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Simone StrasserStephen Pianko
Adverse events and drug interactions
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Learning objectives
• Discuss management of AEs in patients treated with protease inhibitors
• Anaemia• Skin rash
• Discuss drug interactions with direct acting antiviral agents (DAAs)
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Gary
• First seen in 2001• HCV genotype 1a, cirrhosis• History of IDU; on methadone• Cannabis 3-4 days/week• Alcohol: 12 cans beer/day for many years
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Antiviral treatment history2002 – Rebetron (interferon alfa-2b + RBV)• Multiple RBV dose reductions for anaemia• Multiple AEs including fatigue, mood swings, insomnia• HCV RNA positive week 24 – stopped
2003 – Pegasys/RBV (peg-IFN alfa-2a + RBV)• Dose reductions peg-IFN and RBV from week 10• GCSF from week 12• Poorly tolerated• 48 weeks Rx, pEVR, ETR but relapse week 4 FU
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Gary• GT 1a; cirrhosis• Non-responder to Rebetron• Relapser to Pegasys RBV
• No further antiviral treatment offered
• 2012 – He is very anxious about his disease and wants maximal treatment
• Any recommendations?
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REALIZE: Treatment-experienced patients with advanced fibrosis or cirrhosis
• Previous relapsers with liver disease had high SVR rates following treatment with telaprevir plus peg-IFN/RBV
– For previous null responders with cirrhosis, SVR rates similar to peg-IFN/RBV alone
Zeuzem S, et al. EASL 2011. Abstract 5.
Previous Relapsers Previous Partial Responders Previous Null Responders
2/15n/N= 53/
62144/167
12/38 0/5
10/18
34/47
3/17 0/9
15/38
11/32
1/5
No, minimal, or
portal fibrosis
CirrhosisStage
Pooled T12/PR 48Pbo/PR 48
2/15
48/57
24/59
1/18 7/50
1/10
Bridgingfibrosis
No, minimal, or
portal fibrosis
CirrhosisBridgingfibrosis
No, minimal, or
portal fibrosis
CirrhosisBridgingfibrosis
100
0
60
SVR
(%)
80
40
20
86
32
85
13
84
13
72
18
56
0
34
20
41
6
39
014 10
Clinical Care Options: Hepatitis
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Treatment-experienced patients with advanced fibrosis or cirrhosis
• Package inserts for both boceprevir and telaprevir recommend fixed duration therapy rather than response-guided approach in cirrhotics– Supported by RESPOND-2 study data evaluating impact of response-guided
therapy on SVR in cirrhotic patients
Bacon BR, et al. N Engl J Med 2011;364:1207-1217.
100
80
60
40
20
0
23
F0-2 F3-4
SV
R (
%)
14/61
PR BOC RGT BOC PR 48
Advanced fibrosis Cirrhosis
66
77/117
68
81/119
13
2/15
44
14/32
68
21/31
100
80
60
40
20
0
24
No cirrhosis Cirrhosis
SV
R (
%)
16/66
64
85/132
66
85/128
0
0/10
35
6/17
77
17/22n/N = n/N =
Clinical Care Options: Hepatitis
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Gary
• Decision made to proceed to treatment with boceprevir
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Baseline investigations5/9/11
Week B/L
Bilirubin 10
Albumin 38
AST 98
ALT 72
Hb 124
WCC / ANC 2.6 / 1.3
Platelets 135
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Gary – Current medications
• Candesartan 16 mg/day • Pantoprazole 40 mg/day• Methadone 22 mL (110 mg)/day
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• What issues do you anticipate?
• Any planning ahead of treatment?
Questions
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Anaemia in controlled clinical trials of TVR and BOC
Hezode C. Liver Int 2012 Feb;32 Suppl 1:32-8.
Relatively few patients with cirrhosis included in phase III clinical trials of boceprevir (n=115) and telaprevir (n=247)
Patients, % TVR Phase II/III trials BOC phase III trials
TVR Control BOC Control
Anaemia 32 15 49 29
RBV dose reductions 22 9 26 13
EPO use* 1 0 43 24
Blood transfusion 4.6 1.6 3 <1
* EPO use not permitted in TPV trials
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The CUPIC study
• HCV genotype 1 patients, n=455• Compensated cirrhosis (Child Pugh A) genotype 1
• Non-responders– Relapsers– Partial responders ( >2 log10 HCV RNA decline at Week 12)– Null responders theoretically excluded
• Treated in the French ATU
• Safety data available; SVR data awaited
Real-life safety of telaprevir or boceprevir in combination with peg-IFN alfa/RBV in cirrhotic non-responders.
