Treating a patient with liver cirrhosis
“What is happening in real life ?”
Mr. UB, 35 yrs old Turkish engineer living in
Switzerland, highly intelligent,
typical patient of the “informative age”
we live in; knows “a lot” on hepatitis C
treatment, is managed in Switzerland
and Turkey by Swiss and Turkish physicians
Ankara Uni.
16 March 2005:
• ALT: 84 (N< 40), AST: 64 (N <40)
• Alk. Phosphatase: 193 (N <120)
• GGT: 115 (N <50)
• HBsAg and Ab negative, anti HCV positive
• T. Bilirubin: 11.2 (N <17)
• Prothrombin activity: 54%, INR: 1.3
• Albumin: 4g/dL
• Ultrasound: consistent with cirrhosis,
diffuse splenomegaly, no ascites
• Liver biopsy (Metavir): F4, A1
• Endoscopy: Grade II esophageal varices
• Child- Pugh score: 6
• HCV RNA: 4 480 000 IU/mL (7.65 log)
• Viral genotype: 1a
Ankara Uni.
What would you do ?
No treatment, FU with US for HCC and
preparation for future liver tx
2. Tx with standard dose and duration of
pegylated INF/riba
3. Tx with standard dose and prolonged
duration of pegylated INF/riba
4. Titrated tx with peg/riba
5. Start with triple tx
1.
Ankara Uni.
Patient asked for “maximal” therapy !
15.04.2005: Treatment started with PEG2a
180µg/qw + Ribavirin 1200 mg/qd with the
intention to use higher doses of ribavirin,
subject to patient’s tolerability
Ankara Uni.
Tx start date: 15.04.2005
01.04.05
17.05.05
10.06.05
08.07.05
Hb
17.2
14.8
14.1
13.5
Plat.
71
51
44
52
WBC
6.9
3.8
3.1
2.4
Neut.
4.7
1.4
1.2
1.0
T. Bili
30.8
22.0
22.6
24.8
ALT
116
124
107
119
INR
1.3
1.4
1.4
1.2
HCV RNA
7.65 log
NA
NA
3.11 log
At month 3: HCV RNA ↓ by > 2 log
Ursodeoxycholic acid (1000mg/qd) added in 08/2005,
Ribavirin dose increased to 1600 mg/day
Ankara Uni.
•Undetectable since at least week 20 of
treatment commencement
•After 48 weeks of treatment HCV
undetectable
Ankara Uni.
What would you do now ?
1. Discontinue treatment
2. Continue tx with the same regimen to week 72
3. Continue tx with “maintenace dose” for
Pegasys and Ribavirin dose to 90 µg
Ankara Uni.
Situation in depth discussed with patient.
Patient did not want to risk relapse.
It was decided to continue treatment.
Patient did not want to decrease dose
of neither Pegasys nor Ribavirin.
Ankara Uni.
Tx start date: 15.04.2005
April 2005
July 2005
Sep 2005
March 2006
June 2006
ALT
116
119
67
43
38
AST
77
110
88
98
69
T. Bili
30.8
24.8
27.7
34.4
38.1
INR
1.3
1.2
1.3
1.5
1.6
Albumin
4.0
NA
NA
3.3
2.7
HCV RNA
7.65 log
3.11 log
< 15 IU/mL
< 15 IU/mL
< 15 IU/mL
Ankara Uni.
Patient Case 1
• HPI: A 58-year-old woman with newly diagnosed HCV. She
had a blood transfusion at age 28. Current symptoms:
fatigue and myalgias
• PMH: mild depression
• Medications:
– Escitalopram 10 mg po QD, atorvastatin 10mg po QD
• Evaluation:
–
–
–
–
–
HCV genotype 1b
HCV RNA: 1.6 million IU/mL
CBC/platelets and TSH: normal
Ultrasound: increased echogenicity in liver, otherwise normal
Liver biopsy: bridging fibrosis
• Patient decides to start therapy
– Telaprevir + PEG-IFN + RBV
1
0
What would you tell this patient about
her chances of SVR with a course of
PI-based therapy?
A.
B.
C.
D.
