10/4/2014 1 HCV ECHO® WESTERN STATES Original presentation by: Date prepared: Interferon-Free Hepatitis C Regimens: New Therapies, New Recommendations- A Guide for Pharmacists Paulina Deming, PharmD Associate Professor College of Pharmacy Project ECHO University of New Mexico Health Sciences Center October 6, 2014 Paulina Demoing July 19, 2014 HCV ECHO® WESTERN STATES Conflict of Interest Disclosure Statement No conflicts OBJECTIVES 1. Discuss the current standards of care for chronic HCV infections 2. List adverse reactions associated with new treatments for HCV and describe how to manage them 3. Describe how to use an interferon-free treatment regiment 4. Manage drug interactions that are common in patients with HCV and comorbid conditions • According to the AASLD/IDSA guidelines, boceprevir and telaprevir are no longer recommended for the retreatment of HCV G1 prior non-responders because of which of the following reasons? A. Less effective B. Longer duration of therapy C. Poorly tolerated D. All of the above Self-Assessment Questions • Which of the following best describes the role of interferon in HCV therapy? A. It is no longer needed, all new therapies are interferon- free B. It remains a mainstay of therapy in combination with ribavirin C. It remains an option for HCV therapy, although at decreased duration and in combination with new therapies Self-Assessment Questions • Which of the following best describes the drug interactions expected with new therapies? A. Simeprevir has drug-drug interactions with statins which can be managed by reducing the dose of the statin B. Sofosbuvir has substantial clinically relevant drug interactions limiting its use with comorbid conditions C. Both sofosbuvir and simeprevir have substantial drug- drug interactions limiting their use in HIV-HCV coinfection Self-Assessment Questions
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10/4/2014
1
HCV ECHO®WESTERN STATES
Original presentation by: Date prepared:
Interferon-Free Hepatitis C Regimens: New Therapies, New Recommendations- A Guide for PharmacistsPaulina Deming, PharmDAssociate ProfessorCollege of PharmacyProject ECHOUniversity of New Mexico Health Sciences Center
October 6, 2014
Paulina Demoing
July 19, 2014
HCV ECHO® WESTERN STATES
Conflict of Interest Disclosure Statement
No conflicts
OBJECTIVES
1. Discuss the current standards of care for chronic HCV infections
2. List adverse reactions associated with new treatments for HCV and describe how to manage them
3. Describe how to use an interferon-free treatment regiment
4. Manage drug interactions that are common in patients with HCV and comorbid conditions
• According to the AASLD/IDSA guidelines, boceprevirand telaprevir are no longer recommended for the retreatment of HCV G1 prior non-responders because of which of the following reasons?
A. Less effective
B. Longer duration of therapy
C. Poorly tolerated
D. All of the above
Self-Assessment Questions
• Which of the following best describes the role of interferon in HCV therapy?
A. It is no longer needed, all new therapies are interferon-free
B. It remains a mainstay of therapy in combination with ribavirin
C. It remains an option for HCV therapy, although at decreased duration and in combination with new therapies
Self-Assessment Questions
• Which of the following best describes the drug interactions expected with new therapies?
A. Simeprevir has drug-drug interactions with statins which can be managed by reducing the dose of the statin
B. Sofosbuvir has substantial clinically relevant drug interactions limiting its use with comorbid conditions
C. Both sofosbuvir and simeprevir have substantial drug-drug interactions limiting their use in HIV-HCV coinfection
Self-Assessment Questions
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• New HCV treatment guidelines and outcomes in previously treated patients
• Outcomes and drug interaction concerns in patients co-infected with HIV
• Managing HCV drug interactions in patients with dyslipidemia and asthma and in patients post-transplant
• Emerging therapies
Outline Estimated 170 Million Persons With HCV Infection Worldwide
World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C: Global Prevalence:
Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. WasleyA, et al. Semin Liver Dis. 2000;20:1-16.
