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