edited by morris sherman md bch phd frcp(c) associate professor of medicine university of toronto...

Edited by

Morris Sherman MD BCh PhD FRCP(C)

Associate Professor of Medicine

University of Toronto

Protease Inhibitors in Chronic Hepatitis C:An Update

COMPLETE SLIDE DECK (Chapters 1 – 6)

November 2012

Robert P. Myers, MD, MSc Associate Professor, Liver UnitDivision of Gastroenterology

University of Calgary

Management of Hepatitis C:Updated Guidelines from the Canadian Association for the Study of the Liver

(CASL)

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.


Significant medical and economic burden Seroprevalence unknown

Risk Group Population Prevalence Prevalent Cases Proportion of Cases

IDU, total 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%

Remis RS. PHAC 2007


~8,000 incident cases annually (80% IDUs) Proportion diagnosed unclear (<80%) HCV-related complications rising Insufficient manpower to treat all cases

Remis et al. PHAC 2007

800

900

700

600

500

400

300

200100

01967 1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022 2027

Year

Cirrhosis

Decomp

HCC

Transplant

Mod

elle

d in

cide

nce

Davis GL et al. Gastroenterology 2010; 138(2):513-21

* Assumes 30% Dx & up to 25% Rx’d in 2010. Outcomes at 2020.

Antiviral Therapy Must be Maximizedto Make an Impact

30

20

40

50

60

70

80

90

100

Live

r-re

late

d de

ath

vs. n

o tr

eatm

ent (

%)

0 Current* 25% 50% 75% 100%

Proportion of population treated

80% SVR rate60% SVR rate40% SVR rate

68% ↓

34% ↓

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


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.

Who Should Be Treated?CASL Recommendations


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: Is Liver Biopsy Really Necessary?

Test (Reference)

ComponentsCut-off

F2-F4 vs. F0-F1Sensitivity/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 100Platelets

≥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%

FibroSpect II (Patel, 2004)

α2M, HA, TIMP-1 ≥0.36 77% / 73%

Hepascore(Adams, 2005)

α2M, HA, GGT, bilirubin ≥0.50 89% / 63%

FibroMeter (Leroy, 2005)

α2M, HA, AST, platelets, PT, urea

≥0.50 75% / 78%

Pre-Treatment Assessment:Non-invasive Measures of Fibrosis

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.

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



Ge. Nature 2009. Suppiah. Nat Genet 2009. Tanaka. Nat Genet 2009. Thomas. Nature 2009.

Single-nucleotide polymorphisms (SNPs) on chromosome 19

Encodes IFN-λ3

Associated with viral clearance

~50% of ethnic variation in SVR rates

Strongest pre-treatment predictor of SVR, but on-treatment response more important

Interleukin 28B (IL28B)

80

100

60

40

20

0T/T

102

T/C

433

C/C

336

European-Americans

P=1.06x10-25

SV

R (

%)

70

T/C

91

C/C

30

African-Americans

14

T/C

35

C/C

26

Hispanics

P=2.06x10-3 P=4.39x10-3 P=1.37x10-28

186

T/C

559

C/C

392

Combined

rs12979860

SVR (%) Non-SVR (%)

Numbers on bars represent n

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 treatment-experienced patients and those with genotypes other than 1 and 4.

A non-favourable IL28B genotype does not preclude antiviral therapy.



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.

Antiviral Therapy for HCV Genotype 1: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.

Response-Guided Therapy (RGT):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.

Adherence to Antiviral Therapy: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.

Futility Rules:CASL Recommendations


1,230

Slide courtesy of Dr. J. Feld.

1

W0 W1 W2 W3 W4

If futility rules met, RNA is rising!Stop therapy!

106

105

104

103

102

10

1071,800,000

99.9% reduction: Continue?

475

HC

V R

NA

(IU

/mL

)

Futility Rules Indicate Treatment FailureEven if the Viral Load Has Declined

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%)

Adverse Effects of the Protease Inhibitors (PIs)


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.

