Chapters 1 - Canadian Liver Foundation

Report
Protease Inhibitors in Chronic Hepatitis C:
An Update
COMPLETE SLIDE DECK (Chapters 1 – 6)
Edited by
Morris Sherman MD BCh PhD FRCP(C)
Associate Professor of Medicine
University of Toronto
November 2012
Management of Hepatitis C:
Updated Guidelines from the Canadian
Association for the Study of the Liver
(CASL)
Robert P. Myers, MD, MSc
Associate Professor, Liver Unit
Division of Gastroenterology
University of Calgary
Objectives: HCV Management
 Review updated CASL recommendations for
management of HCV genotype 1*
 Burden of HCV in Canada
 Pre-treatment assessment
 Triple therapy including boceprevir and telaprevir
 Adverse effects
 Drug-drug interactions
 Antiviral resistance
* Recommendations for non-1 genotypes are unchanged from the 2007 CASL HCV guidelines.
Burden of HCV in Canada
 Significant medical and economic burden
 Seroprevalence unknown
Risk Group
Population
Prevalence
Prevalent Cases
Proportion of Cases
268,200
52%
140,000
58%
Current IDU
84,400
62%
52,500
22%
Previous IDU
183,800
48%
87,500
36%
Transfusion
3,325,700
0.8%
25,900
11%
Hemophilia
2,200
40%
900
0.4%
Other
27,624,300
0.27%
75,800
31%
Total
31,220,500
0.8%
243,000
100%
IDU, total
Remis RS. PHAC 2007
Burden of HCV in Canada
Modelled incidence




~8,000 incident cases annually (80% IDUs)
Proportion diagnosed unclear (<80%)
HCV-related complications rising
Insufficient manpower to treat all cases
900
Cirrhosis
800
700
600
Decomp
500
400
HCC
300
Transplant
200
100
0
1967 1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022 2027
Year
Remis et al. PHAC 2007
Liver-related death vs. no treatment (%)
Antiviral Therapy Must be Maximized
to Make an Impact

100
90
80% SVR rate
60% SVR rate
40% SVR rate
34% ↓
80
68% ↓
70
60
50
40
30
20
0
Current*
25%
50%
75%
100%
Proportion of population treated
* Assumes 30% Dx & up to 25% Rx’d in 2010. Outcomes at 2020.
Davis GL et al. Gastroenterology 2010; 138(2):513-21
Burden of HCV in Canada:
CASL Recommendations
 A large population-based seroprevalence survey should
be conducted to accurately define the prevalence of
hepatitis C in Canada. The design of the study should
include populations with an increased risk of hepatitis C,
particularly IDUs and immigrants from endemic
countries.
 Increased resources are necessary to improve hepatitis
C treatment capacity in Canada, including the training of
expert treaters and public funding for treatment nurses.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Who Should Be Treated?
CASL Recommendations
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Who Should Be Treated?
CASL Recommendations
 All patients with chronic HCV, particularly those with liver fibrosis,
should be considered candidates for antiviral therapy.
 Patients with extrahepatic manifestations of HCV should be
considered for antiviral therapy.
 Persistently normal ALT does not exclude significant liver
disease nor preclude the need for antiviral therapy.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Pre-Treatment Assessment: Is Liver Biopsy
Really Necessary?
 Some fibrosis assessment necessary
 Prognosis
 Necessity of treatment
 Surveillance for HCC & varices
 F2 threshold less important with improved therapies
 Biopsy is imperfect
 Sampling error; variability in pathologic interpretation
 Numerous noninvasive alternatives to biopsy
Bedossa P et al. Hepatology 2003; 38(6):1449-57
Pre-Treatment Assessment:
Non-invasive Measures of Fibrosis
Test
(Reference)
Components
Cut-off
F2-F4 vs. F0-F1
Sensitivity/specificity
F2-F4 vs. F0-F1
FibroScan
(Castera, 2005)
Liver stiffness by transient
elastography
≥7.1 kPa
67% / 89%
APRI
(Shaheen, 2007)
AST/ULN x 100
Platelets
≥0.5
≥0.7
≥1.5
81% / 50%
84% / 70%
35% / 91%
FibroTest
(Poynard, 2004)
α2M, haptoglobin, apo-A1,
GGT, bilirubin
≥0.58
56% / 83%
α2M, HA, TIMP-1
≥0.36
77% / 73%
α2M, HA, GGT, bilirubin
≥0.50
89% / 63%
α2M, HA, AST, platelets, PT,
urea
≥0.50
75% / 78%
FibroSpect II
(Patel, 2004)
Hepascore
(Adams, 2005)
FibroMeter
(Leroy, 2005)
Pre-Treatment Assessment:
CASL Recommendations
 Assessment of Disease Severity
 All patients with HCV should have an assessment for the
severity of liver fibrosis. Acceptable methods include
liver biopsy, TE (FibroScan), and serum biomarker
panels (e.g. APRI, FibroTest, Fibrometer), either alone or
in combination.
 Alternatively, cirrhosis can be confidently diagnosed in
some patients with clear clinical or radiographic
evidence.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Pre-Treatment Assessment:
CASL Recommendations
 Virologic Testing
 HCV RNA and genotype testing are essential to the
management of patients with chronic hepatitis C.
 HCV RNA testing should be performed using a sensitive
quantitative assay (lower limit of detection ≤ 10-15 IU/mL)
with a broad dynamic range. Standardized results should
be expressed in IU/mL and be available within a maximum
of 7 days in order to facilitate management decisions.
 Although genotype 1b has higher response rates vs.
genotype 1a, testing for HCV subtype is not indicated
 This may change with newer DAAs available in the future
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Interleukin 28B (IL28B)
 Associated with viral clearance
 ~50% of ethnic variation in SVR
rates
 Strongest pre-treatment predictor
of SVR, but on-treatment
response more important
100
P=1.06x10-25
80
SVR (%)
 Single-nucleotide polymorphisms
(SNPs) on chromosome 19
 Encodes IFN-λ3
P=2.06x10-3
P=4.39x10-3
P=1.37x10-28
Numbers on bars represent n
60
40
20
102 433 336
0
70
91
30
14
35
26
186 559 392
T/T T/C C/C
T/C C/C
T/C C/C
T/C C/C
EuropeanAmericans
AfricanAmericans
Hispanics
Combined
rs12979860
SVR (%)
Non-SVR (%)
Ge. Nature 2009. Suppiah. Nat Genet 2009. Tanaka. Nat Genet 2009. Thomas. Nature 2009.
Pre-Treatment Assessment:
CASL Recommendations
 IL28B Genotyping
 The IL28B genotype may provide valuable information
regarding the likelihood of SVR and the probability of
qualifying for shortened treatment duration in previously
untreated patients with genotype 1.
 The role of IL28B genotyping is limited in treatmentexperienced patients and those with genotypes other than
1 and 4.
 A non-favourable IL28B genotype does not preclude
antiviral therapy.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Antiviral Therapy for HCV Genotype 1:
CASL Recommendations
 Triple therapy including peginterferon (PEG-IFN), ribavirin
(RBV), and a protease inhibitor (telaprevir or boceprevir) is
the new standard of care in treatment-naïve and previous
treatment failures.
 Boceprevir (800 mg every 8 hours with food) is administered
after a 4-week lead-in period of PEG-IFN and RBV. Duration
of therapy depends on patient characteristics and treatment
response.
 Telaprevir (750 mg every 8 hours with non-low fat food)
should be started simultaneously with PEG-IFN and RBV and
given for the initial 12 weeks of therapy.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Response-Guided Therapy (RGT):
CASL Recommendations
 RGT - the tailoring of treatment duration based on early viral
kinetics - can be employed in selected patient subgroups.
 Boceprevir: HCV RNA negative at weeks 8 through 24
 Telaprevir: HCV RNA negative at weeks 4 through 12
 SVR rates of ~90% have been reported with 24 to 28 weeks
of therapy in patients qualifying for RGT.
 Partial responders treated with telaprevir, patients with
cirrhosis, and prior null responders should not receive RGT.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Adherence to Antiviral Therapy:
CASL Recommendations
 Adherence to treatment and to futility rules, and close
monitoring of concomitant drugs and side effects are
particularly important with PI-based therapy.
