clinical case discussion on protease inhibitor treatment

Clinical case Discussion on Protease Inhibitor treatment in experienced

patients 2nd Global Workshop on HCV Therapy Advances

New Antivirals in Clinical Practice

G M Dusheiko

Royal Free Hospital London UK

Rationale for treatment with first generation protease inhibitors

• Progressive disease, associated with persistence of viral replication and ongoing necro-inflammation and fibrosis

– Remission (SVR) is associated with loss of active viral replication

– Improvement in hepatic fibrosis

– Probably equates to modification of natural history

The natural history of fibrosis in chronic

viral hepatitis

F0 F2 F3 F4

Courtesy Pierre Bedossa

What have we learned from clinical experience with the first generation PI’s

• Shortening of treatment to 24 weeks therapeutic

advance (naïve patients)

• High positive predictive value of > 90% in patients with RVR – important motivator

• Clinical experience with cirrhosis – tempered by the potential for serious adverse events

– Long duration of interferon treatment

• Management and intensive monitoring

The need to treat cirrhosis; balancing efficacy,

safety and likelihood of response

Patients with cirrhosis at greatest need

Response rates impaired in patients with cirrhosis

Response rates in genotype 1 naive and

experienced patients with cirrhosis improved by

first generation protease inhibitors

Question

You are given a restricted budget for treating non responders

Who would you prioritise:

– A. Prior IFN null responder without cirrhosis?

– B. Prior IFN partial responder without cirrhosis?

– C. Prior IFN relapser irrespective of fibrosis stage?

– D. Prior IFN null responder with cirrhosis

6

REALIZE (telaprevir): SVR by baseline fibrosis

stage and prior response to Peg-IFN/RBV

SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In

case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Pol S, et al. Hepatology 2011;54(Suppl. S1):374A

32

13 7

18

0

20

6 0

10

87 85 84 77

56

34 41 42

14

0

20

40

60

80

100

53/62 n/N= 2/15 12/38 145/167 10/18 0/5 3/17 36/47 16/38 0/9 1/5 11/32

No, minimal

or portal

fibrosis

Cirrhosis Stage

Pbo/PR48

Pooled T12/PR48

SV

R (

%)

48/57 1/15 1/18 24/59 1/10 7/50

Bridging

fibrosis

No, minimal

or portal

fibrosis

Cirrhosis Bridging

fibrosis

No, minimal

or portal

fibrosis

Cirrhosis Bridging

fibrosis

Prior

relapsers

Prior partial

responders

Prior null

responders

RESPOND-2 (boceprevir): SVR by baseline fibrosis

stage and prior response to Peg-IFN/RBV

Prior

relapsers

Prior partial

responders

Prior null

responders

32

20

9

0

75

50 47

30

75

83

55

46

0

20

40

60

80

100

2/10 n/N= 58/77 12/38 59/79 0/5 23/42 2/23 18/38 3/10 6/13

No, minimal

or portal

fibrosis

(F0–F2)

Stage

PR48

BOC RGT

SV

R (

%)

15/18 11/22

Bridging

fibrosis / cirrhosis

(F3/F4)

Excluded from

RESPOND-2

BOC44/PR48

No, minimal

or portal

fibrosis

(F0–F2)

Bridging

fibrosis / cirrhosis

(F3/F4)

Bruno S, et al. J Hepatol 2011;54(Suppl. 1):S4

Week 24 and end-of-treatment response for

DAA-based therapy in Veterans with chronic HCV

692/859 (81%) G1 Veterans had

ended therapy at analysis

532/661 BOC; 160/198 TVR

Backus L, et al. AASLD 2012, Boston, #LB-30

Week 24 and EOT virologic response rates

did not differ between DAAs

Cirrhotics had lower response than

non-cirrhotic

Prior null responders had lower response

rates

BOC

Wk 24 (n/N)

TVR

Wk 24 (n/N)

p-

value

Overall 69% (457/661) 64% (126/198) 0.15

Subgroups of interest:

Naive non-cirrhotic 74% (231/314) 60% (36/60) 0.03

All cirrhotic 64% (103/161) 60% (49/81) 0.60

Prior treatment response (including cirrhotic and non-cirrhotic):

Prior null responder 44% (28/64) 53% (20/38) 0.39

Prior partial responder 69% (50/72) 67% (18/27) 0.79

Prior relapser 76% (91/119) 88% (29/33) 0.15

HCV RNA undetectable rates at Week 24 (n=859)

HCV RNA undetectable rates at EOT (n=692) BOC EOT

(n/N)

TVR EOT

(n/N)

p-

value

Overall 60% (320/532) 55% (88/160) 0.25

Subgroups of interest:

Naive non-cirrhotic 66% (179/270) 60% (31/52) 0.35

All cirrhotic 49% (55/112) 45% (26/58) 0.60

Prior treatment response (including cirrhotic and non-cirrhotic):

