Treating a patient with liver cirrhosis “What is happening in real life ?” Mr. UB, 35 yrs old...

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


• 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

What would you do ?

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


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


Hb Plat. WBC Neut. T. Bili ALT INR HCV RNA01.04.05 17.2 71 6.9 4.7 30.8 116 1.3 7.65 log17.05.05 14.8 51 3.8 1.4 22.0 124 1.4 NA10.06.05 14.1 44 3.1 1.2 22.6 107 1.4 NA08.07.05 13.5 52 2.4 1.0 24.8 119 1.2 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

Tx start date: 15.04.2005


•Undetectable since at least week 20 of treatment commencement

•After 48 weeks of treatment HCV undetectable


What would you do now ?

1. Discontinue treatment2. Continue tx with the same regimen to week 72 3. Continue tx with “maintenace dose” for Pegasys and Ribavirin dose to 90 µg


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 doseof neither Pegasys nor Ribavirin.


ALT AST T. Bili INR Albumin HCV RNAApril 2005 116 77 30.8 1.3 4.0 7.65 logJuly 2005 119 110 24.8 1.2 NA 3.11 logSep 2005 67 88 27.7 1.3 NA < 15 IU/mLMarch 2006 43 98 34.4 1.5 3.3 < 15 IU/mLJune 2006 38 69 38.1 1.6 2.7 < 15 IU/mL

Tx start date: 15.04.2005


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

10

What would you tell this patient about her chances of SVR with a course of PI-based therapy?

A. SVR rate cannot be estimated

B. SVR rate ~25%-35%

C. SVR rate ~40%-50%

D. SVR rate ~70%

HCV Treatment Decisions for Protease InhibitorsPros• PIs substantially increase

chance of SVR across a majority of patient groups

• PIs shorten duration of therapy in many

• Successful treatment improves morbidity and mortality

• Suboptimal response rates or limited/no data in several populations

– HCV-HIV co-infection, tranplant, decompensated cirrhotics

• Complicated regimens, challenging AEs, and DDIs

• Risk of resistance if therapy fails: impact on future options?

Cons

Factors to Consider In Treatment Decisions

Treatment regimen

PEG-IFNRibavirin

DAA

Host factors

Age, gender, race obesity, co-morbidities

Genetic factors (IL28B and ITPA)

Disease features

Fibrosis, steatosis, co-infection (HBV, HIV)

Viral factors

Genotype / SubtypeQuasispecies /

ResistanceViral load

Identifying Candidates For Triple Therapy

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)

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?

Drug Interactions Considerations

Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.

Concomitant Drug Class

Drug(s) with Interaction

PI Involved

Effect on Concentration of PI or Concomitant Drug

Antidepressants

St. John’s Wort

BOC or TVR

CONTRAINDICATED: •May lead to loss of virologic response ( concentrations of PIs)

Trazodone, Desipramine

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

Statins

Lovastatin, Simvastatin

BOC or TVR

CONTRAINDICATED: •Potential for myopathy including rhabdomyolysis

AtorvastatinBOC

atorvastatin: •Titrate slowly; max dose of 20 mg/d

TVR CONTRAINDICATED

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 PatientsChronic HCV Genotype 1, telaprevir 750 mg (two 375 mg tablets) orally 3 times daily (7-9 hrs apart) with food (~ 20 gm fat†)

Treatment Decision Points

Initiate antiviral treatment

Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.

End of 4 Weeks

End of 12 Weeks

End of 24 Weeks

End of 48 Weeks

4 12 24 48

4-week HCV-RNA

0

Telaprevir + PEG-IFN + RBV

eRVR undetectable

at weeks 4 & 12

PEG-IFN + RBVPEG-IFN + RBV

Treatmentcomplete @ 24 weeks

Response-guided therapy

12-week HCV-RNA

Tx-naïve w/ cirrhosis‡

Treat for 48 weeks

†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

Telaprevir: Treatment-Naïve & Prior Relapse PatientsChronic HCV Genotype 1, telaprevir 750 mg (two 375 mg tablets) orally 3 times daily (7-9 hrs apart) with food (~ 20 gm fat)




