Hepatitis C InfectionReview hepatitis and acute viral hepatitis 2. Discuss the epidemiology,...

12/21/2015

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Hepatitis C InfectionTreatment Revolution

Simone Edgerton, PharmD

PGY-1 Pharmacy Resident

Miami VA Healthcare System

Disclosures

I have no relevant financial or non

financial relationships to disclose in

relation to the content of this

presentation

1. Review hepatitis and acute viral

hepatitis

2. Discuss the epidemiology, etiology,

pathophysiology and risk factors of

Hepatitis C infection

3. Describe the clinical features and

presentation of Hepatitis C infection

Objectives

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4. Explain the diagnostic considerations for

Hepatitis C infection

5. Evaluate the goals of therapy,

nonpharmacologic and pharmacologic

treatment of Hepatitis C infection

6. Apply the guidelines and treatment

costs of Hepatitis C infection when

implementing therapy

Objectives

Abbreviations

�DCV – Daclatasvir

�SOF – Sofosbuvir

�SVR 12 – Sustained virologic response

12 weeks post treatment

�RBV – Ribavirin

�LDV – Ledipasvir

Abbreviations

�SMV – Simeprevir

�PEG-IFN – Peginterferon alfa 2a

�ALT – Alanine aminotransferase

�AASLD – American Association for the

Study of Liver Diseases

� IDSA – Infectious Disease Society of

America

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Self-Assessment

Questions

Question 1 Question 2 Question 3

True or False: Hepatitis C infection is preventable with a vaccine


True or False: Most persons are asymptomatic when first contracting hepatitis C infection

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True or False: The most common side effect of Harvoni® (ledipasvir and sofosbuvir) is myelosuppression

What is Hepatitis? 1

�Hepatitis:

� Inflammation of the liver

�Acute viral hepatitis:

� A systemic infection affecting the liver

predominantly

What is Hepatitis? 1

5 Main Hepatitis Viruses

Hepatitis A virus (HAV)

Hepatitis B virus (HBV)

Hepatitis C virus (HCV)

Hepatitis D virus (HDV)

Hepatitis E virus (HEV)

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Hepatitis C Virus

Epidemiology2

� 2.7 million persons are chronically infected

in the United States

� Leading cause of chronic liver disease and

transplantation

� Between 2010 and 2014, more than

190,000 deaths from HCV-related disease

are expected

Etiology3

• Single stranded Ribonucleic acid Type:

• HepacivirusGenus:

• FlavivirdaeFamily:

• 1, 2, 3, 4, 5 and 66 major

genotypes:

• a, b, c, etc.>50 subtypes

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Genotype Prevalence4

Jane P Messina, et al. Hepatology. 2015 January;61(1):77-87

Pathophysiology3,5

Female DJ, et.al. Viruses 2013. 5 (5): 1292-1324

Genetic Organization3,5

Heim MH. Swiss Med Wkly. 2012;142:w13586

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Risk factors3,5,6

• Intravenous and intranasal drug use

Risk behaviors

• Long-term hemodialysis

• Getting a tattoo

• Occupational exposure

• Children born to HCV-infected mothers

Risk exposures

• HIV infection

• Solid organ donors

Other medical conditions

Clinical presentation3,5,7

AnorexiaVague

abdominal discomfort

Nausea

Vomiting Fatigue Fever

JaundiceClay – color

stoolElevated

LFTS

Clinical Features3,5

• 15 – 160 days Incubation period

• Acute � ChronicType of infection

• LiverMajor organ affected

• AdultsPrincipal age distribution

• NoLifelong protection

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Time Course of Progression8

Thornton K. Hepatitis C Online. 2013; 1- 17.

Diagnostic Considerations6,9

• Serologic assays

• Detect Anti-HCV antibodies

• Molecular assays

• Detect HCV RNA levels

• Genotype assays

• Differentiate between genotypes

Laboratory Testing

• History and Physical Examination

• Basic Laboratory Testing

Assessment of Fibrosis Stage

Interpretation of HCV Assays6,9

Anti-HCV

antibodies

HCV RNA

levelsInterpretation

+ + Acute or chronic HCV infection

+ – Resolution of HCV infection

– + Early acute HCV infection

– –Absence of HCV infection

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Treatment

Goals of Therapy6

Reduce all-cause mortality

Eradicate the infection

Prevent the development of complications

Achieve histological improvement

When and In Whom to Initiate

HCV Therapy? 6

• Early in the course of the infection before the development of severe liver disease and other complications

When

• All patients, except those with short life expectancies that cannot be remediated by treatment, by transplantation, or by other directed therapies

Whom

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Nonpharmacologic Treatment6

• Avoid sharing toothbrushes

• Avoid sharing shaving equipment

• Do not donate blood

General

Alcohol abstinence/cessation

• Hepatitis A and hepatitis B vaccines

• There is no hepatitis C vaccine!