Europe
8.9 million
(1.03%)Americas
13.1 million
(1.7%)
Africa
31.9 million
(5.3%)
Western
Pacific
62.2 million
(3.9%)
Eastern
Mediterranean
21.3 million
(4.6%)
Southeast Asia
32.3 million
(2.15%)
Estimated 36,000 persons living with HCV
> 3000 cases reported each year to NMDOH
> 4000 cases in 2012
Highest rate of chronic liver disease/cirrhosis deaths in the nation
Hepatitis C in New Mexico
Hepatitis C Rates
Per 100,000 Population
0 - 60
61 - 97
98 - 117
118 - 214
215 - 345
Hepatitis C Rates by County, 2012 Hepatitis C Prevalence (NHANES Estimate)
Armstrong GL, et al. Ann Intern Med. 2006;144:705-14.;Chak E, et al. Liver Int. 2011;31:1090-1101
3.2 Million HCV Antibody positive
Possibly up to 7.1 Million HCV Antibody positive in US
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• Prevalence among persons born 1945–1965: 3.25%
– 5 x higher than among adults born in other years
Prevalence of HCV in US By Year of Birth:
NHANES Data
Armstrong GL, et al. Ann Internal Med. 2006;144:705-714. Smith BD, et al. AASLD 2011
New screening guidelinesRationale for Recommendations:• 45%-85% of infected
persons are undiagnosed• Limitations of current
risk-based strategies • 75% of chronic infections
are in persons born from 1945-1965
Hepatitis C: Progression of Disease
25-30 yearsNormal Liver
Chronic Hepatitis
HCCESLDDeath
HCV Infection
20-25 years
Cirrhosis
Time
Figure 2
• Disease progression is variable and non-linear
• Modifiable factors are important in disease progression and should be addressed
– Weight loss
– Diabetes control
– Alcohol and marijuana
– Vaccination for HAV, HBV
Progression of HCV Disease
• 40-74% of patients will develop > 1 of the following1
Lawitz et al, Jacobson et al, Nelson et al, Gane et al. EASL 2013. Amsterdam, The Netherlands.
• Drug interaction potential:
– Low
– Expected with potent P-glycoprotein drugs (ex: rifampin, phenytoin, carbamazepine)
What to Expect When Using Sofosbuvir
• Most common reported side effects:
– Headache
– Fatigue
• Laboratory abnormalities:
– Hemoglobin decline when combined with ribavirin
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• Once daily oral HCV NS3/4A protease inhibitor
• Indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen
• Effective in HCV genotype 1 infected subjects
• Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended– Alternative therapy should be considered for patients infected with
HCV genotype 1a containing the Q80K polymorphism
Simeprevir Treatment Duration and Expected Outcomes
SMV, PegIFN, & RBV
PegIFN & RBV Total txtduration
Expected SVR
Naïve and prior relapsers, including cirrhotics
First 12 weeks Addl 12 wks 24 wks Treatment Naïve and Prior Relapsers: ~80%
Prior partial and null responders including cirrhotics
Relapse after completion of therapy accounted for all other virologic failures
Non-cirrhotic
212/250 12/13
94
86/92
Naïve,
Non-cirrhotic
87
87/100
Experienced,
Non-cirrhotic
92
Naïve,
Cirrhotic
60
27/45
Experienced,
Cirrhotic
0
20
40
60
80
10085
Overall
212/250
Overall
Cirrhotic
SV
R12 (
%)
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• Daily sofosbuvir 400 mg and weight based ribavirin and pegylated interferon for 12 weeks
Alternative Regimen for HCV G3 PEG/RBV Non-Responders
http://www.hcvguidelines.org/
Rationale for Adding PegIFN: LONESTAR-2 Virologic Response
HCV GT 3 Treatment-Experienced Patients
SOF + PegIFN + RBV x 12 weeks
Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4
83 83 83
0102030405060708090
100
SV
R1
2 (%
)
Overall
Non-cirrhotic
Cirrhotic
20/24 10/12* 10/12*
*1 patient relapsed and 1 patient was lost to follow-up in each subgroup/12†
• For HCV G1 prior nonresponders, the use of boceprevir or telaprevir as a retreatment strategy with pegylated interferon and ribavirin is not recommended
– Less effective
– Longer duration of therapy
– Poor tolerability
• Pegylated interferon and ribavirin are no longer the mainstay of treatment
Key Points for Retreatment
• Clinical Scenario: 46 yo female with chronic HCV, hypertension and hyperlipidemia
• What drug interactions can be expected and how should they be handled?
Concerns for Concurrent Use of Statins and Boceprevir and Telaprevir
Boceprevir Telaprevir
Atorvastatin Use lowest effective doseMax daily dose of 40 mg
Avoid coadministration
Fluvastatin, pitavastatin, rosuvastatin
Contraindicated in active liver disease- DDI unlikely
Contraindicated in active liver disease- DDI possible
Lovastatin Contraindicated Contraindicated
Pravastatin Caution is warranted Caution is warranted
Simvastatin Contraindicated Contraindicated
Victrelis® Prescribing Information, Merck and Co. Inc. September 2013
Incivek® Prescribing Information, Vertex Pharmaceuticals Inc. October 2013
• Clinical Scenario: 44 yo male coinfected with HIV and HCV.
