Current strategies for the
management of treatment naïve
and treatment-experienced
patients
Mark S. Sulkowski, MD
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and
Gastroenterology/Hepatology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Overview
Treatment-Naive Data
and Regimens
Treatment-Experienced Data
and Regimens
Futility Rules
Adverse Effects
SVR in Treatment-Naive HCV
Genotype-1 Infection
100
SVR (%)
80
70%–79%
60
45%
40
20
0
30%
10%
IFN1
IFN + RBV1
PEG IFN +
RBV2,3
PEG IFN +
RBV + PI4,5
Abbreviations: IFN, interferon; PEG IFN, peginterferon; PI, protease inhibitor; RBV, ribavirin.
1. McHutchison JG, et al. Semin Liver Dis. 1999;19:57-65. 2. Manns MP, et al. Lancet. 2001;358:958-965. 3. Fried
MW, et al. N Engl J Med. 2002;347:975-982. 4. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 5. Poordad
F, et al. N Engl J Med. 2011;364:1195-1206. Graphic courtesy of Dr. David R. Nelson.
Standard of Care for HCV
Genotype 1

Boceprevir or Telaprevir in
combination with PEG IFN/RBV

Adults with compensated liver disease,
including cirrhosis
– Treatment-naive
– Failed previous interferon-based therapy

Must not be used as monotherapy
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
Resistance Develops Rapidly During
Monotherapy with Protease Inhibitor
Telaprevir Dosing
Telaprevir Dosing
8
Patient 1018
6
4
LOD
2
0
Log10 HCV RNA (IU/mL)
Log10 HCV RNA (IU/mL)
8
Patient 1002
6
4
LOD
2
0
1
Days
14
HCV RNA (>100
IU/mL)
Wild-type
T54A
V36A/M
Kieffer TL, et al. Hepatology 2007; 46:631-9.
1
R155K/T
36/155
A156V/T
36/156
Days
14
Overview
Treatment-Naive Data
and Regimens
Treatment-Experienced Data
and Regimens
Futility Rules
Adverse Effects
Boceprevir—RGT in Treatment-Naive
Patients with No Cirrhosis
PEG IFN/RBV for 4 weeks,
followed by boceprevir 800 mg TID + PEG IFN/RBV
HCV RNA
TW8
TW24
Undetectable
Undetectable
Detectable
Undetectable
Recommendation
Administer all 3 drugs
through TW28
Administer all 3 drugs
through TW36, then
administer PEG IFN/RBV
through TW48
Abbreviations: RGT, response-guided therapy; TW, treatment week.
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
HCV RNA Assays—“Not Detected”
Is Required for Shortened Therapy