SVR rate cannot be estimated
SVR rate ~25%-35%
SVR rate ~40%-50%
SVR rate ~70%
HCV Treatment Decisions for
Protease Inhibitors
Pros
Cons
• PIs substantially increase
chance of SVR across a
majority of patient groups
• Suboptimal response rates
or limited/no data in several
populations
• PIs shorten duration of
therapy in many
• Successful treatment
improves morbidity and
mortality
– HCV-HIV co-infection, tranplant,
decompensated cirrhotics
• Complicated regimens,
challenging AEs, and DDIs
• Risk of resistance if therapy
fails: impact on future
options?
Identifying Candidates For Triple
Therapy
Host factors
Treatment regimen
Age, gender, race
obesity, co-morbidities
Genetic factors
(IL28B and ITPA)
PEG-IFN
Ribavirin
DAA
Factors to Consider In
Treatment Decisions
Disease features
Fibrosis, steatosis,
co-infection
(HBV, HIV)
Viral factors
Genotype / Subtype
Quasispecies /
Resistance
Viral load
Candidates for PI-Based Triple Therapy
• Chronic HCV genotype 1
• Fulfill criteria for PEG-IFN/RBV therapy
• If cirrhotic, should be well-compensated
– No variceal hemorrhage, ascites, encephalopathy
• Ability to adhere to treatment goals and
monitoring
• Safety and efficacy has not been established in
HIV or HBV coinfected, pediatric, or pregnant
patients or in organ transplant recipients
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
SPRINT 2: SVR and Relapse Rates (ITT)
Boceprevir: Treatment-naïve HCV G1 patients
SVR*
Relapse Rate
P < 0.001
P = 0.004
P < 0.001
P = 0.04
125
311
37
162
211
316
21/232
213
311
18/230
Non-Black Patients
*All Pts who received treatment
Data from Poordad F, et al. N Engl J Med. 2011;364(13):1195-1206.
12
52
2/14
22
52
3/25
Black Patients
29
55
6
35
ADVANCE: Higher SVR Rates in
Patients Achieving eRVR
Telaprevir: Treatment-naïve HCV G1 patients
97
100
P<0.001
90
SVR, %
80
89
75
T12PR
PR48
31%
70
60
50
54
44
39
40
30
10
0
271/363 158/361
Treatment-naïve
Overall
189/212
28/29
eRVR+
82/151 130/332
eRVR-
• 58% of Pts eligible for RGT (received 24 weeks of TVR-based regimen)
• SVR rates 89% in T12PR
Data from Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Prior to starting PI-based therapy, how
would you counsel the patient regarding
management of her depression?
A. Patients on antidepressants cannot receive
PI-based therapy
B. St. John’s wort is okay to use with PIs
C. Some antidepressants may need to have
doses adjusted during treatment with a PI
D. Patients with a history of depression should
not receive PI-based therapy
Pre-Treatment Evaluation: DDI with PIs
• BOC and TVR are CYP3A4 inhibitors
• Drug interactions may affect blood levels of either PI or
co-administered drug
Inhibito
10
Drug + Inhibitor
Inhibitor blocks
the function of
the CYP enzyme
P450
r
AUC 5
Inducer
AUC 1
1
• 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: www.hep-druginteractions.org
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Ghany MG, et al. Hepatology. 2011;54(4):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.
Patient Case 1 (continued)
• Medications: escitalopram 10 mg po QD,
atorvastatin 10mg po QD
– Do you need to make any changes to the
patient’s medications?
