1 Sponsored for Continuing Medical Education Credit by Rush University Medical Center Supported by an independent educational grant from Vertex Pharmaceuticals Incorporated Management Strategies to Management Strategies to Raise Cure Rates in Patients Raise Cure Rates in Patients With Genotype 1 HCV Infection With Genotype 1 HCV Infection
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1 Sponsored for Continuing Medical Education Credit by Rush University Medical Center Supported by an independent educational grant from Vertex Pharmaceuticals.
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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
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Faculty:Content Development and Training
David R. Nelson, MDDavid R. Nelson, MDProfessor of Medicine
Associate Dean, Clinical and Translational ResearchUniversity of FloridaGainesville, Florida
● 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
Pre
vale
nce
(m
illi
on
s)
2,475,000
825,000715,000
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)
Nu
mb
er o
f C
ases
(in
mill
ion
s)
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
To
tal
HC
V I
nfe
ctio
ns
(mil
lio
ns)
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.
– 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
(lo
g1
0 I
U/m
L)
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
(lo
g1
0 I
U/m
L)
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.
Pro
bab
ility
(%
)
0 2 4 6 8 10 12 14 16 18
Time After Treatment Failure (months)
Loss of Resistant Variant
R155K
V36M
A156S/T
T54A
V36A
Common genotype 1a variantsCommon genotype 1b variants
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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.
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Telaprevir and Boceprevir:Safety Profiles and Drug Interactions
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
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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
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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.
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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.
Pat
ien
ts W
ith
SV
R (
%)
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%
Pat
ien
ts W
ith
SV
R (
%)
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.
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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.
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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.
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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.
Pat
ien
ts (
%)
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
• 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 profiles
Pat
ien
ts (
%)
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.