Sponsored for Continuing Medical Education Credit by Rush University Medical Center

1

Sponsored for Continuing Medical EducationCredit by Rush University Medical Center

Supported by an independent educational grant from Vertex Pharmaceuticals Incorporated

Management Strategies toManagement Strategies toRaise Cure Rates in PatientsRaise Cure Rates in Patients

With Genotype 1 HCV InfectionWith Genotype 1 HCV Infection

2

Faculty:Content Development and Training

David R. Nelson, MDDavid R. Nelson, MDProfessor of Medicine

Associate Dean, Clinical and Translational ResearchUniversity of FloridaGainesville, Florida

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Disclosure Information:Content Faculty

• David R. Nelson, MD– Grants/Research Support

• Abbott, Bayer, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, Merck, Pharmasset, Vertex

– Consultant• Genentech, Pharmasset, Vertex

– Speakers’ Bureau• None

– Stock Shareholder• None

– Other Financial or Material Support• None

4

Learning Objectives (CME/CNE)

● Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine:

– Prescribe anti-HCV regimens in my previously untreated, patients with chronic HCV genotype 1 infection who are candidates for therapy according to the AASLD recommendations

– Utilize strategies to avoid potential resistance associated with antiviral therapy to optimize SVR rates in my previously untreated patients with chronic HCV genotype 1 infection

– Prescribe management approaches for my HCV patients who develop complications associated with antiviral combination therapy

5

Learning Objectives (CPE)

● Upon completion of this activity, the pharmacist should be able to:

– Review anti-HCV regimens in my previously untreated, patients with chronic HCV genotype 1 infection who are candidates for therapy according to the AASLD recommendations

– Utilize strategies to avoid potential resistance associated with antiviral therapy to optimize SVR rates in my previously untreated patients with chronic HCV genotype 1 infection

– Describe management approaches for my HCV patients who develop complications associated with antiviral combination therapy

6

Epidemiologic Trends and MilestonesIn Therapy for Chronic HCV Infection

7

Prevalence of Blood-BorneChronic Viral Infections in the US

HCV

Unaware of infectionAware of infection

Prev

alen

ce (m

illio

ns) 2,475,000

825,000 715,000

385,000231,000

869,000

HBV HIV

Institute of Medicine. Available at: http://www.nap.edu/catalog/12793.html.

75% Unaware75% Unaware

65% Unaware65% Unaware 21% Unaware21% Unaware

8

Chronic HCV Infectionin the United States

• >5.2 million living with chronic HCV in US

– Prevalence: 2%

• Chronic HCV cases not included in NHANES estimate

– Homeless (n=142,761-337,6100)– Incarcerated (n=372,754-664,826)– Veterans (n=1,237,461-2,452,006)– Active military (n=6805)– Healthcare workers (n=64,809-259,234)– Nursing home residents (n=63,609)– Chronic hemodialysis (n=20,578)– Hemophiliacs (n=12,971-17,000)

Num

ber o

f Cas

es (i

n m

illio

ns)

Estimated HCV Cases

1.9

3.2

Not Includedin NHANES

Total NHANES

5.2

Conservative estimateUpper limit of estimate

Chak E, et al. Liver Int. 2011; 31:1090-1101.http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm#section2.

7.1

3.8

9

Epidemiologic Patterns ofHCV Infection in the US

Tota

l HC

V In

fect

ions

(mill

ions

)

Year

Davis GL, et al. Gastroenterology. 2010;138:513-521.

1950 1960 1970 1980 1990 2000 2010 2020 2030

Ever infectedChronic HCVAcute HCVCirrhosis

PeakCirrhosis

10

Successful Treatment of HCV Is Associated With Improved Outcome

• Sustained viral response– Durable

• 99% stay HCV negative for >10 years– Leads to improved histology – Leads to clinical benefits– Decreased decompensation – Prevents de novo esophageal varices– Decreased hepatocellular carcinoma– Decreased mortality

Bruno S, et al. Hepatology. 2010;51:2069-2076.Veldt BJ, et al. Ann Intern Med. 2007;147:677-684.Maylin S, et al. Gastroenterology. 2008;135:821-829.

