Protease Inhibitors Protease Inhibitors for HCV: for HCV:

The devil is in the The devil is in the detailsdetails

Jordan J Feld MD MPHJordan J Feld MD MPH

Assistant Professor of MedicineAssistant Professor of Medicine

Toronto Western HospitalToronto Western Hospital

McLaughlin-Rotman Centre for Global HealthMcLaughlin-Rotman Centre for Global Health

Disclosures – Dr. J. FeldDisclosures – Dr. J. Feld

Dr. Feld has the following financial Dr. Feld has the following financial disclosures relevant to this presentation:disclosures relevant to this presentation: Abbott Laboratories – consultingAbbott Laboratories – consulting Merck (MSD) – consultingMerck (MSD) – consulting Roche Pharmaceuticals – consultingRoche Pharmaceuticals – consulting Vertex Pharmaceuticals – consultingVertex Pharmaceuticals – consulting

Dr. Feld will be discussing the off-label use Dr. Feld will be discussing the off-label use of boceprevirof boceprevir

OutlineOutline1.1. How will the drugs be used?How will the drugs be used?

Response-guided therapyResponse-guided therapy Lead-in vs no lead-inLead-in vs no lead-in

2.2. ResistanceResistance Does it matter?Does it matter? Can it be prevented/minimized?Can it be prevented/minimized?

3.3. IL28B IL28B Still important with DAAs?Still important with DAAs?

4.4. Adverse eventsAdverse events Management strategiesManagement strategies

5.5. Drug-Drug InteractionsDrug-Drug Interactions Key drugs and where to find the rest…Key drugs and where to find the rest…

0%

20%

40%

60%

80%

100%

IFN IFN IFN/R IFN/R PegIFN PegIFN/R

Su

stai

ned

Res

po

nse

16%

55%

6%

The Good NewsThe Good News

34%42% 39%

6 mo 12 mo 6 mo 12 mo 12 mo

1991

1995

1998

20022001

Ribavirin

Peginterferon

Standard Interferon

6-12 mo

75%

2010

DAA

PegIFN/R/DAA12 mo

Response-Guided Response-Guided TherapyTherapy

Follow-up

Wk 8-24 HCV-RNA Detectable

PR + Placebo

Wk 8-24 HCV-RNA <10 IU/mL

Follow-up

Peg2b/R + Boceprevir 800mg q8h PR

lead-inBOCRGT

N = 368

Peg 2a/R + TVR 750 q8h

T12PRN = 363

Follow-up Peg 2a/R

Peg 2a/R

0 4 8 12 24 28 48 72Wks

Advantages of RGTAdvantages of RGT

Allows shortening therapy Allows shortening therapy 44-65% of naïve pts44-65% of naïve pts 46% of trt-experienced pts (36 wks)46% of trt-experienced pts (36 wks)

Reduced exposure to PIReduced exposure to PI Even those who do not have RVR8, stop BOC at wk Even those who do not have RVR8, stop BOC at wk

28 (continue only Peg/RBV to wk 48)28 (continue only Peg/RBV to wk 48)

Follow-upPR alone Peg2b/R + Boceprevir 800mg q8h PR

lead-inBOCRGT

0 4 8 28 48 72Wks

RGT Allows for RGT Allows for Shortening of TherapyShortening of Therapy

59/82

155/161

156/162

55/73

Poordad et al NEJM 2011

44% RVR828 wk of trt

No consequence to shorter BOC

RGT works in treatment- RGT works in treatment- experienced as wellexperienced as well

SV

R (

%)

6474

77

7484

BOC RGT BOC/PR48PR48

2972

865

3070

Bacon et al NEJM 2011

Reduced exposure to PI Reduced exposure to PI with RGT = Reduced with RGT = Reduced

toxicitytoxicity

0 2 4 6 81012 16 20 24 30 34 42 54

Hem

oglo

bin

(g/d

L)

6

8

10

12

14

16

Neutrophil (X10^9)

1

2

3

4

5

Weeks

0 2 4 6 81012 16 20 24 30 36 42 48 52 60 72

Hgb (RGT)Neutrophil (RGT)Hgb (BOC/PR48)

