Managing cirrhotic HCV patients. Whom to treat, how to treat.2014

Marc Bourlière, MDGraham R. Foster, FRCP, PhD

Managing Cirrhotic HCV Patients: Whom to Treat, How to Treat

This program is supported by an educational grant from

clinicaloptions.com/hepatitisManaging Cirrhotic HCV Patients: Whom to Treat, How to Treat

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Disclosures

Marc Bourlière, MD, has disclosed that he has received consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, GlaxoSmithKline, and Roche.

Graham R. Foster, FRCP, PhD, has disclosed that he has received funds for research support from Idenix and Spring Bank; consulting fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, and Roche; and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureaus) from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche

The following planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; Jan Schultz, RN, MSN, CCMEP; Patricia Staples, MSN, NP-C, CCRN; and Eric D. Peterson, EdM, FACEHP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Which Cirrhotic Patients Should be Treated?


Cirrhosis: A Continuous Spectrum of Disease

ESLD

Child-Pugh B

Portal hypertension – high risk

Cirrhosis – treatment candidate

Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD score


Severity of Disease Increases Need for HCV Therapy but Also Impairs Response

May not need immediate treatment

BUT • Easier to treat• High likelihood of response

Advanced disease/ cirrhosis

Mild disease

Greater need for treatment BUT

• Response to current IFN-based therapy may be impaired


Benefits and Challenges of Currently Approved HCV Therapies Currently approved HCV regimens are largely interferon-based

– Genotype 1

– PegIFN/RBV + boceprevir

– PegIFN/RBV + sofosbuvir

– Genotype 2 or 3

– PegIFN/RBV or sofosbuvir + RBV

– Genotype 4

– PegIFN/RBV ± sofosbuvir

Combination of DAA agent with pegIFN/RBV has dramatically increased rates of SVR

However, cirrhotic patients are at increased risk for hematologic side effects (eg, thrombocytopenia and anemia), other adverse effects of treatment, and worsening liver function

– PegIFN/RBV + telaprevir

– PegIFN/RBV + simeprevir


Efficacy of Triple Therapy in Tx-Exp Patients: Clinical Trials vs Real Life*

1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Fontaine H, et al. EASL 2013. Abstract 60. 4. Fontaine H, et al. AFEF 2013. Abstract 26. 5. Vierling JM, et al. DDW 2013. Abstract 869c.

RelapsersREALIZ

E[1

]

EAP[3

]

REALIZE[1

]

CUPIC[4

]

CUPIC[4

]

RESPOND 2[2

]

Null RespondersREALIZ

E[1

]

EAP[3

]

REALIZE[1

]

CUPIC[4

]

CUPIC[4

]

PROVIDE[5

]

SV

R (

%)

Telaprevir

F0-4 F4 F3/4 F4 F0-4 F4 F3/4 F4

*Cross-comparison of studies cannot be carried out

100

80

60

40

20

0

Boceprevir

83

69

84

54

7453

2941

28

29

19

0


CUPIC: High-Risk Patients Less Likely to Achieve SVR CUPIC enrolled treatment-experienced patients with compensated cirrhosis

and notable risk factors

– Patients achieved high SVR rates with TVR or BOC plus pegIFN/RBV

Patients with cirrhosis who present with significant risk factors require careful monitoring when treated with pegIFN/RBV

Factors Platelet Count ≤ 100,000/mm3

Platelet Count > 100,000/mm3

Albumin

< 35 g/L

N 37 31

Complications, n (%) 19 (51.4) 5 (16.1)

SVR12, n (%) 10 (27.0) 9 (29.0)

Albumin

≥ 35 g/L

N 74 305

Complications, n (%) 9 (12.2) 19 (6.2)

SVR12, n (%) 27 (36.5) 168 (54.9)

Fontaine H, et al. AFEF 2013. Abstract 26.


HCV Decompensated Cirrhosis: Treatment With PegIFN/RBV Most in need of treatment (5-yr survival rate: 50%)

SVR rates ranged:

– 7% to 16% in genotypes 1-4[1,2]

– 44% to 57% in genotypes 2/3 [1,2]

Treatment limitation

– Higher risk of infection and deaths related to infection[1]

– More frequent adverse effects in Child-Pugh C (MELD > 18)[3]

Treatment benefit

– Lower rate of decompensation during follow-up[1,4]

– Reduced mortality in responders[1,4]

1. Iacobellis A, et al. J Hepatol. 2007;46:206-212. 2. Iacobellis A, et al. Aliment Pharmacol Ther. 2009;27:1081-1085. 3. Forns X, et al. J Hepatol. 2003;39:389-396. 4. Fattovich G, et al. Gastroenterology. 1997;112:463-472.