11

VA Cohort (2001-2008):Impact of SVR on Survival

• Clinical Case Registry (n=16,864)– HCV patients completing

peginterferon + ribavirin– No HIV or HCC– High rates of comorbidities

• Diabetes mellitus, hypertension, alcohol abuse, coronary artery disease

• SVR rates by genotype– 1 (n=12,166): 35%– 2 (n=2904): 72%– 3 (n=1794): 62%

Impact of SVR onAll-Cause Mortality

Adjusted for demographic, laboratory, comorbidity, and treatment variables.

Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.

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Chronic HCV Infection in the US

• 3.5 million chronically infected

• <25% have been identified

• <20% offered therapy• 33% with cirrhosis at

risk for complications

• Targeted national screening programs

– Birth cohort screening for those born between 1945-1965

• Identify an additional 808,580 infected patients

• New therapies– Higher SVR rates– Shorter duration of therapy

Challenges Opportunities

Rein BD, et al. Ann Intern Med. 2012;156:263-270.

13

Chronic HCV Therapy:Advances in Raising Cure Rates

SVR

(%)

6%

16%

6 Months

34%

55%

>70%

Jacobson IM. Clin Gastroenterol Hepatol. 2009;7:921-930.Ghany MG, et al. Hepatology. 2009;49:1335-1374.Ghany MG, et al. Hepatology. 2011;54:1433-1444.

42% 39%

IFN12 Months 6 Months

IFN + RBV12 Months 12 Months

PegIFN12 Months DAA

PegIFN+ RBV

PegIFN+ RBV

1991

1998

2001

2011

StandardInterferon

Ribavirin

Peginterferon

Direct ActingAntivirals

14

Chronic HCV Infection:Potential Therapeutic Targets

NS3ProteaseAntiviral

Agents

Interferon

Immuno-modulators

TherapeuticVaccines

HostTargets

BoceprevirTelaprevir

IFN-α

IFN-λ

Replicationand Assembly

Entry

NS5BPolymerase

NS5AReplication

Complex

FDA Approved

FDA Approved

15

AASLD Recommendation: Treatmentof Chronic HCV Genotype 1

• The optimal therapy for genotype 1, chronic HCV infection– Boceprevir or telaprevir in combination with

peginterferon alfa and ribavirin

• Boceprevir and telaprevir– Should not be used without peginterferon alfa and

weight-based ribavirin– Not approved for use in patients with HIV coinfection,

decompensated cirrhosis, and after liver transplantation

Ghany MG, et al. Hepatology. 2011;54:1433-1444.

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Telaprevir and Boceprevir

Full prescribing information for telaprevir and boceprevir.

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Telaprevir and Boceprevir in Treatment-Naïve Patients

Full prescribing information for telaprevir and boceprevir.*Also for prior null responders to peginterferon + ribavirin therapy.

18

Telaprevir: RecommendedTreatment Duration (weeks)

Treatment-Naïve or Prior Relapsers (non-cirrhotics)

0 4 12 240 4 12 24

Telaprevir +Telaprevir +pegIFN + RBVpegIFN + RBV pegIFN + RBVpegIFN + RBV

0 4 12 24 0 4 12 24 4848

Telaprevir +Telaprevir +pegIFN + RBVpegIFN + RBV pegIFN + RBVpegIFN + RBV

UndetectableUndetectable UndetectableUndetectable

Detectable (Detectable (<<1000 IU/mL)1000 IU/mL)Week 4 and/or 12Week 4 and/or 12

Treatment futility rules (all patients): HCV RNA >1000 IU/mL at week 4 or 12--discontinue all 3 drugs (telaprevir treatment complete at 12 weeks; HCV RNA >1000 IU/mL at week 24--discontinue pegIFN + RBV.

Full prescribing information for telaprevir.

Undetectable:Undetectable:COBAS TaqManCOBAS TaqMan

(HCV RNA <25 IU/mL)(HCV RNA <25 IU/mL)

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Telaprevir:Treatment Futility Rules (All Patients)

• HCV RNA >1000 IU/mL at week 4 or 12– Discontinue all 3 drugs (telaprevir treatment complete

at 12 weeks)

• Detectable HCV RNA at week 24– Discontinue pegIFN + RBV

Full prescribing information for telaprevir.

