Treatment of Hepatitis C

3/2/2016 Pharmacists Objectives • Describe the route of transmission and provide recommendations to prevent the transmission of hepatitis C (HCV) Tr...
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3/2/2016

Pharmacists Objectives • Describe the route of transmission and provide recommendations to prevent the transmission of hepatitis C (HCV)

Treatment of Hepatitis C

• Identify high risk patients who would benefit from screening and how to interpret diagnostic testing

Jay Hazelcorn, Pharm.D. PGY-1 Pharmacy Resident Broward Health Medical Center

• Develop a guideline-based treatment approach that includes a monitoring plan for adherence, drug interactions, adverse effects, and sustained virologic response

www.fshp.org 3

Disclosure

Technicians Objectives • Recognize the different classes of direct-acting antiviral medications for the treatment of hepatitis C

• I have no financial nor non financial relationships to disclose regarding the content of this presentation

• Recall specific drug-drug interactions and common side effects • Summarize risk factors that could lead to contracting and the spread of hepatitis C

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Resources

Hepatitis

• American Association For the Study of Liver Diseases (AASLD) / Infectious Diseases Society of America (IDSA)

• Hêpar: Greek meaning “liver” • -itis: Greek suffix meaning “inflammation”

– http://hcvguidelines.org/full-report-view – Last updated February 24th 2016

Viral Hepatitis

• CDC Viral Hepatitis

• • • • •

– http://www.cdc.gov/hepatitis/

• Package inserts • Drug interaction database

Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E

– http://hep-druginteractions.org/ http://healer24.com/wp-content/uploads/2015/07/cause_liver_cancer.jpg

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Functions of the Liver

Prevalence

• Many different functions • Filters blood

• The CDC estimates that 2.7 million people are infected with hepatitis C (HCV) in the United States – National Health and Nutrition Examination Survey

– Waste products from cells – Medications & alcohol

• Major limitation does not include homeless and incarcerated

• Production of bile

• Estimation including homeless and incarcerated

– Helps digest fats

– 4.6 million to 4.9 million people in the United States

• Metabolism – Carbohydrates – Fats/Cholesterol – Proteins/Clotting factors

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http://www.humanillnesses.com/photos/cirrhosis-of-the-liver2418.jpg

6 “Viral Hepatitis The Liver” Centers for Disease Control and Prevention., 2016. Web. 21 Feb. 2016

Edlin, Brian R., et al. "Toward a more accurate estimate of the prevalence of hepatitis C in the United States." Hepatology 62.5 (2015): 1353-1363.

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Frequently Asked Transmission Questions

High Risk of HCV and Testing • Born between 1945 - 1965 • Injection drug use (History)

• Chronic hemodialysis patients

• Intranasal illicit drug use

• Known exposures to HCV

• Receiving a tattoo in unregulated settings

• What are ways HCV is NOT spread? – Sharing eating utensils, breastfeeding, hugging, kissing, coughing, sneezing, food, and water

– Needlesticks

• How should blood be cleaned to ensure virus is gone?

– Recipients of blood or organs

• Receiving clotting factor concentrates before 1987

• Human immunodeficiency virus (HIV) infection

• Received blood or solid organ transplant before 1992

• Children born to HCVpositive mothers (~ 6%)

– Virus can live on surfaces for up to 3 weeks – Clean using 1 part household bleach to 10 parts water • ¼ cup bleach with 2 ¼ cup water

• Can I donate blood, or organs if cured from HCV?

• Incarceration

– No; Not if you have ever tested positive for HCV

American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating9 hepatitis C." (2015)

"Hepatitis C FAQs for the Public." Centers for Disease Control and Prevention., 2016. Web. 21 Feb. 2016.

Frequently Asked Transmission Questions

Progression of HCV

• How is HCV spread?

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– Percutaneous/permucosal (Blood to blood contact) – Less common sharing of personal care items

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Patients infected with HCV

75-85 Develop chronic infection

• Razors or toothbrushes

• Can HCV be transmitted through sex?

60-70 Develop chronic liver disease

– Yes; however risk is very low with heterosexual sex • Barrier protection may not be necessary in monogamous partners

5-20 Develop cirrhosis

– Risk  in individuals with: HIV, STD, rough sex, and MSM • Barrier protection is recommended

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Die of cirrhosis or liver cancer

STD= sexually transmitted diseases MSM= men who have sex with men "Hepatitis C FAQs for the Public." Centers for Disease Control and Prevention., 2016. Web. 21 Feb. 2016.