Drug Interactions Considerations
Concomitant
Drug Class
Drug(s) with
Interaction
PI
Involved
CONTRAINDICATED:
•May lead to loss of virologic response
( concentrations of PIs)
St. John’s
Wort
Antidepressants
Trazodone,
Desipramine
Effect on Concentration of PI
or Concomitant Drug
BOC or
TVR
 trazodone,  desipramine:
• Dizziness, hypotension, and
syncope
• Use with caution; consider lower
doses of trazodone/desipramine
Escitalopram
TVR
↔ telaprevir,  escitalopram:
•Dose of escitalopram may need to be
adjusted
Lovastatin,
Simvastatin
BOC or
TVR
CONTRAINDICATED:
• Potential for myopathy including
rhabdomyolysis
BOC
 atorvastatin:
•Titrate slowly; max dose of 20 mg/d
TVR
CONTRAINDICATED
Statins
Atorvastatin
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Birth Control and Pregnancy During
Triple Therapy
• Systemic hormonal contraceptives should not be
relied on as an effective method of contraception
– 2 alternative methods of contraception (barrier
methods or IUDs) should be used during
treatment and for 6 months after
• Triple therapy is contraindicated in pregnant women
and men whose female partners are pregnant
– Ribavirin may cause birth defects and fetal death
– Negative pregnancy test prior to therapy &
monthly during therapy
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Telaprevir: Treatment-Naïve & Prior Relapse Patients
Chronic HCV Genotype 1, telaprevir 750 mg (two 375 mg tablets) orally 3 times
daily (7-9 hrs apart) with food (~ 20 gm fat†)
0
Treatment
Decision
Points
Initiate
antiviral
treatment
4
End of 4
Weeks
12
End of 12
Weeks
Telaprevir + PEG-IFN + RBV
4-week HCV-RNA
24
End of 24
Weeks
PEG-IFN + RBV
12-week HCV-RNA
eRVR
undetectable
at weeks 4 & 12
Responseguided
therapy
48
End of 48
Weeks
PEG-IFN + RBV
Treatment
complete
@ 24 weeks
Tx-naïve w/
cirrhosis‡
†Ingest
food within 30 minutes prior to dose
~20 gm fat: Bagel w/cream cheese; 1/2 cup nuts; 3 tbsp
peanut butter; 1 cup ice cream; 2 oz American or cheddar
cheese; 2 oz potato chips; 1/2 cup trail mix.
Treat for
48 weeks
‡Treatment-naïve
patients with cirrhosis who have
undetectable HCV-RNA at weeks 4 and 12 may benefit
from an additional 36 weeks of PEG-IFN/RBV
(48 weeks total)
For telaprevir, HCV-RNA at wk 4 and wk 12 determine duration of therapy
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Telaprevir: Treatment-Naïve & Prior Relapse Patients
Chronic HCV Genotype 1, telaprevir 750 mg (two 375 mg tablets) orally 3 times
daily (7-9 hrs apart) with food (~ 20 gm fat)
0
Treatment
Decision
Points
Initiate
antiviral
treatment
4
End of 4
Weeks
12
End of 12
Weeks
Telaprevir + PEG-IFN + RBV
4-week HCV-RNA
24
End of 24
Weeks
PEG-IFN + RBV
48
End of 48
Weeks
PEG-IFN + RBV
12-week HCV-RNA
Detectable
Responseguided
therapy
≤1000 IU/mL at
weeks 4 and/or 12
Treatment
complete
@ 48 weeks
For telaprevir, HCV-RNA at wk 4 and wk 12 determine duration of therapy
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Telaprevir: Stopping Rules
0
Treatment
Decision
Points
Initiate
antiviral
treatment
Stopping
Rules
4
End of 4
Weeks
12
End of 12
Weeks
Telaprevir + PEG-IFN + RBV
24
End of 24
Weeks
PEG-IFN + RBV
4-week
HCV-RNA
12-week
HCV-RNA
24-week
HCV-RNA
> 1000 IU/mL
> 1000 IU/mL
Detectable
Treatment
failure
Treatment
failure
Treatment
failure
Stop
Stop
Stop
Apply to
all patients
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
48
End of 48
Weeks
Boceprevir: Treatment-Naïve Patients
Chronic HCV Genotype 1, boceprevir 800 mg (four 200-mg capsules) 3 times daily
(7-9 hrs apart) with food
0
4
Treatment
Decision
Points
Initiate
antiviral
treatment
8
12
End of 8
Weeks
PEGIFN+RBV
End of 12
Weeks
24
28
36
48
End of 24
Weeks
Boceprevir + PEG-IFN + RBV