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Boceprevir: RecommendedTreatment Duration (weeks)

Previously Untreated (non-cirrhotics)

Boceprevir + pegIFN + RBVBoceprevir + pegIFN + RBV

Boceprevir + pegIFN + RBVBoceprevir + pegIFN + RBV pegIFN + RBVpegIFN + RBV

Full prescribing information for boceprevir.

pegIFNpegIFN+ RBV+ RBV

pegIFNpegIFN+ RBV+ RBV

DetectableDetectable UndetectableUndetectable

Undetectable:Undetectable:COBAS TaqManCOBAS TaqMan

(HCV RNA <25 IU/mL)(HCV RNA <25 IU/mL)

Treatment futility rules (all patients): HCV RNA >100 IU/mL at week 12 or detectable HCV RNA at week 24.

UndetectableUndetectable UndetectableUndetectable0 4 8 24 28 0 4 8 24 28

0 4 8 24 36 0 4 8 24 36 4848

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Boceprevir:Treatment Futility Rules (All Patients)

• HCV RNA >100 IU/mL at week 12 or detectable HCV RNA at week 24

Full prescribing information for telaprevir and boceprevir.

22

Cirrhosis: Telaprevir and Boceprevir Recommended Treatment Duration (weeks)

Telaprevir

Full prescribing information for telaprevir and boceprevir.

Boceprevir

Boceprevir + pegIFN + RBVBoceprevir + pegIFN + RBVpegIFNpegIFN+ RBV+ RBV

0 4 12 24 0 4 12 24 4848

Telaprevir +Telaprevir +pegIFN + RBVpegIFN + RBV pegIFN + RBVpegIFN + RBV

0 4 12 24 0 4 12 24 4848

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Telaprevir and Boceprevir:Efficacy Considerations

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ADVANCE Study: Telaprevir +PegIFN Alfa-2a + RBV in Genotype 1

Phase 3 Treatment-naïve

Genotype 1HBsAg negative

HIV negativeNo decompensated

liver disease

Week 0 8 12 24 48 72

PegIFN + RBV

T12/PR

T8/PR

PR48

eRVR (extended rapid virologic response): HCV RNA <25 IU/mL and undetectable at week 4 and week 12.TVR: telaprevir; Pbo: placebo.Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

TVR(750 mg

q8h)PegIFN +

RBV

TVR +(750 mg q8h)PegIFN +

RBV

PegIFN + RBV eRVR(-)

PegIFN + RBV

Follow-UpSVReRVR(+)Follow-Up

SVRFollow-Up

PegIFN +RBV eRVR(-)

PegIFN + RBV

Follow-UpSVReRVR(+)Follow-Up

SVRFollow-Up

Placebo +PegIFN +

RBV

SVRFollow-Up

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ADVANCE Study Outcomes:Telaprevir + PegIFN Alfa-2a + RBV

Patie

nts

(%)

T12/PR(n=363)

Sustained Virologic Response

75%*69%*

44%

*P<0.0001 versus PR48.Overall relapse: patients with undetectable HCV RNA at the last dose of treatment.

T8/PR(n=364)

PR48(n=361)

Patie

nts

(%)

Overall Relapse

9% 9%

28%

T12/PR(n=314)

T8/PR(n=295)

PR48(n=220)

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

26

ADVANCE Study Outcomes:SVR Rates by Predefined Subgroups

Patie

nts

(%)

Genotype

1a(n=213/208)

HCV RNA (IU/mL)

T12/PRPR48

1b(n=149/151)

Patie

nts

(%)

<800,000(n=82/62)

T12/PRPR48

>800,000(n=281/279)

41%

71%79%

48%

70%78%

71%

36%

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

27

ADVANCE Study Outcomes:SVR Rates by Predefined Subgroups

Patie

nts

(%)

Race

White(n=325/318)

Fibrosis

T12/PRPR48

Black(n=26/28)

Patie

nts

(%)

F0-2(n=290/288)

T12/PRPR48

F3/4(n=73/73)

46%

75%

62%

25%

46%

78%

62%

33%

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

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ADVANCE Study: Is IL28B Genotype Predictive of SVR for Telaprevir?