100

NEUTRINO: Virologic Response by Cirrhosis Status With Sofosbuvir + P/R

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

Open-label, single-arm, phase III study

Sofosbuvir 400 mg QD + PegIFN/RBV for 12 wks

Treatment-naive patients with GT 1/4/5/6 HCV

– 17% cirrhosis; platelets ≥ 90,000/mm3

– 89% GT 1, 9% GT 4, < 1% GT 5, 2% GT 6

SV

R12

(%

)

92

80

252/273 43/54

80

60

40

20

0n/N =

GT 1/4/5/6

CirrhoticNoncirrhotic

clinicaloptions.com/hepatitisHCV Phase III Studies and Approved Agents

QUEST-2: SVR12 by Subtype and Fibrosis Level With Simeprevir + PegIFN/RBV RGT Randomized, double-blind, placebo-controlled phase III trial in GT 1 treatment-

naive patients

Treatment regimens:

– Placebo + pegIFN/RBV for 12 wks, followed by pegIFN/RBV for 36 wks

– Simeprevir + pegIFN/RBV for 12 wks, followed by pegIFN/RBV for 12-36 wks (RGT)

Manns M, et al. EASL 2013. Abstract 1413.

No Cirrhosis Cirrhosis

SMV + pegIFN/RBVPegIFN/RBV

189/231

61/119

11/17

6/15

n/N =

100

80

60

40

20

0

SV

R12

(%

)

82

65

5140


FISSION: SVR12 by GT and Cirrhosis Status With SOF + RBV vs PegIFN/RBV Randomized, controlled, open-label phase III noninferiority trial

Sofosbuvir + RBV for 12 wks vs pegIFN + RBV for 24 wks

Treatment-naive patients with GT 2/3 HCV

– 20% to 21% cirrhosis; platelets > 75,000/mm3; 28% GT 2, 72% GT 3

Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Gane E, et al. AASLD 2013. Abstract 5. GT 2 GT 3

SV

R12

(%

)

No Cirrhosis No CirrhosisCirrhosis Cirrhosis

58/59 44/54 10/11 8/13 •89/145 99/139 •13/38 11/37n/N =

100

80

60

40

20

0

98

8291

62 6171

34 30

Sofosbuvir + RBV

PegIFN + RBV

clinicaloptions.com/hepatitisAASLD 2013: HCV Investigational Agents

COSMOS: SVR12 in F3/4 GT 1 Pts Receiving Simeprevir + Sofosbuvir ± RBV

Lawitz E, et al. EASL 2014. Abstract 165.

Open-label, randomized phase IIa study of simeprevir + sofosbuvir with or without RBV for 12 or 24 wks in cirrhotic and noncirrhotic GT 1 treatment naive or previous null responders

Primary endpoint: SVR12

SMV/SOF ± RBV

SMV/SOF + RBV

SMV/SOF + RBV

SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

16/16 12/12 6/6 9/9 15/16 10/11 7/7 6/7 44/45 37/39

F3 fibrosisF4 fibrosis

SV

R12

(%

)

100

80

60

40

20

0

100 100 100 100 10094 91

98

8695

n/N =

clinicaloptions.com/hepatitisAASLD 2013: HCV Investigational Agents

Promising IFN-Free Regimens in Genotype 1 Cirrhotic Patients

RegimenSVR12, %

Tx Naive Tx Exp PI Failure

Sofosbuvir + ledipasvir[1,2] --- 70 (N = 10) 91 (N = 11)

Sofosbuvir + ledipasvir + RBV[1,2] --- 100 (N = 25) 100 (N = 11)

Sofosbuvir + ledipasvir + GS-9669[1] --- 100 (N = 26) ---

Daclatasvir + asunaprevir[3]* 90 (N = 203)† 82 (N = 205)† ---

Daclatasvir + asunaprevir + BMS-791325 75 mg[4] 94 (N = 16) --- ---

Daclatasvir + asunaprevir + BMS-791325 150 mg[4] 89 (N = 18) --- ---

ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5] 94 (N = 86) 87-97 (N = 122) ---

