managing side effects of medications for hcv

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Managing Side Effects of Medications for HCV

Nursing InserviceRajwant Minhas, FH Resident

HIV/AIDS RotationMay 2012

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Objectives• Be aware of common side effects of:

– Peginterferon alfa (PegIFN)– Ribavirin (RBV)– Boceprevir (BOC)– Telaprevir (TVR)

• Name 3 most common side effects more frequent in triple therapy arm vs. Standard of care (SOC)

• Understand how to manage common side effects of HCV therapy

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Hepatitis C Overview

• A chronic liver disease caused by the hepatitis C virus (HCV)

• Most common cause of chronic liver disease and cirrhosis

• Canada: ~242,500 individuals are infected – ~ 21% unaware of infection & remain undiagnosed

• Many are asymptomaticPublic Health Agency of Canada: Hepatitis CAvailable from: http://www.phac-aspc.gc.ca/hepc/index-eng.php

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Signs and Symptoms• Most people are asymptomatic until the virus causes liver damage, which can

take 10 or more years to happen

• Others have one or more of the following symptoms:– Jaundice– Longer time to control bleeding, easy bruising– Ascites, ankle edema– Fever– Nutritional: loss of appetite, blood-sugar disorders– GI: indigestion, diarrhea, nausea, abdominal discomfort– GU: light-colored stools, dark yellow urine– Skin: itchiness– Aches: flu-like illness, joint pain, muscle aches, general weakness, fatigue

NDDIC. Available from: http://digestive.niddk.nih.gov/ddiseases/pubs/hepc_ez/

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HCV Overview• Single stranded

RNA Virus• Replicates in

cytoplasm of hepatocytes

• 6 known genotypes

Available from: http://www.med-ars.it/galleries/virus_4.htm

Protective protein shell Fatty envelope

2 viral envelope glycoproteins: E1&E2

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Natural History of HCV Infection

Chen SL, Int.J.Med.Sci.2006,3

If the virus can still be detected in the body 6 months after becoming infected

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Natural History of HCV Infection

• HCV can cause acute and chronic hepatitis

• Acute process: Self-limited– Rarely causes hepatic failure,

usually leads to chronic infection• Chronic HCV infection: Often follows a

progressive course over many years– Can ultimately result in:

• Cirrhosis• Hepatocellular carcinoma (HCC)• Need for liver transplantation

Chen SL, Int.J.Med.Sci.2006,3

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Risk Factors for HCV Infection• Blood transfusion before 1992• IV drug use• High risk sexual activity• Solid organ transplantation from

an infected donor• Occupational exposure• Hemodialysis• Household exposure• Birth to an infected mother• Intranasal cocaine use

Chen SL, Int.J.Med.Sci.2006,3

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Risk Factors for Developing Chronic HCV Infection

• Age at time of infection > 25 years• Male gender• No jaundice or symptoms during acute

infection• African American race• HIV infection• Immunosuppression

Chen SL, Int.J.Med.Sci.2006,3

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Risk Factors for Advanced Progression of Liver Fibrosis

• Alcohol consumption • Age at time of infection > 40 years• Male gender• Degree of inflammation and fibrosis on liver

biopsy• Coinfection with HIV or HBV• Comorbid disease

Chen SL, Int.J.Med.Sci.2006,3

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Monitoring of On-therapy Response to PegIFN + RBV

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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Goals of Therapy• Eradicate HCV infection

• Endpoint of therapy: Sustained virological response (SVR)

• Once obtained, SVR usually = cure of infection in >99% of patients

• Patients without cirrhosis: SVR is generally associated with resolution of disease

• Patients with cirrhosis: Remain at risk of life-threatening complications– particularly, HCC may occur even after eradication of viral infection

Ghany et al. AASLD Practice Guidelines. Hepatology 54, No.4, 2011

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HCV Treatment• Not treated unless it becomes chronic

• Drugs slow or stop the virus from damaging the liver

• Peginterferon: Weekly shots • Ribavirin: PO daily

• Treatment lasts from 24 to 48 weeks– 48 wks (HCV genotypes 1,4,5 and 6)– 24 wks (HCV genotypes 2 and 3)

Ghany et al. AASLD Practice Guidelines. Hepatology 54, No.4, 2011

Has been the standard of care (SOC)

2 major advances: Development of direct-acting antiviral agents (DAA)