• What kind of response rates can this patient expect?
• What drug interactions can be expected and how should they be handled?
AASLD/IDSA Recommendations for Treatment
HCV Genotype Recommended Treatment
HCV 1 SOF + PEG/RBV x 12 weeksSOF + RBV x 24 weeksSOF + SMV +RBV x 12 weeks
HCV 2 SOF + RBV x 12 weeks
HCV 3 SOF + RBV x 24 weeks
HCV 4 SOF + PEG/RBV x 12 weeks
HCV 5 SOF + PEG/RBV x 12 weeks
No differences in drug therapy for HIV-HCV coinfection
http://www.hcvguidelines.org/
96100
76
0
20
40
60
80
100
Week 4 EOT SVR12
GT 1
HC
V R
NA
< 2
5 I
U/m
L (%
)
110/114 87/114
96 9688
0
20
40
60
80
100
Week 4 EOT SVR12
GT 2
HC
V R
NA
< 2
5 I
U/m
L (%
)
25/26 23/2622/23
Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212
No HCV resistance (S282T) was observed in virologic failures via deep sequencing
Two patients had HCV breakthrough; both had documented non-adherence to SOF
Two patients had transient HIV breakthrough; both had documented non-adherence to ART
100 98
67
0
20
40
60
80
100
Week 4 EOT SVR12
GT 3
HC
V R
NA
< 2
5 I
U/m
L (%
)
41/41 28/42
SOF + RBV x24 weeks SOF + RBV x12 weeks SOF + RBV x12 weeks
All-Oral Therapy of SOF + RBV in Treatment-Naive HIV/HCV Coinfection
PHOTON-1 Virologic Response
100/100 39/40
Osinusi A, et al. JAMA. 2013;310(8):804-811.Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87.
Similar response rates in HIV/HCV coinfected patients compared
to HCV monoinfected patients
GT 1SOF + RBV
24 weeks
GT 2SOF + RBV
12 weeks
GT 3SOF + RBV
12 weeks
All-Oral Therapy of SOF + RBV
Comparison of HCV Monoinfected to HIV/HCV Coinfected
GT 3SOF + RBV
24 weeks
SVR
12
(%
)
6876
0
20
40
60
80
100
SPARE PHOTON-1
SVR
12
(%
)
9388
0
20
40
60
80
100
VALENCE PHOTON-1
SVR
12
(%
) 5667
0
20
40
60
80
100
FISSION PHOTON-1
SVR
12
(%
)
85
0
20
40
60
80
100
VALENCE
Similar response rates in HIV/HCV co-infected patients compared
to HCV mono-infected patients
91 91
0
20
40
60
80
100
NEUTRINO(HCV Mono-infected)
Study 1910(HIV/HCV Co-infected)
SVR
12
(%
)
Rationale for Recommendations: SOF + PegIFN + RBV x 12 Weeks
Comparison of HCV Mono-infected to HIV/HCV Co-infected
Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02 Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
• SOF + RBV resulted in high SVR12 rates in HCV treatment-naïve, HIV-infected patients with GT 1, 2, and 3 coinfection
– Similar to those observed in patients with HCV monoinfection
• SOF + RBV was effectively co-administered with multiple antiretroviral regimens including inhibitors of HIV-1 protease, reverse transcriptase (non-nucleoside/nucleoside) and integrase inhibitor
• Simeprevir use limited to HIV regimens with raltegrevir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricatabine, lamivudine, abacavir
Key Points in HIV-HCV Coinfection
Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212
AASLD/IDSA HCV Guidelines Available at: www.hcvguidelines.org/full-report/unique-patient-populations-hivhcv-coinfection-box-recommendations-hivhcv-coinfected
• Clinical Scenario: 48 yo male with cirrhosis s/p liver transplant, previously treated with pegylatedinterferon and ribavirin, prior non-responder, now planning retreatment of HCV
• What drug interactions can be expected?