CC(n=50/45/55)

Telaprevir 12/PRTelaprevir 8/PRPR48

SVR

(%)

90%84%

64%71%

57%

25%

73%

59%

23%

CT(n=68/76/80)

TT(n=50/45/55)

Jacobson IM, et al. J Hepatol. 2011;54(suppl 1):S542-S543. Abstract 1369.

U.S. Caucasians: 42% of study

29

ILLUMINATE Study: 24 or 48 Weeks of PegIFN Alfa-2a + RBV After 12 Weeks of Telaprevir?

Phase 3 Treatment-naïve

Genotype 1

Week 0 12 20 24 48 72

T12/PR

eRVR (extended rapid virologic response): HCV RNA <25 IU/mL at weeks 4 and week 20.

Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

Telaprevir(750 mg q8h)PegIFN +

RBV

PegIFN + RBV

SVRFollow-Up

PegIFN + RBV

PegIFN + RBV

SVRFollow-Up

With eRVR

SVRFollow-Up

SVRFollow-UpPegIFN + RBV

WithouteRVR

30

ILLUMINATE Study OutcomesPa

tient

s (%

)

Overall(n=540)

Sustained Virologic Response

72%

92%88%

T12/PR24(n=162)

T12/PR48(n=160)

Patie

nts

(%)

Overall Relapse

8% 6% 3%

Difference 4.5%(95% CI -2.1%-11.1%)

Overall(n=469)

T12/PR24(n=159)

T12/PR48(n=154)

Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.

31

Telaprevir Efficacy Summary:Treatment-Naïve HCV Patients

• Telaprevir + peginterferon + ribavirin for 12 weeks, then peginterferon + ribavirin for an additional 12 or 36 weeks

• Response-guided therapy is non-inferior to 48 weeks of treatment in patients with an eRVR (undetectable at week 4 and 24)

– May be possible in up to two-thirds of treatment-naïve patients

• Sustained virologic responses– Significantly improved over standard of care for blacks, Latinos,

and cirrhotic patients• Improvement in SVR regardless of baseline genotype, HCV RNA

level, IL28BJacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S195. Abstract 477.Jacobson IM, et al. J Hepatol. 2011;54(suppl 1):S542-S543. Abstract 1369.

32

SPRINT-2 Study: Boceprevir +PegIFN Alfa-2b + RBV in Chronic HCV

Phase 3 Treatment-naïve

Genotype 1HBsAg negative

HIV negativeNo decompensated

liver disease(nonblack n=938;

black n=159)

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

Week 0 4 28 48 72

Placebo + PegIFN + RBVFollow-Up

LI/B24/PR

PR48

Weight-based ribavirin dosing (600-1400 mg/day).

Boceprevir (800 mg tid) +PegIFN + RBV

Follow-UpLI/B44/PR

Boceprevir(800 mg tid) +

PegIFN + RBV

Leadin

Leadin

Leadin

HCV RNA Detectable*PegIFN + RBV

HCV RNA Undetectable*Follow-Up

Follow-Up

*During treatment week 8 to week 24.

33

SPRINT-2 Study Outcomes:Boceprevir + PegIFN Alfa-2b + RBV

Patie

nts

(%)

Sustained Virologic Response

42%‡

68%* 67%*

40%

*P<0.001, †P=0.004, and ‡P=0.04 versus PR48.

LI/B24/PR(n=316/52)

LI/B44/PR(n=311/55)

PR48(n=311/52)

Patie

nts

(%)

Relapse

53%†

12%9%*17%

23%

8%*

23%

Non-black patientsBlack patients

Non-black patientsBlack patients

LI/B24/PR(n=316/52)

LI/B44/PR(n=311/55)

PR48(n=311/52)

14%

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

34

SPRINT-2 Study:Advanced Liver Disease Subanalysis

Patie

nts

(%)

Sustained Virologic Response

52%

67%

38% 41%

F0-2(n=313/319/328)

Relapse

67%

38%

LI/B44/PRLI/B24/PRPR48

F3-4(n=42/34/24)

Patie

nts

(%)

12%9%

22%18%

F0-2(n=231/233/158)

9%

25%

LI/B44/PRLI/B24/PRPR48

F3-4(n=22/17/12)

Bruno S, et al. J Hepatol. 2011;54(suppl 1):S4. Abstract 7.