 Optimal management of this population should be
conducted by well-trained, experienced personnel.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Futility Rules:
CASL Recommendations
 Strict adherence to futility rules is vital to limit exposure to
potential side effects of these costly therapies that will not
achieve SVR, and to reduce emergence of antiviral
resistance.
 All therapy – including PEG-IFN and RBV – must be
discontinued if futility rules are met:
 Boceprevir: HCV RNA ≥100 IU/mL at week 12 or
detectable at week 24
 Telaprevir: HCV RNA >1,000 IU/mL at week 4 or 12, or
detectable at week 24
 Identical futility rules apply to treatment-naïve and
treatment-experienced patients.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Futility Rules Indicate Treatment Failure
Even if the Viral Load Has Declined
107
1,800,000
HCV RNA (IU/mL)
106
99.9% reduction:
Continue?
105
104
1,230
103
475
102
If futility rules met, RNA is rising!
Stop therapy!
10
1
W0
W1
W2
W3
W4
Slide courtesy of Dr. J. Feld.
Adverse Effects of the Protease Inhibitors (PIs)
 PI-based therapy associated with more adverse effects
than PEG-IFN and RBV dual therapy
 No data to support switching from one PI to another to
manage toxicity
 Major adverse effects differ by PI
 Boceprevir: anemia (~50%), dysgeusia (~40%)
 Telaprevir: anemia (~40%), rash (~40%), anorectal
symptoms (~30%)
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Adverse Effects of the Protease Inhibitors (PIs):
CASL Recommendations
 Treatment with PIs should be supervised by experienced
personnel and adverse effects monitored closely.
 Close monitoring of hemoglobin levels is essential
during antiviral treatment for HCV, particularly during the
administration of PIs.
 Management of anemia may include any of the following
strategies: RBV dose reduction (first line), transfusion of
packed red blood cells, and/or erythropoietin
administration.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Drug-Drug Interactions (DDIs)
 Boceprevir and telaprevir are substrates and inhibitors of
CYP3A4*
 CYP3A4 metabolizes many common drugs
 Potential increased drug concentrations with PI coadministration
 Drugs that induced CYP3A4 may reduce PI concentration
(i.e. antiviral treatment efficacy)
 Numerous potential DDIs with PI-based therapy
 Antiarrhythmics, anticoagulants, anticonvulsants,
antihistamines, antibacterials, antiretrovirals, statins,
herbal products, immunosuppressants, OCPs,
phosphodiesterase inhibitors, and some
sedatives/hypnotics
* Minor elimination pathways include P-glycoprotein and aldoketoreductase.
Drug-Drug Interactions (DDIs):
CASL Recommendations
 Prior to the initiation of PIs, potential DDIs must be
considered, including those attributable to prescription
and over-the-counter pharmaceuticals and herbal
preparations.
 Review product monographs and useful online
resources for potential DDIs prior to initiating therapy.
 http://www.hep-druginteractions.org/
 http://medicine.iupui.edu/clinpharm/ddis/
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Antiviral Resistance




HCV RNA change from
baseline (Log10 IU/mL)
All resistance variants pre-exist
Not caused by PIs, but unmasked by selective pressure
Reflect inadequate response to PEG-IFN/RBV
Predominant cause (80-90%) of incomplete viral suppression,
breakthrough, or relapse
 Genotype 1a > 1b
1
Modest or null IFNa-ribavirin effect
0
-1
-2
Resistant HCV
-3
-4
Wild-type, sensitive HCV
-5
Study time
Pawlotsky JM. Hepatology. 2011 May; 53(5):1742-51
Antiviral Resistance:
CASL Recommendations
 In order to reduce the development of antiviral
resistance to the PIs, patients who meet futility rules
indicating a high likelihood of treatment failure should
discontinue therapy immediately.
 Dosage reductions of boceprevir and telaprevir should
not be utilized to manage treatment-related side effects.
 To prevent resistance, PIs must be stopped if either
PEG-IFN or RBV are discontinued.
 There is no role for pre-treatment resistance testing.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Summary:
CASL Guidelines for the Management of HCV
 Must maximize case-finding, referral, and antiviral Rx to
reduce HCV burden in Canada.
 Barriers to treatment (e.g. need for biopsy) should be
minimized.
 New therapies (boceprevir and telaprevir) markedly
improve SVR rates in genotype 1 (treatment-naïve and
experienced), but are complex and have additional side
effects.
Important Hepatitis C Protease Inhibitor
Drug Interactions in Mono and
HIV Coinfection
Alice Tseng, Pharm.D., FCSHP, AAHIVP
Toronto General Hospital
University of Toronto
Outline
 Review principles of drug interactions
 Understand how the pharmacology of DAAs
contribute to drug interactions
 Highlight important HCV drug interactions
 Outline a strategy for identifying and managing drug
interactions
 Identify pertinent HCV drug interaction resources
Drug Interactions
 Pharmacodynamic
 Change in pharmacological effect of a drug
 Additive, synergistic, or antagonistic activity or toxicity
 e.g., ribavirin + AZT =  anemia
 Pharmacokinetic
 Change in the amount of drug(s) in body
 Absorption, distribution, metabolism, elimination may
be affected
 Often involves CYP450 system or transporters
Interactions Affecting Drug Metabolism
 Majority of drugs transformed to inactive forms prior to elimination
through Phase I (oxidation) or Phase II (conjugation) reactions
 Phase I primarily involves cytochrome P450 system
 Superfamily of microsomal heme-containing enzymes
 Primarily located in liver, small bowel; also kidney, lung, brain
 CYP3A is the most abundantly expressed isoenzyme, is involved in
the metabolism of ~50% of clinically used drugs
 others: CYP2D6, 2C9, 2B6, 1A2, etc.
 P-glycoprotein
 Efflux membrane transporter which prevents drug accumulation in
cells; has broad substrate specificity, and inhibiting or inducing the
activity of this protein can lead to significant alterations in drug
exposure
Terms
Definition
Interaction Impact
Common Examples
Substrate
Agent which is
primarily cleared via a
certain enzymatic
pathway
Rate of drug
breakdown is affected
by presence of enzyme
inhibitors or enzyme
inducers
antidepressants, azoles,
benzodiazepines, statins,
corticosteroids, calcium
channel blockers,
macrolides, rifamycins, HIV
PIs & NNRTIs
Inhibitor
Agent which competes
with another drug for
binding at enzymatic
site
Decreased clearance
macrolides, azoles, HIV
of substrate drug; quick protease inhibitors
onset & resolution of
interaction effect
Inducer
Drug that stimulates
the production of
additional metabolic
enzymes
Increased clearance of
substrate drug; slower
onset and resolution of
interaction effect
anticonvulsants, rifamycins,
HIV NNRTIs, St. John’s
wort
Boceprevir and Telaprevir Pharmacology
Boceprevir
Telaprevir
Dosing
800 mg q8h with food
750 mg q8h with food (20 g
fat)
Substrate
CYP3A4, P-gp, AKR
CYP3A4, Pgp
3A4, P-gp
3A4, P-gp, renal
transporters (?)
Inhibitor
Inducer
No inducing effects in vitro (in vivo?)
= +++ potential for interactions with other drugs
 can be clinically significant
 sometimes unpredictable
Potential Consequences of DAA Drug Interactions
 Interactions may occur in a two-way manner:
 Concentrations of DAA may be altered by other
drug(s)
 Concentrations of concomitant drug(s) may be
altered by DAA
 Potential consequences include:
 Increased risk of toxicity
 Decreased efficacy
Statin Interactions
 Most statins are P450
substrates
 DAAs can significantly
increase statin levels:
 Atorvastatin: 130%  with
boceprevir,
7.88-fold  with telaprevir
 Pravastatin: 60%  with
boceprevir
  risk of toxicity, including
myopathy and rhabdomyolysis
Boceprevir
Lovastatin,
Simvastatin
Telaprevir
CONTRAINDICATED
Atorvastatin
May need to 
atorvastatin dose;
do not exceed
>20 mg/d
CONTRAINDICATED
Pravastatin
Start with
recommended
dose and monitor
for toxicity.