ABT-450/ritonavir/ombitasvir + dasabuvir + RBV[5]* 95 (N = 74) 95-100 (N = 98) ---

1. Gane EJ, et al. AASLD 2013. Abstract 73. 2. Lawitz. E et al. AASLD 2013, Abstract 215. 3. Manns M, et al. EASL 2014. Abstract 166. 4. Everson GT, et al. Gastroenterol. 2014;146:420-429. 5. Poordad F, et al. N Engl J Med. 2014;[Epub ahead of print].

*Treatment duration: 24 weeks; all others 12 weeks.†Genotype 1b HCV-infected patients only


Take Home Points

Cirrhotic patients are the most in need for HCV treatment

Child-Pugh A patients should be strongly advised to undergo therapy

More advanced cirrhosis should be treated with caution on a case-by-case basis

Newest DAA + pegIFN/RBV combinations increase SVR in cirrhotic patients

IFN-free DAA regimens demonstrate significant potency in cirrhotic patients

Ensuring Informed Decision-Making When Treating or Deferring in

Cirrhotic Patients


Ensuring Informed Decision Making for Cirrhotic Patients Patients should be fully informed of the potential risks of

treatment or deferral

Strategy Potential Benefits Potential Risks

Immediate treatment SVR and prevention of disease progression

Serious adverse events (death, infection, severe hepatic decompensation)

Deferring treatment Achieving SVR with a future regimen with fewer adverse events

Liver-related mortality Need for liver transplantation Liver failure Development of HCC


Survival Outcomes in Pts With CHC and Advanced Fibrosis With/Without SVR

Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

30

20

10

00

All

-Cau

se

Mo

rtal

ity

(%)

1 2 3 4 5 6 7 8 9 10Yrs

All-Cause MortalityP < .001

Without SVR

With SVR

Pts at Risk, nWithout SVRWith SVR

405192

393181

382168

363162

344155

317144

295125

25088

20756

16440

13528

30

20

10

00

Liv

er-

Rel

ated

M

ort

alit

y o

r L

iver

T

ran

spla

nta

tio

n (

%)

1 2 3 4 5 6 7 8 9 10Yrs

Liver-Related Mortality or Liver Transplantation

P < .001

Without SVR

With SVR

Pts at Risk, n Without SVRWith SVR

405192

392181

380168

358162

334155

305144

277125

22988

18756

14640

11928

30

20

10

00

Hep

ato

cell

ula

r C

arci

no

ma

(%)

1 2 3 4 5 6 7 8 9 10Yrs

Hepatocellular CarcinomaP < .001

Without SVR

With SVR


405192

390181

375167

349161

326152

294142

269124

22986

19154

15139

12227

30

20

10

00

Liv

er

Fai

lure

(%

)

1 2 3 4 5 6 7 8 9 10Yrs

Liver FailureP < .001

Without SVR

With SVR


405192

384180

361166

337160

314152

288141

259123

21688

18456

14340

11328


CUPIC: Risk–Benefit of Achieving SVR12 vs Developing Serious Complications

Platelet Count ≤ 100,000/mm3

Platelet Count > 100,000/mm3

Albumin

< 35 g/LSerious AEs >> SVR SVR > Serious AEs

Albumin

≥ 35 g/LSVR > Serious AEs SVR >> Serious AEs

Fontaine H, et al. AFEF 2013. Abstract 26.


Real-life Experience in Cirrhotic Patients

33 cirrhotic patients received TVR and 15 received BOC

Almost all patients (22/23; 96%) with Child-Pugh score > 5 and/or baseline platelets < 110,000/µL (Group A/B) had either treatment failure or SAE

Outcome, %

Group APlatelets

< 110,000/µLand

Child-Pugh > 5(n = 7)

Group BPlatelets

< 110,000/µL or

Child-Pugh > 5(n = 16)

Group CPlatelets

≥ 110,000/µLand

Child-Pugh = 5(n = 20)

Treatment failure 100 69 30

SAE 57 63 25

Treatment failure or SAE 100 94 50

Massoumy B, et al. EASL 2013. Abstract 857.


