Transcript PHC

Interactive
How to Optimize Treatment of
GT1 Patients
Sherif M. Abd El-Fattah Sherif
FRCP, FACG
Paris January 31, 2012
Our Patient
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A lady, Mrs. F. R. 45 years, married and has 3 children
She gave no history of blood transfusion or major
surgery, but she had many dental interventions over
the years. She does not drink alcohol
She had some fatigue and on routine check up for
insurance she was found to be anti-HCV positive
She admitted some gain in weight over the years and
on contraceptive pills
Presentation
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Her mother had chronic hepatitis and advanced liver
cirrhosis and they shared a lot together, father was
diabetic and passed away few years ago
There were no manifestations of LCF, fair skin
without jaundice or anemia. No skin manifestations
of advanced liver disease or rash and no edema of
lower limbs
She had no joint swelling but few signs of
osteoarthritis of right knee. There was no
lymphadenopathy
Clinically
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She was a well built lady BMI 31.1 kg/m2, she looked
anxious but not depressed
BP 135/80 P 80/min heart and chest were clinically free
Abdomen was lax, liver was enlarged about 4 finger
breadth below the costal margin in MCL, rounded edge,
rather soft smooth surface.
Spleen was not palpable and no ascites
Clinically
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Anything else?
Thyroid was slightly enlarged and smooth with no
signs of myxedema or thyrotoxicosis
The U/S report was: Bright liver with smooth
contour and no masses detected. The spleen is
minimally enlarged Conclusion: Fatty liver
Is any bright liver = fatty liver?
Yes
No
Laboratory Results
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CBC: Hb 11gm/dl, WBC 4300/cmm (granulocytes
2000/cmm) , platelet count 123,000/cmm
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S. Bil 1.3mg/dl, ALT 50 IU, AST 50 IU (N 40)
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S. Creatinine 0.8 mg/dl
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1.
2.
Fasting blood sugar 115 mg/dl – Should we pursue
this any further?
Yes
No
Laboratory
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2.
3.
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Glycosylated Hb A 1 c and/or HOMA-IR
Glycosylated Hb A 1c was 7.0 – Is it common in GT1?
Do anything about it? Is reducing weight likely to
succeed?
Diet and exercise?
Add metformin or a glitazone
Glucagon - Like –Peptide 1 receptor agonist
(GLP-1R)
How about lipemia ? How important?
S. cholesterol 280, LDL 200mg/dl
Her family Dr. put her on simvastatin
Khattab MA, 2010
Visboll T, 2012
Laboratory Results
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What do we need more other than HCV studies?
Testing for HBsAg
Testing for anti-HBs
Anti-HAV IgG
HIV
All the above
Do we need to test other systems?
Thyroid, fundus
Chest X-ray, ECG
Laboratory Results
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3.
4.
5.
HCV- RNA 350,000 IU/ml
Is viral load important?
What other HCV viral tests?
Genotype – Important? Why?
Prognosis
Decide on length of treatment
Decide on type of treatment
1&2
2&3
Genotype Result
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1.
2.
3.
4.
5.
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HCV GT 1b
Significance?
More difficult to treat?
Worse prognosis?
More prone to cirrhosis and HCC?
All the above?
None of the above
Luckily she was anti-HBs positive, anti-HAV positive
and normal fundus examination and thyroid function
Liver Biopsy
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The patient asked for an alternative to liver biopsy.
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Fibroscan F2
Fibrotest? F2 A2
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How reliable in our patient in view of her BMI & IR?
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Finally we had a liver biopsy
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THE FATTY LIVER
Weighing the Options: Treat or Defer?
Treat
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Consider treatment for all patients
Most treatment-naives and
relapsers
Treatment urgent for medical wellbeing
Motivated patients
Defer
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Adherence issues
Tolerability challenges with IFN
and/or RBV
Very poor prognostic factors
(ie, null and advanced disease)
Patient not motivated, poor timing
with life events
Treatment not urgent
Complicated drug interaction issues
may be considered
Success and Failure Aspects and Factors
Virus
Patient
Therapy
GT2, 3 , 1 & 4
F stage