Possible  in
statin; use with
caution.
Rosuvastatin,
Fluvastatin
Possible  in statin; use with caution.
[Victrelis & Incivek Product Monographs, 2011. FDA HIV/AIDS Drug Safety Communication, March 1, 2012]
Atorvastatin Interactions
with Boceprevir and Telaprevir
 Atorvastatin 20 mg + telaprevir:
 Atorvastatin AUC  7.88-fold
30,000
100
25,000
Atorvastatin alone
Atorvastatin + Boceprevir
20,000
15,000
10,000
5,000
Concentration (ng/mL)
Atorvastatin concentration (pg/mL)
 Atorvastatin 40 mg + boceprevir:
 Atorvastatin AUC  130% and
Cmax  170% vs. atorvastatin alone
0
10.0
With telaprevir
1.00
Without telaprevir
0.10
0.01
0
8
16
24
Time (hrs)
32
40
 Suggest  atorvastatin dose with
concomitant BOC; monitor for symptoms of
statin toxicity if using >40 mg/d atorvastatin
Hulskotte EGJ et al. HEP DART 2011,
Koloa, Hawaii, poster 122
48
0
10
20
30
Nominal time (hrs)
40
50
 Combination is contraindicated
Lee JE et al. Antimicrob Agents Chemother 2011,
55(10):4569-74
Effect of Steady-State Telaprevir on the
Pharmacokinetics of Amlodipine 5 mg
Concentration (ng/mL)
5.00
Calcium channel blockers
(CCBs)
With telaprevir
 Amlodipine, diltiazem, felodipine,
nifedipine, nicardapine, verapamil
are CYP3A4 substrates
 Concentrations may be  by
boceprevir or telaprevir
 Use with caution, clinical
monitoring
 Consider dose reduction
0.50
Without telaprevir
0.05
0.01
0
50
100
150
200
250
Nominal time (hrs)
 Amlodipine AUC  179%
 Monitor for dose-related toxicity
Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74
Antihypertensive Medications
Class
Examples
Potential DAA
Interactions
ACEI
Enalapril, lisinopril, ramipril (renal)
Not expected
ARBs
Losartan (2C9>>3A4 to active metabolite)
Candesartan, irbesartan (2C9)
Eprosartan, olmesartan, telmisartan, valsartan (biliary)
Possible  effect
Low
Not expected
Betablockers
Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4)
Acebutolol, labetalol, metoprolol, pindolol (2D6)
Atenolol, nadolol (renal)
Possible 
Calcium
channel
blockers
Amlodipine, diltiazem, felodipine, nifedipine, verapamil (3A4)
Risk of  CCB
exposures; use with
caution
Diuretics
Hydrochlorothiazide, furosemide, spironolactone (renal)
Indapamide (2C9, 2D6, 3A4)
Not expected
Possible 
Low
Not expected
Treatment of Depression in HCV
Place in
Therapy
Examples (route of metabolism)
Potential DAA
Interactions
First Line
Escitalopram, citalopram (2C19, 3A4>>2D6)
35%  with TVR, no
interaction with BOC
Second Line
Paroxetine, fluoxetine (2D6), bupropion (2B6)
Sertraline (2B6>2C9/19, 3A4, 2D6), venlafaxine
(2D6>3A4), desvenlafaxine (UGT>>3A4),
mirtazapine (2D6, 1A3, 3A4)
Low
Possible 
Third Line
Nortriptyline (2D6)
Imipramine (2D6, 1A2, 2C19, 3A>UGT)
Low
Possible 
No Evidence
Modafinil (3A4; induces 3A4)
Amantadine (not metabolized)
Possible ;  DAA
Not expected
Avoid
Duloxetine (1A2, 2D6) - CONTRAINDICATED
Additive risk of
hepatotoxicity
Methadone Interactions
 Methadone is metabolized by CYP2B6, CYP2C19 & CYP3A,
85% protein bound; R-isomer is biologically active enantiomer
 Boceprevir interaction:
 In the presence of steady-state boceprevir, R-methadone AUC  16%,
Cmax  10%; no clinical effects noted including opioid withdrawal
 Boceprevir exposures not affected by methadone
 Telaprevir interaction:
 In the presence of steady-state telaprevir, R-methadone Cmin  31%,
Cmax  21% and AUC  21%, but median unbound Cmin of
R-methadone was similar before and during telaprevir
coadministration and no withdrawal symptoms were noted
 A priori methadone dose adjustments are not required when initiating
DAA therapy, but close monitoring is recommended, with methadone
dose adjustments if necessary
Hulskotte et al. 2012, Van Heeswijk et al. 2011.
Hormonal Contraceptives with DAAs
 Hormonal contraceptives may not be as effective in
women taking boceprevir or telaprevir
 Boceprevir (Victrelis):
 99%  AUC drospirenone, 24%  AUC EE
 Use 2 alternate effective methods of contraception
during treatment with BOC and Peg IFNa/RBV
 Drospirenone (Yaz®, Yasmin®, Angelique®) is
contraindicated
 Telaprevir (Incivek):
 28%  AUC, 33%  Cmin of EE
 Use 2 additional non-hormonal methods of effective
birth control during TVR dosing and for 2 months after
the last intake of TVR.
Benzodiazepine Interactions
 Majority are substrates of CYP3A4
 Risk for prolonged/excessive sedation
 Oral midazolam & triazolam are contraindicated with
boceprevir and telaprevir
 IV midazolam: consider  dose, close monitoring
for respiratory depression or prolonged sedation
 Other benzodiazepines:  dose and monitor
 Consider using benzodiazepines that are
glucuronidated:
 Lorazepam, oxazepam, temazepam
Inhaled Corticosteroids
 Corticosteroids are CYP3A4 substrates
 Potential for  corticosteroid concentrations resulting in
significantly reduced serum cortisol concentrations
 Inhaled/nasal fluticasone, budesonide:
 Avoid co-administration with HCV PIs if possible,
particularly for extended durations.
 May wish to use corticosteroid associated with less
adrenal suppression (e.g., beclomethasone, ciclesonide)
 Use lowest possible dose, consider non-steroidal
options
Victrelis & Incivek. Product Monographs, 2011
PDE5 Inhibitors
(sildenafil, tadalafil, vardenafil)
 PDE5 inhibitors are substrates of CYP3A4
 Potential for DAAs to  concentrations
 Dose-related side effects (headache, vasodilation,
dyspepsia, visual disturbances)
 Contraindicated with DAAs if using for PAH
 For erectile dysfunction, use a lower dose with DAAs:
 Sildenafil: 25 mg q48h, tadalafil: 10 mg q72h
 Do not use vardenafil
Interactions Between HCV & HIV Medications
 Challenges in treating HIV/HCV co-infected patients
 Additive toxicities:
 Anemia: ribavirin, zidovudine, DAAs
 CNS: interferon, efavirenz
 Potential for negative 2-way interactions
  concentrations of HIV agents
  concentrations of HCV DAAs
Antiretroviral Treatment Options for Patients on
Boceprevir or Telaprevir
Protease Inhibitors (PIs)
Boceprevir
Telaprevir
Avoid with ritonavir-boosted
protease inhibitors
Avoid ritonavir-boosted
darunavir, fosamprenavir and
lopinavir
Atazanavir/ritonavir OK
Non-Nucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)
Integrase Inhibitor
Maraviroc
Nucleoside Reverse
Transcriptase Inhibitors
Avoid efavirenz
Dose  with efavirenz
Etravirine (?)
Etravirine OK
No data
Rilpivirine OK
Raltegravir OK
No data
potential / maraviroc; potential benefit on fibrosis?
Tenofovir OK
Avoid AZT (anemia)
Managing Drug Interactions:
1) Medication Reconciliation
 Ensure medication records are up to date at each visit
 Prescription, OTC, vitamins/herbals, recreational
drugs, inhalers, topical, prn agents
 Confirm doses, prn drugs
 Include all agents that have been started or stopped
 Patient education:
 Encourage patients to ask before taking any new
prescription/non-prescription drug or supplement
 Communication with other HCP!
