Response Guided Vs.Response Unguided Therapy
K.Rajender Reddy M.DProfessor of Medicine
University of PennsylvaniaPhiladelphia, USA
Factors in Complexity of HCV Therapy
Lead In
No Lead In
Age/Gender
IL28B
Relapser
Partial Responder
Null Responder
Treatment Naïve
ObesityObesity
Race/ethnicity
Viral load/Genotype
Protease Inhibitor Based HCV Therapy:Easy to Treat and Difficult to Treat Genotype 1
Patient Populations
Easy to Treat
• Low viral load• Women• Younger age• Absence of fibrosis• IL 28 B CC• Interferon sensitive• Relapsers
Difficult to Treat
• High viral load• Obesity/Metabolic syndrome• Blacks• IL 28 B-C/T, T/T• Cirrhosis• Older population• Interferon insensitive• Partial and Null Responders
Response Guided Therapy
Response Unguided Therapy
Protease Inhibitor Trials: Summary
• Treatment Naïve– Telaprevir (TPV)
• ADVANCE
-- RGT• ILLUMINATE
– RGT and RUGT
– Boceprevir (BOC)• SPRINT-2
– RGT + RUGT
• Treatment Experienced– Telaprevir (TPV)
• REALIZE– RUGT
– Boceprevir (BOC)• RESPOND-2
– RGT + RUGT
Limitations and Unique Aspects of the Trials
• In both TPV and BOC studies, small number of • Patients with cirrhosis• Older population• High BMI patients
( Post-Hoc Analyses)
• IL-28B– Boceprevir – limited data
– Telaprevir – limited data
• Blacks– Boceprevir
• Prospective study
– Telaprevir• Post-hoc analysis
• Prior Treatment Experienced– Boceprevir – RGT + RUGT
– Telaprevir – RUGT
ADVANCE: Overall SVR and Relapse Rates According to Treatment Arm
Jacobson IM et al. N Engl J Med 2011;364:2405-2416.
6%
75%
7%
69%
27%
44%
0
20
40
60
80
100
SVR Relapse
% ofPatients
T12PR
T8PR
PR
271/363 250/364 168/361 17/264 18/247 51/189
ADVANCE: SVR for T12PR in Selected Subgroups
Jacobson IM et al. N Engl J Med 2011;364:2405-2416.
SVR(%)
112/149
244/325
159/214
16/26
Male 45 yrs White
Female >45 to 65 yrs Black
118/142
150/214
ADVANCE: SVR for T12PR in Selected Subgroups
Jacobson IM et al. N Engl J Med 2011;364:2405-2416.
245/328
64/82
26/35
207/281
Hispanic HCV Subtype 1a HCV RNA <800,000
Non-Hispanic HCV Subtype 1b HCV RNA 800,000
152/213
118/149
SVR(%)
ADVANCE: SVR for T12PR in Selected Subgroups
Jacobson IM et al. N Engl J Med 2011;364:2405-2416.
SVR%
117/156
55/77
109/134
87/129
No/Minimal Fibrosis BMI <25 (Normal)
Portal Fibrosis BMI 25 to <30 (Overweight)
Bridging fibrosis BMI 30 (Obese)
Cirrhosis
32/52
129/155
13/21
Cirrhosis
ILLUMINATE(TPV): SVR in Cirrhosis and Blacks in those with eRVR ( T12/PR24 Vs.T12/PR48)
SVR%
T12|PR24(RGT T12|PR24
T12|PR48(RUGT) T12|PR48
RUGT
12/18 11/12 15/17 16/17
FDA analysis and Sherman KE, et al. N Engl J Med 2011;365:1014-24 10
SPRINT-2: SVR and Relapse Rate by Fibrosis Score
SPRINT-2 and RESPOND-2: BOC + PegIFN/RBV in HCV GT 1 with Advanced Fibrosis/Cirrhosis
N=328 N=319 N=24 N=34 N=42 N=158 N=233 N=231 N=12 N=17 N=25N=313
Bruno S, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011; Abst. 7.
