eating a patient with liver cirrhos hat is happening in real life ?” UB, 35 yrs old Turkish engineer living in zerland, highly intelligent, cal patient of the “informative age” ive in; knows “a lot” on hepatitis C tment, is managed in Switzerland Turkey by Swiss and Turkish physicians Ankara Uni. Ankara Uni.
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Treating a patient with liver cirrhosis “What is happening in real life ?” Mr. UB, 35 yrs old Turkish engineer living in Switzerland, highly intelligent,
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Treating a patient with liver cirrhosis
“What is happening in real life ?”
Mr. UB, 35 yrs old Turkish engineer living inSwitzerland, 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.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
1. No treatment, FU with US for HCC and preparation for future liver tx2. Tx with standard dose and duration of pegylated INF/riba3. Tx with standard dose and prolonged duration of pegylated INF/riba4. Titrated tx with peg/riba5. Start with triple tx
Ankara Uni.Ankara Uni.
Patient asked for “maximal” therapy !
15.04.2005: Treatment started with PEG2a180µg/qw + Ribavirin 1200 mg/qd with the intention to use higher doses of ribavirin, subject to patient’s tolerability
Data from Poordad F, et al. N Engl J Med. 2011;364(13):1195-1206.
P < 0.001
P < 0.001
Non-Black Patients
P = 0.04
P = 0.004
Black Patients
SVR* Relapse Rate
1252
2252
29552/14 3/25
635
125311
211316
213311
37162 21/232 18/230
*All Pts who received treatment
Boceprevir: Treatment-naïve HCV G1 patients
ADVANCE: Higher SVR Rates in Patients Achieving eRVR
•58% of Pts eligible for RGT (received 24 weeks of TVR-based regimen)•SVR rates 89% in T12PR
100
90
80
70
60
50
40
30
10
8997
54
39
082/151 130/33228/29189/212
eRVR+ eRVR-
T12PR
PR48
SV
R,
%
Data from Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
75
44
Treatment-naïveOverall
271/363 158/361
P<0.001
31%
Telaprevir: Treatment-naïve HCV G1 patients
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
• 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.orgIncivek (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.
Inhibitor blocks the function of the CYP enzyme
Inhibitor blocks the function of the CYP enzyme
P450
InhibitorAUC 5
10
1
Drug + InhibitorInducerAUC 1
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?
†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.
‡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
• “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
† Usually considered 25 IU/mL, but 23 IU/mL per FDA-approved label
LLOQ Values for Various Assays
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.
Adverse Events Reported More Frequently vs PEG-IFN/RBV
*No EPO used in TVR trials; EPO commonly used in BOC trials**hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning
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/AntiviralDrugsAdvisoryCommittee/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
*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.
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 loose-fitting clothing, use oatmeal or baking soda baths, apply moisturizers at least twice daily after bathing, laundry with mild, unscented detergents
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 Treatment-Experienced Patients in 2011-2012
• Likelihood of response to PI/PEG-IFN/RBV– Previous response pattern– Viral factors
• Likelihood of clinical disease progression– Advanced fibrosis / cirrhosis
• Likelihood of tolerating PEG-IFN/RBV + protease inhibitor
Definitions of Prior Response
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.
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: YesTVR: Yes
Relapse HCV RNA undetectable at the end of therapy, but detectable HCV RNA during follow-up
BOC: YesTVR: 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
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
Foster GR, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin, Germany. Oral Presentation. 6.
REALIZE Study
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. Stop the PI
B. Decrease the dose of RBV
C. Decrease the dose of the PI
D. Epoetin alfa 40,000 IU SC weekly
E. B and D
Boceprevir: Anemia Summary• Higher rates of anemia in patients treated with boceprevir
• 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/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252341.pdf. Accessed April 28, 2011. Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.
Adverse Event, % BOC-Containing Arms(n = 734)
PEG-IFN/RBV Arm(n = 363)
Anemia 45-50 20-30
Boceprevir: SVR According to EPO Use and RBV Dose Reduction
N = 1097 treatment-naïve; N = 403 previous-treatment-failure
Retrospective analysis of SPRINT-2 and RESPOND-2
Sulkowski MS, et al. Poster presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Poster 1800.
Previously Untreated (SPRINT-2)BOC arms only
Previous Treatment-Failures(RESPOND-2)
BOC arms only100
80
60
40
20
0
SV
R (
%)
Noanemia
EPOalone
NeitherBothR dose
reductionalone
Anemia
58
74 7871 68
212363
95129
2937
109153
3044
100
80
60
40
20
0
SV
R (
%)
Noanemia
EPOalone
NeitherBothR dose
reductionalone
Anemia
50
80 8372 73
83165
4759
56
4867
1926
Telaprevir: Anemia Summary• Higher rates of anemia in patients treated with telaprevir
• 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/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.
Adverse Event, % TVR-Containing Arms(n = 1797)
PEG-IFN/RBV Arm(n = 493)
Anemia 36 17
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 inPatients With Insufficient Viral Response
Emergence of Pre-Existing Resistant Variants During Treatment With DAA
Sensitive virusResistant virus
Time on Treatment With DAA Alone
HC
V R
NA
Baseline HCV RNA
Before Treatment
Viral Breakthrough
XX
X
XXX
X XX
Start Treatment
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
284
End of 8 Weeks
End of 12 Weeks
End of 24 Weeks
8 12 24 4836
Boceprevir: Previous Partial Responders or Relapsers
Treatment Decision Points
Initiate antiviral treatment
Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily(7-9 hrs apart) with food
No RGT in partial and null responder patients with TVR
Triple therapy for 12 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