Adverse Effects of the Protease Inhibitors (PIs): CASL Recommendations


Boceprevir and telaprevir are substrates and inhibitors of CYP3A4*

CYP3A4 metabolizes many common drugs

Potential increased drug concentrations with PI co-administration

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)

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/

Drug-Drug Interactions (DDIs):CASL Recommendations



http://medicine.iupui.edu/clinpharm/ddis/

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

Pawlotsky JM. Hepatology. 2011 May; 53(5):1742-51

Antiviral Resistance

-5

-4

-3

-2

-1

0

1

HC

V R

NA

cha

nge

from

ba

selin

e (L

og10

IU/m

L)

Modest or null IFNa-ribavirin effect

Study time

Resistant HCV

Wild-type, sensitive HCV

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.


Antiviral Resistance:CASL Recommendations

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.

Summary:CASL Guidelines for the Management of HCV

Important Hepatitis C Protease Inhibitor Drug

Interactions in Mono and

HIV Coinfection

Alice Tseng, Pharm.D., FCSHP, AAHIVP

Toronto General HospitalUniversity 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 maybe 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 of substrate drug; quick onset & resolution of interaction effect

macrolides, azoles, HIV protease inhibitors

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

= +++ potential for interactions with other drugs can be clinically significant sometimes unpredictable

Boceprevir Telaprevir

Dosing 800 mg q8h with food 750 mg q8h with food (20 g fat)

Substrate CYP3A4, P-gp, AKR CYP3A4, Pgp

Inhibitor 3A4, P-gp 3A4, P-gp, renal transporters (?)

Inducer No inducing effects in vitro (in vivo?)

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


Lovastatin, Simvastatin

CONTRAINDICATED

Atorvastatin

May need to atorvastatin dose;

do not exceed >20 mg/d

CONTRA-INDICATED

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 40 mg + boceprevir: Atorvastatin AUC 130% and

Cmax 170% vs. atorvastatin alone

Suggest atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin

Atorvastatin 20 mg + telaprevir: Atorvastatin AUC 7.88-fold

Combination is contraindicated

Atorvastatin Interactions with Boceprevir and Telaprevir

Hulskotte EGJ et al. HEP DART 2011,Koloa, Hawaii, poster 122

Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

0.010 10 20 30 40 50

0.10

1.00

10.0

100

Nominal time (hrs)

Co

nce

ntr

atio

n (

ng

/mL

)

With telaprevir

25,000

30,000

20,000

15,000

10,000

5,000

00 8 16 24 32 40 48

Time (hrs)

Ato

rva

sta

tin c

on

cen

tra

tion

(p

g/m

L)

Atorvastatin aloneAtorvastatin + Boceprevir

Without telaprevir

Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg

Calcium channel blockers (CCBs)

Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates

Concentrations may be by boceprevir or telaprevir

Use with caution, clinical monitoring

Consider dose reduction

Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

Amlodipine AUC 179% Monitor for dose-related toxicity

0.01

0 250

Nominal time (hrs)

Con

cent

ratio

n (n

g/m

L)

With telaprevir

Without telaprevir

20015010050

0.05

0.50

5.00

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

Beta-blockers

Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4)

Acebutolol, labetalol, metoprolol, pindolol (2D6)

Atenolol, nadolol (renal)

Possible

Low

Not expected

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

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)

LowPossible

Third Line Nortriptyline (2D6)Imipramine (2D6, 1A2, 2C19, 3A>UGT)

LowPossible

No Evidence Modafinil (3A4; induces 3A4)Amantadine (not metabolized)

Possible ; DAANot 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 ofR-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 IFN/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) Avoid with ritonavir-boosted protease inhibitors

Avoid ritonavir-boosted darunavir, fosamprenavir and

lopinavir

Atazanavir/ritonavir OK

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Avoid efavirenz Dose with efavirenz

Etravirine (?) Etravirine OK

No data Rilpivirine OK

Integrase Inhibitor Raltegravir OK

Maraviroc No data potential / maraviroc; potential benefit on fibrosis?

Nucleoside Reverse Transcriptase Inhibitors

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)

1-adrenoreceptor antagonist

Alfuzosin Hypotension, cardiac arrhythmia

Antiarrhythmics Quinidine, propafenone, amiodarone.Flecainide (TVR)

serious/life-threatening cardiac arrhythmia

Antimycobacterials Rifampin Loss of virologic response

Ergot derivatives 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


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


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

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

Additional Resources

http://www.hivclinic.ca/


http://www.hcvdruginfo.ca/

Side Effects of Antiviral Therapy

for Hepatitis C

Dr. Mark Levstik, FRCP(C)Associate Professor MedicineDivision of GastroenterologyMultiorgan 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

Peg Interferon/RBV

Telaprevir/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%

Anorectal 7% 29%

Dysgeusia and anemia increased with boceprevir;Rash, anorectal irritation and anemia increased with telaprevir.