Neutrophil (BOC/PR48)

RGT SummaryRGT Summary

Generally useful paradigmGenerally useful paradigm Allows for shortened therapy in naïve and Allows for shortened therapy in naïve and

experienced patientsexperienced patients Reduces exposure to PIReduces exposure to PI

Reduced toxicity & costReduced toxicity & cost Hb/WBC rebound when BOC is stoppedHb/WBC rebound when BOC is stopped

Requires more frequent HCV RNA testingRequires more frequent HCV RNA testing May be less advisable in harder to treat pop’nMay be less advisable in harder to treat pop’n

Black patientsBlack patients Advanced fibrosisAdvanced fibrosis

Lead-in Lead-in vs vs

No-Lead inNo-Lead in

SPRINT1: Benefit SPRINT1: Benefit to lead-in to lead-in

% S

VR

% S

VR

0

10

20

30

40

50

60

70

80

38

P/R Control 48 wks

P/R 4 wks P/R/B

24 wksN=104

54 56

P/R/B 28 wks

N=107N=103

67

P/R/B

48 wks

P/R 4 wks P/R/B

44 wks

75

N=103

N=103

Lead-inLead-in

Kwo et al Lancet 2010Appeared to modest efficacy advantage to lead-in

w

r

ww

ww

ww

wwwwwww

ww

wwww

ww

ww

ww

www

w

w

w

w

r

r

r

ww

ww

ww

w www

ww

w

The TheoryThe Theory

LLD

0 virions per body

Treatment DurationStart End

w = wild-type virusr = PI resistant virus

Peg/RBV/PI

w w

Peg/RBV

Lower viral load before starting PI = less resistance

LetLet’’s do the math…s do the math…

Therefore…Average number of changes/genome = 0.096/replication cycle

# of nt changes

Probability # of virions/d # of all possible mutants

% of all possible

mutants/d

0 0.91 9.1 x 1011

1 0.087 8.7 x 1010 2.9 x 104 100

2 0.0042 4.2 x 109 4.1 x 108 100

3 0.00013 1.3 x 108 1.0 x 1012 3.4x10-3

Conclusion: ALL single and ALL double mutants are produced everyday. Resistance associated variants (RAVS) all pre-exist. Unless 2-3 log drop in lead-in, no difference to resistance

Rong et al Sci Transl Med 2010

Other advantages of the Other advantages of the lead-inlead-in

1.1. Determination of tolerance and compliance with Determination of tolerance and compliance with Peg/RBVPeg/RBV

2.2. Allow Peg/RBV to reach steady-state – avoid PI Allow Peg/RBV to reach steady-state – avoid PI mono/dual therapymono/dual therapy

3.3. Identify source of adverse event (eg. anemia)Identify source of adverse event (eg. anemia)

4.4. Prognostic information Prognostic information Very helpful in cases where treatment value is unclearVery helpful in cases where treatment value is unclear

5.5. Accurate assessment of IFN-responsivenessAccurate assessment of IFN-responsiveness Strongest predictor of SVRStrongest predictor of SVR Important for treatment-experienced patientsImportant for treatment-experienced patients

SVR by Week 4 PR SVR by Week 4 PR Lead-in Response: Lead-in Response:

RESPOND2RESPOND2

0

33 34

0

20

40

60

80

100

SV

R (

%)

1546

012

1544

BOC RGT BOC/PR48PR48

25

7379

0

20

40

60

80

100

80110

1767

90114

BOC RGT BOC/PR48PR48

Poor IFN Response1 log10 viral load decline at

Treatment Week 4

Adequate IFN Response≥1 log10 viral load decline at

Treatment Week 4

SV

R (

%)