PEG +R
Triple therapy
Viral load
BMI, smoking,
Steatosis & DM
Compliance &
complications
Speed of decline
Alcohol abuse
Immunity state
Duration
Need to tailor
Quasispecies and
associated viruses
IL28B
polymorphism,
host response
Age and Gender
Combination
Therapy or Single
Agent
IL28B Polymorphism (rs12979860)
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1.
2.
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1.
2.
Important? How about others: inosine triphosphatase
(ITPA) and LDL, rs8099917 genotype
How will these affect the prognosis?
If patient is CC or non CC will it affect my decision to
treat or not to treat?
Yes
No
Will it affect my plan of treatment?
No
Yes – How?
Ge et al 2009, Soriano V et al, 2011, Beinhart S et al 2012
Schaefer EA et al 2011, Takita M et al 2011
IL28B Polymorphism (rs12979860)
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3.
4.
Our patient was CT
How will this affect my plan of treatment?
Lead in with interferon/ Ribavirin (IFN+R) then add
Boceprevir [Victrelis]
Start with triple therapy from the start (Telaprevir
[Incivek]+ IFN+R)
Try IFN + R alone
How long will the treatment be?
How to Manage
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SOC for HCV GT1
Pegylated interferon/Ribavirin + protease inhibitor
(PI): telaprevir or Boceprevir
More effective to give combination?
So we gave PEG interferon a2a, ribavirin and
telaprevir
SVR With BOC and TVR+P/R in GT1
Treatment-Naive and -Experienced Pts
100
100
P/R
80
SVR (%)
SVR (%)
80
60
38-44[1-2]
40
17-21[3-4]
20
0
Treatment-Naive
Pts
TreatmentExperienced
P/R+ Protease Inhibitors
63-75[1-2]
59-66[3-4]
60
40
20
0
Treatment-Naive
Pts
TreatmentExperienced
1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon
BR, et al. AASLD 2010. Abstract 216. 4. Foster GR, et al. APASL 2011. Abstract 1529.
Boceprevir or Telaprevir + PegIFN/RBV:
The New Standard of Care for Genotype 1
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Potent inhibitors of HCV NS3/4A protease
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Both approved by FDA and EMA in mid 2011
Indicated in combination with pegIFN/RBV for
treatment of genotype 1 HCV–infected patients
Previously untreated or previous treatment failures
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Does this apply for GT4 or GT2 or 3?
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– Yes
– No
Telaprevir [package insert]. May 2011. Boceprevir [package insert]. May 2011.
ADVANCE:
Overall SVR and Relapse Rates
8-wk TVR + PR + 16/40-wk PR (n = 364)
100
P < .0001 for both treatment
arms vs control
Patients (%)
80
69
12-wk TVR + PR + 12/36-wk PR (n = 363)
48-wk SOC (n = 361)
75
60
44
40
28
20
0
n=
250
271
SVR
158
n=
9
9
28
27
64
Relapse
Jacobson IM, et al. AASLD 2010. Abstract 211.
Difficulties to the New Standard of Care for
Genotype 1
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3.
4.
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1.
2.
Side effects?
Compliance issues?
Both?
Other causes?
Is therapy different with Telaprevir P & R from
Boceprevir P & R ?
Yes
No
Similarities and Differences in Phase III
Studies of TVR and BOC in GT1 Naive Pts
Parameter
TVR[1]
BOC[2]
PR lead-in?
No
Yes: 4 wks
PegIFN alfa formulation
2a
2b
PI dosing requirements
TID; administer with fatty
meal
TID
8-12 wks followed by 12-40
wks PR
24-44 wks after
4 wks PR lead-in
Qualification for shortened therapy
(response guided)
Undetectable HCV RNA until
Wk 12 of triple therapy
Undetectable HCV RNA
until Wk 24 of triple
therapy
Qualified for shortened therapy, %
58 (24 wks)
44 (28 wks)
69-75
63-66
9
9
Rash and pruritus12%,
anemia, nausea
Anemia 10-20%,
dysgeusia
Duration of PI triple therapy
SVR, %
Relapse, %
Adverse events more frequent in PI
arms
1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB-4.
Adherence
Typical Student
Monday
Monday
6:00 AM TVR/BOC (with food) + RBV
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Triple therapy presents
challenges with already
busy schedules[143]
– TID dosing
– Food requirements
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Data show pegIFN/RBV
adherence decreases
over time[5]
– Addition of PIs may
exacerbate this trend
Busy Sales Professional
TVR/BOC (with food) + RBV
7:00 AM
8:00 AM
9:00 AM
Daily Team Conference Call
Patient Appointments
English Composition
12:00 PM
Lunch
Lunch
Biology
TVR/BOC
(with food)
4:00 PM
Work
TVR/BOC
(with food)
Travel to and
Meet With
Clients
5:00 PM
Dinner
RBV
7:00 PM
8:00 PM
1. Telaprevir [package insert]. May 2011.
2. Boceprevir [package insert]. May 2011.
9:00 PM
3. EMA. Boceprevir [package insert] 2011.
4. EMA. Telaprevir [package insert] 2011.
10:00 PM
5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