Victrelis Product Monograph, August 2012

Incivek Product Monograph, June 2012

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 excludedTreated in the French early access program

(From February 2011)

Safety of Protease Inhibitors in Real Life: CUPIC Study

Hezode C et al. EASL 2012, Abstract 8

Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a

+ RBV Follow-up

CUPIC: Treatment Regimen

484 160 128Weeks

72

SVR assessment

Follow-upPeg-IFN + RBV

36

Interim analysis


BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d

BOC + Peg-IFN α-2b + RBV

TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000- 1200 mg/d

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 Null responders 3 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 discontinuationDue to SAEs (%)

23.97.4

26.014.5

Death (%) 1.3 2.0

Infection (Grade 3/4) (%) 2.5 8.8

Rash Grade 3 (%) Grade 4 (SCAR) (%)

00

6.80.7

Pruritus (Grade 3/4) (%) 0.6 3.7

Hepatic decompensation (%) 4.4 4.4


Patients, n(% patients with ≥ 1 event)

Boceprevir (n=159)

Telaprevir (n=296)

Anemia (%) Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8,0 g/dL) EPO use Blood transfusion

22.610.166.010.7

19.610.156.815.2

Neutropenia (%) Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use

4.40.63.8

4.00.72.4

Thrombopenia (%) Grade 3 (25 000 – <50 000) Grade 4 (<25 000) Thrombopoïetin use

6.30.61.9

11.8 1.3 1.7


CUPIC: Preliminary Safety Findings (16-Week Interim Analysis)

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

After completion of 4 week PEG-IFN/RBV lead-in, all patients initiated boceprevir

Hemoglobin ≤100 g/L

Ribavirin dose reduction (DR)n = 249

Erythropoietin (40,000 IU/wk SC)n = 251

Hemoglobin ≤ 85 g/L: Secondary Strategy (EPO, RBV DR, transfusion)EPO: erythropoietin

PEG-IFN: peginterferonRBV: ribavirin

Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline

687 patients treated with boceprevir RGT

Poordad et al. EASL 2012, Abstract 1419

Randomisation

Results – Primary and Key Efficacy End PointsP

atie

nts

(%)

(95% CI)

-0.7% (-8.6, 7.2)*

End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms

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

82

71

10

82

71

10

0

25

50

75

100

EOT Response SVR Relapse

RBV DR

EPO

205/251203/249 19/196 19/197178/249 178/251

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


RBV dose reductionUp to 3 x 200 mg increments*

Reduce RBV to 600 mg/day

Hb > 85 g/L

Maintain RBVdose 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

Hb < 85 g/L

EPO: 40-60,000 IU/wk AND/OR

Transfusion

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, 2012Hézode C. Liver International. 2012; 32 Suppl 1:32-8Cacoub 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


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


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 FRCPCMedical 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

Myers RP et al. Can J Gastroenterol. 2010 Nov;24(11):661-70

1.00

0.75

0.50

0.25

0.00

0.250.00 0.50 0.75 1.00

Sen

sitiv

ity

1-Specificity

AUROC (95% CI)≥ F2: 0.74 (0.68-0.80)≥ F3: 0.89 (0.84-0.94) F4: 0.94 (0.90-0.97)

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

HCV RNA 5.29 logs -- Undetectable

ALT 106 53 33

Hb 144 120 108

Plts 295 236 214

Neutrophils 6.0 2.0 2.0

Given the undetectable HCV RNA at the end of WK4 lead-in (dual therapy), is adding Boceprevir necessary?

Significance of Lead-in Response

Vierling et al. EASL 2011.