Below lower limit of quantification (LLOQ) but still
“detectable” is not sufficient to shorten therapy—ie,
patient should continue for 48 weeks
Harrington P, et al. Frequency and Clinical Relevance of Detectable/<LLOQ HCV RNA in Boceprevir
and Telaprevir Trials. United States Food and Drug Administration (FDA), FDA Division of Antiviral
Products; June 30, 2011.
SPRINT-2—BOC/PR: Overall SVR and
Relapse Rate by Cohort and Treatment Arm
SVR
211/
316
213/ 125/
311 311
22/
52
Relapse
29/
55
12/
52
21/
232
18/
230
37/
162
3/
25
Abbreviations: RGT, response-guided therapy; SVR, sustained virologic response.
Nonblack N = 938; black N = 159.
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
6/
35
2/
14
SPRINT-2—BOC/PR: SVR According
to HCV RNA Response at Week 8
HCV RNA
Undetectable Wk 8
170/ 166/ 48/
190 182 56
14/
18
18/
22
3/
4
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
HCV RNA
Detectable Wk 8
38/ 44/ 73/
104 102 233
8/
25
8/
29
8/
38
44% of all patients eligible for 28 weeks
Boceprevir—Treatment-Naive
Non-RGT Regimens
Poor Interferon Responsiveness1
Consideration should be given to extending treatment
for treatment-naive patients with poor interferon
responsiveness (< 0.5 or 1-log drop2) at week 4:
4 weeks of P/R followed by 44 weeks of B + P/R
Compensated Cirrhosis1
4 weeks of P/R followed by 44 weeks of B + P/R
1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
SPRINT-2—BOC/PR: SVR Based on
Week 4 Lead-In Response
IFN Responsiveness*
Poor IFN Response†
187/ 21/
228 73
178/ 31/
218 79
121/
234 3/62
Nonblacks
*Undetectable or ≥1-log decline.
†<1-log decline.
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
16/
24
6/
24
22/
36
5/
16
Blacks
12/
26
SPRINT-2—BOC/PR: SVR in
Advanced Fibrosis/Cirrhosis
213/
319
211/
313
123/
328
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
14/
34
22/
42
9/
24
Baseline predictors of SVR:
SPRINT-2
Effect
Odds Ratio (95% CI)
Baseline HCV-RNA:
≤400,000 vs. >400,000
IL-28B rs12979860 genotype:
CC vs. TT
IL-28B rs12979860 genotype:
CC vs. CTa
IL-28B rs12979860 genotype:
CT vs. TT
11.6 (1.5, 87.8)
P value
2.6 (1.3, 5.1)
0.02
0.006
2.1 (1.2, 3.7)
0.01
1.2 (0.7, 2.2)
0.48
Cirrhosis no vs. yes
Genotype: 1b vs. 1a
4.3 (1.6, 11.9)
2.0 (1.2, 3.4)
0.004
0.005
Race: non-black vs. black
2.0 (1.1, 3.7)
0.03
BMI ≤ 30 vs. >30
1.6 (1.0, 2.5)
0.07
Poordad et al. Gastroenterology 2012 in press
SVR Rate according to IL28B:
Boceprevir - SPRINT-2
Poordad F et al. EASL 2011
% Patients with
undetectable HCV-RNA
by TW8
BOC/PegIFN/RBV: IL-28B polymorphism is
a strong predictor of TW8 response
100
89
CC
82
CT + TT
80
60
52
51
40
20
118
132
0
158
304
SPRINT-2
41
50
80
156
RESPOND-2
Predictors of SVR include HCV RNA
decline at week 4: SPRINT-2
Odds Ratio (95% CI)
P value
Baseline HCV-RNA:
≤400,000 vs. >400,000
Decline in HCV-RNA at week 4
(≥ 1 vs. < 1 log10 decline)
Cirrhosis no vs. Yes
8.4 (1.0, 68.6)
0.046
8.2 (4.5, 15.0)
3.5 (1.1, 11.3)
<.0001
0.04
BMI ≤ 30 vs. >30
2.5 (1.4, 4.2)
0.001
Genotype: 1b vs. 1a/other/missing
2.1 (1.2, 3.6)
0.01
Race: non-black vs. black
1.8 (0.9, 3.6)
0.08
IL-28B rs12979860 genotype:
CC vs. TT
IL-28B rs12979860 genotype:
CC vs. CTa
IL-28B rs12979860 genotype:
CT vs. TT
1.2 (0.6, 2.7)
0.59
1.1 (0.6, 2.1)
0.76
1.1 (0.6, 2.2)
0.73
Effect
Poordad et al. Gastroenterology 2012 in press
SPRINT-2: SVR Based on Early Interferon
Response
% of Patients With SVR
PR48
All Patients (Cohort 1 + Cohort 2)
BOC/RGT
Log10 Viral Load Decrease After 4 week of P/R Lead-in
Vierling JM, et al. 46th EASL; Berlin, Germany; March 30-April 3, 2011: Abst. 481.
BOC/PR48
HCV RNA suppression after 4 weeks of
PegIFN/RBV according to IL28B genotype
Poordad et al. Gastroenterology 2012 in press
Telaprevir—RGT in
Treatment-Naive Patients
Telaprevir 750 mg TID, PEG IFN, and RBV
starting on day 1
HCV RNA
Recommendation
Undetectable at TW4
and TW12
Administer all 3 drugs through
TW12, then administer
PEG IFN/RBV through TW24
Detectable (≤1000 IU/mL) Administer all 3 drugs through
at TW4 and/or TW12
TW12, then administer
PEG IFN/RBV through TW48
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
ADVANCE—TVR/PR: Overall RVR,
eRVR, and SVR Rates
Patients eligible
to receive 24
wks of total
treatment
246/
246/ 242/
242/
363
363 364
364
(Wk 4)
34/
34/
361
361
212/
29
212/ 207/
207/
29
363
/361
363 364
364 /361
(Wk 4 and 12)
P <.001
P <.001
271/
158/
271/ 250/
250/ 158/
363
364
361
363
364 361
(Wk 24 postEOT)
Abbreviations: EOT, end of treatment; eRVR, extended rapid virologic response; P, peginterferon;
R, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; T, telaprevir.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
ILLUMINATE—TVR/PR: SVR and
Relapse Rates
388/
540
149/
162
SVR
140/
160
37/469
9/159
Relapse
Abbreviations: ITT, intent-to-treat; SVR, sustained virologic response.
Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.
4/154
ADVANCE: Week 4 HCV RNA not detected
according to IL28B genotype
SVR according to IL28B:
Telaprevir - ADVANCE
Jacobson et al. EASL 2011
Telaprevir—Treatment-Naive
NonRGT Regimens
Compensated Cirrhosis
Treatment-naive patients with cirrhosis and undetectable
HCV RNA at weeks 4 and 12 may benefit from continuing
PEG IFN/RBV through week 48
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
ADVANCE—TVR/PR: Impact of
Host and Viral Factors
Results from the
T12/PR24 Group
64/
82
207/
281
Low* High*
118/ 152/
149 213
1b
1a
Viral Load Genotype
*<800,000 IU/mL vs ≥800,000 IU/mL.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
244/
325
16/
26
109/
134
32/
52
Non- Black
black
F0-2 F3-4
Race
Fibrosis
Overview
Treatment-Naive Data
and Regimens
Treatment-Experienced Data
and Regimens
Futility Rules
Adverse Effects
Treatment-Experienced Patients
are Heterogeneous