Factors Associated With Hepatic Decompensation During P/R Therapy In retrospective cohort study, 68 pts with HCV-associated liver cirrhosis treated with

pegIFN/RBV

– Mean age: 51 yrs; baseline MELD: 9.2 (5-20)

Hepatic decompensation observed in 36.8% of patients

Baseline MELD score associated with hepatic decompensation in multivariate analysis: OR: 1.56 (1.18-2.07; P = .002)

Dultz G, et al. PLoS One. 2013;8:e71262.

100

80

60

06

Fre

qu

enc

y o

f D

eco

mp

en

sati

on

(%

)

40

20

8 10 12 14 16 18 20MELD Score

22%59%

83%


Factors Associated With Greater Benefit or Greater Risk of Treatment in Cirrhotics

Factors Associated With Greater Benefit of Therapy

Factors Associated With Greater Risks of Therapy

↓ Child-Pugh score

↓ MELD score

↑ Platelet count

↑ Albumin level

↓ Age

↑ Child-Pugh score

↑ MELD score

↓ Platelet count

↓ Albumin level

↑ Age


Take Home Points

HCV treatment in cirrhotic patients is associated with high rates of treatment-related adverse events and lower response rates than in patients with less advanced disease

However, immediate treatment could lead to SVR and prevent disease progression

For every patient, an informed choice is critical

Optimizing Outcomes in Patients Who Wish

To Be Treated


Pretreatment Optimization Strategies

Lifestyle changes

Pretreatment initiation of eltrombopag

Ultrasound to exclude ascites

Check recent endoscopy report

Consider antibiotics in cirrhotic patients with upper gastrointestinal bleeding[1]

1. Chavez-Tapia NC, et al. Cochrane Database Syst Rev. 2010;9:CD002907.


ENABLE: Eltrombopag Enables HCV Tx Initiation Through Higher Platelet Counts Patients with platelet counts < 75,000/µL received open-label eltrombopag in a

dose-escalating fashion dependent on platelet response for 2-9 wks until platelet counts increased sufficiently to initiate antiviral therapy

773/805

694/715

ENABLE-1 (90,000/µL)

ENABLE-2(100,000/µL)

9697100

80

60

40

20

0

Pat

ien

ts A

chie

vin

g R

equ

ired

P

late

let

Th

resh

old

(%

)

Afdhal NH, et al. Gastroenterology. 2014;146:442-452.

Adverse Event, % ENABLE-1(N = 715)

ENABLE-2(N = 805)

Any 37 34

Grade ≥ 3 adverse events 2 3

Blood bilirubin level increased < 1 < 1

Hepatic neoplasm malignant <1 <1

Serious adverse events 1 1

Hepatic neoplasm malignant < 1 < 1


On-Treatment Optimization Strategies

Anemia management

– RBV dose reductions

– Addition of erythropoietin

– Transfusions

Management of thrombocytopenia

– On-treatment initiation of eltrombopag

Monitoring of renal function


Wk 2 Hb Level Predicts Subsequent Onset of Anemia (REALIZE: TVR + PegIFN/RBV)

Pts

Wit

h A

nem

ia A

fter

Wk

2 (%

)

10/13 19/4832/60 15/59 7/5818/27

< 11 11 to < 12 12 to < 30 13 to <14 14 to 15 ≥ 15

Hb at Wk 2 (g/dL)

Proportion of Patients With Occurrence of Hb < 10 g/dL After Wk 2 According to Hb Level at Wk 2

Zeuzem S, et al. J Hepatol. 2014;[Epub ahead of print].

100

80

60

40

20

0

77

67

53

40

25

12


CUPIC: Anemia Management in Cirrhotics According to Age

22/221

Grade 3/4

Anemia

Transfusions

10

100

80

60

40

20

0

Pat

ien

ts (

%)

Hezode C, et al. AASLD 2013. Abstract 1845.