35

SPRINT-2 Subanalysis: Impact of Baseline HCV RNA on Outcomes

Patie

nts

(%)

Sustained Virologic Response

59%

83%

67%

41%

<1(n=122/62)

Relapse

63% 65%

Pooled boceprevirPR48

Patie

nts

(%)

Gordon SC, et al. Hepatology. 2011;54(suppl):812A. Abstract 961.

Baseline HCV RNA(million IU/mL)

>2 to <5(n=261/127)

>5 to <10(n=150/87)

>10(n=171/68)

<1(n=63/47)

Baseline HCV RNA(million IU/mL)

>2 to <5(n=195/53)

>5 to <10(n=100/41)

>10(n=124/35)

Pooled boceprevirPR48

32% 31%

12%

3%11%

17%10%

23%

40%

36

Boceprevir Subanalysis: Is IL28B Genotype Predictive of SVR?

Patie

nts

(%)

SPRINT-2

80% 78%

CC(n=55/77/64)

RESPOND-2

82%

LI/B44/PRLI/B24/PRPR48

TT(n=44/42/37)

Patie

nts

(%)

LI/B44/PRLI/B24/PRPR48

Poordad F, et al. J Hepatol. 2011;54(suppl 1):S6. Abstract 12.

CT(n=115/103/116)

71%

28%

65%59%

27%

55%

CC(n=22/28/13)

TT(n=18/11/10)

CT(n=66/62/29)

77%

46%

79%73%

61%

72%

55%

17%

50%

Retrospective analysis.

37

Boceprevir Efficacy Summary:Treatment-Naïve HCV Patients

• Boceprevir + peginterferon + ribavirin– Will require 4-week lead-in with peginterferon + ribavirin– Critical HCV RNA at treatment week 8 (after 4 weeks of boceprevir)

• Response-guided therapy– eRVR: total 28 weeks of therapy (eRVR: undetectable at weeks 8 to 24)

• 4-week LI, 24-weeks boceprevir + peginterferon + ribavirin– No eRVR: total 48 weeks of therapy

• 4-week LI, 24-weeks boceprevir + peginterferon + ribavirin, 20-weeks peginterferon + ribavirin

• Significantly improved over standard of care for black and cirrhotic patients

– Improvement in SVR regardless of baseline genotype, HCV RNA level, IL28B

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Poordad F, et al. J Hepatol. 2011;54(suppl 1):S6. Abstract 12.Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S194-S195. Abstract 476.

38

Telaprevir and Boceprevir:Resistance Considerations

39

Different Virus Replication Strategies:Different Treatment Goals

Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212.

HCV(No Latent Reservoir)

HCV RNA

Definitive Viral Clearance:

SVR Possible for HCV

HBV(Latent Reservoir)

Host DNAHost DNA

Host cell

Nucleus

cccDNAcccDNA

Long-Term Reduction of Viral Replication to Lowest Possible Level

HIV(Latent Reservoir)

Proviral DNAProviral DNA

Lifelong Suppression of Viral Replication

cccDNA = covalently closed circular DNA.

40

Telaprevir Monotherapy and Development of Resistance

Kieffer TL, et al. Hepatology. 2007;46:631-639.

Sample Patient #1

HC

V R

NA

(log

10 IU

/mL)

Wild typeT54AV36A/MR155K/T

36/155A156V/T36/156

LOD

LOD: sequencing limit of detection (100 IU/mL)

1 14Telaprevir Monotherapy (day)

Sample Patient #2

HC

V R

NA

(log

10 IU

/mL)

Wild typeT54AV36A/MR155K/T

36/155A156V/T36/156

LOD

1 14Telaprevir Monotherapy (day)

41

Telaprevir and BoceprevirHave Similar Resistant Variants

Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212.

42

ADVANCE and REALIZE Studies:Loss of Resistance by NS3 Position

Sullivan JC, et al. J Hepatol. 2011;54(suppl 1):S4. Abstract 8.

Population sequence analysis in patients not achieving a sustained virologic response with resistant variants at baseline. Hash marks indicate censored observations.