Prior relapsers1
– Undetectable HCV RNA at the end of therapy but
detectable during follow-up

Prior partial responders1
– ≥2-log drop HCV RNA at week 12 but never
undetectable

Prior null responders
– <2-log drop HCV RNA at week 122,3

Included in telaprevir trials2

Excluded from boceprevir trials; Interferon
responsiveness assessed with 4 week lead-in3
1. Ghany MG, et al. Hepatology. 2009;49:1335-1374. 2. Zeuzem S, et al. N Engl J Med. 2011;364:24172428. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
Boceprevir—RGT in Prior Partial
Responders or Relapsers Without Cirrhosis
PEG IFN/RBV for 4 weeks,
followed by boceprevir 800 mg TID + PEG IFN/RBV
HCV RNA
TW8
TW24
Undetectable Undetectable
Detectable
Undetectable
Recommendation
Complete 3-medicine
regimen at TW36
Continue all 3 medicines
through TW36, then
administer PEG IFN/RBV
through TW48
Abbreviations: RGT, response-guided therapy; TW, treatment week.
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
RESPOND-2—BOC/PR: Relapsers and
Partial Responders
95/ 107/ 17/
162 161 80
23/
57
30/
58 2/29
72/ 77/ 15/
105 103 51
Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d;
RGT, response-guided therapy;
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
Boceprevir—Treatment-Experienced
Non-RGT Regimens
Compensated Cirrhosis
4 weeks of P/R followed by 44 weeks of B + P/R
Null Responders
4 weeks of P/R followed by 44 weeks of B + P/R
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
RESPOND-2—BOC/PR: SVR by Week 4
Lead-In Response to Peginterferon/Ribavirin
15/
46
15/
44
80/
110
90/
114
17/
67
Change in HCV RNA from Baseline
Abbreviations: B, boceprevir 800 mg TID; P, PEG IFN -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d;
RGT, response-guided therapy.
With permission from Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
RROVIDE: SVR and Relapse Rates,
by Prior Treatment Response
19/47 53/78
5/9
81/138
3/22
9/62
SVR was also achieved in all 4 patients with ‘other’ prior non-response.
1/6
13/94
Telaprevir—RGT in
Prior Relapsers
Telaprevir 750 mg TID, PEG IFN, and RBV
starting on day 1
HCV RNA
Recommendation
Undetectable at TW4
and TW12
Administer all 3 drugs through
TW12, then administer
PEG IFN/RBV through TW24
Administer all 3 drugs through
Detectable (≤1000 IU/mL)
TW12, then administer
at TW4 and/or TW12
PEG IFN/RBV through TW48
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
Telaprevir—Non-RGT in
Prior Partial or Null Responders
Telaprevir 750 mg TID, PEG IFN, and RBV
starting on day 1
Recommendation
Administer all 3 drugs through TW12,
then administer
PEG IFN/RBV through TW48
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
REALIZE: SVR by Baseline Fibrosis Stage
and Prior Response
Prior
relapsers
Prior partial
responders
Prior null
responders
Pooled T12/PR48
SVR (%)
Pbo/PR48
n/N=
144/167 12/38
Stage
No, minimal Bridging
or portal
fibrosis
fibrosis
53/62 2/15
48/57 2/15
34/47 3/17
10/18
0/5
Cirrhosis No, minimal Bridging
or portal
fibrosis
fibrosis
Zeuzem S, et al. N Engl J Med 2011;364:2417-27
11/32
1/5
24/59 1/18
15/38
0/9
Cirrhosis No, minimal Bridging
or portal
fibrosis
fibrosis
7/50
1/10
Cirrhosis
SVR by Response at Week 4 in
Lead-In Arm of REALIZE:
HCV RNA at Week 4 in Nonresponders
94
%
62
59
56
54
15
Decline in HCV RNA at week 4
Foster G et al, EASL 2011
Overview
Treatment-Naive Data
and Regimens
Treatment-Experienced Data
and Regimens
Futility Rules
Adverse Effects
Boceprevir—Futility (Stopping)
Rules
STOP
ALL
DRUGS
Week 12 HCV RNA ≥100 IU/mL
OR
Week 24 HCV RNA confirmed detectable
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
Retrospective Analysis of SPRINT-2 Underscores
Validity of BOC Futility Rules
• Earliest 100% negative predictive time point for SVR which spared
largest number of patients from continuing failing regimen was
HCV RNA ≥ 100 IU/mL at Week 12
Stopping Rule
Stopped by
TW12 Rule, n
Additional
stopped by TW24
rule , n
Total Stopped, n
SVR missed
using TW12
rule, n
> LLD, 9.3 IU/mL
144
20
164
21
> LLQ, 25 IU/mL
83
41
124
5
≥ 50 IU/mL
78
43
121
4
≥ 100 IU/mL
65
49
114
0
≥ 1000 IU/mL
43
61
104
0
< 2 log decline
24
71
95
0
< 3 log decline
34
66
100
0
Jacobson IM, et al. AASLD 2011. Abstract 954.
Telaprevir—Futility (Stopping)
Rules
STOP
ALL
DRUGS
Week 4 and/or Week 12 HCV RNA >1000 IU/mL
OR
Week 24 HCV RNA confirmed detectable
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
Retrospective Analysis of TVR Ph III Trials
Underscores Validity of TVR Futility Rules