End of 4 Weeks

End of 12 Weeks

End of 24 Weeks

End of 48 Weeks

4 12 24 480

Telaprevir + PEG-IFN + RBV

Treatmentcomplete @ 48 weeks

PEG-IFN + RBVPEG-IFN + RBV

12-week HCV-RNA

For telaprevir, HCV-RNA at wk 4 and wk 12 determine duration of therapy

Detectable≤1000 IU/mL at weeks 4 and/or 12Response-

guided therapy

4-week HCV-RNA

End of 4 Weeks

End of 12 Weeks

End of 24 Weeks

End of 48 Weeks

4 12 24 480

Telaprevir: Stopping Rules



PEG-IFN + RBVTelaprevir + PEG-IFN + RBV

4-weekHCV-RNA

> 1000 IU/mL

Treatment failure

12-weekHCV-RNA

> 1000 IU/mL

Treatment failure

24-weekHCV-RNA

Detectable

Treatment failure


Apply to all patients

Stop Stop

Stopping Rules

Stop

284

Boceprevir: Treatment-Naïve Patients


End of 8 Weeks

End of 12 Weeks

End of 24 Weeks


8 12 24 480


Chronic HCV Genotype 1, boceprevir 800 mg (four 200-mg capsules) 3 times daily(7-9 hrs apart) with food

PEG-IFN+RBV

8-week HCV-RNA

Undetectable

36

Treatment complete @ 28 wks

Undetectable

24-week HCV-RNA

Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.

Boceprevir + PEG-IFN + RBV

Continue Treatment

For boceprevir, HCV-RNA at wk 8 and wk 24 determine duration of therapy

284



End of 8 Weeks

End of 12 Weeks

End of 24 Weeks

Endof 48Wks


8 12 24 480

Chronic HCV Genotype 1, boceprevir 800 mg (four 200 mg capsules) 3 times daily(7-9 hrs apart) with food

8-week HCV-RNA

36

UndetectableTreatmentcomplete @ 48 wks

24-week HCV-RNA



Detectable

PEG-IFN+ RBV


Stop BOC at Wk 36

PEG-IFN+RBV

Continue TreatmentResponse-guided therapy

284



End of 8 Weeks

End of 12 Weeks

End of 24 Weeks

Endof 48Wks


8 12 24 480


36

Poorly IFN-responsive*


< 1 log10 IU/mL decline in viral

load at Wk 4


Treatmentcomplete @ 48 wks

Triple therapy for 44 weeks

Assess interferon responsiveness after lead-in with PEG-IFN/RBV

*Standard stopping rules assessed at Wk 12 and 24 still apply

PEG-IFN+RBV

284

Boceprevir: Stopping Rules


End of 8 Weeks

End of 12 Weeks

End of 24 Weeks

Endof 48Wks


8 12 24 480 36

±BOC + PEG-IFN+

RBV

Stopping Rules

Stop

Treatment failure

Stop

Detectable

Treatment failure

12-weekHCV-RNA

24-weekHCV-RNA


≥ 100 IU/mL


Apply to all patients

PEG-IFN

+RBV

HCV-RNA Levels and Lab Assays

Assay Name LLOQ

Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV Test

43 IU/mL

Roche COBAS® TaqMan® HCV Test, v2.0

25 IU/mL†

Abbott RealTime HCV Assay

12 IU/mL

• “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.

Telaprevir and Boceprevir Adverse Events

Telaprevir1

1Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.2Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.

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

Adverse Event, % Boceprevir-Containing Arms(n = 734)


Anemia* 45-50 20-30

Dysgeusia 35-44 11-16

Boceprevir2

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

• 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

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


• 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

72105

1551

77103

2757

3058

Prior Relapsers Prior Partial Responders

BOC RGT

BOC/PR48

PR48 BOC RGT

BOC/PR48

PR48

HCV G1 patients with previous treatment failure

n/N= 229

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

SV

R (

%)

Prior Relapsers

Prior Partial Responders

Pbo/PR48

4/27

T12/PR48

29/49

LI T12/PR48

26/48n/N =

Pbo/PR48

2/37

T12/PR48

21/72

LI T12/PR48

25/75

Pbo/PR48

16/68

T12/PR48

121/145

LI T12/PR48

124/141

Prior Null Responders

**

**

**

*P < 0.001 vs Pbo/PR48Data from Zeuzem S, et al. N Engl J Med. 2011;364(25):2417-2428.