Prob

abili

ty (%

)

0 2 4 6 8 10 12 14 16 18Time After Treatment Failure (months)

Loss of Resistant Variant

R155K

V36M

A156S/T

T54A

V36A

Common genotype 1a variantsCommon genotype 1b variants

43

Direct Acting Antiviral Agents: Considerations for Preventing Resistance

• Achieving a sustained virologic response– Best way to prevent resistance

• Patient education prior to treatment initiation• Emphasize and take steps to maximize adherence to regimen• Manage adverse events• Closely monitor HCV RNA levels during therapy

– Early stopping rule

• Further study is needed for combination regimens with agents that have complementary mechanisms of action and non-overlapping resistance

Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.Sarrazin C, et al. Gastroenterology. 2010;138:447-462.

44

Telaprevir and Boceprevir:Safety Profiles and Drug Interactions

45

Telaprevir:Adverse Events

• Most common– Itching, nausea, diarrhea, anal or rectal problems

(hemorrhoids, discomfort/itching), dysgeusia, fatigue

• Most common serious adverse events– Rash– Anemia

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Full prescribing information for telaprevir.

46

Telaprevir:Rash

• Overall incidence (56%)• Mild-to-moderate rash

– Mild: maculopapular– Moderate: some diffuse red

spots

• Management (mild-to-moderate rash)

– Monitor– Oral antihistamines or topical

corticosteroids may provide relief, but unproven

– Systemic corticosteroids are not recommended

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Lawitz EJ. Gastroenterol Hepatol. 2011;7:469-471.Full prescribing information for telaprevir.

Mild Rash Moderate Rash

47

Telaprevir:Severe Rash (Incidence 4%)

• Management– Discontinue telaprevir (continue peginterferon

and ribavirin)– If after 7 days there is no improvement,

consider sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa

– Monitor patients until rash resolves– Telaprevir must not be restarted if

discontinued due to rash

• Considerations– Oral antihistamines or topical corticosteroids

may provide relief, but unproven– Systemic corticosteroids are not recommended

(if used, discontinue HCV therapy)

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Lawitz EJ. Gastroenterol Hepatol. 2011;7:469-471.Full prescribing information for telaprevir.

Severe Rash

Maculopapular, confluence of red spots, eczematous, somewhat raised

48

Telaprevir:Anemia

• Mainly grade 1-2 in severity– Overall incidence: 36%

• Discontinuation due to anemia– Telaprevir only: 4%– Telaprevir, peginterferon, ribavirin: 1%

• Management– Ribavirin dose reduction– Monitor hemoglobin every 4 weeks– If ribavirin dose reductions are inadequate

• Consider telaprevir discontinuation• Telaprevir must not be restarted if discontinued due to anemia

Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Full prescribing information for telaprevir.

49

ADVANCE and ILLUMINATE Studies: SVR Rates by Anemia and Ribavirin Dosing Status

Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S195. Abstract 477.

Patie

nts

With

SVR

(%)

Anemia(n=196/165/361/92)

Anemia Status

76%72%

No Anemia(n=269/259/324/262)

74%

50%

77%73%

41%

T12/PR24T12/PR48

T12/PR PR

70%

Patie

nts

With

SVR

(%)

Dose Reduction(n=172/148/320/89)

Ribavirin Dose Reduction Status

78%73%

No Dose Reduction(n=293/272/565/285)

76%

54%

75% 72%

41%

T12/PR24T12/PR48

T12/PR PR

69%

Retrospective pooled analysis.

50

Boceprevir:Adverse Events

• Most common– Fatigue, anemia, nausea, headache, dysgeusia

• Most common serious adverse events– Anemia– Neutropenia

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.Full prescribing information for boceprevir.

51

Boceprevir:Anemia

• Overall incidence: 50%• Anemia consequences (boceprevir versus controls)

– Dose reduction: 21% versus 13%– Erythropoietin: 43% versus 24%– Transfusion: 3% versus 1% – Discontinuation: 2% versus 1%

• Management– Ribavirin dose reduction and or erythropoietin– If ribavirin dose reductions are inadequate

• Consider discontinuation of all 3 drugs in regimen• Boceprevir must not be restarted if discontinued due to anemia

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.Full prescribing information for boceprevir.