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"Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016.

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HCV Genome

Clinical Presentation • Most patients will be asymptomatic • 20-30% of people develop symptoms of acute illness – 4-12 weeks from exposure Symptoms

Direct-Acting Antiviral Drugs

Fever

Fatigue

Dark urine

Abdominal pain

Loss of appetite

Clay-colored stool

Nausea & Vomiting

Joint pain

Jaundice

Drug Class

NS3/4A Inhibitors

NS5A Inhibitors

NS5B Inhibitors

Drug

Grazoprevir Paritaprevir Simeprevir

Daclatasvir Elbasvir Ledipasvir Ombitasvir

Sofosbuvir Dasabuvir

Mechanism of Action

Protease inhibitor

Replication complex inhibitor

Polymerase inhibitor

Suffix

-previr

-asvir

-buvir

• Chronic HCV – Asymptomatic until decompensated – Screened for blood or elevated liver enzymes "Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016.

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NS= non-structural protein

15 Feeney, Eoin R., and Raymond T. Chung. "Antiviral treatment of hepatitis C." (2014): g3308.

Life Cycle of HCV

Genotypes • 6 different genotypes with 50 subtypes – Genotype 1 highest prevalence in the United States • Historically the most difficult to treat

• Genotyping will determine treatment and duration • Once identified it does not need to be tested again – Will not change during course of infection

14 Feeney, Eoin R., and Raymond T. Chung. "Antiviral treatment of hepatitis C." (2014): g3308.

"Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016.

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Management of Acute HCV

CDC Testing Sequence to Identify HCV

• Monitor HCV RNA every 4-8 weeks for 6 -12 months – To assess for spontaneous clearance

• Avoid hepatotoxic insults (i.e. acetaminophen) and alcohol consumption • Council on taking precautions to reduce the risk of HCV transmission to others • Addiction specialists if related to IVDU • Treatment is the same as for chronic infection IVDU= intravenous drug use Source: CDC. Testing for HCV infection: An update of guidance for clinicians and laboratorians. MMWR 2013;62(18).

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American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating 19 hepatitis C." (2015)

Diagnostic Testing Test Outcome

Interpretation

Further Actions

Positive HCV Antibody

Test for HCV RNA to Presumed HCV infection confirm diagnosis

Negative HCV Antibody

No HCV infection

No further action required*

Positive HCV Antibody HCV RNA Detected

Current HCV infection

Link patient to care

No current HCV infection

Prior exposure and cleared virus. Can be naturally or from treatment

Positive HCV Antibody HCV RNA Undetectable

Goal of Treatment • Reduce all-cause mortality and adverse consequences • Prevent clinical progression • End stage liver disease • Hepatocellular carcinoma

• How? – Sustained virologic response

*If exposed within in the last 6 months or immunocompromised test for HCV RNA RNA= Ribonucleic acid Source: CDC. Testing for HCV infection: An update of guidance for clinicians and laboratorians. MMWR 2013;62(18)

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American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating hepatitis C." (2015)

http://cdn.hepwebstudy.org/doc/34-1/natural-historyfollowing-initial-infection-hcv.jpg

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Sustained Virologic Response (SVR)

When and Whom to Treat • All patients with chronic HCV

• SVR

– Earlier the better to prevent disease progression

– A marker for cure – Defined as undetectable HCV RNA in the patient's blood

• SVR24

• Except those with a short life expectancy

– Undetectable HCV RNA 24 weeks after completion of treatment

• SVR12 – Undetectable HCV RNA 12 weeks after completion of treatment

– Treatment of HCV with medications or by transplantation would not extend the patients life – Patients should receive expert consultation

• 99 % of SVR12 patients remained undetectable at 5 yrs – SVR12 used to determine “virologic cure” American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. (2015) "Hepatitis C FAQs for Health Professionals." Centers for Disease Control and Prevention, 2016. Web. 21 Feb. 2016.

