Jacob George

Predictors of treatment response, baseline and on-treatment

Learning objectives• Understand the evolution of HCV therapies over the last

decade• Be able to define baseline and on-treatment predictors of

treatment response following:– Peg-IFN and RBV dual therapy– Triple therapy regimens

• Understand role of genetic polymorphisms in predicting response

• Develop an understanding of decision-making in complex patients

• Understand risks and benefits of HCV therapies

Ms X

•First seen September 2000

•45 yo Caucasian soldier in Australian Army

•Incidental diagnosis of HCV during medical

•Born in Australia

•Smoker: 10 cigarettes/day

•Alcohol: 30 g/day

•No medications apart from OCP

Ms X – Past medical history

•1970: Jaundice 3 weeks post-transfusion for placenta praevia

•Tattoos at age 18

•Denies IDU; has snorted cocaine

•Has had body piercing

•No family history of DM

Ms X – Examinations/Investigations•NAD•BMI: 18 kg/m2

Labs:•Bili 6 umol/L (0-20)•Albumin 40 g/L (38-55)•AST 40 U/L (0-40)•ALT 41 U/L (0-40)•GGT 39 U/L (0-45)FBC•Hb 109 g/L (119-160)•WCC 7.1x109/L (4-11)•Platelets 294 x109/L (150-400)

Ms X – Results

• HBsAg - HBcAb -

• HCV Ab positive

• HCV PCR positive

• Genotype 1a

• HCV viral load: >850,000 IU/mL

Ms X – Salient features

•45 yo female

•Duration of infection: 31 years

•Alcohol consumption: Moderate

•HCV genotype 1a, high vial load

•What next?

Ms X – Liver biopsy

•12 portal tracts•Portal activity: 2•Lobular activity: 2•Fibrosis stage: 3

•Would you treat?•Likely response rate?

Omland LH, et al. J Hepatol. 2010;53:36-42.

Time (years)

Cum

ulati

ve In

cide

nce

0.10

0.08

0.06

0.04

0.02

0.00

0 2 4 6 8

chroniccleared

Liver-related deaths Non–Liver-related deaths

Time (years)

Cum

ulati

ve In

cide

nce

0.10

0.08

0.06

0.04

0.02

0.00

0 2 4 6 8

chroniccleared

Standard of care & mortality

307 patients with F3/F4 treated with peg-IFN/RBV: 103 (33%) achieved SVR

Cardosa et al. J Hepatol 2010;52:652-657

Treatment of HCV prevents complications

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12

Years post-treatment

% H

epat

ocel

lula

r car

cino

ma

SVR (n=103)

No SVR (n=204)

p<0.001

(a) Hepatocellular carcinoma

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12

Years post-treatment

% L

iver

Fai

lure

SVR (n=103)

No SVR (n=204)

p<0.001

(b) Hepatic decompensation

Cardosa et al. J Hepatol 2010;52:652-657

Predictors of treatment response

•Genotype 2 or 3 (not 1, 4)•Lower HCV viral load•Milder fibrosis (F0-F1 vs F3-4)•Lower body weight/insulin resistance•Younger•Adherence to treatment•Female

IDEAL: Importance of adherence

peg-IFN 2b 1.5/RBV

peg-IFN 2b 1.0/RBV

peg-IFN 2a/RBV

80/80/80* 70% (319/456)

74% (327/442)

61% (324/528)

Non 80/80/80

16% (87/563)

10% (59/574)

20%(99/507)

Data on File, Schering-Plough Corporation.

*80% peg-IFN/ 80% ribavirin/ 80% duration.*McHutchison JG, et al. Gastroenterology. 2002;123:1061–1069.

Ms X •Shocked by Dx; not keen to start treatment•Concerns re. working in army•May 2001: Agreed to therapy•IFN: 3 miu tiw/RBV (1 g/day)•Hb 9.9 at week 5; RBV reduced to 600 mg/day, increased to 800 mg/day•Hb stable at 10.2•Week 24: PCR-positive – treatment ceased•Nov 2001: What next?

Ms X – Enrolled in EPIC retreatment study

•Started Rx 28 Jan 2003•Baseline VL: 14,098,837 IU/mL (7.2 log)•Peg-IFN 100 ug/mL weekly•RBV 400 mg BD•Coped with treatment•Week 12: HCV RNA: 4,011,628 IU/mL (6.6 log)•Patient decided to stop Rx

Ms X – Disappeared from follow up

•Returned for review in April 2011•Wanting permission to travel overseas with army

Examination•NAD•BMI: 19 kg/m2

Ms X – InvestigationsLabs:•Bili 10 umol/L (0-20)•Albumin 33 g/L (38-55)•AST 105 U/L (0-40)•ALT 109 U/L (0-40)•GGT 214 U/L (0-45)FBC•Hb 133 g/L (119-160)•WCC 4.7x109/L (4-11)•Platelets 122 x109/L (150-400)•AFP 52 IU/mlHCV genotype 1aVL 2.77 x106 IU/mL

Ms X – What next?