No pt with HCV RNA > 1000
IU/mL at Wk 4 (n = 25) or Wk
12 (n = 12) had SVR
Viral kinetic analysis of pts
with HCV RNA > 1000 IU/mL
at Wk 4
–
–

23 of 25 reached HCV RNA
nadir before Wk 4
In most pts, HCV RNA already
increasing from nadir by Wk 4
Emergence of TVR-resistant
variants in most pts with HCV
RNA > 1000 IU/mL at Wk 4
Tx Naive (n = 14)
Tx Experienced (n = 11)
108
HCV RNA, IU/mL

107
108
107
106
106
105
105
104
104
103
103
102
102
10
10
0
2
4
6
8
10 12
Wks on Treatment
0
2
4
6
8
10 12
Wks on Treatment
Level of TVR
Resistance
Tx-Naive Pts With HCV RNA
> 1000 IU/mL at Wk 4, n (n = 14)
Tx-Exp’d Pts With HCV RNA
> 1000 IU/mL at Wk 4, n (n = 11)
V36M + R155K
High
12
8
A156S/T/V
High
1
0
R155K
Low
0
2
Wild type
None
1
1
HCV NS3/4A
Variant
Jacobson IM, et al. EASL 2012. Abstract 55.
Overview
Treatment-Naive Data
and Regimens
Treatment-Experienced Data
and Regimens
Futility Rules
Adverse Effects
Drug Interactions with Telaprevir and
Boceprevir
 BOC
and TVR are CYP3A4 inhibitors
 Drug interactions may affect blood levels of either PI or
Inhibitor
co-administered drug
AUC
Drug + Inhibitor
Inhibitor blocks
the function of
the CYP enzyme
Inducer
AUC
P450
• Caution is needed with ALL co-administered medications
–
–
–
–
Review package inserts for interaction lists
Reconcile patient medication list
Patient needs to communicate new meds started by other health care providers
Other resource: hcvadvocate.org; hep-druginteractions.org
Boceprevir [package insert]. May 2011.
Telaprevir [package insert]. March 2012.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Figure adapted from: Back D. Drug-drug interactions (in relation to HCV). Presented at: 7th International Workshop on
HIV & Hepatitis Co-infection; June 1-3, 2011; Milan, Italy. Lecture.
Drug-Drug Interaction Resource
Boceprevir Triple Therapy—
Adverse Effects
Pooled Data from Treatment-Naive Population
(SPRINT-1, SPRINT-2)
Adverse
Effect
Boceprevir +
PEG IFN/RBV
(n = 1225)
PEG
IFN/RBV
(n = 467)
Anemia*
50%
30%
Neutropenia
25%
19%
Dysgeusia
35%
16%
*Anemia
was managed with erythropoiesis-stimulating agents, with or without RBV dose reduction
(boceprevir + PEG IFN/RBV, 43%; PEG IFN/RBV, 24%).
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
Randomized controlled trial: RBV dose
reduction Vs. EPO for anemia during
BOC + PegIFN/RBV
• 687 HCV genotype 1, treatment naïve patients enrolled
•Hb at screening < 15 g/dL for men and women
• 500 met protocol defined anemia and were randomized:
RBV DR, n=249; EPO, n=251
Anemia Management: Erythropoietin vs Ribavirin
Dose Reduction Primary and Key Efficacy End Points