Dentist Appt
Patient
Appointments
TVR/BOC (with
food)
Calls to Clients
3:00 PM
6:00 PM
Travel to and Meet With
Client
Lunch
1:00 PM
2:00 PM
TVR/BOC (with food) + RBV
Wake, feed, and dress children
for school
School and daycare drop-off,
commute to work
Chemistry Lab
10:00 AM
11:00 AM
Mother With Small Children
and Full-time Nurse
Monday
Pick up kids, commute home
RBV
Running Club
Study Group
Dinner
Researching Trade Articles
TVR/BOC (with food)
TVR/BOC (with food)
Dinner
RBV
Get children ready for and in to
bed
Dinner cleanup, make lunches
for next day
TVR/BOC (with food)
Current Standard-of-Care Therapy Is
Complex
Mean Adherence (%)
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Adherence to pegIFN/RBV
therapy decreases over time
100
80
60
100
95 95
89
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Treatment
Wk
97
0-12
86 84
13-24
76
25-36
37-48
–
–
–
–
40
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20
0
PegIFN
Ribavirin
(N = 5706)
Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
Triple therapy has greatly
increased treatment
complexity, involves
multiple daily pills plus
injection drug
BOC TID: 12 pills/day
TVR TID: 6 pills/day
RBV BID: 4-6 pills/day
PegIFN: QW injection
Increased risks with
nonadherence to triple
therapy include potential
for resistance and
mutations
Do Mutations Occur ?
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Would this affect the prognosis or further therapy?
Treatment-Emergent Substitutions
During PI-Based Therapy
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Pooled analyses of subjects who had on-treatment failure or relapse during
clinical trials with boceprevir or telaprevir
– Patterns of treatment-emergent substitutions varied by subtype 1a vs 1b
– Resistance most common among previous null responders and patients with
subtype 1a
HCV Genotype 1
Subtype
Treatment-Emergent Substitutions
Telaprevir[1]
Boceprevir[2]
1a
V36M
R155K
Combination of V36M and R155K
V36M
T54S
R155K
1b
V36A
T54A/S
A156S/T
T54A/S
V55A
A156S
I/V170A
1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011.
Loss of Detectable Resistance in Patients
Stopping BOC or TVR + PegIFN/RBV
Telaprevir[2]
Boceprevir*[1]
Cumulative Rate of
Wild-Type Variant (%)
100
80
Pts With Wild-Type Virus (%)
V36M
T548
R155K
Any mutation
60
40
20
0
0
6
12
18
Most After End of Therapy
24
Genotype 1a HCV
Genotype 1b HCV
100
87
80
66
60
0
100
94
60
46
40
20
98
32
22
16
0
3
6
12
Most After Treatment Failure
*Data from phase II studies.
1. Vierling JM, et al. EASL 2010. Abstract 2016. 2. Sullivan J, et al. EASL 2011. Abstract 8.
16
Optimum Therapy Courses
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1.
2.
What are the stopping rules?
Each has side effects; can therapy be shortened
without compromising results of therapy?
Yes
No
Telaprevir in Genotype 1 Patients
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750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g, eg,
1/2-cup nuts or 2-oz cheddar cheese)
Treatment Naive and Previous Relapsers
TVR + PR
PR
eRVR; stop at Wk 24
No eRVR; PR
Previous Partial or Null Responders
TVR + PR
0
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4
PR
12
24
48
Treatment-naive patients with compensated cirrhosis and eRVR may benefit from
additional 36 wks of pegIFN + RBV (ie, to Wk 48)
Time Point
Criterion
Stopping Rule
Wk 4 or 12
HCV RNA > 1000 IU/mL
Discontinue all therapy
Detectable HCV RNA
Discontinue PR
Discontinuation of PR for any reason
Discontinue TVR
Wk 24
Any
Telaprevir [package insert]. May 2011. EMA. Telaprevir [package insert] 2011.
Boceprevir in Genotype 1 Patients
800 mg (four 200-mg capsules) q8hr with meal or light snack
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Treatment Naive
BOC + PR
PR
Early response; stop at Wk 28
BOC + PR
PR
Previous Relapsers or Partial Responders
PR
0
Wks
4
BOC + PR
Early response;
stop at Wk 36
BOC + PR
PR
8
12
24
28
36
48
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All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks
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If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks
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EMA
label recommends fixed-duration
therapy for all trt-expd patients: LIStopping
+ 32 wks Rule
triple + 12 wks
Time
Point
Criterion
PR
Wk 12
HCV RNA ≥ 100 IU/mL
Discontinue all therapy
Wk 24
Any
Detectable HCV RNA
Discontinue all therapy
Discontinuation of PR for any reason
Discontinue BOC
Boceprevir [package insert]. May 2011. EMA. Boceprevir [package insert] 2011.
Drug-Drug Interactions Represent a
Clinical Challenge*
Drug Class
Contraindicated With BOC[1]
Contraindicated With TVR[2]
