin≤10g/dL≤8.5g/dL

63 (46)

19 (14)

156 (40)

49 (13)

NeutrophilsGrade 3 (500 to <750/mm3)Grade 4 (<500/mm3)Grade 3/4

35 (25)

10 (7)

45 (32)

68 (17)

9 (2)

77 (19)

PlateletsGrade 3 (25,000 to <50,000/mm3)Grade 4 (<25,000/mm3)Grade 3/4

16 (12)

2 (1)

18 (13)

12 (3)

1 (<1)

13 (3)

Safety and efficacy of twice daily versus every 8 hour TVR with PR in patients with cirrhosis

Horsmans Y, et al. EASL 2013, Amsterdam, #826

BID and TID dose comparable in efficacy Cirrhotic with RVR offered RGT but high rate relapse in 24-week arm Higher anemia signal in cirrhotics treated with BID, but marginally significant after adjusting

for baseline factors

80 79 80

59 57 60

77 77 78

51 4954

0

20

40

60

80

100

Allpts

TVRq8h

TVRbid

Allpts

TVRq8h

TVRbid

Allpts

TVRq8h

TVRbid

Allpts

TVRq8h

TVRbid

F0–F2 F3/F4 No cirrhosis

Cirrhosis

n/N=421/529

208/262

213/257

123/210

62/108

61/102

491/636

248/321

245/315

53/103

24/49

29/54

n/N= 399/450

197/222

202/228

36/57

17/29

19/28

92/186

49/99

43/87

17/46

7/20

10/26

Nocirrhosis Cirrhosis

Nocirrhosis Cirrhosis

24 weeks 48 weeksPlanned overall duration

Pat

ient

s w

ith S

VR

12 (%

)

Pat

ient

s w

ith S

VR

12 (%

)

BID BID BID BID

Liver cirrhosis

• Continuous spectrum of disease– Liver function– Portal hypertension– Hypersplenism– Aszites– Hepatic encephalopathy

• Not optimal represented by Child-Pughstage (A, B, C) or MELD score

Inclusion criteria in phase III trials

• ADVANCE: platelets > 90,000 / ul• Illuminate: platelets > 90,000 / ul• REALIZE: platelets > 90,000 / ul• SPRINT-1: platelets > 100,000 / ul,

bilirubine and albumin within normal limits

• RESPOND-2: platelets > 100,000 / ul

Treatment in Patients with cirrhosis and portal hypertension

kPa

< F 1,2,3 > Cirrhosis (F4)

< 10 mmHg > 10 mmHg

significant and symptomaticportal hypertension

Portosystemic gradient

80 ‐

70 ‐

60 ‐

50 ‐

40 ‐

30 ‐

20 ‐

10 ‐

0 ‐

Cirrhosis spectrum

Number of prevalentpatients

Efficacy of tripletherapy

Side effects

CPT score A B C

22%

59%

83%

0

25

50

75

100

<10 10 - 13 >13Dec

ompe

nsat

ion

(%)

MELD score (BL)

Retrospective cohort study 68 HCV-infected patients with liver

cirrhosis treated with PR Hepatic decompensation observed in

36.8% of patients Patients with hepatic decompensation

had higher MELD scores and higher mean bilirubin levels BL MELD score can indicate the

probability of hepatic decompensation during antiviral therapy In patients with a baseline MELD

score above 13, decompensation and deterioration of liver function has to be anticipated

Dultz G, et al. EASL 2012, Barcelona, #1105

1 12

11

1617

56

1 1 10 0

1

5

1

7

10 0

10

0

5

10

15

20

-5 -3 -2 -1 0 +1 +2 +3 +4 +5 +20

No. of casesSVR

Change in MELD score

Hepatic decompensation

Pat

ient

s

Number of cases/SVR

–

BL characteristics predict hepatic decompensation during antiviral therapy in chronic HCV patients with advanced liver cirrhosis

ANRS CO20-CUPIC: Week 16 analysis of safety and efficacy – AASLD 2012 N=497/674 G1 Child A cirrhosis

reached W16 of therapy History of prior non-response

Multivariate analysis: Baseline predictors severe complications Plts ≤100,000/mm3

Albumin <3.5 g/L

Multivariate analysis: Baseline predictors anemia/transfusion Female gender No lead-in Age ≥65 y Low Hb