•CT: No tumour•Fibroscan: 15.6 kPa (IQR 1.7)•IL28B:

• rs12979860: CT (N Responder) • rs8099917: TT (Responder)

•IL28B R Rate: 54%

Fischer et al. Hepatology 2012

*

*

Role of rs12979860 and 8099917

Ms X – Questions

Would you treat? • Triple therapy?• Wait for 4/5 drug regimen?• IFN-free regimen?

What are the risks of treatment?

HCV treatment has improved in Asian patients but response rates are still suboptimal in GT1

Yu ML & Chuang WL. J Gastoenterol Hepatol 2009;24:336-45.

Alfa, peg-interferon alfa; IFN, interferon alfa MU, million units; RBV, ribavirin

1991 2009

SVR

(%)

HCV genotype 1/4HCV genotype 2/3

10

25 22

40 40

85

49

90

70

95

50

80

0

10

20

30

40

50

60

70

80

90

100

IFN 3MU24 wks

IFN 6MU24 wks

IFN/RBV24 wks

Alfa/RBV24 wks

Alfa/RBV48 wks

Alfa/RBV48 wks

ASIA GLOBAL

Ms XCommenced triple therapy

•Week 2: Hb 10.8, platelets 98, N 2.5•Week 4:

• Hb 10, platelets 153, N 2.4• HCV VL 1.54E5 IU/mL (17-fold, 5.18 log)• Commenced on BOC

•Week 6: Hb 9.4, Platelets 101, N 1.3

IL28B is a strong baseline predictor of IFN response at end of lead-in (≥1 log decline at TW 4)

RESPOND-2 (effect) Odds Ratio (95% CI) p-value

IL28B genotype: CC vs. Non-CC 4.5 (1.5 – 13.7) 0.007 Previous response: relapser vs

nonresponder 3.2 (1.6 – 6.4) <0.001

BOC/PR48 vs PR48 0.2 (0.05 – 0.7) 0.01BOC/RGT vs PR48 0.14 (0.4 – 0.5) 0.004

SPRINT-2 (effect) Odds Ratio (95% CI) p-value

IL28B genotype: CC vs. Non-CC 15.8 (6.3 – 39.8) <0.001Baseline HCV-RNA: ≤400,000 vs

>400,0004.3 (1.3 – 14.6) 0.02

Steatosis 0 vs >0 2.6 (1.6 – 0.7) 0.0003Race (non-black vs black) 2.1 (1.2 – 3.7) 0.007Gender (female vs male) 1.7 (1.1 – 2.6) 0.03BMI: ≤25 kg/m2 vs >30 kg/m2 0.4 (0.2 to 0.7) 0.001

Ms X

• Week 8: HCV PCR negative, Hb 8.7, platelets 97, N 1.0

• Week 10:• Hb 8.4, WCC 2.9, platelets 73• N 1.3• RBV reduced to 600 mg• Coping with treatment

• What next?

Multiple stepwise logistic regression model of predictors of SVR including treatment Week 4 response

RESPOND-2 (effect) Odds Ratio (95% CI) p-valueBOC/PR48 vs PR48 11.4 (4.6 to 28.0) <.0001 BOC/RGT vs PR48 7.9 (3.3 to 18.9) <.0001Previous response: relapser vs nonresponder 2.2 (1.2 to 4.3) 0.01 Log decline in HCV-RNA at TW 4 (continuous variable) 1.8 (1.3 to 2.4) <.0001

BMI: ≤25 kg/m2 vs >30 kg/m2 3.4 (1.4 to 8.2) 0.01 SPRINT-2 (effect) Odds Ratio (95% CI) p-value

BOC/PR48 vs PR48 7.0 (4.1, 12.0) < 0.0001 BOC/RGT vs PR48 6.0 (3.5, 10.2) < 0.0001 Baseline HCV-RNA: ≤400,000 vs. >400,000 IU/mL 5.8 (1.9, 17.5) 0.002

Log decline in HCV-RNA at TW 4 (continuous variable) 2.6 (2.1, 3.0) < 0.0001

Genotype: 1b/others vs 1a 2.3 (1.5, 3.6) < 0.001 BMI: 25-30 kg/m2 vs. >30 kg/m2 2.3 (1.4, 3.9) 0.002 BMI: ≤25 kg/m2 vs. >30 kg/m2 1.9 (1.1, 3.3) 0.02 Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table. Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table.