First results of the French early access program (ANRS CO20-CUPIC)
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CUPIC: BOC and TVR – Safety findings (EASL 2012)Patients, % Boceprevir (n=159) Telaprevir (n=296)
Serious AEs 38.4 48.6
Discontinuation due to serious AE 7.4 14.5
Death n (%) 2 (1.3%) 6 (2%)
Rash Grade 3 SCAR
00
7.50
Infection 2.5 8.8Anaemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion
22.610.166
10.7
19.610.156.815.2
Neutropenia Grade 3/4 (<500 – <1000/mm3) G-CSF use
53.8
4.72.4
Thrombocytopenia Grade 3/4 (<25,000 – <50,000) Use of thrombopoietin
6.91.9
13.11.7
Deaths: TPV – sepsis (2); pneumopathy (1); BOV (1); HE (1); Ca lung (1) BOC – pneumonia (1); sepsis (1)
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• 4 week peg-IFN/RBV lead-in phase
• Expect 48 weeks total treatment duration with BOC plus peg-IFN/RBV
• Will stop if detectable HCV RNA week 12 or week 24
Anticipated treatment duration
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On-treatment investigationsB/L Wk 4
Dose 180/1000
Bilirubin 10 20Albumin 38 40AST 98 50ALT 72 30
Hb 124 110WCC / ANC 2.6 / 1.3 5.9/4.7Platelets 135 71HCV RNA 230,000 341Support GSF x3/wk
Weeklyblood tests
Commenced wk2
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Symptoms• Fatigue• Insomnia• Bone pain since starting GCSF
Discussion prior to commencing BOC• Management plan for side-effects• Education re. drug interactions with BOC• Correspondence with GP re. treatment
Week 4 peg-IFN/RBV
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On-treatment investigationsB/L Wk 4 Wk 5
Dose 180/1000 180/1000BOC 800 tds
Bilirubin 10 20 25
Albumin 38 40 35
AST 98 50 39
ALT 72 30 22
Hb 124 110 97
WCC / ANC 2.6 / 1.3 5.9/4.7 7.8/6.5
Platelets 135 71 61
HCV RNA 230,000 341
Support GSF x3/wk GSF x3/wk
?
Weeklyblood tests
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Gary – Anaemia at week 5
What options?
1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce RBV?4. Dose reduce boceprevir?5. Blood transfusion?6. Erythropoietin?
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1.
2.
Poordad F et al. EASL 2012
Hb every 2 weeks from TW 0 to 20; then every 4 to 8 weeksRBV DR 200-400 mg/day then further 2 x DR of 200 mg/day
A randomised trial comparing RBV dose reduction vs EPO for anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
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Poordad F et al. EASL 2012
A randomised trial comparing RBV dose reduction vs EPO for anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
(73%)
n (%)
RA
ND
OM
ISA
TIO
N
®ns
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Poordad F et al. EASL 2012
®
n (%)
ns
A randomised trial comparing RBV dose reduction vs EPO for anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
(73%)
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Gary – Anaemia at week 5
What options?1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce RBV?4. Dose reduce boceprevir?5. Blood transfusion?6. Erythropoietin?
Decision to reduce RBV by 200 mg to 800 mg/wk
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On-treatment investigationsB/L Wk 4 Wk 5 Wk 6
Dose 180/1000 180/1000BOC 800 tds
180/800BOC 800 tds
Bilirubin 10 20 25 13
Albumin 38 40 35 34
AST 98 50 39 35
ALT 72 30 22 19
Hb 124 110 97 88
WCC / ANC 2.6 / 1.3 5.9/4.7 7.8/6.5 6.2/5.3
Platelets 135 71 61 56
HCV RNA 230,000 341
Support GSF x3/wk GSF x3/wk GSF x3/wk
Weeklyblood tests
• Pale • SOBOE• Fatigue• Nausea• Insomni
a
Symptoms
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Gary – Worsening anaemia at week 6 despite RBV dose reduction
What options?1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce RBV?4. Dose reduce boceprevir?5. Blood transfusion?6. Erythropoietin?
Decision to reduce RBV to 600 mg/wk
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On-treatment investigationsWk 4 Wk 5 Wk 6 Wk 8
Dose 180/1000 180/1000BOC 800 tds
180/800BOC 800 tds
180/600BOC 800 tds
Bilirubin 20 25 13 12
Albumin 40 35 34 35
AST 50 39 35 40
ALT 30 22 19 22
Hb 110 97 88 88
WCC / ANC 5.9/4.7 7.8/6.5 6.2/5.3 13.6/12.4
Platelets 71 61 56 55
HCV RNA 341 Not det
Support GSF x3/wk GSF x3/wk GSF x3/wk GSF x2/wk
Weeklyblood tests
• SOBOE• Fatigue
Symptoms
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Gary – Remains anaemic at week 8 despite RBV dose reduction to 600 mg daily
What options?