Bacon et al NEJM 2011

Real-Time Interferon Real-Time Interferon response for trt-response for trt-

experiencedexperienced%

of

Pat

ien

ts W

ith

Wee

k 4

Res

po

nse

Historical Response

Week 4 Response

10

10

56140 56140

84140 84140

46253 46253

207253207253

Respond 2

26% null response despite at least partial historical response

Esteban EASL 2011

Summary Lead-inSummary Lead-in

Very useful prognostic information from lead-in, Very useful prognostic information from lead-in, ie. IFN-responseie. IFN-response May even change your decision to treatMay even change your decision to treat eg. Previous relapser with <1 log drop in lead-in and eg. Previous relapser with <1 log drop in lead-in and

mild fibrosis…may wait for future therapymild fibrosis…may wait for future therapy Useful to determine compliance/toleranceUseful to determine compliance/tolerance Value to starting Peg/RBV separatelyValue to starting Peg/RBV separately Probably little effect on risk of resistanceProbably little effect on risk of resistance

Resistance…Resistance…Are we doomed?Are we doomed?

If PI resistant virus pre-If PI resistant virus pre-exists, why do PIs work at exists, why do PIs work at

all?all?

Resistance: A new issue in Resistance: A new issue in HCVHCV

IFN Receptor

IFN

ISGs

Jak-STAT

Multi-pronged attackNo IFN resistanceEffective against PI-resistant HCV

DAA

Potent but uniform attackRapid DAA resistance

Not just theoryNot just theory

Keiffer Hepatology 2007

IFN response predicts IFN response predicts resistanceresistance

0

100

50

25

75

4% 6%

52%

40%

Boc

epre

vir

Res

ista

nce

%

RGT BOC48 RGT BOC48

>1 log declineduring lead-in

<1 log declineduring lead-in

SPRINT 2

Poordad et al NEJM 2011

Maximize Peg/RBVResponse: - Obesity - Insulin resistance - Vit D - Coffee

Factors Limiting Growth of Factors Limiting Growth of Resistant MutantsResistant Mutants

1.1. FitnessFitness

2.2. Genetic barrierGenetic barrier

3.3. Antiviral potencyAntiviral potency

4.4. Degree of resistanceDegree of resistance

Fitness is a moving target: Fitness is a moving target: Compensatory mutationsCompensatory mutations

Fitn

ess

No Drug PI Treatment Continued PI Treatmentdespite resistance

WT PI-R WT PI-R WT PI-Rx x x xxxx

PI-resistant virus will become more fit over time if the PI is continuedTherefore: Stop the PI as soon as resistance emerges

Composition of viral pop’n

Genetic Barrier: Not all HCV Genetic Barrier: Not all HCV Genotype 1 is created Genotype 1 is created

equalequal Genetic Barrier refers to the ‘difficulty’ for a given virus to Genetic Barrier refers to the ‘difficulty’ for a given virus to develop resistance to an antiviraldevelop resistance to an antiviral Number of mutations necessary for resistanceNumber of mutations necessary for resistance

For PIs – genetic barrier differs by subtype – 1a vs 1bFor PIs – genetic barrier differs by subtype – 1a vs 1b

G1a G1a R155K = 1 nt change R155K = 1 nt change AGG AGG A AAAG G

G1b G1b R155K = 2 nt changes R155K = 2 nt changes CGG CGG AAAAGG

Brass EASL 2011

B for Bom

Does resistance Does resistance disappear?disappear?

Answer to this question determined by:Answer to this question determined by:

1.1. Archiving of resistanceArchiving of resistance Persistence of resistant virus after drug Persistence of resistant virus after drug

discontinuationdiscontinuation

2.2. Fitness of resistant virusFitness of resistant virus

HCV has no reservoir for HCV has no reservoir for archivingarchiving

HCV

Polx

x

RT

CD4+

x

x

xHIV x

HBV

RT

xx

x

cccDNA

xpgRNA

What happens if treatment What happens if treatment stops?stops?

Fitn

ess

No Drug PI Treatment Continued PI Treatmentdespite resistance

WT PI-R WT PI-R WT PI-Rx x x xxxx

PI-resistant virus may persist even after drug withdrawal if fitness hasimproved significantly with compensatory mutations during treatment

Composition of viral pop’n

WT PI-Rx xxxx

?Drug discontinuation

What happens in What happens in patients?patients?