Alpha 1-adrenoreceptor
antagonist
Alfuzosin
Alfuzosin
Anticonvulsants
Carbamazepine, phenobarbital, phenytoin
N/A
Antimycobacterials
Rifampin
Rifampin
Ergot derivatives
Dihydroergotamine, ergonovine,
ergotamine, methylergonovine
Dihydroergotamine, ergonovine,
ergotamine, methylergonovine
Herbal products
Hypericum perforatum (St John’s wort)
Hypericum perforatum
HMG CoA reductase inhibitors
Lovastatin, simvastatin
Atorvastatin, lovastatin, simvastatin
Oral contraceptives
Drospirenone
N/A
Neuroleptic
Pimozide
Pimozide
PDE5 inhibitor
Sildenafil or tadalafil when used for tx of
pulmonary arterial hypertension
Sildenafil or tadalafil when used for tx of
pulmonary arterial hypertension
Sedatives/hypnotics
Triazolam; orally administered midazolam
Orally administered midazolam, triazolam
*Studies of drug-drug interactions incomplete.
1. Boceprevir . May 2011. 2. Telaprevir May 2011.
Helpful Drug-Drug Interaction Resource
Complications During Treatment
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1.
2.
3.
4.
5.
She had complied mostly to regimen of IFN, R, TVR
When she came after 4 weeks HCV RNA 90 IU/ml &
Hb 9 g complaining of:
– Usual aches and pains after injections
– Mild itchy rash manageable by an anti-histamine
and local emollient
– Fatigue: caused by ?
Anemia
Depression
Thyrotoxicosis
1&2
1&3
Our Patient Under Treatment
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1.
2.
3.
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At weeks 12 also virus was undetectable
Fatigue was marked: cause?
Anemia
Depression
Thyroid disease
Hb remained 9 gm/dl and she showed no sign of
depression; but had some tachycardia
How Would You React?
1.
2.
3.
4.
5.
6.
Give EPO
Reduce dose of RBV
Test thyroid functions
Test autoantibodies
Reduce dose of IFN
A combination of the above
Thyroid Dysfunction after Interferon Therapy
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Prediction
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Thyroperoxidase (TPO) and thyroglobulin (TG)
antibodies more frequent before antiviral treatment
in patients with dysthyroidism (10 folds risk)
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Low fibrosis found to be a predictive factor of
dysthyroidism, mostly hypothyroid
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S.T thyrotoxicosis
Our Patient Under Treatment
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1.
2.
3.
4.
T3 and T4 raised -TSH lowered – what is my next step
Treat thyrotoxicosis
Investigate further: how?
Stop anti-viral treatment
All the above
Thyroid Further Investigated
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Radioactive iodine uptake proved destructive
thyroiditis – How?
Destructive thyroiditis:
 RAIU &  TSHAb
Continue treatment + propranolol
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Graves’ hyperthyroidism
 RAIU &  TSHAb
Stop treatment and treat thyroid disease
Results of Therapy
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1.
2.
3.
Week 4 - Hb 9 g/dl, HCV-RNA 90 IU/ml
At week 8 HCV – RNA was undetectable
At week 12 – EVR (virus undetectable)
At week 24 - virus undetectable
Shall we:
Continue till week 48 – then follow up till week 72
Stop at 24 - then follow up till week 48
Give 72 weeks – and follow up for further 24
weeks
Another Problem
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1.
2.
3.
4.
At some stage her GP phoned for a Question: Platelet
count is down to 60,000/cmm
How much thrombocytopenia can we allow?
If it gets lower then:
Stop therapy
Reduce interferon
Stop Interferon alone
Non of the above
ENABLE 1: Eltrombopag as Adjunct
Therapy for Thrombocytopenia in HCV
Before HCV Antiviral Therapy
Open-Label Eltrombopag Treatment Phase (2-9 wks)
HCV-infected patients
with platelets
25 mg Platelets ≥ 90K/μL
< 75K/μL (N = 716†)
Platelets < 90K/μL
50 mg Platelets ≥ 90K/μL
Platelets < 90K/μL
75 mg Platelets ≥ 90K/μL
Platelets < 90K/μL
Double-Blind Phase (≤
48 wks*)
Eltrombopag +
PegIFN alfa-2a/RBV
2:1 randomization
24 wks
follow-up
Placebo +
PegIFN alfa-2a/RBV
100 mg Platelets ≥ 90K/μL
Platelets < 90K/μL
Withdrawal
Growth factor support allowed for anemia and neutropenia. PegIFN alfa-2a reduced or discontinued for thrombocytopenia.
Eltrombopag/matched placebo could be titrated during treatment to maintain platelets between 90-200K.
*24 wks if HCV genotype 2/3; otherwise 48 wks.
†Demographics balanced between eltrombopag and placebo groups. Median age: 51-52 yrs; 59% to 69% male; 72% white;
66% to 68% IFN-naive; 64% to 65% genotype 1; 94% Child-Pugh 5-6; 72% to 73% platelets ≥ 50,000.
Afdhal N, et al. AASLD 2011. Abstract LB-3.
ENABLE 1: Eltrombopag as Adjunct
Therapy for Thrombocytopenia in HCV