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When and Whom to Treat Previously was stratified into priorities High priority groups

To Prevent Transmission

• • • •

• • • • •

Advanced fibrosis Liver transplant recipients Extrahepatic manifestations HIV or HBV co-infection

Intravenous drug use High risk sexual practices Incarcerated people Hemodialysis patients Women who wish to become pregnant

American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating 23 hepatitis C." (2015)

Treatment Options FDA-Approved Medications Daclatasvir (Daklinza®)

Simeprevir (Olysio®)

Elbasvir-Grazoprevir (Zepatier®)

Sofosbuvir (Sovaldi®)

Ledipasvir-Sofosbuvir (Harvoni®)

Peginterferon alfa-2a (Pegasys®)

Ombitasvir-Paritaprevir-Ritonavir (Technivie®)

Peginterferon alfa-2b (PegIntron®)

Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®)

Ribavirin (Copegus®, Rebetol®, Ribasphere®)

Discontinued Medications Boceprevir (Victrelis®)

Telaprevir (Incivek®)

HBV= hepatitis B virus

22 American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Recommendations for testing, managing, and treating hepatitis C." (2015)

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Daclatasvir (Daklinza®)

Elbasvir-Grazoprevir (Zepatier®) • Combination of a NS5A and NS3/4A inhibitor

• Non-structural viral protein 5A (NS5A) inhibitor



─ Replication complex inhibitor

• Indication and Usage – Genotype 1 and 3 – HCV/HIV co-infection – Always dosed with sofosbuvir – With and without cirrhosis ± ribavirin – Post-transplant with ribavirin

Replication complex inhibitor & Protease inhibitor

• Indication and Usage

• Duration

– Genotype 1 and 4 – HCV/HIV co-infection – Resistance testing

– 12 week treatment

• Preparations – 60 mg and 30 mg tablets

• Genotype 1a SVR12 ↓ from 98% to 70% • Add ribavirin ↑ SVR12 to 100%

• Duration – 12-16 week treatment

• Preparations – Co-formulated tablet – 50 mg of elbasvir – 100 mg of grazoprevir

– With and without cirrhosis ± ribavirin 25

Daclatasvir (Daklinza®) package insert. Bristol-Myers Squibb Company, Princeton, NJ 08543, USA

27 Elbasvir-Grazoprevir (Zepatier®) package insert. Merck & CO., INC., Whitehouse Station, NJ 08889, USA

Elbasvir-Grazoprevir (Zepatier®)

Daclatasvir (Daklinza®)

• Dosing: 1 tablet (50 mg/100 mg) by mouth once daily • Contraindications:

• Dosing: 60 mg tablet daily with sofosbuvir • Dose Modifications:

– Child Pugh B or C; ↑ drug levels and risk of ↑ liver enzymes – Organic anion transporting polypeptides (OATP1B1/3) inhibitors – Cytochrome P450 3A (CYP3A) inducers and efavirenz

– Strong CYP3A inhibitors ↑ drug levels • Reduce dose to 30 mg once daily

– Moderate CYP3A inducers and nevirapine ↓ drug levels • Increase dose to 90 mg once daily • Strong inducers are contraindicated

– No renal adjustments

CYP3A inducers

OATP1B1/3 inhibitors

Phenytoin Carbamazepine St. John’s Wort

Rifampin HIV protease inhibitors Cyclosporine

Please refer to package insert for complete list

• Highly protein bound, unlikely removed by dialysis

• Adverse effects

• Common adverse effects

– FaVgue, headache, nausea, ↑ alanine aminotransferase > 5x normal (1%)

– Headache, fatigue, nausea, and diarrhea Daclatasvir (Daklinza®) package insert. Bristol-Myers Squibb Company, Princeton, NJ 08543, USA

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Elbasvir-Grazoprevir (Zepatier®) package insert. Merck & CO., INC., Whitehouse Station, NJ 08889, USA

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Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®)

Ledipasvir-Sofosbuvir (Harvoni®) •

• Combination of a NS5B and NS5A inhibitor ─

• Indication and Usage

• Indication

• Duration

– – – –

– Genotype 1, 4, 5 or 6 – 12-24 week treatment – HCV/HIV co-infection • Preparations – With and without cirrhosis – Co-formulated tablet ± ribavirin – 90 mg of ledipasvir – Post-transplant with – 400 mg of sofosbuvir ribavirin

Ledipasvir-Sofosbuvir (Harvoni®) package insert. Gilead Sciences, Inc. Foster City, CA 94404

• Duration

Genotype 1 HCV/HIV co-infection Post-transplant with ribavirin With and without cirrhosis ± ribavirin

– 12-24 week treatment

• Preparations – Ombitasvir-ParitaprevirRitonavir (fixed dose 12.5/75/50 mg) – Dasabuvir 250 mg

• Dose – 2 tablets of OmbitasvirParitaprevir-Ritonavir daily – 1 tablet of dasabuvir twice a day – Given with food 29

Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®) package insert. AbbVie Inc., North Chicago, IL 60064

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Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®)

