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Predictors of treatment response,
baseline and on-treatment
Jacob George
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
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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:
Labs:
• Bili
• Albumin
• AST
• ALT
• GGT
FBC
• Hb
• WCC
• Platelets
18 kg/m2
6 umol/L
40 g/L
40 U/L
41 U/L
39 U/L
(0-20)
(38-55)
(0-40)
(0-40)
(0-45)
109 g/L
7.1x109/L
294 x109/L
(119-160)
(4-11)
(150-400)
Ms X – Results
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HBsAg - HBcAb HCV Ab positive
HCV PCR positive
Genotype 1a
HCV viral load: >850,000 IU/mL
Ms X – Salient features
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45 yo female
Duration of infection: 31 years
Alcohol consumption: Moderate
HCV genotype 1a, high vial load
• What next?
Ms X – Liver biopsy
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12 portal tracts
Portal activity:
Lobular activity:
Fibrosis stage:
• Would you treat?
• Likely response rate?
2
2
3
Standard of care & mortality
Liver-related deaths
Non–Liver-related deaths
0.10
chronic
cleared
0.08
Cumulative Incidence
Cumulative Incidence
0.10
0.06
0.04
0.02
0.00
chronic
cleared
0.08
0.06
0.04
0.02
0.00
0
2
4
6
Time (years)
8
0
2
4
6
Time (years)
Omland LH, et al. J Hepatol. 2010;53:36-42.
8
Treatment of HCV prevents complications
307 patients with F3/F4 treated with peg-IFN/RBV: 103 (33%) achieved SVR
(b) Hepatic decompensation
100%
100%
80%
80%
% Liver Failure
% Hepatocellular carcinoma
(a) Hepatocellular carcinoma
No SVR (n=204)
60%
p<0.001
40%
20%
60%
p<0.001
No SVR (n=204)
40%
20%
SVR (n=103)
SVR (n=103)
0%
0%
0
2
4
6
8
Years post-treatment
10
12
0
2
4
6
8
10
Years post-treatment
al. J Hepatol 2010;52:652-657
Cardosa et al. JCardosa
Hepatolet
2010;52:652-657
12
Predictors of treatment response
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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
80/80/80*
Non
80/80/80
peg-IFN 2b
1.5/RBV
peg-IFN 2b
1.0/RBV
peg-IFN 2a
/RBV
70%
74%
61%
(319/456)
(327/442)
(324/528)
16%
10%
20%
(87/563)
(59/574)
(99/507)
*80% peg-IFN/ 80% ribavirin/ 80% duration.
*McHutchison JG, et al. Gastroenterology. 2002;123:1061–1069.
Data on File, Schering-Plough Corporation.
Ms X
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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
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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 – Investigations
Labs:
• Bili
10 umol/L
• Albumin 33 g/L
• AST
105 U/L
• ALT
109 U/L
• GGT
214 U/L
FBC
• Hb
133 g/L
• WCC
4.7x109/L
• Platelets 122 x109/L
• AFP
52 IU/ml
HCV genotype 1a
VL 2.77 x106 IU/mL
(0-20)
(38-55)
(0-40)
(0-40)
(0-45)
(119-160)
(4-11)
(150-400)
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%
Role of rs12979860 and 8099917
*
*
Fischer et al. Hepatology 2012
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
ASIA
100
HCV genotype 1/4
HCV genotype 2/3
90
95
90
85
GLOBAL
~80
80
70
SVR (%)
70
60
49
50
40
40
30
25
20
10
0
~50
40
22
10
IFN 3MU IFN 6MU IFN/RBV Alfa/RBV Alfa/RBV
Alfa/RBV
24 wks
24 wks
24 wks
24 wks
48 wks
48 wks
2009
1991
Alfa, peg-interferon alfa; IFN, interferon alfa
MU, million units; RBV, ribavirin
Yu ML & Chuang WL. J Gastoenterol Hepatol 2009;24:336-45.
Ms X
Commenced triple therapy
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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)
IL28B genotype: CC vs. Non-CC
Previous response: relapser vs
nonresponder
BOC/PR48 vs PR48
BOC/RGT vs PR48
SPRINT-2 (effect)
IL28B genotype: CC vs. Non-CC
Baseline HCV-RNA: ≤400,000 vs
>400,000
Steatosis 0 vs >0
Race (non-black vs black)
Gender (female vs male)
BMI: ≤25 kg/m2 vs >30 kg/m2
Odds Ratio (95% CI)
p-value
4.5 (1.5 – 13.7)
3.2 (1.6 – 6.4)
0.007
<0.001
0.2 (0.05 – 0.7)
0.14 (0.4 – 0.5)
0.01
0.004
Odds Ratio (95% CI)
p-value
15.8 (6.3 – 39.8)
4.3 (1.3 – 14.6)
<0.001
0.02
2.6 (1.6 – 0.7)
2.1 (1.2 – 3.7)
1.7 (1.1 – 2.6)
0.4 (0.2 to 0.7)
0.0003
0.007
0.03
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-value
BOC/PR48 vs PR48
11.4 (4.6 to 28.0)
<.0001
BOC/RGT vs PR48
7.9 (3.3 to 18.9)
<.0001
Previous 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
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
SPRINT-2 (effect)
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
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
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Treatment regimen
Interim analysis
Peg-IFN
+ RBV
BOC + Peg-IFN α-2b + RBV
Follow-up
BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day
TVR + Peg-IFN α-2a +
RBV
Peg-IFN α-2a + RBV
Follow-up
TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day
0
4
8
12
36
16
Weeks
48
72
SVR assessment
http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf
http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf
30
Telaprevir: preliminary safety findings
Patients, n (% patients with at least one event)
Telaprevir n=296
Serious adverse events (SAEs)*
144 (48.6%)
Premature discontinuation
Due to SAEs
77 (26.0%)
43 (14.5%)
Death
6 (2.0%)
Septicaemia, septic shock, pneumopathy, oesophageal varices
bleeding, encephalopathy, lung carcinoma
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
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Boceprevir: preliminary safety findings
Patients, n (% patients with at least one event)
Boceprevir n=159
Serious adverse events (SAEs)*
61 (38.4%)
Premature discontinuation
Due to SAE
38 (23.9%)
12 (7.4%)
Death
Bronchopulmonary 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)
0
0
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
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Preliminary conclusions
• 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
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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

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