95% of patients were eligible to start antiviral therapy following openlabel eltrombopag
Use of eltrombopag associated with significantly improved response
rates to HCV therapy
Virologic Response (ITT)
100
P < .0001
Patients (%)
80
66
60
P < .0001
50
40
P = .7495
20
17 16
0
Placebo
Eltrombopag
RVR
42
26
P = .008
48
37
P = .0064
23
14
EVR
Afdhal N, et al. AASLD 2011. Abstract LB-3.
cEVR
ETR
SVR
Eltrombopag

How safe?
At the End of Therapy



1.
2.
3.
We went on with treatment and platelets remained
at 55000/cmm
If at week 48 HCV- RNA was not detectable by RTPCR followed up every 3 months? or 6 months?
What shall we test for on follow up?
HCV-RNA
Mutations
Liver enzymes
If The Patient Relapses

1.
2.
3.

What shall we tell our patient?
Re-Treat?
We will take a rest then think about it?
Consider as non-responder and follow up?
Our action should depend on the patients physical,
psychological, stage of liver disease and history of
compliance during treatment – also the availability of
newer drugs
DAA Target HCV Life Cycle
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
(+) RNA
Translation
NS3/4 and
protease
polyprotein
inhibitors
processing
Membranous
web
LD
ER lumen
LD
Virion
assembly
LD
ER lumen
NS5A* inhibitors
*Role in HCV life cycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
NS5B polymerase
RNA
replication
inhibitors
Nucleoside/nucleotide
Nonnucleoside
Each Drug Class Has Unique Features
NS3/4A
Protease
Inhibitors
 High efficacy
 Low genetic
barrier to
resistance
 Macrocyclic
or linear
 Phase III:
BI 201335,
TMC435
NS5B Polymerase Inhibitors
Nucleos(t)ide
Analogue
 Mimic natural
substrates of the
polymerase
 Incorporated into
RNA chain
causing chain
termination
 Broad genotypic
coverage
 High genetic
barrier to
resistance
 Phase III:
PSI-7977
NS5A
Inhibitors
Cyclophilin A
Inhibitors
 Bind to several
different
allosteric
enzyme sites;
results in
conformational
change
 NS5A has role
in assembly of
replication
complex
 Supports HCVspecific RNA
replication,
protein
expression
 Resistance
more frequent
than nucs
 Phase III:
Daclatasvir
(BMS-790052)
Nonnucleos(t)ide
 Several agents
in phase II
 Mechanism of
inhibition
under study
 Interacts with
NS2, NS5A,
NS5B
 May regulate
polypeptide
processing,
viral assembly
 Phase III:
Alisporivir
Some Agents Under Investigation Have
Broad Genotypic Coverage

Majority of protease inhibitors have targeted
genotypic coverage
– MK-5172, TMC435 have broad coverage[1,2]




Nonnucleoside polymerase inhibitors active against
GT1
Most nucleos(t)ide analogue polymerase inhibitors
are pan-genotypic
Most NS5A inhibitors have targeted genotypic
coverage
Cyclophilin inhibitors are pan-genotypic
1. Brainard DM, et al. AASLD 2010. Abstract 807.
2. 2. Fried M, et al. AASLD 2010. Abstract LB-5 .
New Agents Generally Maintain or Improve
Upon Efficacy in GT1 Treatment-Naive
Phase II Studies, Drug + PegIFN/RBV
Not head-to-head comparisons
100
SVR (%)
80
63-75
60
71-83 68-85 65-85 75-86 61-84
42-83
38-50
53-76
56
40
20
0
BOC or
TVR [1,2]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79. 5. Vierling JM, et al. AASLD
2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82.
8. Jacobson I, et al. EASL 2010. Abstract 2088. 9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011.
Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.
Combination Therapy for Null
Responders

Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032)
BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks
US Study[1]
100
90
Japan Study[2]
Daclatasvir + Asunaprevir
90*
Daclatasvir + Asunaprevir + PR
SVR24 (%)
80
60
40
36
20
0
1. Lok A, et al. EASL 2011. Abstract 1356.
2. Chayama K, et al. AASLD 2011. Abstract LB-4.
N/A
*all genotype 1b patients.
Combination Therapy for Null
Responders
 Additional announced IFN-free study designs in
treatment-experienced patients
Protease inhibitor
Nucleos(t)ide analogue polymerase inhibitor
Nonnucleoside polymerase inhibitor
Drug 1
Drug 2
Overall
Regimen
TMC435 QD
PSI-7977 QD
± RBV
12 or 24 wks
ABT-450/RTV
QD
ABT-333 BID
+ RBV
Danoprevir/
RTV BID
Mericitabine
BID
+ RBV
24 wks
Several Drugs in Development Are
Dosed Once or Twice Daily
QD
BID
TID
ABT-072
ABT-267
ABT 450*
ACH-1625
BI 201335
Daclatasvir
GS 5885
GS9451
IDX 184
INX-189
MK-5172
Narlaprevir*
PSI-7977
PSI-938
TMC435
ABT-333
Asunaprevir
BI 201335
BI 207127
BMS 791325
Danoprevir*
Filibuvir
GS9256
Mericitabine
Setrobuvir
Tegobuvir
Vaniprevir
VX-222
BI 207127
Danoprevir
*With RTV boosting.
Future Directions: Patient/Virus Factors
Determine Course?
Favorable response profile
Course 1:
Combination
DAAs
Fails?
Unfavorable response profile
Course 1:
PegIFN/RBV +
combination
DAAs
Course 2:
PegIFN/RBV +
combination
DAAs
Conclusion: The Beckoning Future
Current Phase III Trials
Telaprevir in GT1 IL28B CC patients
PSI-7977 across genotypes
TVR BID + PR
PSI-7977 + R
TVR BID + PR
PR
Telaprevir + VX-222 + PR in GT1
QUAD
TMC435 in GT1 patients
TMC435 + PR
PR
TMC435 + PR
PR
Daclatasvir in GT1/4 patients
Daclatasvir + PR
PR
Daclatasvir + PR
BI 201335 in GT1 patients
BI 201335 + PR
PR
BI 201335 + PR
BI 201335 + PR
PR
PR
Evaluation of Combination Regimens in
GT1 Treatment-Naive Patients

Strategy: protease inhibitor
(telaprevir) + nonnucleoside
polymerase inhibitor (VX-222)[1]
– ± pegIFN/RBV for 12 wks, then RGT
VX-222 400 mg BID + TVR + PR
VX-222 100 mg BID + TVR + PR
Patients (%)
100
80
93
82
87
83
60

Strategy: protease
inhibitor (ABT-450/r) +
nonnucleoside polymerase
inhibitor (ABT-333 or ABT072)*
– + RBV for 12 wks
– All 44 patients achieved cEVR
– Of 10 patients tested thus far,
9 achieved SVR24
40
20
0
SVR24; 12 total wks SVR12; 24 total wks
of therapy
of therapy
1. Nelson DR, et al. AASLD 2011. Abstract LB-14.
*These data are available in press release format
only, have not been peer reviewed, may be
incomplete, and we await presentation or
publication in a peer-reviewed format before
conclusions should be made from these data.
Ongoing Research Evaluates Potential
for All-Oral Therapy
Several all-oral regimens under
investigation
IFN-free regimens shown to be
highly effective in GT2/3[1]
Protease inhibitor
NS5A inhibitor
Nucleos(t)ide analogue polymerase inhibitor
Nonnucleoside polymerase inhibitor

Drug 2
Drug 3
RBV
BI 201335
BI 207127
N/A
±
PSI-7977
PSI-938
N/A
±
ABT-450/
RTV
ABT-333
or ABT-072
N/A
PSI-7977
Daclatasvir
N/A
±
GS-9256
Tegobuvir
N/A
±
GS-9451
GS-5885
± Tegobuvir
±
Asunaprevir
Daclatasvir
BMS791325
N/A
+
All-oral regimens of single drug + RBV also
under investigation.
100
100
100
100
100
PSI-7977
+ 0 wks
PegIFN
(IFN-free)
PSI-7977
+ 4 wks
PegIFN
PSI-7977
+ 8 wks
PegIFN
PSI-7977
+ 12 wks
PegIFN
80
SVR (%)
Drug 1
Nucleotide analogue PSI-7977 + RBV
for
12 wks
– PegIFN included for 0, 4, 8, or 12 wks
60
40
20
0
1. Gane EJ, et al. AASLD 2011. Abstract 34.
Fewer AEs With Some Investigational Agents
Studies displayed include those with data through at least 12 wks and with discontinuation rates lower than BOC/TVR.
Agent
AEs More Frequent in
Experimental Arm vs PegIFN/RBV
Discontinuations
due to AEs, %
(Wk)
Anemia, dysgeusia, neutropenia, rash, anorectal
symptoms
13-14 (48)
ABT-072[3] (N = 27)
Headache
0 (12)
ABT-333[3] (N = 18)
None
0 (12)
ABT-450/r[4] (N = 30)
None
0 (12)
Alisporivir[5] (N = 215)
Transient hyperbilirubinemia
5 (48)
Asunaprevir[7] (N = 36)
Fatigue
11 (12)
BI 201335[6] (N = 355)
GI events, jaundice, and rash
8 (48)
Daclatasvir[8] (N = 36)
None
8 (12)
ALT elevation, neutropenia, nausea, diarrhea
4 (12)
Mericitabine[10] (N =
81)
None
6 (36)
PSI-7977[11] (N = 95)
None
3 (12)
Setrobuvir[12] (N = 63)
Rash
2 (12)
TMC435[13] (N = 309)
Mild bilirubin increases
7 (24)
GI events
6 (48)
Boceprevir/Telapre
vir[1,2]
Danoprevir[9] (N =
194)
Vaniprevir[14] (N =
169)
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Gaultier, et al. APASL 2011.
4. Lawitz E, et al. EASL 2011. Abstract 1220. 5. Flisiak R, et al. EASL 2011. Abstract 4. 6. Bronowicki JP, et al. EASL 2011. Abstract 1195.
7. Sulkowski M, et al. EASL 2011. Abstract 60. 8. Pol S, et al. EASL 2010. Abstract 1189. 9. Terrault N, et al. AASLD 2010. Abstract 32.
10. Pockros P, et al. EASL 2011. Abstract 1359. 11. Nelson D, et al. EASL 2011. Abstract 1372. 12. Lawitz E, et al. AASLD 2010. Abstract 31.
13. Fried M, et al. AASLD 2010. Abstract LB-5. 14. Lawitz E, et al. AASLD 2011. Abstract LB-13.
BMS-790052 + BMS-650032 Alone or
With PegIFN/RBV: Wk 12 – Null Responders
Interim Analysis
100
BMS-790052* + BMS-650032
BMS-790052* + BMS-650032 + PR
90
Patients (%)
80
60
64
60
60
46
36
40
20
0