52

Boceprevir Subanalysis: SVR Ratesby Method of Anemia Management

SPRINT-2 (Boceprevir Arms)

Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S194-S195. Abstract 476.Retrospective analysis.

Patie

nts

(%)

58%

74%

NoAnemia(n=363)

75% 71% 68%

Erythropoietin(n=129)

RibavirinDose Reduction

(n=37)

Both(n=153)

Neither(n=44)

No anemiaAnemia

53

Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management

• Data from fixed-dose (n=111)* and response-guided boceprevir arms (n=576) combined

– Hemoglobin (males 12-15 g/dL, females 13-15 g/dL)

• Patients randomly assigned when hemoglobin <10 g/dL (stratified by race and anemia onset)

– Ribavirin dose reduction (200-400 mg/day)

– Erythropoietin (40,000 IU/week)

• Secondary anemia management if hemoglobin <8.5 mg/dL

• Primary endpoint: SVR

Poordad FF, et al. J Hepatol. 2012;56(suppl 2):S559. Abstract 1419.

*Patients enrolled in fixed-dose arm (4-week lead-in then 48 weeks of boceprevir 800 mg tid + pegIFN + RBV) before protocol amendment allowed the response-guided paradigm.

0 4 12* 24* 28 48 72

Boceprevir (800 mg tid) + PegIFN + RBV

Follow-Up

Weight-based ribavirin dosing (600-1400 mg).

Boceprevir (800 mg tid) + PegIFN + RBV

Follow-UpLeadin

Leadin

*Stopping rules: HCV RNA detectable at week 12.

HCV RNA Undetectableat Treatment Week 8-24

HCV RNA Detectable at Treatment Week 8-24

Response-Guided Therapy

Weeks

54

Ribavirin Dose Reduction Versus Erythropoietin for Anemia Management

• Both anemia management arms had similar end-of-treatment response, SVR, and relapse rates

• SVR rates were similar with ribavirin dose reduction and erythropoietin management regardless of race, sex, body weight, fibrosis score, and IL28B genotype

• Similar safety profilesPa

tient

s (%

)

EOT(n=249/251)

EOT, SVR, and Relapse Rates

82%

Poordad FF, et al. J Hepatol. 2012;56(suppl 2):S559. Abstract 1419.

SVR(n=249/251)

Relapse(n=196/197)

82%

71% 71%

10% 10%

EOT: end-of-treatment.

Ribavirin dose reductionErythropoietin

55

Boceprevir:Neutropenia

• Overall incidence*:– 7% compared with 4% in the pegIFN + RBV arms

• Management– Complete blood counts

• Prior to therapy and during treatment weeks 4, 8, and 12• Monitor closely at other time points, as clinically appropriate

– May require dose reduction or discontinuation of peginterferon alfa and ribavirin

• Discontinue boceprevir if peginterferon and ribavirin are discontinued

Poordad F, et al. N Engl J Med. 2011;364:1195-1206.Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.Full prescribing information for boceprevir.

Neutropenia in phase 2 and 3 clinical trials (neutrophil counts <0.5 x 109/L).

56

Telaprevir and Boceprevir:Drug Interactions

• Telaprevir– Inhibitor of CYP3A and p-glycoprotein– Substrate for CYP3A and p-glycoprotein

• Boceprevir– Strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5– Substrate for CYP3A and p-glycoprotein

• It is particularly important to review drug interaction information listed in the package insert for each of the drugs before starting

• Other helpful drug interaction resources– FDA Web site: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm – http//:222.drug-interactions.com – www.hep-druginteractions.org

Ghany MG, et al. Hepatology. 2011;54:1433-1444.Full prescribing information for telaprevir and boceprevir.

57

Raising Cure Rates inChronic HCV Infection: Conclusions

• Boceprevir or telaprevir + pegIFN + RBV is the optimal therapy for genotype 1, chronic HCV infection– SVR rate: 65% to 75% of patients

• Interferon responsiveness, genotype subtype (1a versus 1b), and fibrosis impact SVR rate

• Response-guided therapy allows for shorter duration of therapy

• Need to identify infected HCV populations (birth-cohort screening)