Managing Drug Interactions:
2) Identify Potential Interactions
 Use a systematic approach to identify combinations of
potential concern
 Apply knowledge of known PK characteristics
 Overlapping CYP pathways, substrate, inducer,
inhibitor
 High index of suspicion with key classes of drugs
 Utilize current drug information resources:
 Product monographs, CPS, literature
 Conference abstracts, specialized HCV drug
interaction websites
Drugs Contraindicated with Boceprevir and
Telaprevir (1)
a1-adrenoreceptor
antagonist
Alfuzosin
Antiarrhythmics
Quinidine, propafenone, serious/life-threatening cardiac
amiodarone.
arrhythmia
Flecainide (TVR)
Antimycobacterials
Rifampin
Ergot derivatives
Hypotension, cardiac arrhythmia
Loss of virologic response
Acute ergot toxicity
Herbal product
St. John’s wort
Loss of virologic response
Statins
Lovastatin, simvastatin.
Atorvastatin (TVR)
Myopathy including rhabdomyolysis
Neuroleptic
Pimozide
Serious/life-threatening cardiac
arrhythmia
Victrelis & Incivek. Product Monographs, 2011
Drugs Contraindicated with Boceprevir and
Telaprevir (2)
PDE-5 inhibitor
Sildenafil.
tadalafil (BOC); vardenafil
(TVR)
Visual abnormalities, hypotension,
prolonged erection, syncope
Sedatives/ hypnotics
Oral midazolam, triazolam
Increased sedation or respiratory
depression
Other
Cisapride, astemizole,
terfenadine
Serious/life-threatening cardiac
arrhythmia
Anticonvulsants
(BOC)
Carbamazepine, phenytoin,
phenobarbital
Loss of virologic response
OC (BOC)
Drospirenone
Hyperkalemia
Aldosterone
antagonist (TVR)
Eplerenone
Hyperkalemia
Triptans (TVR)
Eletriptan
Coronary artery vasospasm, MI, vent.
tachycardia, VF
Victrelis & Incivek. Product Monographs, 2011
Managing Drug Interactions:
Therapeutic Options
 Determine clinical significance
 Evaluate therapeutic options:
 Alter drug dose/dosing frequency
 Substitute with alternate agent
 Can any drugs be permanently or temporarily
discontinued while on DAA treatment?
 Consider patient convenience and cost factors
 Patient counselling & close monitoring is critical
Summary
 High potential for pharmacokinetic interactions between
directly acting antivirals and other drug classes
 Consequences may include therapeutic failure and
increased toxicity
 Often, interactions can be managed, but heightened
level of awareness is needed
 Use a systematic approach to identify and manage
individual drug regimens
 Importance of a specialized, inter-disciplinary team
including pharmacy
Additional Resources
 General
 Hansten PD. Science Med 1998;16-25.
 Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases,
2nd edition, c. 2005, pp:13-39.
 Metheny CJ et al. Pharmacotherapy 2001;21:778-96.
 Interactions in HCV and HIV:
 Kiser J et al. Hepatology 2012;55:1620-8.
 Tseng & Foisy. Curr Infect Dis Rep 2012;14:67-82.
 Internet
 Toronto General Hospital Immunodeficiency Clinic; www.hivclinic.ca
 Liverpool Pharmacology Group; www.hep-druginteractions.org
 www.hcvdruginfo.ca
Side Effects of Antiviral Therapy
for Hepatitis C
Dr. Mark Levstik, FRCP(C)
Associate Professor Medicine
Division of Gastroenterology
Multiorgan Transplant Unit
London Health Sciences Centre
Side Effects with Boceprevir and Telaprevir
 Hematological: (common to both PIs)
 Anemia, Neutropenia
 Effect is additive with INF and RBV
 Gastrointestinal
 Dysgeusia (BOC)
 Diarrhea (TVR & ? BOC)
 Anorectal irritation (TVR)
 Dermatological
 Telaprevir specific rash
Side Effect Comparison of Phase III studies
Adverse Effect
Peg Interferon/
RBV
Boceprevir/
P/R
Anemia <100g/dl
30%
50%
17%
36%
Rash
19%
17%
34%
56%
Fatigue
59%
58%
50%
56%
Diarrhoea
15%
20%
17%
26%
Nausea
42%
46%
28%
39%
Dysgeusia
16%
35%
3%
10%
7%
29%
Anorectal
Peg Interferon/ Telaprevir/
RBV
P/R
Dysgeusia and anemia increased with boceprevir;
Rash, anorectal irritation and anemia increased with telaprevir.
Incivek Product Monograph, June 2012
Victrelis Product Monograph, August 2012
Safety of Protease Inhibitors in Real Life:
CUPIC Study
Patients
 HCV genotype 1 infection
 Compensated cirrhosis (Child Pugh A)
 Treatment-experienced
 Relapsers
 Partial responders ( >2 log10 HCV RNA decline
at Week 12 but never negative)
 Null responders theoretically excluded
 Treated in the French early access program
(From February 2011)
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Treatment Regimen
Interim analysis
Peg-IFN
+ RBV
BOC + Peg-IFN α-2b + RBV
Follow-up
BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d
TVR + Peg-IFN α-2a
+ RBV
Peg-IFN α-2a + RBV
Follow-up
TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000- 1200 mg/d
0
4
8
12
16
36
Weeks
48
72
SVR assessment
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Patients Characteristics
 Baseline patient characteristics similar between BOC and TVR
 The CUPIC cohort had more advanced liver disease than in
registration trials.
 In BOC arm 26% would not meet RESPOND-2 inclusion
criteria
 In TVR arm 34% would not meet REALIZE inclusion
criteria
 Previous treatment response (%)
BOC
TVR
 Partial responders
49
52
 Relapsers
48
40
3
8
 Null responders
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Preliminary Safety Findings
(16-Week Interim Analysis)
Patients, n
(% patients with ≥ 1 event)
Boceprevir
n=159
Telaprevir
n=296
Serious adverse events (%)
38.4
48.6
Premature discontinuation
Due to SAEs (%)
23.9
7.4
26.0
14.5
Death (%)
1.3
2.0
Infection (Grade 3/4) (%)
2.5
8.8
0
0
6.8
0.7
Pruritus (Grade 3/4) (%)
0.6
3.7
Hepatic decompensation (%)
4.4
4.4
Rash
Grade 3 (%)
Grade 4 (SCAR) (%)
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Preliminary Safety Findings
(16-Week Interim Analysis)
Patients, n
(% patients with ≥ 1 event)
Anemia (%)
Grade 2 (8.0 – <10.0 g/dL)
Grade 3/4 (<8,0 g/dL)
EPO use
Blood transfusion
Neutropenia (%)
Grade 3 (500 – <1000/mm3)
Grade 4 (<500/mm3)
G-CSF use
Thrombopenia (%)
Grade 3 (25 000 – <50 000)
Grade 4 (<25 000)
Thrombopoïetin use
Boceprevir
(n=159)
Telaprevir
(n=296)
22.6
10.1
66.0
10.7
19.6
10.1
56.8
15.2
4.4
0.6
3.8
4.0
0.7
2.4
6.3
0.6
1.9
11.8
1.3
1.7
Hezode C et al. EASL 2012, Abstract 8
Take Home Message from CUPIC
 PI therapy in patients with cirrhosis is associated
with more severe and more frequent AEs
 Anemia
 Increased EPO use, ribavirin dose reductions
and transfusions
 Increased risk of severe infection
 Increased risk of hepatic decompensation
Boceprevir Specific Side Effects
 Dysgeusia and decreased appetite more prevalent than control
 Hematological side effects more prevalent than control in
Phase 2/3 naïve studies:
 Neutropenia (<0.75 x 109 /L): 31% vs. 18% in controls
 Platelets (< 50 x 109 /L): 3% vs. 1 % in controls
 Anemia: 50% vs. 30% in controls
 Grade II (<100 g/L): 49% vs. 29%
 Grade III (<85 g/L) : 6% vs. 3%
 Erythropoietin use 47% vs. 24% and pRBC 3% vs. 1%
Victrelis Product Monograph, August 2012
Telaprevir Specific Side Effects
 Rash, anorectal disorders, diarrhea and anemia more
common than control
 Rash seen > 50%, leads to 6% discontinuations
 Mild – 37%
 Moderate – 14%
 Severe – 5%
 Anorectal disorders seen with increase in diarrhea,
itching and burning: 29% vs. 7% in controls
 Anemia: 32% vs. 15% in controls
 Grade II (<9.0-9.9 g/dL): 27% vs. 27%
 Grade III (7.0-8.9 g/dL) : 51% vs. 24%
Incivek Product Monograph, June 2012
Anemia Management
Mechanism of RBV-Associated Anemia
 RBV uptake into RBC  adenosine kinase  RBV-triphosphate
 Erythrocytes lack enzymes to hydrolyze RBV phosphates
 RBV-phosphates are “trapped”
 Erythrocyte T1/2 > 40 days
 RBV concentration in RBC 60-fold higher than serum (60:1)
 Marked depletion of RBC adenosine triphosphate (ATP)
 Impairs anti-oxidant defense mechanisms
 Induces RBC oxidative membrane damage
 Premature extravascular RBC removal by the
reticuloendothelial system
De Franceschi L. Hepatology 2000; 31:997-1004
Ribavirin Dose Reduction vs. EPO ?