8-week HCV-RNA
Responseguided
therapy
24-week HCV-RNA
Continue Treatment
Undetectable
Undetectable
Treatment complete
@ 28 wks
For boceprevir, HCV-RNA at wk 8 and wk 24 determine duration of therapy
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Boceprevir: Treatment-Naïve Patients
Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily
(7-9 hrs apart) with food
0
4
Treatment
Decision
Points
Initiate
antiviral
treatment
8
End of 8
Weeks
PEGIFN+RBV
12
End of 12
Weeks
24
28
End of 24
Weeks
36
48
End
of 48
Wks
PEGIFN+
RBV
Boceprevir + PEG-IFN + RBV
24-week HCV-RNA
8-week HCV-RNA
Stop BOC at Wk 36
Responseguided
therapy
Continue Treatment
Detectable
Undetectable
Treatment
complete @
48 wks
For boceprevir, HCV-RNA at wk 8 and wk 24 determine duration of therapy
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Boceprevir: Treatment-Naïve Patients
Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily
(7-9 hrs apart) with food
0
4
Treatment
Decision
Points
Initiate
antiviral
treatment
8
End of 8
Weeks
PEGIFN+RBV
Poorly IFNresponsive*
12
End of 12
Weeks
24
28
End of 24
Weeks
36
48
End
of 48
Wks
Boceprevir + PEG-IFN + RBV
Triple therapy
for 44 weeks
< 1 log10 IU/mL
decline in viral
load at Wk 4
Treatment
complete @
48 wks
*Standard stopping rules assessed at Wk 12 and 24 still apply
Assess interferon responsiveness after lead-in with PEG-IFN/RBV
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Boceprevir: Stopping Rules
4
0
Treatment
Decision
Points
Initiate
antiviral
treatment
Stopping
Rules
Apply to all
patients
8
End of 8
Weeks
PEGIFN
+RBV
12
End of 12
Weeks
24
End of 24
Weeks
28
36
End
of 48
Wks
±BOC +
PEG-IFN+
RBV
Boceprevir + PEG-IFN + RBV
12-week
HCV-RNA
24-week
HCV-RNA
≥ 100 IU/mL
Detectable
Treatment
failure
Treatment
failure
Stop
Stop
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
48
HCV-RNA Levels and Lab Assays
• “Undetectable” result is
required for assessing
RGT eligibility
• Below LLOQ but still
“detectable” is not
sufficient to shorten
therapy—ie, patient should
continue for full 48 wks
LLOQ Values for Various Assays
Assay Name
LLOQ
Roche COBAS®
AmpliPrep/COBAS®
TaqMan® HCV Test
43 IU/mL
Roche COBAS® TaqMan® 25 IU/mL†
HCV Test, v2.0
Abbott RealTime HCV
Assay
12 IU/mL
† Usually
considered 25 IU/mL, but 23 IU/mL per
FDA-approved label
COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. Roche Molecular Diagnostics. http://molecular.roche.com /
assays/Pages/COBASAmpliPrepCOBASTaqManHCVTest.aspx. Accessed July 19, 2011.
Harrington P, Naeger L. 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.
Telaprevir and Boceprevir Adverse Events
Adverse Events Reported More Frequently vs PEG-IFN/RBV
Telaprevir1
Adverse Event, %
Telaprevir-Containing Arms
(n = 1797)
PEG-IFN/RBV Arm
(n = 493)
Rash
56
34
Pruritus
47
28
Anemia*
36
17
Anorectal AEs**
29
7
*No EPO used in TVR trials; EPO commonly used in BOC trials
**hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning
Boceprevir2
Adverse Event, %
Boceprevir-Containing Arms
(n = 734)
PEG-IFN/RBV Arm
(n = 363)
Anemia*
45-50
20-30
Dysgeusia
35-44
11-16
1Incivek
(telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
(boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
2Victrelis
Telaprevir: Rash Summary
• In most subjects, the rash was mild-moderate
– Typically eczematous, maculopapular, and
papular-lichenoid
• 4% severe—resulted in discontinuation of
telaprevir in 6% of subjects
• < 1% SJS or drug rash with eosinophilia and
systemic symptoms (DRESS)
• Can occur at anytime
• Improvement occurs after dosing completion or
D/C; may take weeks for complete resolution
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.