Ledipasvir-Sofosbuvir (Harvoni®) • Dosing: 1 tablet (90 mg/400 mg) by mouth once daily • Drug interactions

• Lots of drug interactions

– Acid-reducing agents can ↓ ledipasvir concentraVons • Antacids, H2 antagonists, PPI (refer to package insert)

– Amiodarone • Symptomatic bardycardia (avoid co-administration)

– Pgp inducers can ↓ ledipasvir-sofosbuvir concentrations • St. John’s Wort, rifampin, carbamazepine, etc. (avoid co-administration)

– Tenofovir disoproxil fumarate (can ↑ tenofovir levels)

Drug Interactions – AVOID

Drug Interactions- MONITOR

Anticonvulsants Statins – Lovastatin and Simvastatin PDE5 inhibitors Antiretrovirals Oral contraceptives Gemfibrozil Herbal products

Antiarrhythmics Statins – Rosuvastatin and Pravastatin Immunosuppressants Amlodipine Omeprazole Furosemide Alprazolam

Please refer to package insert for complete list

• Monitor renal function

• Adverse effects

• Adverse effects

─ Fatigue, nausea, pruritus, insomnia

– Fatigue, headache, and nausea Ledipasvir-Sofosbuvir (Harvoni®) package insert. Gilead Sciences, Inc. Foster City, CA 94404

NS5A, NS3/4A, and NS5B inhibitor with booster ─ Replication complex, protease, and polymerase inhibitor

Polymerase inhibitor & Replication complex inhibitor

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Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®) package insert. AbbVie Inc., North Chicago, IL 60064

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Ombitasvir-Paritaprevir-Ritonavir (Technivie®)

Sofosbuvir (Sovaldi®)

• NS5A, and NS3/4A inhibitor with booster

• NS5B inhibitor

─ Replication complex and protease inhibitor

• Indication and Usage – Genotype 4 without cirrhosis – Given with ribavirin

• Dose – 2 tablets daily with food

─ Polymerase inhibitor

• Duration

• Indication and Usage

– 12 week treatment

– Combination therapy ONLY – Genotype 1 and 4

• Preparations

– 12 to 24 week treatment

• Preparations – Sofosbuvir 400 mg tablet

• Given with peginterferon + ribavirin

– Ombitasvir-ParitaprevirRitonavir (fixed dose 12.5/75/50 mg)

Ombitasvir-Paritaprevir and Ritonavir (TECHNIVIE®) package insert. AbbVie Inc., North Chicago, IL 60064

• Duration

– Genotype 2 and 3 • Given with ribavirin – HCV/HIV co-infection 33

Ombitasvir-Paritaprevir-Ritonavir (Technivie®)

Sofosbuvir (Sovaldi®) package insert. Gilead Sciences, Inc. Foster City, CA 94404

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Sofosbuvir (Sovaldi®)

• Viekira Pak – dasabuvir = Technivie®

• Dosing: 400 mg daily by mouth with or without food • Drug interactions

– Dasabuvir intrinsically resistant to genotype 1

– P-glycoprotein inducers decrease drug concentrations • Examples: St. John’s Wort, rifampin

• Lots of drug interactions

• Adverse effects

– CYP3A substrates – CYP3A inducers

– Nausea, fatigue, headache, insomnia, anemia

• Patients awaiting liver transplantation – With hepatocellular carcinoma – Given with ribavirin for up to 48 weeks to prevent posttransplant HCV reinfection

• Adverse effects – Fatigue, nausea, potential hepatoxicity

Ombitasvir-Paritaprevir and Ritonavir (TECHNIVIE®) package insert. AbbVie Inc., North Chicago, IL 60064

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Sofosbuvir (Sovaldi®) package insert. Gilead Sciences, Inc. Foster City, CA 94404

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Simeprevir (Olysio®) • NS3/4A inhibitor

• Ribavirin (Copegus®) dosing:

• Duration

─ Protease inhibitor

• Indication and Usage

Ribavirin and Peginterferon – < 75 kg: 1000 mg/day (400 mg AM / 600 mg PM) – > 75 kg: 1200 mg/day (600 mg twice a day)

– 12-24 week treatment

• Preparations

– Genotype 1 and 4 – Given with peginterferon + ribavirin – Screen for resistance

– Simeprevir 150 mg tablet

(Pegasys ®) Peginterferon alfa-2a • 180 mcg subQ weekly • Proclick autoinjectors

• Genotype 1a • Avoid with Q80K polymorphism

Simeprevir (Olysio®) package insert. Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560