 Retrospective analyses of Boceprevir phase III studies
have suggested that reducing the dose of RBV did not
alter the SVR rate.
 In patients treated with PEG+RBV (dual therapy), the
effect of RBV dose reduction ON SVR was minimal if
occurring when HCV-RNA was undetectable.
Sulkowski MS et al. J Hepatol 2011; 54:S194-5.
Reddy KR et al. Clin Gastroenterol Hepatol 2007; 5:124-9
Boceprevir Anemia Management:
Erythropoietin vs. Ribavirin Dose Reduction Study
Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline
687 patients treated with boceprevir RGT
After completion of 4 week PEG-IFN/RBV lead-in,
all patients initiated boceprevir
Hemoglobin ≤100 g/L
Randomisation
Erythropoietin (40,000 IU/wk SC)
n = 251
EPO: erythropoietin
PEG-IFN: peginterferon
RBV: ribavirin
Ribavirin dose reduction (DR)
n = 249
Hemoglobin ≤ 85 g/L: Secondary Strategy
(EPO, RBV DR, transfusion)
Poordad et al. EASL 2012, Abstract 1419
Results – Primary and Key Efficacy End Points
End-of-treatment response, relapse, and SVR were comparable
between RBV DR and EPO arms
 (95% CI)
100
82
82
RBV DR
71
75
Patients (%)
-0.7% (-8.6, 7.2)*
71
EPO
50
25
203/249
205/251
178/249
178/251
10
10
19/196
19/197
0
EOT Response
SVR
Relapse
DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response.
*The stratum-adjusted difference (EPO vs. RBV DR) in SVR rates, adjusted for stratification factors and protocol
cohort.
Poordad et al. EASL 2012, Abstract 1419
Summary - Anemia Management
 Ribavirin dose reduction does not decrease SVR
 No advantage to Erythropoietin use, but may be used
 Consider pRBC transfusion to maintain safe Hb
 DAA should not be reduced
 DAA should not be restarted or continued without
Peg/RBV
 Ribavirin may be increased once Hb recovers
Protease Inhibitors: Management of Anemia
Hb < 100 g/L any time during treatment
Boceprevir
Telaprevir
RBV dose reduction
Up to 3 x 200 mg increments*
Reduce RBV to
600 mg/day
Hb < 85 g/L
Hb > 85 g/L
EPO: 40-60,000 IU/wk
AND/OR
Transfusion
Maintain RBV
dose reduction
* Note: First dose reduction of 400mg if patient receiving 1400mg/day
RBV dose reduction to 600 mg can be used with Boceprevir as wel
Rash Management - Telaprevir
Rash
 Rash more prevalent in DAA but >50% with Telaprevir
 Rash can be categorized:
 Mild to moderate: < 30% of skin area
 Moderate: 30-50% of skin area
 Severe: generalized rash may progress with
bullae, vesicles < 5% of patients
Incivek Product Monograph, 2012
Rash Management Recommendations
 Mild: Watchful monitoring
 Oral antihistamines, moisturizers, topical steroids
 Moderate: < 50% body
 Monitor closely for progression/systemic symptoms
 Antihistamines, moisturizers, topical steroids
 Worsening/Severe: > 50% body ( < 4% of patients )
 Stop telaprevir, observe closely for 7 days
 IF no better, stop Ribavirin, observe for 7 days.
 IF no better, stop Pegylated Interferon
Incivek Product Monograph, 2012
Hézode C. Liver International. 2012; 32 Suppl 1:32-8
Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63
Telaprevir Severe Rash < 1%
 DRESS:
 Drug rash with eosinophilia and systemic symptoms
 Rash, fever, facial edema ± hepatitis/nephritis
 Eosinophils may not be present
 Stevenson-Johnson Syndrome
 Fever, target lesions and mucosal erosions/ulcers
 STOP ALL drugs
 Requires hospitalization
 May require systemic steroids
Incivek Product Monograph, 2012
Hézode C. Liver International. 2012; 32 Suppl 1:32-8
Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63
Other Side Effects of
Boceprevir and Telaprevir
Gastroenterological Side Effects
 Nausea, vomiting, diarrhea
 Small meals three times daily with PI dosing useful
 Fiber, loperamide aid with loose stool
 Dysgeusia noted in Boceprevir patients
 Metallic taste, rarely leads to dose reduction or
discontinuation
 Improved with chocolate administration
Gastroenterological Side Effects: Telaprevir
 Nausea, vomiting and diarrhea common with
TPV/PEG/RBV
 Anorectal irritation:
 Anorectal burning, itch and hemorrhoidal irritation
common: > 29%
 Therapy:
 Frequent small meals, 21g fat per dose
 Fiber, loperamide and topical hydrocortisone
therapy, help relieve symptoms
Incivek Product Monograph, 2012
Hézode C. Liver International. 2012; 32 Suppl 1:32-8
Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63
Management of Depression
 Occurs in up to 37% of patients
 Conduct pre-therapy and routine assessments with
CES-D or other depression scale
 Adjust interferon dose or discontinue therapy
according to depression severity
 May warrant use of antidepressants
 Recommended agents to use with BOC and TVR:
Escitalopram, citalopram (see Dr. Tseng’s chapter
on DDIs)
Direct-Acting Antiviral Therapy:
Boceprevir and Telaprevir
 Patient side-effect education is important to success
 Pre-therapy recommendations include:
 Multivitamin, hydration, acetaminophen analgesia
 Dietary recommendations to decrease GI toxicity
effects ( small meals, fiber, loperamide )
 Skin care through moisturizers and antihistamines
 Close patient and hepatitis team communication
 Monitor and pre-empt severe side effects
 Drug and duration specific
Case Study:
Treatment Naive
Edward Tam MD FRCPC
Medical Director
LAIR Centre
Ms. MH
 31 year old female
 Diagnosed in 2004 with genotype 1a HCV
 Previous IVDU
 Otherwise healthy
 Meds: Milk thistle
 No Biopsy
 ALT 1-2 x ULN on serial monitoring
Ms. MH
 Followed periodically with monitoring of liver
biochemistry
 FibroScan December 9, 2010: 4.9 kPa
 What evidence supports the use of Milk Thistle?
 Is FibroScan a reliable and accurate tool for fibrosis
assessment?
 Does it represent a viable alternative to liver biopsy?
FibroScan versus Liver Biopsy
1.00
Sensitivity
0.75
0.50
AUROC (95% CI)
≥ F2: 0.74 (0.68-0.80)
≥ F3: 0.89 (0.84-0.94)
F4: 0.94 (0.90-0.97)
0.25
0.00
0.00
0.25
0.50
0.75
1.00
1-Specificity
Myers RP et al. Can J Gastroenterol. 2010 Nov;24(11):661-70
Ms. MH
 FibroScan December 9, 2010: 4.9 kPa (consistent with
stage 0 – 1 fibrosis)
 Discussions with patient throughout 2011 regarding
therapy
 Although no medical urgency, very keen to pursue
therapy for personal reasons
Ms. MH
 January 6, 2012, treatment initiated with pegylated
interferon alpha-2b (120mcg) plus ribavirin (500mg BID),
as planned lead-in to boceprevir-based treatment.