End-of-treatment response, relapse, and SVR were
comparable between RBV DR and EPO arms
Patients, %
 (95% CI)
–0.7% (– 8.6 , 7.2)*
203/249
205/251
178/249
178/251
19/196
CI, confidence interval; DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin;
SVR, sustained virologic response.
*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort.
Poordad F et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1419.
19/197
Patients, %
Anemia Management: Erythropoietin vs
Ribavirin Dose Reduction SVR by Secondary Anemia Intervention
Secondary Anemia Intervention
DR, dose reduction; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response.
Poordad F et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1419.
BOC/PR: Exposure-Response
Relationships for Anemia
% of Pts with Anemia from P05101
and P05216 vs Boceprevir
% of Pts with Anemia from P05101
and P05216 vs RBV steady-state AUC
Observations were binned as quartiles and plotted at the median quartile value. The total
number of subjects with hemoglobin <10 g/dL for each quartile and total number of subjects
per quartile bin (in parentheses) are shown along the x-axis.
US Food and Drug Administration; April 27, 2011.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisory
Committee/UCM252341.pdf. Accessed April 26, 2011.
Telaprevir Triple Therapy—
Adverse Effects
Pooled Data from Treatment-Naive and -Experienced
Populations (ADVANCE, ILLUMINATE, REALIZE)
Adverse
Effect
Telaprevir +
PEG IFN/RBV
(n = 1797)
PEG IFN/RBV
(n = 493)
Rash
56%
34%
Anemia*
36%
17%
Anorectal Effects
29%
7%
*Anemia was managed with RBV dose reduction; ESA not permitted. (Telaprevir + PEG
IFN/RBV, 32%; PEG IFN/RBV, 12%).
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
Nadir Hemoglobin, Discontinuation for
Anemia, and Median Hemoglobin Levels
Hemoglobin nadir during TVR/Pbo Phase
T8PR
N=364
PR
N=361
Hemoglobin <10 g/dL
36
40
14
Hemoglobin <8.5 g/dL
9
9
2
% of Patients with
•
•
Per protocol, anemia was to be managed
with RBV dose modifications and ESAs
were not allowed
1%, 3% and 1% of patients in T12PR,
T8PR and PR, respectively discontinued
all drugs due to anemia events
TVR
….
TVR
Median Hemoglobin (g/dL)
T12PR
N=363
Median Hemoglobin
15
14
T12PR (n=363)
T8PR ( (n=364)
13
PR (control) (n=361)
12
11
•
4%, 2% and 0% of patients in T12PR,
T8PR and PR, respectively discontinued
telaprevir/placebo only
0
0
4
8
12
16
Weeks
Jacobson IM, et al.N Engl J Med 2011;364:2405-16
20
24
Telaprevir Treatment-Naïve Studies:
RBV dose reduction was common
Treatment-naïve Patients From ADVANCE and ILLUMINATE During the Overall Treatment
Phase (T12PR, N=885)
SVR According to Minimum Ribavirin Dose/Day
During Telaprevir Treatment Phase
Ribavirin dose reduction:
Proportion of Patients who Achieved SVR
Treatment Naïve (T12PR)
0-4 Weeks Post
First Dose
n/N = 160/221
>4-12 Weeks Post
First Dose
>12-24 Weeks Post
First Dose
>24-48 Weeks Post
First Dose
171/237
85/99
36/43
Timing of First Ribavirin Dose Reduction
Sulkowski M et al. 47th EASL; Barcelona, Spain; April 18-22, 2012. Abst. 1162.
Advisory Committee Briefing Materials for
Telaprevir: RBV Effect on Hemoglobin Toxicity
Effect of Ribavirin (RBV) Exposure on
Hemoglobin Toxicity
Hemoglobin toxicity of
Grade 2+ (Grade 2+ Hgb Tx)
was defined as Hgb < 10
g/dL or any decrease from
baseline
>3.5 g/dL. Vertical bars
represent rates of Hgb
toxicity in each quartile of
AUC. The horizontal bar
along the AUC axis
represents the distribution of
AUC 3rd (5%-95%, 1st to 3rd
quartile, mean, median).
Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugs
AdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.
Telaprevir—Rash Summary from
Pooled Safety Database