REALIZE: SVR by Baseline Fibrosis Stage and Prior Response

Prior Relapsers

Prior Partial Responders

Prior Null Responders

2/15n/N = 53/62144/16712/38 0/5 10/1834/473/17 0/9 15/3811/321/5

No, minimal or portal fibrosis

CirrhosisStage

SV

R (

%)

2/15 48/57 24/591/18 7/501/10

Bridgingfibrosis


CirrhosisBridgingfibrosis


CirrhosisBridgingfibrosis

Zeuzem S, et al. Presented at: EASL: The International Liver Congress 2011; March 30-April 3, 2011; Berlin, Germany. Oral Presentation 5.


• 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?

IL28B Genotype

SVR, % (n/N)

PR48 BOC-RGT BOC-PR48

RESPOND-2: Boceprevir

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

SVR, % (n/N)

PR48 TVR12-PR48 (pooled regimens)

REALIZE: Telaprevir

C/C 29 (5/17) 79 (60/76)

C/T 16 (9/58) 60 (160/266)

T/T 13 (4/30) 61 (49/80)

Genetic Variant Near the Gene Encoding Interferon-lambda-3(IL28Brs12979860, a C to T Change)

Incivek (telaprevir) film coated tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals; 2011.Victrelis (boceprevir) capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc.; 2011.

SVR Rates by IL28B Genotype in Subjects who Previously Failed Therapy

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)

• What does this lead-in response mean?

Baseline 6.24 log10

Week 4 4.95 log10

Difference 1.29 log10 decrease

Interferon Responsiveness Was Predictive of SVR With BoceprevirFrom 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

SV

R,

%


Telaprevir: SVR by Prior Response Category and Week-4 Response to PEG-IFN/RBV Lead-in

≥1 log10 HCV RNA Reduction at Week 4

Prior relapsersPrior partial respondersPrior null responders

<1 log10 HCV RNA Reduction at Week 4

Pat

ien

ts (

%)

100

80

60

40

20

0

94

5954

SVR rate

6256

15

SVR rate

Foster GR, et al. Presented at: EASL: The International Liver Congress 2011; March 30 - April 3, 2011; Berlin, Germany. Oral Presentation. 6.

REALIZE Study


• 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)


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)


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.


• 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

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

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

* 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

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




PEG-IFN+RBV



Undetectable Undetectable


Treatment complete @ 36 wks

24-week HCV-RNA

Continue Treatment

8-week HCV-RNA


284

Boceprevir: Previous Partial Responders or Relapsers


End of 8 Weeks

End of 12 Weeks

End of 24 Weeks

Endof 48Wks


8 12 24 480


PEG-IFN+RBV

8-week HCV-RNA

36

Undetectable Treatmentcomplete @ 48 wks

24-week HCV-RNA



Detectable

PEG-IFN+ RBV


Stop BOC at Wk 36

Continue TreatmentResponse-guided therapy

284

Boceprevir: Nonresponders & Cirrhotics


End of 8 Weeks

End of 12 Weeks

End of 24 Weeks

Endof 48Wks


8 12 24 480


PEG-IFN+RBV

36





RGT was not studied in patients with < 2 log10 HCV-RNA decline by wk 12 during prior therapy with PEG-IFN/RBV


Prior null responders

Patients with compensated cirrhosis

End of 4 Weeks

End of 12 Weeks

End of 24 Weeks

End of 48 Weeks

4 12 24 480

Telaprevir: Treatment of Prior Partial & Null RespondersChronic HCV Genotype 1, telaprevir 750 mg (two 375 mg tablets) orally 3 times daily (7-9 hrs apart) with food (~ 20 gm fat)



PEG-IFN + RBVTelaprevir + PEG-IFN + RBV

Treatmentcomplete@ 48 weeks


No RGT in partial and null responder patients with TVR



• 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.

Treating a patient with liver cirrhosis “What is happening in real life ?” Mr. UB, 35 yrs old...

Documents

Transcript of Treating a patient with liver cirrhosis “What is happening in real life ?” Mr. UB, 35 yrs old...