Week 0
HCV RNA
5.29 logs
ALT
106
Hb
144
Plts
295
Neutrophils
6.0
Ms. MH: Week 4 Results
Week 0
Wk 2
Wk 4
5.29 logs
--
Undetectable
ALT
106
53
33
Hb
144
120
108
Plts
295
236
214
Neutrophils
6.0
2.0
2.0
HCV RNA
Given the undetectable HCV RNA at the end of WK4 lead-in
(dual therapy), is adding Boceprevir necessary?
Significance of Lead-in Response
SPRINT-2: SVR based on degree of early interferon response
(log decline in HCV RNA at week 4 of P/R in all patients (cohort 1 + cohort 2)
PR48
BOC RGT
100
% of patients with SVR
89 90 90
89 89 89
97
80
79
80
BOC/PR48
70
72 74
65
60
58
60
45
40
33
43
28 28
30
21
20
0
0
5
Log10 viral load decrease after weeks of P/R lead-in
Vierling et al. EASL 2011.
Results Through Week 12
Wk 4
Wk 6
Wk 8
Wk 10
Wk 12
Undetectable
--
Undetectable
--
Undetectable
ALT
33
27
26
22
28
Hb
108
107
101
91
94
Plts
214
179
177
175
174
Neutrophils
2.0
1.3
1.6
1.2
1.2
HCV RNA
 Boceprevir added with 5th interferon injection
 HCV RNA remains undetectable
 Due to worsening anemia and fatigue, RBV dose
reduced to 600mg total daily dose after wk 10 results
Results Through Week 24
Wk 12
Wk 16
Wk 20
Wk 24
Undetectable
--
--
Undetectable
ALT
28
32
25
24
Hb
94
105
101
103
Plts
174
171
164
169
Neutrophils
1.2
1.4
1.0
1.0
HCV RNA
 HCV RNA remained undetectable through week 24, and
patient qualifies for shortened duration therapy (to D/C at
week 28)
Case Study:
Cirrhosis
Nir Hilzenrat, MD
Gastrointestinal Division, Department of Medicine,
SMBD- Jewish General Hospital,
Associate Professor of Medicine,
McGill University, Montreal, Quebec
Case History
 58 year old woman, acquired hepatitis C from
blood transfusion 30 years prior
 Symptoms – mild fatigue and depression
 ALT 2xULN
 Synthetic function normal
 Viral load 3x105 IU/mL
 Liver biopsy (2002)
 F 3/4, activity 2/4
Case History
 Previous treatment in 2000 with pegylated interferon
and ribavirin
 < 1 log drop at week 12
 Treatment discontinued
 Treatment-related side effects
 Severe fatigue
 Fall in Hb level (148 g/L to 108 g/L).
Comments
Previous treatment failures classified into
 Null responder
 Viral load does not fall by 2 logs at week 12
 Partial responder
 Viral load falls by > 2 logs, but never negative
 Relapser
 Viral load negative on therapy but positive after therapy
 Telaprevir (REALIZE study ) response in null responders
was 29% (21/72)
 Boceprevir (PROVIDE study) response in null responders
was 40% (19/47)
Zeuzem, S. et al. N Engl J Med 2011; 364: 2417-28
Bronowicki, JP., International Liver Congress 2012, Abstract 204, EASL 2012
Comments
 Probability of response with F3 or F4 and prior treatment
failure (48 weeks of therapy)
Telaprevir
Boceprevir
%
n
%
n
Relapser
87
48/55
83
15/18
Partial responder
34
11/32
46
6/13
Null responder
14
7/50
-
-
Vertex Pharmaceutical (Canada) Incorporated. Product Monograph: Incivek (Telaprevir
tablets). http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf (Accessed February 1, 2012)
Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced
Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011
Case Continued
 Patient made aware of low probability of cure (15-40%)
 However, she was willing to start treatment
 It was accepted that we will assess the continuity of the
treatment based on the response rate, i.e., HCV-RNA
level, and the severity of adverse effect during the
treatment
 Fibroscan prior suggested cirrhosis
 ALT x 4 ULN
 Liver synthetic function normal
 Viral load 2.8x106 IU/ml
Case Continued
 Treatment was started with Peg INF/RIBA and
boceprevir
 At week 4 viral load decline was 0.8 logs
Question
 How important is the magnitude of the decline in viral
load following the lead-in phase (TW4) of the PR & BOC
treatment?
Importance of 4-Week HCV RNA in Boceprevir
Triple Therapy
 In RESPOND-2 likelihood of SVR for relapsers and
partial-responders was associated with response to
interferon in the lead-in phase
SVR in all patients
SVR in F3/F4
< 1 log drop at wk 4
33%
14-25%
> 1 log drop at wk 4
73%
55-87%
Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced
Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011
Bacon BR et al. N Engl J Med 2011;364:1207-17
Comments
 In the PROVIDE study, the SVR for null responders
was 40%
 Week 4 HCV RNA < 1 log decline from baseline
 SVR 36%
 Week 4 HCV RNA >1 log decline from baseline
 SVR 55%
Bronowicki, JP., Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures
After Retreatment with Boceprevir (BOC) + PR: PROVIDE Study Interim Results, International Liver Congress
2012, Abstract 204, EASL 2012
Case Continued
 The result was discussed with the patient.
 She was made aware that the likelihood of achieving
SVR is poor.
 However, the patient asked to reassess the probability
of her success rate after 4W of PR & BOC treatment,
i.e., 8W of the whole treatment.
Question
 The HCV RNA at week 8 was undetectable
 What is the likelihood of achieving SVR?
Question
 How long should she be treated for?
 At week 12 and 24 the HCV RNA remained undetectable
 Usual side effects, anemia, fatigue and depression
Question
 What are the recommended approaches for this
patient (i.e. cirrhotic null responder to previous
PR treatment) according to the American
Association of the Study of Liver Diseases
(AASLD) and Canadian Association of the Study
of Liver Diseases (CASL) updated guidelines?
Investigational Anti-HCV Drugs
Beyond Boceprevir and Telaprevir
Stephen D. Shafran MD, FRCPC, FACP
Professor, Division of Infectious Diseases
Department of Medicine
University of Alberta
Investigational Drugs for HCV with Activity
in Humans
 Direct-acting antivirals (DAAs)
 Non-DAAs
 Peginterferon lambda (IFN-)
 Tarabivirin
 Pro drug of ribavirin
 Higher ratio of liver to RBC distribution than RBV
 Less anemia than with RBV
 Silibinin (milk thistle extract, IV formulation)
 Cyclophilin inhibitors (eg. Alisporivir*)
* Development on hold due to cases of pancreatitis
Pegylated Interferon Lambda
 IFN- (a type III interferon) receptors are expressed
in hepatocytes but in fewer other cells than IFN-a
(a type I interferon).