1. Further RBV dose reduction?2. Blood transfusion?3. Erythropoietin?4. Other?
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Secondary interventionImpact on SVR
• 18% of patients randomly assigned to RBV DR and 38% of patients randomly assigned to EPO received secondary anaemia management intervention
SV
R
• Patients who received additional secondary intervention had a numerically higher SVR rate than those who only received primary intervention
Poordad F et al. EASL 2012
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Use of EPO for early anaemia may prevent treatment discontinuation
The IDEAL trial
Sulkowski M et al. Gastroenterology 2010;139:1602–1611
Early anaemia/No ESA
Early anaemia/ESALate anaemia
Tre
atm
ent
Dis
cont
inua
tion
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Gary – Progress
• Commenced darbepoetin 60 mcg/wk from week 8
• Maintained RBV 600 mg/day
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d
On-treatment investigationsWk 6 Wk 8 Wk 12
Dose 180/800BOC 800 tds
180/600BOC 800 tds
180/600BOC 800 tds
Bilirubin 13 12 14
Albumin 34 35 33
AST 35 40 37
ALT 19 22 17
Hb 88 88 81
WCC / ANC 6.2/5.3 13.6/12.4 6.3/5.2
Platelets 56 55 27
HCV RNA Not det Not det
Support GSF x3/wk GSF x2/wkAranesp 60/wk
GSF x2/wkAranesp 60/wk
Weeklyblood tests
• Dysgeusia
• SOBOE• Fatigue• Nausea• Dry skin• 5 kg wt
loss
Symptoms
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Gary – Worsening anaemia at Week 12 despite RBV dose reduction and EPO; marked thrombocytopenia
What options?
1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce/omit RBV?4. Dose reduce/stop boceprevir?5. Blood transfusion?6. Erythropoietin?
Omitted RBV and reduced peg-IFN
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Gary – Progress to Week 18• Peg-IFN reduced to 90 mcg/wk for 2 weeks
then increased to 135mcg weekly
• Blood transfusion (2 units) at week 14 (Hb 77)
• Darbepoetin increased to 60 mcg twice weekly
• RBV restarted after 1 week off at 400 mg/day
• Dietician review – ENSURE 2-3/day
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On-treatment investigationsWk 6 Wk 8 Wk 12 Wk 18
Dose 180/800BOC 800 tds
180/600BOC 800 tds
180/600BOC 800 tds
180/400BOC 800 tds
Bilirubin 13 12 14 10
Albumin 34 35 33 29
AST 35 40 37 42
ALT 19 22 17 20
Hb 88 88 81 100
WCC / ANC 6.2/5.3 13.6/12.4 6.3/5.2 5.9/5.2
Platelets 56 55 27 39
HCV RNA Not det Not det
Support GSF x3/wk GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60 x2/wk
Weeklyblood tests
• Dysgeusia
• SOBOE• Fatigue• Nausea• Dry skin• 10 kg wt
loss
Symptoms
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Gary – Progress to Week 24
• Weekly blood tests
• Peg-IFN at varying doses 90/135/180 mcg/wk according to platelet count (27-40)
• Darbepoetin continued at 60 mcg twice weekly
• RBV maintained at 600 mg daily
• Oedema, no ascites or HE, Fatigue
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On-treatment investigationsWk 8 Wk 12 Wk 18 Wk 24
Dose 180/600BOC 800 tds
180/600BOC 800 tds
180/400BOC 800 tds
90-180/600BOC 800 tds
Bilirubin 12 14 10 9
Albumin 35 33 29 31
AST 40 37 42 40
ALT 22 17 20 19
Hb 88 81 100 99
WCC / ANC 13.6/12.4 6.3/5.2 5.9/5.2 2/1.2
Platelets 55 27 39 36
HCV RNA Not det Not det Not det
Support GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60 x2/wk
GSF x2/wkEPO 60 x2/wk
Weeklyblood tests
• Dysgeusia
• SOBOE• Fatigue• Nausea• Oedema
on Ensure
Symptoms
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Gary – Progress to-date (Week 32)
• Weekly blood tests
• Continues to struggle with symptoms
• Seeing psychologist and dietician regularly
• Keen to continue therapy
• Aim to continue triple therapy to week 48
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• Treatment with PI in cirrhotics is complex. Requires significant clinic resources including nurse and doctor time, blood tests, growth factors, BTx etc.
