edited by morris sherman md bch phd frcp c associate professor of medicine university of toronto n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine PowerPoint Presentation
Download Presentation
Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine

Loading in 2 Seconds...

play fullscreen
1 / 29

Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine - PowerPoint PPT Presentation


  • 128 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine' - valora


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
edited by morris sherman md bch phd frcp c associate professor of medicine university of toronto
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

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
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
Side Effect Comparison of Phase III studies

Dysgeusia and anemia increased with boceprevir;

Rash, anorectal irritation and anemia increased with telaprevir.

Incivek Product Monograph, June 2012

Victrelis Product Monograph, August 2012

slide5

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
CUPIC: Treatment Regimen

Interim analysis

TVR + Peg-IFN α-2a + RBV

Peg-IFN α-2a + RBV

Follow-up

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 : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000- 1200 mg/d

72

36

4

0

12

16

48

8

Weeks

SVR assessment

Hezode C et al. EASL 2012, Abstract 8

cupic patients characteristics
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

slide8

CUPIC: Preliminary Safety Findings

(16-Week Interim Analysis)

Hezode C et al. EASL 2012, Abstract 8

slide9

CUPIC: Preliminary Safety Findings

(16-Week Interim Analysis)

Hezode C et al. EASL 2012, Abstract 8

take home message from cupic
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
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
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

mechanism of rbv associated anemia
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
Ribavirin Dose Reduction vs. EPO ?

Sulkowski MS et al. J Hepatol 2011; 54:S194-5.

Reddy KR et al. Clin Gastroenterol Hepatol 2007; 5:124-9

  • 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.
boceprevir anemia management erythropoietin vs ribavirin dose reduction study
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

Ribavirin dose reduction (DR)

n = 249

Hemoglobin ≤ 85 g/L: Secondary Strategy (EPO, RBV DR, transfusion)

EPO: erythropoietin

PEG-IFN: peginterferon

RBV: ribavirin

Poordad et al. EASL 2012, Abstract 1419

results primary and key efficacy end points
Results – Primary and Key Efficacy End Points

100

 (95% CI)

-0.7% (-8.6, 7.2)*

82

82

RBV DR

71

71

75

EPO

50

Patients (%)

25

10

10

203/249

205/251

178/251

19/197

19/196

178/249

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.

End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms

Poordad et al. EASL 2012, Abstract 1419

summary anemia management
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
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

slide21
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
Rash Management Recommendations

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

    • 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
telaprevir severe rash 1
Telaprevir Severe Rash < 1%

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

  • 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
gastroenterological side effects
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
Gastroenterological Side Effects: Telaprevir

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

  • 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
management of depression
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
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
slide29

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.