Prior null responder 19% (9/48) 26% (8/31) 0.46

Prior partial responder 59% (32/54) 62% (13/21) 0.83

Prior relapser 67% (64/95) 85% (22/26) 0.08

Demographic and clinical data BOC TVR

Age (y) 57 ± 6 58 ± 5

Sex = male 95% 97%

Race/ethnicity

Black

Hispanic

White

25%

6%

60%

30%

6%

58%

Cirrhosis 24% 41%

Diabetes 23% 29%

Naive 59% 49%

Prior null responder 10% 19%

Prior partial responder 11% 14%

Prior relapser 18% 17%

Albumin and MELD score predict decompensation in patients

with HCV cirrhosis and thrombocytopenia on IFN therapy:

Analysis from the ENABLE studies

Afdhal N, et al. AASLD 2012, Boston, #1138

IFN therapy increases the risk of hepatic decompensation

MELD score and albumin are most robust indicators of

disease progression in multivariate analysis

Patients with decompensation rarely achieved SVR ≤10%

Compensated disease and

thrombocytopenia (<75,000/µL)

N=1439

955 IFN/RBV/eltrombopag

484 IFN/RBV/placebo

252 events

13% on eltrombopag

6% ascites; 3% hepatic encephalopathy

7% on placebo

3% ascites; <1% hepatic encephalopathy

Risk factors for decompensation included:

Age ≥50

MELD ≥10

Albumin ≤3.5 g/L

ALT <3x ULN

Bilirubin >0.7 mg/dL

History of alcohol abuse

Multivariate analysis of risk factors for

hepatic decompensation

Treatment

(eltrombopag vs placebo)

Age (50–60 vs <50)

Age (>60 vs <50)

MELD score (≥10 vs <10)

Albumin (≤35 vs >35)

Total bilirubin

(>1.0 vs ≤1.0 mg/mL)

ALT (<3x vs ≥3x ULN)

Alcohol abuse (Yes vs No)

0.1 10 Adjusted odds ratio

1

p

0.0024

0.0038

0.0038

0.0022

0.0002

0.0497

0.0216

0.0021

Case 1

11

• 66-year-old woman • Prior relapser after PEG IFN and RBV

Description

• Genotype 1b – IL28b CC • Non-biopsy proven cirrhosis with MRI scan appearance of portal

hypertension

• Fibroscan 26.3 kPa (5 July 2011) • Ultrasound showed irregular liver outline and coarse echotexture in

keeping with CLD (14 September 2012) • Splenomegaly (MRI)

HCV disease characteristics

• Weight: 65kg

Other medical information

Question

• The patient chooses to be retreated with a first generation protease inhibtior. For how long should this patient be treated with the interferon and ribavirin backbone?

A. 12 weeks

B. 24 weeks

C. 48 weeks

DAA regimens for treatment-experienced

patients with compensated cirrhosis

48 4 0 12 36 24

Telaprevir

+ Peg-IFN + RBV Peg-IFN + RBV

Peginterferon alfa-2b 135 µg/week + ribavirin 1200 mg/day

Boceprevir

Peg-

IFN +

RBV

Boceprevir + Peg-IFN + RBV

Telaprevir EU SmPC; Boceprevir EU SmPC

Start treatment: Boceprevir

Time Hb

(g/dL

)

Platelets

(x 103/mm3)

Neutrophils

(x 103/mm3)

Albumin

(g/dL)

Bilirubin

(μmol/L)

ALT

(IU/L)

HCV RNA

(IU/mL)

Baseline 12.3 61.0 0.95 45.0 27.0 69.0 2,403,150

Week 4 9.7 72.0 0.75 43.0 30.0 36.0 1,205

Week 8 8.5 67.0 0.55 38.0 19.0 29.0 Not

detected

Week 12* 7.4 74.0 0.37 34.0 17.0 24.0 Not

detected

*Admitted to hospital; Hb: hemoglobin; ALT: alanine aminotransferase

Subsequent course

Week 12 – admitted to hospital

– Pyrexial illness with neutropenia

– Positive blood cultures with gram-negative rods

– E-coli detected (UTI with bacteraemia)

– Sensitive to Augmentin; responded well

– Required GCSF

Week 28 – developed painful skin rash

– Saw dermatologist same day in clinic

– Responded well to topical corticosteroids

Continued throughout treatment with low neutrophils requiring

GSCF (last day of treatment = 0.19 GCSF given in clinic)

Treatment weeks 24_36_48 – HCV RNA not detected

UTI: urinary tract infection; GCSF: granulocyte colony stimulating factor

Case 2

17

• 59 year old male. Criminal lawyer

• Prior null responder after PEG IFN and RBV (2006)