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Protease Inhibitors

• Boceprevir (BOC)• Telaprevir (TVR)

– HCV nonstructural protein 3/4A (NS3/4A) serine protease inhibitors

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Peginterferon• 2 pegylated IFN-a molecules:

– Pegylated IFN-alfa2a and pegylated IFN-alfa2b– Different pharmacokinetics – Difference in efficacy is still debated

• Pegasys: PegIFN alfa-2a• Pegeteron: RBV 200 mg capsules + PegIFN alfa-2b powder for

Solution• Victrelis Triple: BOC 200 mg capsules + RBV 200 mg capsules +

PegIFN alfa-2b powder

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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Peginterferon Alfa Side EffectsHeadache, fatigue, depression, insomnia, dizziness

N, V, anorexia, diarrhea

Hair loss

Injection site reaction

Small meals helpAnemia,

neutropenia, thrombocytopenia

Flu like signsBlurry vision, change in thinking clearly

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264Victrelis triple product monograph. Merck 2011

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How to Manage Side Effects?

Side Effect How to manage

Flu like symptoms AcetaminophenAttenuate after 4–6 weeks of therapy

Neutropenia, anemia, thrombocytopenia, ↑ in ALT

Assess at weeks 1, 2, and 4 of therapy, and at 4–8 week intervals thereafterStop if ALT levels >10 UNL or if severe bacterial infection occurs regardless of neutrophil counts

Dizziness, cough, SOB Elevate head of bed if a problem during the nightExercise as tolerated

TSH and free thyroxine Measure every 12 wks while on therapy

Depression Do not isolate yourself, antidepressants

Skin reactions Good skin care practices, antihistamines

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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When to Reduce or Stop PegIFN?When to reduce? When to stop?

•Clinical symptoms of severe depression •If the ANC falls <0.75X109/L •Platelet count falls < 50X109/L

•In case of marked depression•If the neutrophil count falls < 0.5X109/L•Platelet count falls < 25X109/L

Reducing the dose:

When using pegylated IFN-a2a:Dose can be ↓ from 180 to 135 mcg/week and then to 90 mcg/week.

When using pegylated IFN-a2b:Dose can be ↓ from 1.5 to 1.0 mcg/kg/week and then to 0.5 mcg/

kg/week.

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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Ribavirin (RBV)• Synthetic nucleoside analogue

• Recommended dose: 800-1400 mg daily based upon patient weight divided in 2 doses with food (Victrelis Triple monograph)

• Dose depends on product used

• Risk of teratogenicity contraception required for 6 months beyond treatment

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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Boceprevir (BOC)• Indication is specifically for adults with CHC genotype 1 with:

– Compensated liver disease including cirrhosis– Previously untreated – Who have failed previous IFN and RBV therapy

• Regimen: 4-week lead-in PegIFN/RBV, then add boceprevir 800 mg PO TID (ie q7-9hr) with food

• Duration of treatment: Depends on HCV-RNA levels at treatment wks 8, 12 and 24

Ghany et al. AASLD Practice Guidelines. Hepatology 54, No.4, 2011

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Boceprevir (VICTRELIS) Side EffectsAnemia and neutropenia

Dysgeusia, dry mouth

Anemia (<100g/L): 49% in BOC group vs. 29% SOC<85 g/L: 9%

Headache, dizziness

Fatigue, chills

Insomnia

Irritability

Alopecia

N, V, D, ↓ in appetite

Thrombocytopenia

Boceprevir capsules [package insert]. Merck & Co., Inc.; 2011.

Underlined: most common in triple therapy

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How to Manage Side Effects?Side effect How to manage

Decreased appetite, nausea, weight loss, dysgeusia, dry mouth, abdominal pain, diarrhea

Small meals more frequently, do not fast, avoid foods that increase nausea, take dimenhydrinate (50-100 mg q 4 hours, max: 400 mg per 24 hrs)

Alopecia Temporary, monitor thyroid

Aches Acetaminophen 325 mg q 4-6 hrs if necessary (max: 1-2 g/day)Ibuprofen 400 mg q 6 hours (max: 1.2 g/day)

Itchy skin Oatmeal bath products and lotionAvoid long hot baths/showersAdequate fluid intake: 8-10 glasses water/day

Irritability Let others know how you feel, do not isolate yourselfRecognize what situations intensify these feelings