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Drug Rash Due to Telaprevir
Slide courtesy of Dr. Stuart Gordon
Rash Management Plan: Telaprevir
Rash
Description
Management
Mild to
moderate
rashes
—
—
—
•
Continue all drugs; TVR dose should not be reduced or interrupted
Monitor for rash progression or development of systemic symptoms
Oral antihistamines and/or topical corticosteroids
Systemic corticosteroids are not recommended*
Severe rash — Discontinue TVR, continue PEG-IFN/RBV
— If no improvement within 7 days (or earlier if indicated), consider D/C
of PEG-IFN and/or RBV
— Oral antihistamines and/or topical corticosteroids
• Systemic corticosteroids are not recommended*
— Consider dermatology consult
Serious skin reactions (SJS or DRESS): Discontinue all medications
immediately; Refer for urgent medical care
All patients
with rash
Consider good skin care practices: limit sun exposure, wear loosefitting clothing, use oatmeal or baking soda baths, apply moisturizers at
least twice daily after bathing, laundry with mild, unscented detergents
*Systemic corticosteroids & telaprevir drug-drug interactions: prednisone/methylprednisolone (CYP3A substrates) and
telaprevir (potent CYP3A inhibitor) – plasma concentrations of corticosteroids can be increased significantly. Systemic
dexamethasone (induces CYP3A) can decrease telaprevir plasma concentrations (may result in loss of therapeutic effect)
Vertex Medical Information Letter: Rash in patients receiving Incivek (telaprevir) combination treatment. Published July 2011.
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
On-Treatment Consideration for
Managing Triple Therapy in the
Treatment-Experienced Patient
Patient Case 2
• HPI: 58-year-old woman with HCV Genotype
1a
– Biopsy in 2003 showed cirrhosis
– No evidence of clinical decompensation
• MELD = 8 and platelet count was 115,000/mm3
• CT scan with contrast reveals nodular liver but
no HCC
– Her most recent treatment course was
PEG-IFN alfa-2a + RBV
• She is anxious to start therapy with an HCV
protease inhibitor
Considerations for TreatmentExperienced Patients in 2011-2012
• Likelihood of response to PI/PEG-IFN/RBV
– Previous response pattern
– Viral factors
• HCV genotype and HCV RNA level
– Host factors
• IL28B genotype
• Race
• Obesity/insulin resistance
• Likelihood of clinical disease progression
– Advanced fibrosis / cirrhosis
• Likelihood of tolerating PEG-IFN/RBV + protease inhibitor
Definitions of Prior Response
Response
Definition
Evaluated in
clinical trials?
Partial
Response
HCV RNA decline ≥ 2 log10 IU/mL from
baseline at week 12, but never achieved
undetectable HCV RNA
BOC: Yes
TVR: Yes
Relapse
HCV RNA undetectable at the end of
therapy, but detectable HCV RNA during
follow-up
BOC: Yes
TVR: Yes
Null Response HCV RNA decline < 2 log10 IU/mL from
baseline at week 12 of prior therapy
BOC: Yes*
TVR: Yes
*PROVIDE study, AASLD 2011
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011. 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/AntiviralDrugsAdvisoryCommittee/UCM252561
.pdf. Accessed April 26, 2011. VierlingJM, et al. Poster presented at: AASLD The Liver Meeting 2011; November 4-8,
2011; San Francisco, CA. Poster 931.
Patient Case 2 (continued)
• Prior treatment course resulted in ~ 2.1 log10
reduction in HCV RNA after 12 weeks with no
further decrease after 24 weeks; stopped at
24 weeks
– She developed hypothyroidism and is on
replacement therapy
– During prior therapy, Hgb decline was
~4 g/dL, but RBV was not reduced
– No PEG-IFN dose reductions
– IL28B genotype is not known
RESPOND-2: SVR in Prior Relapsers
and Prior Partial Responders
Prior Relapsers
n/N=
Prior Partial
Responders
15
51
72
105
77
103
2
29
27
57
30
58
PR48
BOC
RGT
BOC/
PR48
PR48
BOC
RGT
BOC/
PR48
HCV G1 patients with previous treatment failure
Bacon B, et al. N Engl J Med. 2011;364(13):1207-1217. Copyright © 2011 Massachusetts Medical Society.
REALIZE: SVR in Prior Relapsers, Prior Partial
Responders, and Prior Null Responders
Prior
Relapsers
*
Prior Partial
Responders
Prior Null
Responders
*
SVR (%)
*
*
*
n/N =
*
Pbo/ T12/ LI T12/
PR48 PR48 PR48
Pbo/
PR48
T12/ LI T12/
PR48 PR48
Pbo/
PR48
T12/ LI T12/
PR48 PR48
16/68 121/145 124/141
4/27
29/49
2/37
21/72
Data from Zeuzem S, et al. N Engl J Med. 2011;364(25):2417-2428.
