Transcript Protease inhibitors in chronic hepatitis C

Protease Inhibitors in Chronic Hepatitis C:
An Update
Chapter 3 – Side Effects of Antiviral Therapy for Hepatitis C
Edited by
Morris Sherman MD BCh PhD FRCP(C)
Associate Professor of Medicine
University of Toronto
November 2012
Side Effects of Antiviral Therapy
for Hepatitis C
Dr. Mark Levstik, FRCP(C)
Associate Professor Medicine
Division of Gastroenterology
Multiorgan 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
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%
7%
29%
Anorectal
Peg Interferon/ Telaprevir/
RBV
P/R
Dysgeusia and anemia increased with boceprevir;
Rash, anorectal irritation and anemia increased with telaprevir.
Incivek Product Monograph, June 2012
Victrelis Product Monograph, August 2012
Safety of Protease Inhibitors in Real Life:
CUPIC Study
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 excluded
 Treated in the French early access program
(From February 2011)
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Treatment Regimen
Interim analysis
Peg-IFN
+ RBV
BOC + Peg-IFN α-2b + RBV
Follow-up
BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d
TVR + Peg-IFN α-2a
+ RBV
Peg-IFN α-2a + RBV
Follow-up
TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000- 1200 mg/d
0
4
8
12
16
36
Weeks
48
72
SVR assessment
Hezode C et al. EASL 2012, Abstract 8
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
3
8
 Null responders
Hezode C et al. EASL 2012, Abstract 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 discontinuation
Due to SAEs (%)
23.9
7.4
26.0
14.5
Death (%)
1.3
2.0
Infection (Grade 3/4) (%)
2.5
8.8
0
0
6.8
0.7
Pruritus (Grade 3/4) (%)
0.6
3.7
Hepatic decompensation (%)
4.4
4.4
Rash
Grade 3 (%)
Grade 4 (SCAR) (%)
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Preliminary Safety Findings
(16-Week Interim Analysis)
Patients, n
(% patients with ≥ 1 event)
Anemia (%)
Grade 2 (8.0 – <10.0 g/dL)
Grade 3/4 (<8,0 g/dL)
EPO use
Blood transfusion
Neutropenia (%)
Grade 3 (500 – <1000/mm3)
Grade 4 (<500/mm3)
G-CSF use
Thrombopenia (%)
Grade 3 (25 000 – <50 000)
Grade 4 (<25 000)
Thrombopoïetin use
Boceprevir
(n=159)
Telaprevir
(n=296)
22.6
10.1
66.0
10.7
19.6
10.1
56.8
15.2
4.4
0.6
3.8
4.0
0.7
2.4
6.3
0.6
1.9
11.8
1.3
1.7
Hezode C et al. EASL 2012, Abstract 8
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
Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline
687 patients treated with boceprevir RGT
After completion of 4 week PEG-IFN/RBV lead-in,
all patients initiated boceprevir
Hemoglobin ≤100 g/L
Randomisation
Erythropoietin (40,000 IU/wk SC)
n = 251
EPO: erythropoietin
PEG-IFN: peginterferon
RBV: ribavirin
Ribavirin dose reduction (DR)
n = 249
Hemoglobin ≤ 85 g/L: Secondary Strategy
(EPO, RBV DR, transfusion)
Poordad et al. EASL 2012, Abstract 1419
Results – Primary and Key Efficacy End Points
End-of-treatment response, relapse, and SVR were comparable
between RBV DR and EPO arms
 (95% CI)
100
82
82
RBV DR
71
75
Patients (%)
-0.7% (-8.6, 7.2)*
71
EPO
50
25
203/249
205/251
178/249
178/251
10
10
19/196
19/197
0
EOT Response
SVR
Relapse
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
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
Boceprevir
Telaprevir
RBV dose reduction
Up to 3 x 200 mg increments*
Reduce RBV to
600 mg/day
Hb < 85 g/L
Hb > 85 g/L
EPO: 40-60,000 IU/wk
AND/OR
Transfusion
Maintain RBV
dose 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
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, 2012
Hézode C. Liver International. 2012; 32 Suppl 1:32-8
Cacoub 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
Incivek Product Monograph, 2012
Hézode C. Liver International. 2012; 32 Suppl 1:32-8
Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63
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
Incivek Product Monograph, 2012
Hézode C. Liver International. 2012; 32 Suppl 1:32-8
Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63
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
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.
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.