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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Management of Anemia• CBC pretreatment, q 2 wks until tx week 8, then monthly

• Primary strategy: RBV dose reductions

• Hgb <100 g/L: ↓ in dosage or interruption of RBV is recommended

• Hgb <85 g/L: discontinue all therapy

• If RBV is permanently dced, BOC or TVR also must be D/C

• Do not reduce PI dose to manage anemia

• Once RBV dose reduction has been tried, erythropoietin can be considered

• TVR: RBV dose reductions; if inadequate consider d/c TVR

Nelson, D et al. HCV Clinical Management

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Management of Anemia/Neutropenia

• Use of growth factors helpful in limiting treatment dose reductions

• Recombinant erythropoietin: To maintain or ↑ Hgb levels (to avoid RBV dose reductions or interruptions)

• No clear evidence indicating that neutropenia during pegylated IFN-a and RBV therapy, a common event in cirrhotic patients, has an adverse effect

• No evidence that G-CSF ↓ the rate of infections and/or ↑ SVR rates

EASL Clinical Practice Guidelines. J. of Hepatology vol. 55, 245-264

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RBV Dose ReductionStarting dose (mg)

Dose after 1st dose reduction

Dose after 2nd reduction, if required

Previously untreated patients

800 600 4001000 800 6001200 1000 8001400 1000 800

Previous treatment failure

800 600 4001000 800 6001200 800 6001400 1000 800

Victrelis product monograph. Merck 2011

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VICTRELIS TRIPLE• Boceprevir PO 200 mg capsule• Ribavirin PO 200 mg capsule• Peginterferon alfa-2b SC• Powder for solution in REDIPEN single dose delivery system

– 80 mcg/0.5 mL– 100 mcg/0.5 mL– 120 mcg/0.5 mL– 150 mcg/0.5 mL

• Indicated for treatment of CHC genotype 1 infection in >18 years with:– Compensated liver disease including cirrhosis who are previously

untreated or who have failed previous therapy

Victrelis product monograph. Merck 2011

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Pharmacare CoverageSpecial Authority for BOC

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Telaprevir (TVR)• Recommended dose:

750 mg with food (not low-fat) TID (q 7-9 hrs) + PegIFN alfa + weight-based RBV

• Duration: 12 weeks followed by an additional 12-36 weeks of PegIFN alfa and RBV

Ghany et al. AASLD Practice Guidelines. Hepatology 54, No.4, 2011

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Telaprevir (TVR)

• Due to high rates of early viral suppressionand

• Low rates of relapse after therapy cessation–Therapy could be shortened to 24 weeks in patients who have a rapid virologic response (RVR)

Ghany et al. AASLD Practice Guidelines. Hepatology 54, No.4, 2011

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Telaprevir Side Effects

Rash

Anemia

Pruritus

Taste changes

N, V, D

T12PR:Hgb <100 g/L: 36% vs. 14% SOC groupHgb <85 g/L: 9%

Telaprevir tablets [package insert] Vertex Pharmaceuticals Incorporated; 2011.

Anal or rectal problems: hemorrhoids, discomfort, itching or burning around or near the anus

Fatigue

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TVR: Rash ManagementType of rash Description

Mild Localized rash and/or a rash with limited distribution, with or without pruritus

Moderate Diffuse rash, with or without superficial skin peeling, or mucous membrane involvement, with no ulceration

Severe Generalized rash with or without pruritus OR rash with vesicles, bullae, or ulcerations

Serious skin infections

Stevens-Johnson syndrome (SJS) or drug rash with eosinophilia and systemic symptoms (DRESS)

Nelson, D et al. HCV Clinical Management

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TVR: Rash Management Rash Description Management

Mild to moderate rashes •Continue all drugs•Monitor for rash progression or development of systemic symptoms•TVR dose should not be reduced or interrupted•Oral antihistamines and/or topical corticosteroids •Good skin care practices

Severe rash Discontinue TVRContinue PEG-IFN/RBVIf no improvement within 7 days (or earlier if indicated), consider D/C of PEG-IFN and/or RBVGood skin care practicesOral antihistamines and/or topical corticosteroids TVR dose should not be reduced or interruptedConsider dermatology consult

Serious skin reactions(SJS or DRESS)

Discontinue all medications immediatelyUrgent medical care

Nelson, D et al. HCV Clinical Management

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THANK YOU!Questions?