7/11 6/10
4/11 6/10
5/11 9/10
RVR
eRVR
cEVR
All viral breakthroughs occurred in patients with GT1a, not receiving PR
*NS5A polymerase inhibitor Daclatasvir
Lok A, et al. AASLD 2010. Abstract LB-8.
INFORM-1 Polymerase + PI without P/R
Mean log10 HCV RNA change
from baseline (IU/mL)
1
0
-1
63–71% patients
HCV RNA <40 IU/mL
-2
-3
-4
Dosing
R7128: bid
R7227: q8h
(Danoprevir)
-5
-6
-7
0
2
4
R7128 500 mg/R7227 100mg
R7128 1000 mg/R7227 100 mg
6
Day
8
10
12
14
R7128 500 mg/R7227 200mg
R7128 1000 mg/R7227 200mg
Gane EJ, et al. EASL 2009. Abstract LB 1046
Placebo
SOUND C1: BI 207127 + BI 201335 and
RBV in Naive GT1 Pts

Randomized, open-label trial of BI 207127 (NS5B nonnucleoside
polymerase inhibitor) and BI 201335 (NS4 protease inhibitor) in an
interferon-sparing strategy
Wk 4
Treatmentnaive
patients with
GT1 HCV
(N = 32)
Wk 48
BI 207127 400 mg TID+
BI 201335 120 mg QD +
RBV*
(n = 15)
BI 201335 + PegIFN/RBV†
BI 207127 600 mg TID+
BI 201335 120 mg QD +
RBV*
(n = 17)
BI 201335 + PegIFN/RBV†
*RBV 1000-1200 mg/day in 2 doses.
†PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.
Zeuzem S, et al. AASLD 2010. Abstract LB-7.
Pts With HCV RNA < 25 IU/mL (%)
SOUND C1: Week 4 Results
BI 207127 400 mg
BI 207127 600 mg

100
100
100

82
80
67
73
60
40

40

20
0
6/15 14/17
10/15 17/17
11/1517/17
Day 15
Day 22
Day 29
Zeuzem S, et al. AASLD 2010. Abstract LB-7.
1 viral breakthrough in
400-mg arm
GT1a pts had lower
response rate in lowdose arm
AEs: mild GI events,
rash, photosensitivity
No severe AEs and no
tx discontinuations in
first 4 wks
Ongoing Research Evaluates Potential
for All-Oral Therapy
Several all-oral regimens under
investigation
IFN-free regimens shown to be
highly effective in GT2/3[1]
Protease inhibitor NS5A inhibitor
Nucleos(t)ide analogue polymerase inhibitor
Nonnucleoside polymerase inhibitor
Drug 2
Drug 3
RBV
BI 201335
BI 207127
N/A
±
PSI-7977
PSI-938
N/A
±
ABT-450/
RTV
ABT-333
or ABT-072
N/A
PSI-7977
Daclatasvir
N/A
±
GS-9256
Tegobuvir
N/A
±
GS-9451
GS-5885
± Tegobuvir
±
Asunaprevir
Daclatasvir
BMS791325
N/A
All-oral regimens of single drug +
RBV also under investigation.
+
100
Nucleotide analogue PSI-7977 + RBV
for 12 wks
– PegIFN included for 0, 4, 8, or 12
wks
100
100
100
100
80
SVR (%)
Drug 1

