edited by morris sherman md bch phd frcp(c) associate professor of medicine
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Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto. Protease Inhibitors in Chronic Hepatitis C: An Update Chapter 3 – Side Effects of Antiviral Therapy for Hepatitis C. November 2012. Side Effects of Antiviral Therapy for Hepatitis C. - PowerPoint PPT PresentationTRANSCRIPT
Edited byMorris Sherman MD BCh PhD FRCP(C)
Associate Professor of MedicineUniversity of Toronto
Protease Inhibitors in Chronic Hepatitis C:An Update
Chapter 3 – Side Effects of Antiviral Therapy for Hepatitis C
November 2012
Side Effects of Antiviral Therapy for Hepatitis C
Dr. Mark Levstik, FRCP(C)Associate Professor MedicineDivision of GastroenterologyMultiorgan 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
Peg Interferon/RBV
Telaprevir/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%
Anorectal 7% 29%
Dysgeusia and anemia increased with boceprevir;Rash, anorectal irritation and anemia increased with telaprevir.
Victrelis Product Monograph, August 2012Incivek Product Monograph, June 2012
Patients HCV genotype 1 infection Compensated cirrhosis (Child Pugh A) Treatment-experienced
RelapsersPartial responders ( >2 log10 HCV RNA decline
at Week 12 but never negative)Null responders theoretically excludedTreated in the French early access program
(From February 2011)
Safety of Protease Inhibitors in Real Life: CUPIC Study
Hezode C et al. EASL 2012, Abstract 8
Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBV Follow-up
CUPIC: Treatment Regimen
484 160 128Weeks
72
SVR assessment
Follow-upPeg-IFN + RBV
36
Interim analysis
Hezode C et al. EASL 2012, Abstract 8
BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d
BOC + Peg-IFN α-2b + RBV
TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000- 1200 mg/d
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 Null responders 3 8
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 discontinuationDue to SAEs (%)
23.97.4
26.014.5
Death (%) 1.3 2.0
Infection (Grade 3/4) (%) 2.5 8.8
Rash Grade 3 (%) Grade 4 (SCAR) (%)
00
6.80.7
Pruritus (Grade 3/4) (%) 0.6 3.7
Hepatic decompensation (%) 4.4 4.4
Hezode C et al. EASL 2012, Abstract 8
Patients, n(% patients with ≥ 1 event)
Boceprevir (n=159)
Telaprevir (n=296)
Anemia (%) Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8,0 g/dL) EPO use Blood transfusion
22.610.166.010.7
19.610.156.815.2
Neutropenia (%) Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use
4.40.63.8
4.00.72.4
Thrombopenia (%) Grade 3 (25 000 – <50 000) Grade 4 (<25 000) Thrombopoïetin use
6.30.61.9
11.8 1.3 1.7
Hezode C et al. EASL 2012, Abstract 8
CUPIC: Preliminary Safety Findings (16-Week Interim Analysis)
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
After completion of 4 week PEG-IFN/RBV lead-in, all patients initiated boceprevir
Hemoglobin ≤100 g/L
Ribavirin dose reduction (DR)n = 249
Erythropoietin (40,000 IU/wk SC)n = 251
Hemoglobin ≤ 85 g/L: Secondary Strategy (EPO, RBV DR, transfusion)EPO: erythropoietin
PEG-IFN: peginterferonRBV: ribavirin
Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline
687 patients treated with boceprevir RGT
Poordad et al. EASL 2012, Abstract 1419
Randomisation
Results – Primary and Key Efficacy End PointsP
atie
nts
(%)
(95% CI)-0.7% (-8.6, 7.2)*
End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms
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
82
71
10
82
71
10
0
25
50
75
100
EOT Response SVR Relapse
RBV DR
EPO
205/251203/249 19/196 19/197178/249 178/251
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 reductionUp to 3 x 200 mg increments*
Reduce RBV to 600 mg/day
Hb > 85 g/L
Maintain RBVdose 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
Hb < 85 g/L
EPO: 40-60,000 IU/wk AND/OR
Transfusion
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, 2012Hézode C. Liver International. 2012; 32 Suppl 1:32-8Cacoub 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, 2012Hézode C. Liver International. 2012; 32 Suppl 1:32-8Cacoub 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, 2012Hézode C. Liver International. 2012; 32 Suppl 1:32-8Cacoub 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 (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.
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.