26/48
25/75
*P < 0.001 vs Pbo/PR48
REALIZE: SVR by Baseline Fibrosis
Stage and Prior Response
Prior Partial
Responders
Prior Null
Responders
SVR (%)
Prior
Relapsers
n/N =
Stage
12/38 144/167 2/15
53/62 2/15
48/57 3/17
34/47
0/5
10/18
1/5
11/32
1/18 24/59
0/9
15/38 1/10
No, minimal Bridging Cirrhosis No, minimal Bridging Cirrhosis No, minimal Bridging
or portal
fibrosis
or portal
fibrosis
or portal
fibrosis
fibrosis
fibrosis
fibrosis
7/50
Cirrhosis
Zeuzem S, et al. Presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany.
Oral Presentation 5.
Patient Case 2 (continued)
• She is a prior “partial responder” with slightly more
than 2 log10 decline
– Last treatment ~ 2003
– Biopsy showed cirrhosis
– In the interval, she has developed type 2 diabetes
mellitus, controlled with metformin
– She is also taking simvastatin and lisinopril
• Current Hgb 13.8 g/dL, platelet count 111,000/mm3
and HCV RNA 1.74 million IU/mL (6.24 log10)
• Is there a role for IL28B testing prior to treatment?
SVR Rates by IL28B Genotype in Subjects who
Previously Failed Therapy
Genetic Variant Near the Gene Encoding Interferon-lambda-3
(IL28Brs12979860, a C to T Change)
IL28B
Genotype
RESPOND-2:
Boceprevir
PR48
BOC-RGT
BOC-PR48
C/C
46 (6/13)
79 (22/28)
77(17/22)
C/T
17 (5/29)
61 (38/62)
73 (48/66)
T/T
50 (5/10)
55 (6/11)
72 (13/18)
IL28B
Genotype
REALIZE:
Telaprevir
SVR, % (n/N)
SVR, % (n/N)
PR48
TVR12-PR48
(pooled regimens)
C/C
29 (5/17)
79 (60/76)
C/T
16 (9/58)
60 (160/266)
T/T
13 (4/30)
61 (49/80)
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Patient Case 2 (continued)
• She initiates PEG-IFN + RBV 600 mg po BID with
plans to add boceprevir 800 mg po every 8 hours
after treatment week 4
– Simvastatin is held due to concerns for possible
drug-drug interaction with boceprevir
• After completion of the “lead-in” phase, her Hgb
level is 10.5 g/dL and her HCV RNA is 89,000 IU/mL
(4.95 log10)
Baseline
6.24 log10
Week 4
4.95 log10
Difference
1.29 log10 decrease
• What does this lead-in response mean?
Interferon Responsiveness Was
Predictive of SVR With Boceprevir
SVR, %
From RESPOND-2: Patients who failed previous therapy with PEG-IFN/RBV
Week 4 Response
Responsiveness
≥ 1 log10 Decline in VL
IFN Response
< 1 log10 Decline in VL
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Telaprevir: SVR by Prior Response Category
and Week-4 Response to PEG-IFN/RBV Lead-in
<1 log10 HCV RNA
Reduction at Week 4
100
≥1 log10 HCV RNA
Reduction at Week 4
94
Prior relapsers
Prior partial responders
Prior null responders
Patients (%)
80
62
60
59
56
54
40
20
15
0
SVR rate
SVR rate
REALIZE Study
Foster GR, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin,
Germany. Oral Presentation. 6.
Patient Case 2 (continued)
• Boceprevir is added to
her regimen at treatment
week 5
• After 8 weeks of
treatment, she reports
fatigue, dyspnea on
exertion, and shortness
of breath
• Hgb level is now 8.9 g/dL
For this patient, what is the most
appropriate initial management of her
anemia?
A.
B.
C.
D.
E.
Stop the PI
Decrease the dose of RBV
Decrease the dose of the PI
Epoetin alfa 40,000 IU SC weekly
B and D
Boceprevir: Anemia Summary
• Higher rates of anemia in patients treated with boceprevir
Adverse Event, %
Anemia
BOC-Containing Arms
(n = 734)
PEG-IFN/RBV Arm
(n = 363)
45-50
20-30
• Patients treated with boceprevir had:
–
Average additional decrease of Hgb of approximately 1 g/dL
–
Higher frequency of hemoglobin reductions to Grade 3 or higher toxicity
• Mechanism of anemia thought to be result of bone marrow
suppressive effect associated with boceprevir, not due to RBC
hemolysis, as observed with ribavirin
• Management strategies during clinical trials:
–
RBV dose reduction or erythropoietin alone or in combination
–
RBC transfusion
US Food and Drug Administration; April 27, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/Committees
MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252341.pdf. Accessed April 28, 2011.