Description

Hepatomegaly

ALT 61 AST 72 albumin 43 bilirubin 5

Genotype 1 infection HBsAg negative

Liver biopsy Nov 2005

Liver distortion, fibrous expansion portal tracts spicule formation

focal portal linking and bridging mod steatosis

August 2007 Fibroscan median stiffness 9/2.3/100%

IL28b genotype -860 TT genotype

Intermittently raised AFP


3-4 bottles wine per week; refused gastroscopy

2011 anal cancer treated radiotherapy and chemotherapy


Subsequent course

4 Feb 2012

– Ultrasound irregular liver no obvious focal lesions

– Slight but definite rise in AFP: 27

MRI scan 14 May 16 x 10 mm arterialised lesion in segment 8

– exhibits washout consistent with HCC

– Spleen normal size no ascites

26 June 2012

– Segment 8 wedge resection HCC + radiofrequency ablation

Moderately differentiated HCC 20 x 16 mm and 16 mm from

nearest surgical margin; No microvascular invasion

– Separate focus small cell dysplasia

Liver moderate chronic hepatitis moderate steatosis and

developing cirrhosis

Requested retreatment

Commenced treatment 17 August 2012

Telaprevir 750 mg tds peg alpha 2a 180 ug and ribavirin 600 mg

bd

Amlodipine interaction?

Time Hb (g/dL)

Platelets (x 103/mm3)

Neutrophils (x 103/mm3)

Albumin (g/dL)

Bilirubin (μmol/L)

ALT (IU/L)

HCV RNA (IU/mL)

Baseline 14.2 210 1.94 46 5 56 2,129,500

Week 4 10.8 177 1.59 44 16 31 3716

Start telaprevir, PEG IFN and ribavirin

What would you do next

A.Continue treatment and measure HCV RNA at week 8

B.Stop all treatment

C.Switch to boceprevir

D. Continue treatment to 12 weeks?

Time Hb (g/dL)

Platelets (x 103/mm3)

Neutrophils (x 103/mm3)

Albumin (g/dL)

Bilirubin (μmol/L)

ALT (IU/L)

HCV RNA (IU/mL)

Baseline 14.2 210 1.94 46 5 56 2,129,500

Week 4 10.8 177 1.59 44 16 31 3716

Stopped treatment Week 4 post treatment

44 6 44 426,216

Start telaprevir, PEG IFN and ribavirin

Stopping rules during telaprevir dosing period

Telaprevir EU SmPC

0 Weeks 4 8 12

If >1000 IU/mL at Week 4 or 12:

stop all drugs*

*In prior null responders, consideration should be given to conducting an additional HCV RNA test between Weeks 4 and 12.

If the HCV RNA concentration is >1000 IU/mL, telaprevir and Peg-IFN/RBV should be discontinued

Viral kinetics in patients who met the >1000 IU/mL

HCV RNA Week 4 stopping rule with telaprevir

Adda N, et al. HepDART 2011. Abstract 45

Treatment-naïve

patients

Treatment-experienced

patients

108

107

106

105

104

103

102

10 0 4 6 8 12 10 2

Weeks

HC

V R

NA

(IU

/mL

)

0 4 6 8 12 10 2

Weeks

HC

V R

NA

(IU

/mL

)

108

107

106

105

104

103

102

10

REALIZE (telaprevir): baseline factors and eRVR

status as predictors of SVR*

Variable

eRVR

Prior response to PR

LDL (mmol/L)

Fibrosis stage

Baseline log10 HCV RNA (IU/mL)

HCV genotype subtype (1a/1b)

Maximum ALT, AST

0.1 1 10

Odds ratio (95% CI)

With eRVR included

0.1 1 10

Odds ratio (95% CI)

Without eRVR included

Berg T, et al. Hepatology 2011;54(Suppl. S1):375A *Multiple logistic regression analysis subset (N=465); telaprevir treatment arms were pooled

Additional factors included in the analyses but found to be non-significant include: medical history of hypertension; age; BMI; triglycerides; HDL; gender; log HOMA-IR; race (black/nonblack); and GGT

Case 3

27

• 64year old male.