EXTEND trial- Long-term f/u of Telaprevir-treated pts- 79 non-SVRs

- 56 with TVR-resistant mutants at EoT- Median 25 mo f/u- NS3 by population sequencing (~20%)

- No longer detectable in 50/56 (89%)

Does this really mean the resistance is gone?Probably NOT!!!

Zeuzem et al AASLD 2010

Population sequencing: Tip of the Population sequencing: Tip of the icebergiceberg

015

20

40

60

80

100

--

-

-

-

-

-

PopulationSequencing

ClonalSequencing

DeepSequencing

% t

hre

sho

ld f

or

det

ecti

ng

re

sist

ant

viru

sWild-type virusResistant virus

Even if undetectable by population sequencing…may be lotsof resistant virus

Prevention of ResistancePrevention of Resistance Compliance, compliance, compliance – more Compliance, compliance, compliance – more

important than with Peg/RBVimportant than with Peg/RBV Maximize Peg/RBV responseMaximize Peg/RBV response Carefully consider need for treatment in patients Carefully consider need for treatment in patients

with poor Peg/RBV response – especially if mild with poor Peg/RBV response – especially if mild liver diseaseliver disease• Prior null respondersPrior null responders• Patients with poor prognostic features (non-CC, black Patients with poor prognostic features (non-CC, black

race, obese etc.)race, obese etc.) Follow stopping rules and stop promptly if signs Follow stopping rules and stop promptly if signs

of resistance to prevent compensatory mutationsof resistance to prevent compensatory mutations

No Inter-Class Cross No Inter-Class Cross ResistanceResistance

PI=‘Intra’ Class Pol= no ‘Intra’ Class

SummarySummary Resistance to PIs (and all DAAs) pre-exists in allResistance to PIs (and all DAAs) pre-exists in all Risk factors for resistanceRisk factors for resistance: Poor IFN response, gt 1a: Poor IFN response, gt 1a Resistant variants are less fit than wild-type but gain fitness Resistant variants are less fit than wild-type but gain fitness

with exposure to PI through compensatory mutations with exposure to PI through compensatory mutations stop PI if resistance presentstop PI if resistance present

Resistance will persist for some time after stopping PI Resistance will persist for some time after stopping PI detection limited with population sequencingdetection limited with population sequencing

Resistance can be overcome with combination therapy – Resistance can be overcome with combination therapy – either either PI + Peg/RBV or DAA combinationsPI + Peg/RBV or DAA combinations

PI resistance may affect future therapy so consider need for PI resistance may affect future therapy so consider need for therapy and optimize treatment to prevent resistancetherapy and optimize treatment to prevent resistance

IFN-Lambda ManiaIFN-Lambda Mania

IL28b SNP associated with SVR & spontaneous clearance

SVR according to IFN SVR according to IFN λλ SNP SNP

Ge Nature 2009

Does IL28B help with Does IL28B help with PIs?PIs?

SV

R (

%)

Jacobson et al EASL 2011

IL28B tested in 454 (42%) of ADVANCE

T12PR T8PR PR 48

CC CT TT

TVR helps all IL28B genotypes? T12 more important in non-CC

20/80

45/50

39/45

35/55

48/68

44/76

16/22

19/32

6/26

What about IL28B and What about IL28B and BOC?BOC?

SV

R (

%)

Poordad et al EASL 2011

IL28B tested in 653 (62%) SPRINT-2

CC CT TT

BOC helps only non-CCs…BUT

33/116

BOC/PR RGT BOC/PR 48 PR 48

63/77

44/55

50/64

67/103

82/115

23/42

26/44

10/37

SVR Among CC’s TVR vs SVR Among CC’s TVR vs BOCBOC

SV

R (

%)

Comparison of CC only

T12PR T8PR PR PR BOC PR48 BOC RGT

• PIs improve SVR in non-CC’s• CC’s less clear - ?shorten therapy

TVR BOC

50/64

35/55

IL28B in Trt-ExperiencedIL28B in Trt-ExperiencedS

VR

(%

)