• SVR rates with PI higher among anaemic vs non-anaemic patients
• RBV dose reduction does not impair efficacy and should be initial management for anaemia
• Use of ESA for early anaemia may maintain patients on treatment, but availability limited in Australia
Summary
Worth it for an SVR?
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Telaprevir rash
• Who has seen it?
Adverse Event, % Telaprevir + peg-IFN/RBV(n=1797)
peg-IFN/RBV(n=493)
Rash 56 % 34 %
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Grading telaprevir rashGrade Severity Features
Grade 1 Mild Localised or limited distribution
Grade 2 Moderate Diffuse, up to 50% body surface area. Mucosal inflammation without ulceration. No epidermal detachment or target lesions. May have fever, eosinophilia, joint pain.
Grade 3 Severe Over 50% body surface area ± vesicles/bullae, superficial mucosal ulceration, DRESS, EM, AGEP
Grade 4 Life-threatening Generalised bullous eruption, SJS, TEN
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Management of telaprevir rash
• Grade 1 and 2: – Limit sun exposure, oatmeal baths, loose fitting clothing, topical/systemic
antihistamines, topical urea/corticosteroid creams, consider stopping telaprevir if rash progresses/does not improve
• Grade 3: – As above, may require oral CS. Cease telaprevir and do not recommence.
Dermatology consultation. May need to stop peg-IFN/RBV if not improving within 7 days
• Grade 4:– As above, stop all medications. Management as indicated.
Recommendation: Ensure access to dermatologist
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Drug interactions
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Learning objectives
• To consider drug interactions with DAAs when treating HCV
• Peg-IFN/RBV – minimal drug-drug interactions
• DAAs – many potential interactions with commonlyprescribed drugs
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• Previously treated in USA with peg-IFN/RBV for 48 weeks (breakthrough-non-responder)
• 2010 – Enrolled in a study of DEB025 A2210 cyclophilin inhibitor (Alisporivir) for prior IFN/RBV non-response
• peg-IFN/RBV + DEB/placebo
Alison
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Concomitant Medications:
• Lamotrigine• Venlafaxine • Oral Contraceptive
Alison
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Consider potential drug interactions
1. Alisporivir (Debio 025)
2. Lamotrigine(Lamictal)
3. Venlafaxine (Efexor)
4. Oral contraceptive
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What resources are available to help with drug interactions?
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What resources are available to help with drug interactions?
• Pharmacists• Websites• Product Information • Pharmaceutical companies• Understanding of how drug is metabolised
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Potential drug interactions
www.drugs.com/drug-interactions/
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• Lamotrigine dosing:• peg-IFN/RBV/Deb started 11/10 • Initial dose of lamotrigine 150 mg/day
• 1/11 dose 300 mg/d• 4/11 dose 500 mg/d• 7/11 dose 600 mg/d
Alison
• HCV treatment ceased week 4 per protocol due to non-response
For reduction inserum drug levels
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• Any concerns?
Alison
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Any concerns?• What to do with lamotrigine dosing?
Alison
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Lamotrigine dosing:• On cessation of therapy, bipolar disorder
became unstable; lamotrigine drug levels became toxic
• Cessation of peg-IFN and toxicity from lamotrigine
• Dose of lamotrigine reduced by private psychiatrist
Alison
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Lamotrigine dosing:• Lamotrigine (antiepileptic drug of the
phenyltriazine class) is metabolised predominantly by glucuronidation
• Drug interaction had not been anticipated
Alison
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What about drug-drug interactions with protease inhibitors?
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Drug CYP P-glycoprotein Non-CYP metabolism
Telaprevir CYP 3A4• Substrate• Inhibitor
• Substrate• Inhibitor
Boceprevir CYP 3A4/5• Substrate• Inhibitor
• Substrate • Substrate (aldo-keto reductase 1C2/1C3)
Pharmacologic characteristics of TVR and BOC
Magnitude of drug interaction cannot be predicted and must be studied
Hezode C. Liver International 2012
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How will drug-drug interaction management change with approval of TVR and BOC?
• Potential for increased PK interactions between HCV PIs and other medications
• TPV and BOC may be primarily metabolised by CYP3A• Suggests many interactions with HIV PIs and NNRTIs, other
CYP3A inducers/inhibitors• Concomitant drugs may reduce or potentially enhance
efficacy of PIs• Potential for overlapping toxicities• Other agents associated with anemia, rash, etc.• Toxicity of the concomitant drugsSeden K, et al. J Antimicrob Chemother 2010;65:1079-1085.
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Drug interactions – Conclusions
• Consider all drugs as having potential for interactions with PIs
• Mechanism of concomitant drug metabolism needs to be understood
• Utilise pharmacists and Web-based help
• Remember dose adjustments both on and after cessation of therapy of concomitant medications
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