 In a phase-IIa trial in treatment-naïve patients,
pegIFN- 120-180 μg weekly + RBV resulted in
similar or higher virologic responses at weeks 4 and
12 vs. pegIFNa-2a + RBV with less toxicity.1
1. Muir A et al. AASLD 2010. Abstract 821
EMERGE: PegIFN-λ/RBV vs. PegIFNa-2a/RBV
Wk 24: GT 2 or 3
Wk 48: GT 1 or 4
PegIFNa-2a 180 μg/wk + RBV
(n=133)
Treatment naïve patients
with genotype 1-4 HCV
infection (n=526)
PegIFN- 120 μg/wk + RBV
(n=128)
PegIFN- 180 μg/wk + RBV
(n=131)
PegIFN- 240 μg/wk + RBV
(n=134)
Zeuzem S et al. EASL 2011. Abstract 1360
EMERGE: PegIFN-/RBV vs. PegIFNa-2a/RBV:
Preliminary Results to Week 12
PegIFNa-2a
Parameter (%)
PegIFN-
180 μg
120 μg
180 μg
240 μg
GT1/4 RVR
5.8
6.0
14.7*
16.5*
GT1/4 cEVR
38
55*
56*
56*
GT 2/3 RVR
31
43
76*
67*
GT 2/3 cEVR
86
90
97
83
Myalgia
30
11
6.1
9.0
Fever
29
7
7
6
Hb < 10 g/dL
44
21
15
13
ANC < 750
15
0
0.8
0
PLT < 25
1.5
0
0
0
Conjugated bilirubin
2.3
5.5
8.5
19.7
* p<0.05 compared with PegIFNa-2a
Zeuzem S et al. EASL 2011. Abstract 1360
EMERGE: PegIFN-/RBV vs. PegIFNa-2a/RBV:
Efficacy and Safety in Genotypes 2 & 3

SVR rates comparable in pegIFN arm vs. pegIFNa-2a
100
SVR24 (%)
Lambda
180 µg
(N = 29)
Alfa
180 µg
(N = 30)
6.9
44.8
RBV dose reduction
(Hb associated)
0
23.3
Neutrophils < 750/mm3
0
27.6
Platelets < 100,000/mm3
0
24.1
PegIFN dose reduction
(hematologic reason)
0
23.3
6.9
13.3
75.9
65.5
60.0
53.3
40
20
0
Fewer hematologic AEs and
ALT/AST elevations with pegIFN-
Adverse Event, %
80
60

N = 30
29
29
30
Alfa Lambda Lambda Lambda
180 µg 120 µg 180 µg 240 µg
Hb < 10 g/dL or
∆ > 3.4 g/dL
ALT/AST > 5 to 10 x ULN

PegIFN- 180 μg dosage chosen
for phase III trials
Zeuzem S et al. EASL 2012. Abstract 10
Proteins encoded by the HCV genome:
Three validated targets and four classes of DAAs
5’ UTR
region
3’ UTR
region
9.6 kb RNA
Polyprotein
C
E1
E2
p7 NS2
NS3
4A
Polyprotein
NS4B
NS5A
Polyprotein processing
1
C
Core
E1
E2
Envelope
Glycoproteins
NS5B
p7 NS2
Protease
2
NS3
NS4A
Serine Helicase Serine
Protease
Protease
Cofactor
NS4B
NS5A
RNA
binding
NS5A
inhibitors
NS3-4A
protease
inhibitors
2
3
NS5B
RNA-dependent
RNA polymerase
NS5B
polymerase
inhibitors
1
Nucleoside analogs
Non-nucleoside analogs
3
4
Adapted from Asselah T et al. Liver International 2011; 31 Suppl 1:68-77
HCV NS3/NS4A Protease Inhibitors (1)
 Inhibit cleavage of viral polyprotein chain, essential to HCV
replication.
 Very active against genotype (GT) 1.
 A single nucleotide mutation in the NS3 region (R155K)
results in resistance in GT 1a, but two mutations are
required for resistance in GT 1b.
 Some have activity against non-1 genotypes, but very little
clinical data exist.
 “First generation” NS3 PIs (boceprevir and telaprevir) are
linear ketoamides and are associated with anemia;
 “Second generation” NS3 PIs are macrocyclic and are not
associated with anemia.
HCV NS3/NS4A Protease Inhibitors (2)
 The two most developed after BOC/TVR are simeprevir
(TMC-435)1 and faldaprevir (BI-201335)2. Both are in fully enrolled
phase 3 clinical trials vs. dual PegIFN + RBV controls; results are
expected in early 2013.
 Simeprevir and faldaprevir are dosed once daily (150 and 120 mg,
respectively) and do not produce additive anemia beyond PegIFN +
RBV.
 Simeprevir is associated with some increase in bilirubin due to
reversible inhibition of OATP1B1 and MRP2 transporters.
 Faldaprevir inhibits glucuronyl transferase and can cause a Gilbert’s
like syndrome (similar to the HIV protease inhibitor, atazanavir).
 Faldaprevir is also associated with rash and photosensitivity.
1. Fried MW et al. AASLD 2010. Abstract LB-5
2. Sulkowski M et al. EASL 2011. Abstracts 60 and 66
HCV NS3/NS4A Protease Inhibitors (3)
 Two NS3 PIs (danoprevir1 and ABT-4502) are being
developed for administration with low dose ritonavir.
 Ritonavir, an HIV protease inhibitor, is a potent inhibitor
of CYP3A4; ritonavir increases exposure of drugs
metabolized principally via CYP3A4.
 Other NS3 PIs are under development, including
asunaprevir (BMS-650032), MK-5172, GS-9451,
sovaprevir (ACH-1625), whereas the development of
several others has been terminated.
1. Rouzier R et al. EASL 2011. Abstract 62
2. Lawitz E et al. EASL 2011. Abstract 1220
HCV NS5A Inhibitors
 NS5A is a protein with no known enzymatic function, but
a definite, yet poorly defined role in viral replication.
 NS5A inhibitors are very potent and pangenotypic in the
replicon system1. They are significantly more active vs.
genotype 1b than genotype 1a.
 Daclatasvir, the most developed NS5A inhibitor, is given
once daily, and is in phase 3 in treatment naïve patients
with genotypes 1 and 4, and in phase 2 for genotypes 2
and 3, and for genotype 1 in the HIV co-infected.
 NS5A inhibitors in phase 2 are ABT-267 and GS-5885
 NS5A inhibitors have no “signature” toxicity to date2.
1. Gao M et al. Nature 2010; 465:96-100
2. Pol S et al. Lancet Infect Dis 2012; 12(9):671-7
Antiviral Activity of Daclatasvir in Combination with
PegIFNa2a + RBV in Treatment of Naïve Patients
with Chronic HCV Genotype 1 Infection
Day 1
Week 48
Placebo +
PegIFNa-2a 180 µg/wk + RBV 1000/1200 mg/d
Treatment
naïve HCV
GT1 patients
n=48
Week 72
SVR 24
Daclatasvir 3 mg QD +
PegIFNa-2a 180 µg/wk + RBV 1000/1200 mg/d
Daclatasvir 10 mg QD +
PegIFNa-2a 180 µg/wk + RBV 1000/1200 mg/d
Daclatasvir 60 mg QD +
PegIFNa-2a 180 µg/wk + RBV 1000/1200 mg/d
Pol S et al. Lancet Infect Dis 2012; 12(9):671-7
Daclatasvir (DCV) with PegIFNa-2a + RBV:
Virologic Response at Weeks 4, 12 & SVR (ITT)
PR
Percent HCV RNA negative
(<10 IU/mL by Roche TaqMan)
100
PR + DCV 3 mg
PR + DCV 10 mg
PR + DCV 60 mg
92
83
83
83
83
83
80
58
60
42
40
42
42
25
20
8
0
RVR
cEVR
SVR (24)
12 patients per treatment arm; the 60 mg QD dose was selected for phase 3
Pol S et al. Lancet Infect Dis 2012; 12(9):671-7
HCV NS5B Polymerase Inhibitors
 NS5B is a RNA-dependent RNA polymerase, responsible for
viral RNA synthesis
 The viral polymerase is the “classic” target for antiviral drugs
(eg. DNA-dependent DNA polymerase in HSV and VZV or
RNA-dependent DNA polymerase [reverse transcriptase] in
HIV and HBV)
 As with HIV RT inhibitors, there are two subtypes of NS5B
inhibitors,
 Nucleoside/nucleotide analogues
 Act as RNA chain terminators
 High barrier to resistance
 Pan-genotypic
 Non-nucleoside inhibitors
 Least potent class of DAA
 Low barrier to resistance
HCV NS5B Polymerase Inhibitors:
Drugs with Antiviral Activity in Humans
 Nucleoside/nucleotide analogues
 Mericitabine (RG-7128)
 Sofosbuvir (GS-7977/ PSI-7977)
 VX-135 (ALS-2200)
 Non-nucleoside inhibitors
 Tegobuvir (GS-9190)
 Setrobuvir (ANA-598)
 ABT-333 (lead Abbott NNI)
 ABT-072 (back-up Abbott NNI)
 VX-222
 BI-207127
IFN-Free, All Oral Regimens with SVR Data
 As of October 2012, 5 pharmaceutical companies have
presented pilot data demonstrating that SVR can be
achieved in small numbers of patients.