• Vials for reconstitution

(Pegintron ®) Peginterferon alfa-2b • 1.5 mcg/kg subQ weekly • Redipens • Vials for reconstitution – 50 - 150 mcg vials

Ribavirin (Copegus®) Package Insert Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110-1199 Pefinterferon alfa-2a (Pegasys ®) package insert Hoffmann-La Roche, Inc. c/o Genentech, Inc. South San Francisco, CA 94080-4990 Pefinterferon alfa-2b (Pegintron ®) package insert. Merck & CO., INC., Whitehouse Station, NJ 08889, USA

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Simeprevir (Olysio®)

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Ribavirin and Peginterferon

• Dosing: 150 mg tablet by mouth daily with food • Limitations of use:

Ribavirin

– Not recommended as monotherapy – Resistance screening for Q80K strongly recommended – Sever hepatic impairment

• • • •

• Fatal cases have been reported

– Patients who have failed treatment with protease inhibitors

Adverse effects Peginterferon alfa

Anemia Hemolytic anemia Nausea, vomiting, diarrhea Teratogenicity – Males and Females must use contraception during and 6 months post-treatment

• Not recommended (i.e. boceprevir, telaprevir)

– Drug interactions

• Adverse effects

• Flu-like symptoms • Psychiatric symptoms • Depression

• • • • •

Neutropenia Thrombocytopenia Alopecia Injection site reactions Cough

– Photosensitivity, rash, nausea, myalgia, and dyspnea Simeprevir (Olysio®) package insert. Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560

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Ribavirin (Copegus®) Package Insert Roche Laboratories Inc. 340 Kingsland Street Nutley, New Jersey 07110-1199 Pefinterferon alfa-2a (Pegasys ®) package insert Hoffmann-La Roche, Inc. c/o Genentech, Inc. South San Francisco, CA 94080-4990

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Treatment Monitoring

Cost

• Prior to starting therapy • Wholesaler acquisition (WAC) cost for Harvoni ®

– Barriers to compliance and drug interactions – HCV genotype, subtype and HCV RNA viral load – ± resistance testing

– $94,500 - $189,900 – Estimated cost is $1,125 per pill

• CBC, INR, hepatic function panel, renal function

• With exception of mandated rebates, negotiation of drug prices are considered confidential

– Baseline, week 4, and as indicated

– Lack of transparency regarding actual prices – Negotiated discount is reported to be 46% off of the WAC

• HCV RNA viral load – Baseline, week 4, and 12 months after treatment end date

• Difficult to estimate true cost and cost-effectiveness

• If detectable at week 4, check again at week 6 • If viral load has increased by 10-fold discontinue therapy

– Government and pharmaceutical companies collaborating

• Thyroid-stimulating hormone (if using interferon)

• To help bring affordability and access to all who need it

– Every 12 weeks American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "Monitoring Patients Who Are Starting HCV Treatment, Are On Treatment, Or Have Completed Therapy." (2015)

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American Association for the Study of Liver Diseases, and Infectious Diseases Society of America. "OVERVIEW OF COST, REIMBURSEMENT, AND COST-EFFECTIVENESS CONSIDERATIONS FOR HEPATITIS C TREATMENT REGIMENS." (2015)

The Role of the Pharmacist

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Future Therapies • Pan-genotypic regimes

• Assessing barriers to compliance • Selection of drug regimen • Screening for drug interactions – Package insert or http://hep-druginteractions.org/

• Monitoring for adverse effects • Patient education

• If Approved – Would be the first all-oral pan-genotypic single tablet regimen for chronic HCV 42

"Gilead Announces SVR12 Rates from Four Phase 3 Studies Evaluating a Once-Daily, Fixed-Dose Combination of Sofosbuvir (SOF) and Velpatasvir (VEL) (GS-5816) for the Treatment of All Six Hepatitis C Genotypes. N.p., 21 Sept. 2015. Web. 29 Feb. 2016.

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Assessment Questions 1. The center for disease control (CDC) recommends that heterosexual monogamous partners use barrier protection such as condoms to prevent the transmission of hepatitis C from an infected partner to a non-infected partner. False

2. Acid reducing agents will decrease the absorption of both sofosbuvir and ledipasvir. False

3. Everyone who contracts hepatitis C must receive treatment. False 45

Treatment of Hepatitis C Jay Hazelcorn, Pharm.D. PGY-1 Pharmacy Resident Broward Health Medical Center

www.fshp.org

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