Hezode C, et al. AASLD 2012, Boston, #51

TVR n=292 BOC n=205SAEs 45% 32.7%Discontinuation (SAEs) 14.7% 7.3%Death 5 1Infection (G3/4) 6.5% 2.4%Hepatic decompensation 2% 2.9%Anemia G2: 8.0 – <10.0 g/dL 18.8% 23.4%G3/4: <8.0 g/dL 11.6% 4.4%EPO use 53.8% 46.3%Transfusion 16.1% 6.3%RBV dose reduction 13% 10.7%G4: <500/mm3 2 (0.7%) 3.4%Thrombopenia G3: 25000 – <50000/mm3 9.6% 4.9%Undetectable HCV RNA (PP/ITT) W4 58/55 3/2W8 92/80 42/38W12 93/79 64/55W16 92/67 77/58

High rates of anemia/SAEs Few RBV dose reductions High rates of viral response

Viro

logi

cfa

ilure

(%)

*22 without failure

ANRS CO20-CUPIC: SVR12 rates and safety of TVR or BOC in 485 cirrhotic non-responders

Fontaine H, et al. EASL 2013, Amsterdam, #60

Virologic efficacy

High rates of SAE including anemia, EPO use and transfusion G1b higher SVR Early viral kinetics remain strongly predictive

Efficacy by prior treatment Treatment failure53

32 29

0102030405060

Relapsers Partialresponders

Nullresponders

p=0.004

5140

11

0102030405060

Relapsers Partialresponders

Nullresponders

p=0.04

TVR BOC

*10 without failure

Pat

ient

s w

ith u

ndet

ecta

ble

HC

V R

NA

(%),

ITT

SV

R12

(%

), IT

T

ANRS CO20-CUPIC: SVR12 rates and safety of TVR or BOC in 485 cirrhotic non-responders

Fontaine H, et al. EASL 2013, Amsterdam, #60

Safety BOCn=190

TVRn=295

Overall SAE 51.0% 54.2%Discontinuation/due to SAEs

42.1/14.2%

47.1/21.3%

Death 1.6% 2.4%Infection (Grade 3/4) 4.2% 9.1%Hepaticdecompensation(Grade 3/4)

4.7% 5.1%

Rash (SCAR) 1.0% 0.6%Anemia (<8 g/dL) 10.0% 12.9%EPO /transfusion

62.6/13.7%

56.9/18%

RBV dose reduction* 10.7% 13%

*Hezode C, et al. AASLD 2012, Boston, #51

Characteristic BOC (n=190) TVR (n=295)Male, % 133 (70) 201 (68)Mean age, years (range)Mean BMI, SD (kg/m2)

57 (34–79)26 (18.1–39.4)

57 (27–83)27 (18.2–40.4)

HCV G1 subtype, n (%)1a1bOther

77 (41)96 (51)16 (8)

98 (33)162 (55)33 (11)

HCV RNA ≥800,000 IU/mL, n (%) 122 (64) 182 (62)Treatment history, n (%)

Prior relapsePrior partial responsePrior null responseOthers

85 (45)80 (42)9 (5)16 (8)

116 (39)135 (46)28 (10)15 (5)

Child–Pugh score A/B, n (%) 177 (93)/1 (1) 280 (95)/6 (2)MELD score, mean (range) 8.1 (6–28) 8.1 (6–22)Prothrombin time ratio, mean % (range)

87 (23–100) 86 (27–100)

Serum albumin g/L, mean (range) 40.7 (27.0–50.3) 40.0 (20.7–53.2)Total bilirubin µmol/L, mean (range) 15.2 (4.0–78.0) 15.5 (4.0–73.0)Hb level g/dL, mean (range) 14.8 (10.8–18.4) 14.5 (9.0–19.7)Neutrophils, mean (range) (109/mm3)

3.2 (0.5–8.5) 3.3 (0.8–8.5)

Platelet count, mean (range) (103/mm3)

144 (34–346) 151 (18–604)

Esophageal varices, n (%) 37/97 (38.1) 51/145 (35.2)

Key messages

• Don‘t be afraid of triple therapy, but be carefully prepared !!

• The more fibrosis/portal hypertension the more caution is required !!– Platelets < 100 x103/μL– Albumin < 3.5 g/dL

• Differentiate between stages of cirrhosis; data for pts with advanced cirrhosis are very limited

• Know about future treatment developments and advice your patients accordingly