< 65 yrs

≥ 65 yrs

21

16/78

26/221

12

35

27/78

106/221

48

81

63/78

EPO

P = .028

P < .001

P < .001

Grade 3/4

Anemia

Transfusions

7

100

80

60

40

20

0

18

8/44

16/168

1020

9/44

89/168

53

68

30/44

EPO

P = .032P ≤ .063

P = .088

Telaprevir Boceprevir

11/168


SVR by RBV Dose Reduction During First 4 Wks of Tx and HCV RNA Status Retrospective analysis of ADVANCE/ILLUMINATE studies of TVR +

pegIFN/RBV

SVR rates in pts with vs without RBV dose reduction between Wks 0-4 of Tx, analyzed by whether HCV RNA was detectable or undetectable

120/176

40/45

Undetectable HCV RNA

Detectable HCV RNA

68

89100

80

60

40

20

0

SV

R (

%)

Sulkowski MS, et al. EASL 2012. Abstract 1162.

347/405

86

168/259

65

RBV dose reduction

No RBV dose reduction


Similar SVR When RBV Dose Modification or EPO Used to Manage Anemia on BOC 500/687 treatment-naive GT 1 pts on BOC-based therapy developed anemia

(Hb ≤ 10 g/dL or expected to reach that nadir before next visit)

Randomized to EPO (40,000 units/wk SC) or RBV dose reduction (by 200-400 mg/day)

178/251

178/249

RBV Dose Reduction

EPO Use

7172

100

80

60

40

20

0

SV

R (

%)

Poordad F, et al. Gastroenterology. 2013;145:1035-1044.


ENABLE: Higher SVR Rates in Patients Receiving Eltrombopag vs Placebo Patients randomized 2:1 to either placebo or eltrombopag + pegIFN alfa-2a (ENABLE-1)

or placebo or eltrombopag + pegIFN alfa-2b (ENABLE-2)

Higher platelet counts in eltrombopag arms vs placebo by Wk 2 of treatment, enabling full dose of pegIFN to be maintained

– ENABLE-1: 11,000/µL vs 79,000/µL

0

20

40

80

100

SV

R (

%) 60

32/232

14

ENABLE-1 ENABLE-2

103/449

33/252

96/506

2313

19

Placebo

Eltrombopag

n/N =

P = .0064 P = .0202

Afdhal NH, et al. Gastroenterology. 2014;146:442-452.

– ENABLE-2: 124,000/µL vs 89,500/µL


ENABLE: Safety Considerations in Antiviral Phase

Greater proportion of placebo pts D/C HCV treatment due to AEs (27% vs 19%)

Cataracts more common in eltrombopag arm vs placebo for ENABLE-1 (8% vs 3%) but similar for ENABLE-2 (7% vs 6%)

Hepatic decompensation (ascites, hepatic encephalopathy, variceal hemorrhage, or spontaneous bacterial peritonitis) more common in eltrombopag vs placebo-treated pts (10% vs 5%)

Boxed warning: eltrombopag in combination with IFN + RBV may increase risk of hepatic decompensation

1. Afdhal NH, et al. Gastroenterology. 2014;146:442-452.

AE, %[1]

ENABLE-1 ENABLE-2

Placebo(n = 232)

Eltrombopag (n = 449)

Placebo(n = 252)

Eltrombopag (n = 506)

Any 97 96 93 94

Grade ≥ 3 AE 56 51 51 48

Serious AE 15 20 15 20


Increased Risk of Renal Impairment With Triple Therapy Containing TVR or BOC Observational study of 1185 patients with GFR data at baseline

Results emphasize that renal function must be assessed during treatment

PR BOC PR

4.7(10/211)

0.9(1/109)

100

80

60

40

20

0

Ren

al Im

pai

rmen

t at

Wk

12 in

P

ts W

ith

No

rmal

Ren

al

Fu

nct

ion

at

Bas

elin

e (%

)

Mauss S, et al. EASL 2013. Abstract 872.

6.6(38/575)

TVR PR

P = .0753

P = .0188

Risk Factor for Renal Insufficiency P Value

Age < .001

Hypertension < .001

Diabetes < .05

Triple therapy < .05


Take Home Points

Hb level should be frequently assess during treatment and anemia should be treated as early as possible

– EPO and RBV dose reductions for anemia lead to similar SVR rates in BOC-treated patients

In HCV patients with platelet counts < 70,000/µL, eltrombopag may increase platelet counts to levels that allow HCV therapy to be initiated and may allow for higher SVR rates with a reduced need for pegIFN dose reductions

Renal function must be assessed during treatment

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Managing cirrhotic HCV patients. Whom to treat, how to treat.2014