Rash was primarily eczematous
–
Mild to moderate in most
–
Severe rash in 4%
–
May occur at any time during telaprevir exposure
Led to discontinuation of telaprevir in 6%
–

Serious skin reaction in <1%, including Stevens-Johnson
Syndrome or DRESS
Treat with oral antihistamines and/or topical
corticosteroids
–
Systemic steroids are not recommended
Abbreviation: DRESS, Drug Rash with Eosinophilia and Systemic Symptoms.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
Severe Rash on Telaprevir
Rash Management
Rash description
Management
Mild: Localized, limited distribution, with or without
pruritus
• Continue all drugs
• Monitor for rash progression or development of
systemic symptoms
• TVR dose should not be reduced or interrupted
• Oral antihistamines and /or topical corticosteroids
• Systemic corticosteroids not recommended
• Good skin care practices
Moderate: Diffuse (up to 50% BSA) with or without
superficial skin peeling, pruritus, or mucous membrane
involvement with no ulceration
Severe: Generalized rash involving either >50% BSA
or any of the following:
• Vesicles or bullae
• Superficial ulceration of mucous membranes
• Epidermal detachment
• Atypical or typical target lesions
• Palpable purpura, non-blanching erythema
• Discontinue TVR; continue Peg-IFN/RBV
• If no improvement within 7 days (or earlier if
indicated), consider discontinuation of Peg-IFN
and/or RBV
• Good skin care practices
• Refer to dermatologist
• Oral antihistamines and/or topical corticosteroids
• Systemic corticosteroids not recommended
Serious skin reactions: Toxic epidermal necrolyosis,
SJS, DRESS, acute generalized exanthematous
pustulosis, rash that requires therapy with systemic
corticsteroids, erythema multiforme (not lifethreatening)
• Discontinue all medications immediately
• Refer for urgent medical care
Cacoub P, et al. J Hepatol. 2012;56:455-463.
Adherence is critical
Typical Student
Monday

Triple therapy
presents challenges
[143]

TID dosing
–
Food requirements
Data show
pegIFN/RBV
adherence decreases
over time[5]
–
Addition of PIs may
exacerbate this
trend
Monday
6:00 AM TVR/BOC (with food) + RBV
TVR/BOC (with food) + RBV
7:00 AM
8:00 AM
9:00 AM
–
Busy Sales Professional
Daily Team Conference Call
Patient Appointments
English Composition
12:00 PM
Lunch
Lunch
Biology
TVR/BOC
(with food)
4:00 PM
Work
TVR/BOC
(with food)
Travel to and
Meet With
Clients
5:00 PM
Dinner
RBV
7:00 PM
8:00 PM
1. Telaprevir [package insert]. May 2011.
2. Boceprevir [package insert]. May 2011.
9:00 PM
3. EMA. Boceprevir [package insert] 2011.
4. EMA. Telaprevir [package insert] 2011.
10:00 PM
5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
Dentist Appt
Patient
Appointments
TVR/BOC (with
food)
Calls to Clients
3:00 PM
6:00 PM
Travel to and Meet With
Client
Lunch
1:00 PM
2:00 PM
TVR/BOC (with food) + RBV
Wake, feed, and dress children
for school
School and daycare drop-off,
commute to work
Chemistry Lab
10:00 AM
11:00 AM
Mother With Small Children
and Full-time Nurse
Monday
Pick up kids, commute home
RBV
Running Club
Study Group
Dinner
Researching Trade Articles
TVR/BOC (with food)
TVR/BOC (with food)
Dinner
RBV
Get children ready for and in to
bed
Dinner cleanup, make lunches
for next day
TVR/BOC (with food)