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Boceprevir: SVR According to EPO
Use and RBV Dose Reduction
Retrospective analysis of SPRINT-2 and RESPOND-2
Previously Untreated (SPRINT-2)
BOC arms only
Previous Treatment-Failures
(RESPOND-2)
BOC arms only
100
100
74
60
71
58
40
20
0
212
363
80
68
SVR (%)
SVR (%)
80
78
95
129
29
37
109
153
30
44
No
EPO
Both Neither
R dose
anemia alone
reduction
alone
Anemia
60
80
83
47
59
5
6
72
73
48
67
19
26
50
40
20
0
83
165
No
EPO
Both Neither
R dose
anemia alone
reduction
alone
Anemia
N = 1097 treatment-naïve; N = 403 previous-treatment-failure
Sulkowski MS, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin,
Germany. Poster 1800.
Telaprevir: Anemia Summary
• Higher rates of anemia in patients treated with telaprevir
Adverse Event, %
Anemia
TVR-Containing Arms
(n = 1797)
PEG-IFN/RBV Arm
(n = 493)
36
17
• Patients treated with telaprevir had:
– A higher frequency of hemoglobin reductions to Grade 3 or higher
(55% vs 25%)
– A higher frequency of Hgb level < 8.5 g/dL (14% vs 5%)
– More anemia-related SAEs (2.5% vs < 1%)
– A higher frequency of anemia-related discontinuations
(4% vs < 1%)
• EPO was not used during clinical trials
• Anemia was managed with RBV dose reduction
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
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.
Anemia Management Recommendations
With PI-based Therapy
• Monitor closely for Hgb < 10 g/dL
• CBC pretreatment, every 2 weeks until treatment week
8, then monthly
• Primary strategy: RBV dose reduction
– If RBV is D/C, BOC or TVR also must be D/C
– Do not reduce PI dose to manage anemia
• Hgb < 8.5 g/dL: discontinue all therapy
• Once RBV dose reduction has been tried, EPO can
be considered (off-label)
PEGASYS (peginterferon alfa-2a) injection for subcutaneous use [package insert]. South San Francisco, CA:
Genentech, Inc.; September 2011. PegIntron (peginterferon alfa-2b) injection, powder for solution for subcutaneous
use [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek (telaprevir) film coated tablets
[package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011. Victrelis (boceprevir) capsules [package insert].
Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Patient Case 2 (continued)
• Her anemia was managed with RBV dose
reduction from 600 mg PO BID to 800 mg/day
– After 2 weeks, her Hgb was stable but symptoms
continued
– Epoetin alfa 40,000 IU SC weekly was added
• After 12 weeks of treatment, her HCV RNA is
detectable at 38 IU/mL
– Should treatment continue?
– If yes, how long should she be treated with
boceprevir and/or with PEG-IFN/RBV?
Triple Therapy Should Be Stopped in
Patients With Insufficient Viral Response
Telaprevir*
Timepoint
Criteria for Stopping
Action
Week 4 or 12
HCV-RNA > 1000 IU/mL
Discontinue TVR/PEG-IFN/RBV
Week 24
HCV-RNA detectable
Discontinue PEG-IFN/RBV
Boceprevir**
Timepoint
Criteria for Stopping
Action
Week 12
HCV-RNA ≥ 100 IU/mL
Discontinue BOC/PEG-IFN/RBV
Week 24
Confirmed, detectable HCV-RNA
Discontinue BOC/PEG-IFN/RBV
* Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
** Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Emergence of Pre-Existing Resistant
Variants During Treatment With DAA
HCV RNA
Baseline HCV RNA
Start
Treatment
Viral Breakthrough
X XXX
X X
X
X X
Before Treatment
Time on Treatment With DAA Alone
Resistant virus
Sensitive virus
Adapted from: Forum for Collaborative HIV Research and Hepatitis C Virus Drug Development Advisory Group. A New
Perspective on HCV Drug Resistance: Multiple Paths to Sustained Viriologic Response: Resistance Can Be Overcome
[PowerPoint]. Washington, DC; 2011.