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)

30

43

60

72 74

89 90 90

<0.5

0.5-

<1.0

1.0-

<1.5

1.5-

<2.0

2.0-

<3.0

3.0-

<4.0

≥4.0

Und

etec

tabl

e

28 28

7065

8089 89 89

<0.5

0.5-

<1.0

1.0-

<1.5

1.5-

<2.0

2.0-

<3.0

3.0-

<4.0

≥4.0

Und

etec

tabl

e

05

21

33

45

58

7997

0

20

40

60

80

100

<0.5

0.5-

<1.0

1.0-

<1.5

1.5-

<2.0

2.0-

<3.0

3.0-

<4.0

≥4.0

Und

etec

tabl

e

PR48 BOC RGT BOC/PR48

Log10 viral load decrease after weeks of P/R lead-in

% o

f pat

ient

s w

ith S

VR

Results Through Week 12

Wk 4 Wk 6 Wk 8 Wk 10 Wk 12

HCV RNA 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

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

HCV RNA 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 remained undetectable through week 24, and patient qualifies for shortened duration therapy (to D/C at week 28)

Case Study:

Cirrhosis

Nir Hilzenrat, MDGastrointestinal 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: 2417-28Bronowicki, 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 - -

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

Vertex Pharmaceutical (Canada) Incorporated. Product Monograph: Incivek (Telaprevir tablets). http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf (Accessed February 1, 2012)

http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf

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, FACPProfessor, Division of Infectious Diseases

Department of MedicineUniversity 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

PegIFNa-2a 180 μg/wk + RBV(n=133)

PegIFN-l 120 μg/wk + RBV(n=128)



Treatment naïve patients with genotype 1-4 HCV

infection (n=526)

Wk 24: GT 2 or 3Wk 48: GT 1 or 4

Zeuzem S et al. EASL 2011. Abstract 1360

EMERGE: PegIFN-l/RBV vs. PegIFNa-2a/RBV: Preliminary Results to Week 12

Parameter (%)PegIFNa-2a PegIFN-l

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

Zeuzem S et al. EASL 2011. Abstract 1360* p<0.05 compared with PegIFNa-2a

SVR rates comparable in pegIFN-l arm vs. pegIFNa-2a

PegIFN-l 180 μg dosage chosen for phase III trials

EMERGE: PegIFN-l/RBV vs. PegIFNa-2a/RBV: Efficacy and Safety in Genotypes 2 & 3

Fewer hematologic AEs and ALT/AST elevations with pegIFN-l


SV

R24

(%

)

0

40

60

80

100

65.5

20

75.9

60.053.3

N = 29 29 3030

Lambda120 µg

Lambda180 µg

Lambda240 µg

Alfa180 µg

Adverse Event, %Lambda180 µg

(N = 29)

Alfa180 µg

(N = 30)

Hb < 10 g/dL or ∆ > 3.4 g/dL 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

ALT/AST > 5 to 10 x ULN 6.9 13.3

Proteins encoded by the HCV genome: Three validated targets and four classes of DAAs

5’ UTRregion

3’ UTRregion

9.6 kb RNA

Polyprotein

Polyprotein

Polyprotein processing

C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B

C E1 E2 p7 NS2 NS3 NS4A NS5A NS5B

Core EnvelopeGlycoproteins

Protease SerineProtease

Helicase RNAbinding

RNA-dependentRNA polymerase

NS4B

SerineProteaseCofactor

Adapted from Asselah T et al. Liver International 2011; 31 Suppl 1:68-77

NS5Bpolymerase

inhibitors

Nucleoside analogs Non-nucleoside analogs

3

3 4

NS5Ainhibitors

2

2

NS3-4Aprotease inhibitors

1

1

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.


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-52. Sulkowski M et al. EASL 2011. Abstracts 60 and 66


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 622. Lawitz E et al. EASL 2011. Abstract 1220

HCV NS5A Inhibitors

1. Gao M et al. Nature 2010; 465:96-1002. Pol S et al. Lancet Infect Dis 2012; 12(9):671-7

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.