RESPOND-2: SVR by Cirrhotics (F4) vs. Non-Cirrhotics (F0/1/2/3) According to Treatment
Arm
24%
0%
64%
35%
66%
77%
0
20
40
60
80
100
Cirrhosis No Cirrhosis
% ofPatients
PR 48 RGT BOC/PR48
0/10 6/17 17/22 16/66 85/132 85/128
RUGT
Bacon BR et al. N Engl J Med 2011;364:1207-1217.
Treatment Naïve-Blacks
SPRINT-2: SVR in Primary Patient Cohorts According to Treatment Arm
Poordad F et al. N Engl J Med 2011:364:1195-1206.
23%
40%38%42%
67%63%
53%
68%66%
0
20
40
60
80
100
PR48 RGT BOC/PR48
p<0.001
p<0.001
p<0.001
p<0.001
p=0.004
p=0.04
All Patients(Both Cohorts)
Nonblack Cohort Black Cohort
137/363
233/368
242/366
137/363
125/311
211/316
213/311
12/52
22/52
29/53
SVR(%)
RUGT
Prior Treatment Experienced
RESPOND-2: SVR and Relapse Rates for All Subjects According to Treatment Arm
28%23%
14%
59%
12%
66%
0
20
40
60
80
100
SVR Relapse
% ofPatients
PR48
RGT
BOC/PR48
n=80 n=162 n=161 n=25 n=111 n=121
Bacon BR et al. N Engl J Med 2011;364:1207-1217.
RESPOND-2: SVR by Response to Previous Peg-IFN/RBV Therapy According to Treatment
Arm*
31%
7%
70%
40%
75%
52%
0
20
40
60
80
100
Previous Partial Responder Previous Relapser
PR 48 RGT BOC/PR48
2/29 23/57 30/58 16/51 73/105 77/103
SVR(%)
RUGT
Bacon BR et al. N Engl J Med 2011;364:1207-1217.
RESPOND-2: SVR According to Viral Load
Bacon BR et al. N Engl J Med 2011;364:1207-1217.
17%
40%
56%
80%
65%
80%
0
20
40
60
80
100
Low ( 800,000 IU/mL) High (>800,000 Iu/mL)
PR48 RGT BOC/PR48
12/15 11/65 83/147 91/14116/206/15
SVR(%)
RGT vs RUGT
Interferon Response
SPRINT-2 and RESPOND-2: Evaluation of Predictive Value of PegIFN/RBV 4-week
Lead-in Therapy
Vierling JM, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011: Abst. 481.
Relationships Between Week 4 Lead-in and SVR
Poorly responsive to interferon <1.0 log10 viral load decline at treatment
Week 4
Responsive to interferon ≥1.0 log10 viral load decline at treatment
Week 4
133/ 203/ 200/3/83 27/97 36/95 0/12 15/46 15/44 260 252 254 17/67 80/110 90/114
IL 28 B
SPRINT-2 ( Treatment Naïve): SVR by IL28B Polymorphism
% S
VR
5064
6377
4455
33116
67103
82115
1037
2342
2644
* ~90% eligible for short duration therapy
*
Poordad F, et al. EASL 2011, Abst..
RGT vs RUGT
RESPOND-2( Treatment Experienced): SVR by IL28B Polymorphism
613
2228
1722
529
3862
4866
510
611
1318
* ~80% eligible for short duration therapy
Poordad F, et al. EASL 2011, Abst..
% S
VR
*
RUGT
HCV Therapy:Candidates for Response Unguided Therapy
Easy to Treat
• Absence of fibrosis • Low viral load• Younger age• Women• IL 28 B CC• Interferon sensitive• Relapsers
Difficult to Treat
• High viral load• Obesity/Metabolic syndrome• Blacks• IL 28 B-C/T, T/T-Treatment
Experienced• Cirrhosis• Older population• Interferon insensitive• Null and Partial Responders
Response Unguided Therapy