Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine

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.