Pol et al EASL 2011

IL28B tested in 527 (80%) of REALIZE

CC CT TT

Rel Partial Null Rel Partial Null

T12PR48 PR48

Prior response trumps IL28B

Lead-in trumps IL28BLead-in trumps IL28B

PR RGT BOC48 PR RGT BOC48

<1 log >1 log

CC CT TT

Poordad EASL 2011

Summary IL28BSummary IL28B

PIs still improve outcome in all IL28B genotypesPIs still improve outcome in all IL28B genotypes Benefit greatest in non-CCsBenefit greatest in non-CCs CCs do well without PICCs do well without PI

Consider shorter therapy for CCs with PIConsider shorter therapy for CCs with PI Response trumps IL28BResponse trumps IL28B

Naïve – if RVR, do well if CC/non-CC + vice versaNaïve – if RVR, do well if CC/non-CC + vice versa Experienced – IL28B of limited utilityExperienced – IL28B of limited utility

- May combine with other factors to predict- May combine with other factors to predict

Adverse EventsAdverse Events

No Free LunchNo Free Lunch

BoceprevirBoceprevir

Poordad et al NEJM 2011

• Anemia• Dysgeusia

AnemiaAnemia

• Anemia associated with SVR• Managed with EPO/RBV dose reductions• Cannot reduce BOC dose

Summary AEsSummary AEs

More manageable with experienceMore manageable with experience Anemia – managed with EPO or RBV doseAnemia – managed with EPO or RBV dose

Rarely leads to discontinuationRarely leads to discontinuation Dysgeusia – annoying but tolerableDysgeusia – annoying but tolerable

Drug-Drug Drug-Drug InteractionsInteractions

Put your pharmacist’s number on Put your pharmacist’s number on speed-dial!speed-dial!

Farmacia1 800 AJUDE-ME

PI MetabolismPI Metabolism

CYP3A4PI Metabolites

• BOC & TVR are both substrates & inhibitors of CYP3A4 & P-gp• CYP3A4 – metabolizes many common drugs• P-gp – common pathway for drug elimination

Drugs cleared by CYP3A4/P-gp Increased drug concDrugs that induce CYP3A4/P-gp Decrease PI conc

A few important onesA few important ones

Seizure meds – contraindicatedSeizure meds – contraindicated Midazolam – 5x increase exposure to drug!!Midazolam – 5x increase exposure to drug!! Oral contraceptive – unreliable levels – need Oral contraceptive – unreliable levels – need

another methodanother method HAART – variable but MANY interactionsHAART – variable but MANY interactions CsA/Tacrolimus – marked increase exposureCsA/Tacrolimus – marked increase exposure Sildenafil – sorry gents…contraindicated!Sildenafil – sorry gents…contraindicated!

Useful resources: 1.http://www.hep-druginteractions.org/2.http://medicine.iupui.edu/clinpharm/ddis/

Final SummaryFinal Summary1.1. RGT useful for most patientsRGT useful for most patients

Consider longer therapy in Blacks, Advanced fibrosisConsider longer therapy in Blacks, Advanced fibrosis

2.2. Lead-in usefulLead-in useful Compliance, tolerance of IFN/RBV, IFN responseCompliance, tolerance of IFN/RBV, IFN response

3.3. Resistance pre-existsResistance pre-exists More common 1a than 1bMore common 1a than 1b Risk related to IFN responsivenessRisk related to IFN responsiveness Unknown if persists but stop PI once resistance presentUnknown if persists but stop PI once resistance present

4.4. IL28B useful but response more usefulIL28B useful but response more useful May consider shortening therapy in CCs – stay tuned…May consider shortening therapy in CCs – stay tuned…

5.5. Drug Interactions – a big issue, check all drugs!!Drug Interactions – a big issue, check all drugs!!

Obrigado!Obrigado!

SVR Among CC’s TVR vs SVR Among CC’s TVR vs BOCBOC

SV

R (

%)

Comparison of CC only

PR PR

• PIs improve SVR in non-CC’s• CC’s less clear - ?shorten therapy

TVR BOC

50/64

35/55