Antiviral Activity of Daclatasvir in Combination with PegIFN2a + RBV in Treatment of Naïve Patientswith Chronic HCV Genotype 1 Infection

Placebo +PegIFN-2a 180 µg/wk + RBV 1000/1200 mg/d

Daclatasvir 10 mg QD +PegIFN-2a 180 µg/wk + RBV 1000/1200 mg/d


Treatmentnaïve HCV

GT1 patientsn=48

Pol S et al. Lancet Infect Dis 2012; 12(9):671-7


Day 1 Week 48 Week 72

SVR 24

Daclatasvir (DCV) with PegIFN-2a + RBV:Virologic Response at Weeks 4, 12 & SVR (ITT)

Per

cent

HC

V R

NA

neg

ativ

e(<

10 IU

/mL

by R

oche

Taq

Man

)

RVR cEVR

PR PR + DCV 3 mg PR + DCV 10 mg

SVR (24)

PR + DCV 60 mg

0

20

40

60

80

100

8

42

25

42 42

58

8383 8383 83

92

Pol S et al. Lancet Infect Dis 2012; 12(9):671-7

12 patients per treatment arm; the 60 mg QD dose was selected for phase 3

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)

Lok AS et al. EASL 2011; NEJM 2012;366:216-24

SVR was achieved in 2/9 GT 1a and 2/2 GT 1b prior null responders to PRwith 24 weeks of DCV + ASV (all enrolled patients were non-cirrhotic)

On therapy breakthrough was common in GT 1a

7

5

4

3

2

1

6

0 1 2 3 4 6 8 10 12 16 20 24

PT4

PT8

PT1

2P

T24

PT3

6P

T48

HC

V R

NA

(lo

g 10

IU/m

L)

Week

LLOQLLOD

Follow-upDaclatasvir+asunaprevir

Dual Oral Therapy with Daclatasvir and Asunaprevir x 24 Weeks for HCV GT1b

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

Study conducted in Japan All had genotype 1b Treated with asunaprevir (NS3 PI) and daclatasvir

(NS5A inhibitor) x 24 weeks

PILOT: NS3 PI + NN + RBV:Virologic Responses 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

Lawitz E, et al. EASL 2012. Abstract 13

Wk 4(RVR)

Wk 12(EOT)

SVR12 SVR24

HC

V R

NA

Ne

gativ

e (

%)

0

40

60

80

100

20

100 100

91 9182

SVR36

11/11 11/11 10/11 10/11 9/11n/N

CO-PILOT: NS3 PI + NN + RBV:Virologic Responses

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)

Poordad F et al. EASL 2012. Abstract 1399

HC

V R

NA

neg

ativ

e (%

)

0

40

60

80

100

20

ABT-450/r 250/100 mg QD+ ABT-333 + RBVTreatment naive

(n = 19; 17 G1a, 2 G1b)

ABT-450/r 150/100 mg QD+ ABT-333 + RBVTreatment 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)

RVReRVRSVR4SVR12

90 90 95 95

79 79

93 93

77

5947 47

* 11 partial responders, 6 null responders

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

Gane E et al. EASL 2012. Abstract 1412

SV

R12

(%

)

0

40

60

80

100

20

Overall CC Non-CCIL28B Genotype

n/N =

41

26

71

3227

5044

25

76

All (n = 64)GT1a (n = 43)GT1b (n = 21)

26/64 11/43 15/21 6/19 4/15 2/4 20/45 7/28 13/170

40

60

80

100

20

n/N =

68

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


SV

R12

(%

)

0

40

60

80

100

20

BID28 wks+ RBV

TID28 wks

(no RBV)

TID40 wks+ RBV

TID28 wks+ RBV

TID16 wks+ RBV

59 6156

39

BI 207127Dosing

48/81 49/80 43/77 53/78 18/46n/N

SOUND-C2 BID Dosing Arm: Higher SVR12 in Patients With GT1b or GT1a-IL28B CC

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


SV

R12

(%

)

n/N =

32

7584 82

1anon-CC

1aCC

1bnon-CC

1bCC

SVR According to IL28B and HCV Subtype:BID 28 Wks + RBV (ITT)

0

40

60

80

100

20

7/22 6/8 31/37 9/11

HCV Subtype and IL28B Genotype

Sofosbuvir (GS-7977)

Gane E et al. EASL 2012. Abstract 1113

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

Sofosbuvir + RBV x 12 Weeks:Results in GT1 Treatment Naïve Patients

1. Gane E et al. EASL 2012. Abstract 11132. Gilead Press Release, Apr 19, 2012

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

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.

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.

http://www.liver.ca/

edited by morris sherman md bch phd frcp(c) associate professor of medicine university of toronto...

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