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Challenges of Boceprevir and Telaprevir in Post-Transplant Setting
Cyclosporine Tacrolimus
Telaprevir Increase Cmax by 32%Increase AUC by 4.6x
Increase Cmax by 9.35xIncrease AUC by 70.3x
Boceprevir Increase Cmax by 101%Increase AUC by 168%
Increase Cmax by 10xIncrease AUC by 17x
• Require frequent monitoring of immunosuppressive agent
• Require (substantial) dose reductions and/or decreased frequency of dosing
Victrelis Prescribing Information, Merck and Co. Inc. September 2013
Incivek Prescribing Information, Vertex Pharmaceuticals Inc. October 2013
Drug Interactions with Simeprevir and Immunosuppressive Agents
Drug Effect Recommendations
Cyclosporine Increases cyclosporine No dose adjustmentMonitor cyclosporine levels
Tacrolimus Decreases tacrolimus No dose adjustmentMonitor tacrolimus levels
PDUFA: Oct 10, 20141. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172; 3. SOVALDI® [PI]. Gilead Sciences, Inc. Foster City, CA December 2013
LDV/SOF + RBV
LDV/SOF
LDV/SOF + RBV
LDV/SOF
Wk 0 Wk 12 Wk 24
LDV/SOF
LDV/SOF + RBV
Wk 8
ION-1 treatment naïve: N = 865
ION-2 treatment experienced: N = 440
ION-3 treatment naïve: N = 647
N=1952 total patients
ION-1
ION-2
ION-3
LDV/SOF Phase 3 Program (ION-1, ION-2, ION-3)
LDV/SOF Phase 3 Program
0
20
40
60
80
100
ION-1GT 1 treatment-naïve
including cirrhotics
ION-3GT 1 treatment-naïve
non-cirrhotic
ION-2 GT 1 treatment-experienced
including cirrhotics and PI failures
99 97 98 99 94 93 95 94 96 99 99
LDV/SOF LDV/SOF+RBV
12 Weeks 24 Weeks 12 Weeks 24 Weeks12 Weeks
Efficacy Summary
ION Phase 3 Program (ION-1, ION-2, ION-3)
SVR
12
(%
)
Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print] Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]
8 Weeks
107/111
102/109
108/109
110/111
211/217
211/214
212/217
215/217
202/215
201/216
206/216
Error bars represent 95% confidence intervals.
• 97% (1886/1952) overall SVR rate
Retreatment of Relapsers to SOF+RBV with LDV/SOF STR for 12 Weeks
14/14 14/14 14/14 14/14 14/14 14/14
100 100 100
0
20
40
60
80
100
Week 4 EOT SVR12
% o
f p
atie
nts
with
HC
V
RN
A <
LL
OQ
14/14 14/14 14/14
SYNERGY Trial (NIAID, LDV/SOF)
Osinusi A, EASL, 2014, O11
IFN and RBV free regimen of LDV/SOF resulted in 100% SVR12 rates in patients who had previously failed SOF+RBV 24 week therapy
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LDV/SOF ± RBV in Difficult-to-Treat HCV Populations
ELECTRON-2 (LDV/SOF±RBV)
Gane E, EASL, 2014, O6
Wk 0 Wk 12 Wk 24
SVR12
LDV/SOFGT 1; n=20
CTP class B cirrhotics
LDV/SOF + RBVGT 1; n=19
Prior SOF exposure
LDV/SOF + RBV, n=26
LDV/SOF, n=25GT 3; n=51
Treatment naïve,
including cirrhosis
Random
ized
• Prior treatment history of SOF relapsers included SOF + RBV ± DAA
• Cirrhosis was present in all CTP class B and 16% of GT 3 patients
SVR12 Results with LDV/SOF±RBV for 12 Weeks
100
65 64
100
0
20
40
60
80
100
GT1 Retreatment GT1 CPT Class B GT3 Naïve GT3 Naïve
SV
R1
2 (
%)
LDV/SOF + RBV LDV/SOF LDV/SOF LDV/SOF + RBV
13/20 16/25 26/2619/19
The regimens were safe and well tolerated
Gane E, EASL, 2014, O6
ELECTRON-2 (LDV/SOF±RBV)
LDV/SOF STR for 12 weeks in HCV GT 1 Treatment-naïve Co-infected with HIV
100 100 100 100 100 100100 100 100 100
0
20
40
60
80
100
Week 4 Week 8 EOT SVR4 SVR8 SVR12
% o
f patien
ts w
ith
HC
V R
NA
<
LL
OQ
ARV Untreated ARV Treated
13/13
37/37
13/13
37/37
13/13
30/30
12/12
22/22
10/10
10/10
ERADICATE Study (NIAID, LDV/SOF)
Osinusi A, EASL, 2014, O14 Source: Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.
Hepatitis C Cascade of Care in United States
100%
50%
35%
9% 6%
• Chronic HCV infections pose substantial healthcare burden in the US and in NM
• All oral, interferon free regimens are available and emerging therapies will provide additional interferon free treatment options
• Newer treatments improve cure rates even among previously difficult to treat patients
• Rapidly evolving field of HCV therapy
– Treatment duration approaching 12 weeks
– Complexity of treatment will likely further decrease