• G1 b

• Jan 2010 PEG IFN RBV 48 week

• Undetectable at EOT: relapse

Description

• Diffuse large cell B cell lymphoma stage 4b well controlled

• Reactivation hepatitis B during treatment

• Fibroscan 3.5/0.9/100%

• ALT 32 AST 61



• Creatinine133 creatinine clearance 49 ml/s

• Doppler ultrasound portal vein

• Single functioning kidney

– Telaprevir, IFN RBV 1000 mg started 7 Oct 2011

TW 4 Nov 2011 Platelets 22

1 Dec 2011 TW8 Platelets 23

Subsequent course

What would you do next

A.Reduce dose of interferon

B.Reduce dose of both interferon and ribavirin

C.Stop all treatment

D.Give eltrombopag or romiplostin

TW 44 Nov 2011 Platelets 22

1 Dec 2011 TW8 Platelets 23

Eltrombopag started 25 mg increased to 50 mg; given one month

TW11 (22 Dec 2011) platelets 48

TW12 (29 Dec 2011) platelets 47

TW 20 (31 May 12) Platelets 34

TW24 (5 July 2012) Platelets 48

Current platelet count 48

Subsequent course

Side effects: Anemia

– Anaemia:

– Transfusion 3 units blood December 2012

– Haemoglobin rose from 6.2 to 9.7

– Dose reductions Ribavirin

– Erythropoetin

EPO 20,000 per week

RBV 200 mg /day 45 ug IFN

– HB 7.7, eGFR 34 ALT 11 AST 17

Patient 8 DF

HCV RNA 401,752 iu/ml at baseline

Start treatment October 2011

TW4 Undetectable

TW12 undetectable

Subsequently undetectable

End of treatment: HCV RNA undetectable

End of treatment blood tests:

HB 7.9 WCC 3.76 platelets 135,000; ALT 26 AST 36

Creatinine 129, eGFR 50 ml/min

Subsequent SVR

HCV RNA concentrations

35

EASL 2012 – Abstract #279

Eltrombopage: Enable 2: Median Platelet Counts (ITT)

AVB, antiviral baseline; OLB, open-label baseline.

Part 1 Part 2 Follow-Up

Me

dia

n P

late

let C

ou

nt

(x1

03/µ

L)

// //

Time Since Randomization (Weeks)

Threshold for dose reduction

OLB 2 AVB 1 2 4 6 8 12 16 20 24 28 32 36 40 44 4 12 24

160

140

120

100

80

60

40

20

0

Placebo

94% of patients from Part 1 entered Part 2

714 530

Placebo

Eltrombopag

238 247 244 228 206 192 176 145 134 99 74 67 63 58 59 221 209 201

460 494 492 487 473 473 451 405 378 263 212 199 185 174 168 424 430 395 Eltrombopag

Protease inhibitor regimens with PEG IFN RBV

Requisite backbone of PEG IFN:

– All problems associated with PEG IFN and RBV use

Including depression, psychiatric symptoms worsening of liver function and severe infections

(Prolonged) use required in patients with cirrhosis?

– render a large group requiring careful management

Predicted impact of treatment on reduction in cumulated

incidence of HCV-related cirrhosis 2012–2021

13

24

18

8

14

8

16

34

24

10

18

12

27

37

30

20

34

31

0

10

20

30

40

50

Belgium France Germany Italy Spain UK

Pegylated bitherapy

PI-based triple therapy

PI-based triple therapy + reinforcement of HCV screening and treatment access

Red

ucti

on

in

in

cid

en

ce o

f H

CV

-rela

ted

cir

rho

sis

(%

)

Deuffic-Burban S, et al. Gastroenterology 2012 [ePub ahead of print]

The paradox of progress

• Advances have brought higher rates of cure

– but more complexity to treatment of hepatitis C- a paradox of progress

– Do not make treatment more straightforward

– Complex process of decision making is required to assess

What threat do you think resistance to a first generation protease inhibitor poses?

A. No threat at all

B. A major problem

C. A problem but one that future regimens will solve

Will we have better, more tolerable interferons?

First SVR24 results from EMERGE:

PegIFN-λ1A (lambda) vs PegIFN-α2A (alfa) P

atie

nts

95%

CI (%

)

58.3

70.6

62.5 66.7

70.6

83.3

57.1

40.0

0

25

50

75

100

G2

n = 12 17 17 12 16 14 15 15

Lambda

120 μg

Lambda

180 μg

Lambda

240 μg

Alfa

180 μg

SVR24 by HCV genotype

Zeuzem S, et al. EASL 2012, Barcelona, #10

G2 G2 G2 G3 G3 G3 G3

Overcoming null response

• May be nullified in patients treated with potent regimens given for sufficient time to effect clearance of HCV from the liver and perhaps extrahepatic sites.

• An inverse correlation between the influence of the innate response and potency of DAA agents?

• Need more data

Decision process

• Ultimately what drives a patient, averse to inteferon to be treated with telaprevir or boceprevir and PEG IFN and RBV?

• What motivates a patient, already treated with IFN, want to do it again with a first generation PI regimen?

• What role does the physician have in influencing those choices?

• Unique decision process: – pushes the doctor - patient relationship, past easily

defined boundaries

– Need Aronsohn A, Jensen D. Informed deferral: A moral requirement for entry into the HCV treatment warehouse. Hepatology 2012;10.

clinical case discussion on protease inhibitor treatment

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