Ms X•Rash on face, cough

•Husband asked her to see GP

•‘Going well’; “I’ll be OK’

•Admitted to hospital Week 11

•Septic shock

•All medications ceased

Safety of telaprevir or boceprevir in combination with peg-interferon alfa/ribavirin, in cirrhotic non responders.

First results of the French Early Access Program (ANRS CO20-CUPIC)

C Hézode1, C Dorival2, F Zoulim3, T Poynard4, P Mathurin5, S Pol6, D Larrey7, P Cacoub4, V de Ledinghen8, M Bourlière9, PH Bernard10, G Riachi11, Y Barthe2, H Fontaine6, F Carrat2, JP Bronowicki12

for the CUPIC study group (ANRS CO 20)

Hôpital Henri Mondor, Créteil1, UMR-S 707, Paris2, INSERM U871, Lyon3, Hôpital de la Pitié-Salpêtrière, Paris4, Hôpital Claude Huriez, Lille5, Hôpital Cochin, Paris6, Hôpital Saint-Eloi, Montpellier7, Hôpital

Haut-Lévèque, Pessac8, Fondation Hôpital Saint Joseph, Marseille9, Hôpital Saint André, Bordeaux10, Hôpital Charles Nicolle, Rouen11, Hôpital de Brabois, Nancy12, France

29

French Early Access Program

ATU

The Temporary Authorisation for Use (ATU) is an Early Access Program for medicinal products which have undergone full clinical development and are waiting for marketing authorisation by the French Health Products Safety Agency (Afssaps)

CUPIC

Compassionate Use of Protease Inhibitors in viral C Cirrhosis National multicentre observatory in the setting of the ATU Promoter: ANRS

Aim: To prospectively collect clinical data and biological specimen

30

Treatment regimen

Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBV Follow-up

484 160 128Weeks

72

SVR assessment

BOC + Peg-IFN α-2b + RBV Follow-upPeg-IFN + RBV

36

http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdfhttp://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf

BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day

TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day

Interim analysis

31

Patients, n (% patients with at least one event) Telaprevir n=296

Serious adverse events (SAEs)* 144 (48.6%)

Premature discontinuationDue to SAEs

77 (26.0%)43 (14.5%)

DeathSepticaemia, septic shock, pneumopathy, oesophageal varices bleeding, encephalopathy, lung carcinoma

6 (2.0%)

Infection (Grade 3/4) 26 (8.8%)

Asthenia (Grade 3/4) 14 (4.7%)

Rash Grade 3 Grade 4 (SCAR)

20 (6.8%)2 (0.7%)

Pruritus (Grade 3/4) 11 (3.7%)

Hepatic decompensation (Grade 3/4) 13 (4.4%)

*407 SAEs in 144 patients; SCAR: severe cutaneous adverse reaction

Telaprevir: preliminary safety findings

32

Patients, n (% patients with at least one event) Boceprevir n=159

Serious adverse events (SAEs)* 61 (38.4%)

Premature discontinuationDue to SAE

38 (23.9%)12 (7.4%)

DeathBronchopulmonary infection, sepsis 2 (1.3%)

Infection (Grade 3/4) 4 (2.5%)

Asthenia (Grade 3/4) 9 (5.7%)

Rash Grade 3 Grade 4 (SCAR)

00

Pruritus (Grade 3/4) 1 (0.6%)

Hepatic decompensation (Grade 3/4) 7 (4.4%)

*158 SAEs in 61 patients; SCAR: severe cutaneous adverse reaction

Boceprevir: preliminary safety findings

33

• The safety profile of DAAs among compensated cirrhotic patients treated in the CUPIC cohort was poor, but associated with high rates of on-treatment virologic response

– Compatible with the use in real-life practice

• We observed a high rate of SAEs (38.4 to 48.6%) compared to phase III trials results (9 to 14%) and high rate of discontinuation due to SAEs (7.4 to 14.5%)

• Based on preliminary results of the CUPIC cohort, patients with cirrhosis should be treated cautiously and should be carefully monitored, especially because of a high incidence of anaemia with poor response to EPO

• SVR rates in a real-world setting are awaited in this population

Preliminary conclusions

Summary• Baseline and on-treatment predictors of

response can aid therapeutic decision making• IL28B SNPs are useful in predicting response in

CHC• Triple therapies have significantly improved

cure rates for genotype 1 CHC, but should be used with caution in those with advanced liver disease