SVR Is the Best Way to Prevent
Resistance
• Never use PIs as monotherapy; always use PIs in
combination with PEG-IFN/RBV
• Maximize adherence to all 3 drugs in regimen
– Multidisciplinary approach to management:
physicians, NPs, PAs, nurses, and pharmacists
• Aggressive management of side effects
• Careful assessment of viral response and application
of “stopping rules”
• Resistance is typically observed in persons for
whom PEG-IFN/RBV is not effective
– Novel treatment paradigms will be needed
Boceprevir: Previous Partial Responders or Relapsers
Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily
(7-9 hrs apart) with food
4
Treatment
Decision
Points
Initiate
antiviral
treatment
8
End of 8
Weeks
PEGIFN+RBV
12
End of 12
Weeks
24
28
36
48
End of 24
Weeks
Boceprevir + PEG-IFN + RBV
24-week HCV-RNA
8-week HCV-RNA
Responseguided
therapy
Continue Treatment
Undetectable
Undetectable
Treatment complete
@ 36 wks
For boceprevir, HCV-RNA at wk 8 and wk 24 determine duration of therapy
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Boceprevir: Previous Partial Responders or Relapsers
Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily
(7-9 hrs apart) with food
0
4
Treatment
Decision
Points
Initiate
antiviral
treatment
8
End of 8
Weeks
PEGIFN+RBV
12
End of 12
Weeks
24
28
End of 24
Weeks
36
48
End
of 48
Wks
PEGIFN+
RBV
Boceprevir + PEG-IFN + RBV
24-week HCV-RNA
8-week HCV-RNA
Stop BOC at Wk 36
Responseguided
therapy
Continue Treatment
Detectable
Undetectable
Treatment
complete @
48 wks
For boceprevir, HCV-RNA at wk 8 and wk 24 determine duration of therapy
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Boceprevir: Nonresponders & Cirrhotics
Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily
(7-9 hrs apart) with food
0
Treatment
Decision
Points
Initiate
antiviral
treatment
4
8
End of 8
Weeks
PEGIFN+RBV
12
End of 12
Weeks
24
28
End of 24
Weeks
36
48
End
of 48
Wks
Boceprevir + PEG-IFN + RBV
Treatment
complete @
48 wks
Prior null
responders
Triple therapy
for 44 weeks
Patients with
compensated
cirrhosis
Treatment
complete @
48 wks
RGT was not studied in patients with < 2 log10 HCV-RNA decline by wk 12
during prior therapy with PEG-IFN/RBV
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Telaprevir: Treatment of Prior Partial & Null Responders
Chronic HCV Genotype 1, telaprevir 750 mg (two 375 mg tablets) orally 3 times
daily (7-9 hrs apart) with food (~ 20 gm fat)
0
Treatment
Decision
Points
Initiate
antiviral
treatment
4
End of 4
Weeks
12
End of 12
Weeks
Telaprevir + PEG-IFN + RBV
24
End of 24
Weeks
48
End of 48
Weeks
PEG-IFN + RBV
Triple therapy
for 12 weeks
No RGT in partial and null responder patients with TVR
Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.
Treatment
complete
@ 48 weeks
Patient Case 2 (continued)
• After 24 weeks of treatment, she has
improved symptoms with minimal
shortness of breath and no major
complaints
– Hgb 11.2 g/dL
– Epoetin alfa is decreased to 20,000 IU weekly
– HCV RNA not detected
• She will continue triple therapy with
boceprevir + PEG-IFN/RBV for a total of
48 weeks
Treatment-Experienced Patients:
Take-Home Points
• Higher SVR rates with boceprevir or telaprevir +
PEG-IFN/RBV
• Response rate is highly dependent on prior IFN/RBV
response and fibrosis stage:
– Relapser: 70%-88%
– Partial responder: 40%-59%
– Null responder: 29%-33%
• Potential for increased side effects
• Potential for resistance associated variants
• For patients that fail PI, combination DAAs may be an
option in the future
Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck and Co, Inc.; 2011.
Zeuzem S, et al. N Engl J Med. 2011;364(25):2417-2428.