 The majority of IFN-free regimens to date continue to
include ribavirin.
 Only one study to date has included patients with
cirrhosis (SOUND C-2).
 The most common combination of agents in IFN-free
regimens for genotype 1 has been a 3-drug combination
of a NS3 PI, a NS5B non-nucleoside (NN) inhibitor and
ribavirin.
 For GT 2 & 3, IFN-free regimens demonstrating SVR are
sofosbuvir with either RBV or daclatasvir.
IFN Free SVR: The Very First Report (Daclatasvir
+ Asunaprevir in GT1 Prior Null Responders)
Daclatasvir+asunaprevir
Follow-up
HCV RNA (log10 IU/mL)
7
6
5
4
3
2
LLOQ
LLOD
1
0 1 2 3 4 6 8 10 12 16 20 24
Week
 SVR was achieved in 2/9 GT 1a and 2/2 GT 1b prior null responders to PR
with 24 weeks of DCV + ASV (all enrolled patients were non-cirrhotic)
 On therapy breakthrough was common in GT 1a
Lok AS et al. EASL 2011; NEJM 2012;366:216-24
Dual Oral Therapy with Daclatasvir and
Asunaprevir x 24 Weeks for HCV GT1b
 Study conducted in Japan
 All had genotype 1b
 Treated with asunaprevir (NS3 PI) and daclatasvir
(NS5A inhibitor) x 24 weeks
Virologic Response (%)
Prior Null
Responders
(n=21)
[6 IL-28B CC]
IFN
Ineligible/Intolerant
(n=22)
[16 IL-28B CC]
Week 4 RVR
52
86
Week 12 cEVR
91
91
EOTR
91
86
SVR24
91
64
Suzuki F, et al. EASL 2012. Abstract 14
PILOT: NS3 PI + NN + RBV:
Virologic Responses
HCV RNA Negative (%)
 n = 11, HCV GT1, treatment-naïve, non-cirrhotic; 8 GT1a, 3 GT 1b
 Only IL-28B CC patients were enrolled, so that they would have a high
probability of salvage with PegIFN + RBV in the event that all-oral
therapy failed
 All were treated with ABT-450/r 150/100 mg QD +
ABT-072 400 mg QD + RBV 1000/1200 mg/d
100
100
100
91
91
82
80
60
40
20
n/N
11/11
11/11
10/11
10/11
9/11
Wk 4
(RVR)
Wk 12
(EOT)
SVR12
SVR24
SVR36
0
Lawitz E, et al. EASL 2012. Abstract 13
CO-PILOT: NS3 PI + NN + RBV:
Virologic Responses
HCV RNA negative (%)
 Because of the favorable results in PILOT, CO-PILOT was open to all IL-28B
genotypes and explored prior PR non-responders;
 All had genotype 1 and were non-cirrhotic
 In CO-PILOT, a different NS5B non-nucleoside inhibitor was used (ABT-333)
than in PILOT (ABT-072)
100
90
90
95
95
93
79
80
RVR
eRVR
SVR4
SVR12
93
79
77
59
60
47
47
40
20
0
ABT-450/r 250/100 mg QD
+ ABT-333 + RBV
Treatment naive
(n = 19; 17 G1a, 2 G1b)
* 11 partial responders, 6 null responders
ABT-450/r 150/100 mg QD
+ ABT-333 + RBV
Treatment naive
(n = 14; 11 G1a, 3 G1b)
ABT-450/r 150/100 mg QD
+ ABT-333 + RBV
Prior PR Non-responders*
(n = 17; 16 G1a; 1 G1b)
Poordad F et al. EASL 2012. Abstract 1399
INFORM-SVR: NS3 PI + Nucleoside + RBV in GT1:
SVR12 by HCV Subtype and IL28B Genotype

Data shown are patients treated with 24 weeks of mericitabine +
danoprevir/r + ribavirin; all were treatment naïve and non-cirrhotic
SVR12 rates were encouraging in GT1b but disappointing in GT1a

100
80
SVR12 (%)
All (n = 64)
GT1a (n = 43)
GT1b (n = 21)
100
71
60
76
80
60
50
44
41
40
40
27
26
20
n/N =
0
32
25
20
26/64 11/43 15/21
Overall
n/N =
0
6/19 4/15
CC
2/4
20/45 7/28 13/17
IL28B Genotype
Non-CC
Gane E et al. EASL 2012. Abstract 1412
SOUND-C2: NS3 PI + NN ± RBV:
SVR12 by Study Arm




N=362; the largest IFN-free study to date
All had GT1 and were treatment naïve; 10% had cirrhosis
All received faldaprevir 120 mg QD + RBV 1000/1200 mg/d
Patients were randomized to 5 arms, 4 containing BI-207127, 600 mg TID
(3 arms) or 600 mg BID (one arm) for 3 different durations
 RBV-free arm was stopped prematurely due to high relapse rate
SVR12 (%)
100
80
60
59
61
68
56
39
40
20
n/N
0
BI 207127
Dosing
48/81
49/80
43/77
53/78
18/46
TID
16 wks
+ RBV
TID
28 wks
+ RBV
TID
40 wks
+ RBV
BID
28 wks
+ RBV
TID
28 wks
(no RBV)
Zeuzem S et al. EASL 2012. Abstract 101
SOUND-C2 BID Dosing Arm: Higher SVR12 in
Patients With GT1b or GT1a-IL28B CC
SVR According to IL28B and HCV Subtype:
BID 28 Wks + RBV (ITT)
100
82
75
80
SVR12 (%)
84
60
40
32
20
n/N =
0
7/22
6/8
31/37
9/11
1a
non-CC
1a
CC
1b
non-CC
1b
CC
HCV Subtype and IL28B Genotype
 Boehringer Ingelheim has decided to undertake additional studies of this 3-drug
regimen only in patients with GT1b and those with GT1a who are IL-28B CC
Zeuzem S et al. EASL 2012. Abstract 101
Sofosbuvir (GS-7977)







Nucleotide NS5B inhibitor
Once daily oral dosing with no food effect
No described toxicity to date
Pangenotypic
No virological breakthroughs reported to date
Studied in combination with RBV or daclatasvir or simeprevir*
In GT2 & 3, sofosbuvir + RBV x 12 weeks achieved SVR24 in
10/10 patients; sofosbuvir + RBV x 8 weeks achieved SVR12 in
10/10 patients (all non cirrhotic)
 Two phase 3 RCTs are fully enrolled in GT2 & 3 (including
cirrhotics); results expected EASL 2013
 FISSION: Treatment naïve patients randomized to sofosbuvir + RBV
x 12 weeks vs. PegIFN + RBV x 24 weeks
 FUSION: Treatment failure patients randomized to 12 wk vs. 16 wk of
sofosbuvir + RBV
* No data have been presented on sofosbuvir + simeprevir
Gane E et al. EASL 2012. Abstract 1113
Sofosbuvir + RBV x 12 Weeks:
Results in GT1 Treatment Naïve Patients
 In ELECTRON, 25/25 achieved EOT; 22/25 (88%)
achieved SVR4 and 3/25 (12%) relapsed1
 In QUANTUM, 17/17 achieved EOT; 10/17 (59%)
achieved SVR4, and 7/10 (41%) relapsed2
 Combined ELECTRON and QUANTUM SVR in GT1
naives is 32/42 (76%)
 Only non-cirrhotic patients were enrolled in ELECTRON
and QUANTUM
 Future studies in GT1 will examine
 Longer treatment durations of Sofosbuvir + RBV
 The addition of a third antiviral drug
1. Gane E et al. EASL 2012. Abstract 1113
2. Gilead Press Release, Apr 19, 2012
The Canadian Liver Foundation gratefully acknowledges the participating health care professionals
for their contributions to this project and for their commitment to the liver health of Canadians.
The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and
education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the
country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease,
raise funds for research and provide support to individuals affected by liver disease.
For more information visit www.liver.ca or call 1-800-563-5483.
This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein
are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc.

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