60
40
20
0
PSI-7977 PSI-7977 PSI-7977 PSI-7977
+ 0 wks + 4 wks + 8 wks + 12 wks
PegIFN
PegIFN
PegIFN
PegIFN
(IFN-free)
1. Gane EJ, et al. AASLD 2011. Abstract 34.
Nitazoxanide



It increases PKR phosphorylation and inhibits RNA
formation
suppresses viral replication
Given in combination with P/R improved SVR in
genotype 4 CHC
Tried with IFN a2a without R; gave better results than
IFN alone
Jama M Darling, Michael Fried. Gastroenterology 2009;3; 856 862
+ 24 references to the subject
Future Regimens Have Potential to
Shorten Duration, Simplify Therapy
Boceprevir/telaprevir



New options under
investigation Protease Inhibitor BID
24/28 wks min, 48 wks max
Duration varies: dependent on
treatment experience, treatment
response, fibrosis level
Additional assessments for futility
in IL28B CC
Novel Therapies Currently in Trials
Boceprevir
Telaprevir
0 4
12
24 28
36
48
0
4
12
24
48
Conclusion 1



P/R are still main pillar of SOC till at least the end of 2013
with strict inclusion & exclusion criteria – will be in
therapy program up to year 2018 - RVR and cEVR stand
an excellent chance of cure
First generation protease inhibitors (Boceprevir and
Telaprevir) are suitable only for HCV genotype 1
Second generation protease inhibitors some are genotype
specific and some are pangynotypic; so also nucleoside
polymerase & NS5A inhibitors pangynotypic but not nonnucleosides polymerase inhibitors
Conclusion 2


Nitazoxanide deserves further evaluation in our protocol
The dream of using routinely just oral therapy
is slowly becoming a reality
With the help of God
We will keep trying with Every New Day
Predictors of Response to Boceprevir in
Poorly Interferon-Responsive Patients

Among poorly IFN-responsive patients in boceprevir arms of phase III
studies, 0% of individuals with < 3 log decline in HCV RNA at Wk 8 of
therapy achieved SVR
– Poor IFN responsiveness: < 1 log HCV RNA decline by Wk 4 of lead-in
Wk 8 Log10 HCV RNA Decline From Baseline
<3
SVR* (%)
100
3-4
4-5
>5
91
38
40
20
0
50
33
0
RESPOND-2
n/N = 0/16
3/8
6/28 10/20 10/11
49
48
21
0
83
79
80
60
Undetectable
9
30
0
SPRINT-2
0/28
2/23 23/70 15/31 23/29
16
Combined
0/44
Bacon BR, et al. AASLD 2011. Abstract 33
Poordad F, McCone J, Bacon BR, et al.. N Engl J Med. 2011;364:1195-1206.
Bacon BR, Gordon SC, Lawitz E, et al. N Engl J Med. 2011;364:1207-1217.
5/31 29/98 25/51 33/40
*Boceprevir arms combined.
Pre-existing or new mutations may be selected with
protease inhibitors
HCV RNA viral load
Plasma drug concentrations
Direct acting antiviral
e.g. NS3/4A protease inhibitor
HCV RNA
detection limit
0
24
48
72
96
120
Time (hours)
144
Virus sensitive to small molecule
Naturally occurring drug-resistant mutant variant
168
192
216
New drug-resistant mutant variant
HCV RNA change from baseline
(Log10 IU/mL)
Synergistic reductions in HCV RNA with
Telaprevir plus P/R
1
0
Baseline
-1
-2
Resistant mutations suppressed by PEG-IFN
-3
-4
Telaprevir
(N=8)
-5
-6
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15
Telaprevir +
PEG-IFN -2a
(N=8)
Study time (days)
Kieffer TL, et al. Hepatology 2007; 46:631–639
SVR Rates With BOC or TVR in
Genotype 1 Treatment-Naive Patients
100
SVR (%)
80
63-75
60
38-44
40
20
0
PegIFN/RBV
BOC or TVR +
PegIFN/RBV
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
SVR Rates With BOC or TVR in
GT1 Treatment-Experienced Patients
100
PegIFN + RBV
69-83
BOC or TVR + PegIFN + RBV
SVR (%)
80
40-59
60
40
29-38
24-29
20
7-15
5
0
Relapsers
Partial Responders
Null
Responders
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Vierling JM, et al. AASLD 2011. Abstract 931.
Telaprevir and Boceprevir SVR in
Difficult to Treat Patients
100
75-83[1,2]
SVR (%)
80
68-75[3,4]
53-62[3-4]
60
5259[1,2]
29-38[1,6]
40
20
0
14[5]*
Relapser
Naive
Naive Black
Partial
White/
Responder
Nonblack
Null
Responder
Cirrhotic
Null
Responder
*Pooled TVR arms of REALIZE trial.
1. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
5. Zeuzem S, et al. EASL 2011. Abstract 5. 6. Vierling JM, et al. AASLD 2011. Abstract 931.