Vaccinations

Pharmacologic Treatment6

DaclatasvirLedipasvir/

Sofosbuvir

Ombitasvir/

Paritaprevir/

Ritonavir;Dasabuvir

Simprenavir RibavirinPeginterferon

alfa-2

Daclatasvir (Daklinza®) 10

Therapeutic Class

• NS5A inhibitor

Contraindications

• Strong inducers of CYP3A including: phenytoin, rifampin, carbamazepine, and St. John’s Wort

Core E1 E2 Ns2 Ns3 Ns4A Ns4B Ns5A Ns5B

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Dosing

Dosage

Form

Tablets:

30 mg & 60 mg

Genotype 3 60 mg daily

30 mg & 60 mg

(28)$25200.00

Pricing

http://static.progressivemediagroup.com


Special Population

• No renal or hepatic adjustment necessary

Administration

• Administer with or without food

http://apisynthesisint.blogspot.com


ALLY-3 Study

• Study Design

• Open-label, two-cohort phase-III, multicenter study of a 12 week regimen of DCV plus SOF in genotype 3 infection

• Patient population

• Genotype 3, treatment-naïve and experienced patients with or without cirrhosis

• Primary endpoint

• SVR12

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ALLY-3 Study

• Results

Treatment-naïve Patients

No cirrhosis Cirrhosis

97% (73/75) 58% (11/19)

Treatment-experienced Patients


94% (32/34) 69% (9/13)

All Patients


96% (105/109) 63% (20/32)


European Compassionate Use Program

• Study Design

• 24 week regimen of DCV+SOF versus DCV+SOF+RBV in genotype 3 infection


• Genotype 3, treatment-naïve and experienced patients with and without cirrhosis


• SVR12


European Compassionate Use Program

• Results (Interim Analysis)

DCV + SOF

All Cirrhosis

86% (42/49) 88% (37/42)

DCV + SOF + RBV

All Cirrhosis

88% (29/33) 86% (25/29)

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Ledipasvir/Sofosbuvir (Harvoni®)13

Therapeutic Class

• Ledipasvir: NS5A inhibitor

• Sofosbuvir (Sovaldi®): NS5B polymerase inhibitor

Pharmacokinetics

• Sofosbuvir � Prodrug


Dosing

Dosage

FormTablets: 90 mg

(L) & 400 mg (S)

Genotype 1 1 tablet daily

90mg/400 mg

(28)$37,800.00

Pricing

http://www.empr.com


Drug-drug Interaction

• Drugs that increase gastric pH

• Digoxin, HIV antiretroviral, rosuvastatin

Administration

• Antacids: Separate by 4 hours

• H2RAs: Administer with or separate by 12 hours

• PPIs: Administer under fasting conditions

http://newdrugapprovals.org


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ION-1 Study

• Study Design

• Open-label, multicenter study in which patients were randomly assigned in a 1:1:1:1 ratio of the 4 regimens: LDV-SOF for 12 or 24 weeks, LDV-SOF+RBV for 12 or 24 weeks


• Genotype 1, treatment-naïve patients with or without cirrhosis


• SVR12


ION-1 Study

• Results

12 week Regimen

LDV-SOF LDV-SOF+RBV

99% (211/214) 97% (211/217)

24 week Regimen

LDV-SOF LDV-SOF+RBV

98% (212/217) 99% (215/217)


Therapeutic Class

• Ombitasvir: HCV NS5A inhibitor

• Paritaprevir: HCV NS3/4A protease inhibitor

• Dasabuvir: HCV RNA polymerase inhibitor

• Ritonavir: Potent CYP3A inhibitor that ↑ paritaprevir levels

Contraindications

• Moderate to severe hepatic impairment (Child-Pugh B and C)

• Moderate to strong inducers of CYP3A4

• Strong inducers and inhibitors of CYP 2C8


Ombitasvir/Paritaprevir/Ritonavir;

Dasabuvir (Viekira Pak®) 15

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Dosing

Pricing

Genotype 1

2 ombitasvir,

paritaprevir, ritonavir tablet once daily and

1 dasabuvir tablet

twice daily

12.5-75-50 &

250 mg (112)$33,327.60



http://www.wsj.com

PEARL-IV Study

• Study Design

• Double-blinded, multicenter study in which patients were assigned in a 1:2 ratio (genotype 1a study) or a 1:1 ratio (genotype 1b study) to receive Viekira Pak ± ribavirin


• Genotype 1, treatment-naïve patients without cirrhosis

• Primary endpoints

• SVR12

• Non-inferiority (margin -10.5%) of SVR12 in each study group



PEARL-IV Study

• Results

Genotype 1a

Viekira Pak+RBV Viekira Pak

97% (97/100) 90% (185/205)

Genotype 1b

Viekira Pak+RBV Viekira Pak

99.5% (209/210) 99% (207/209)

95% CI, -12.0 to -1.5

Not non-inferior

95% CI, -2.1 to 1.1

Non-inferior

Non-inferior margin: - 10.5



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Therapeutic Class

• HCV NS3/4A protease inhibitor

Drug-drug Interactions

• Substrate of CYP 3A4 (major) and P-glycoprotein transporter

• Inhibited by amiodarone, azithromycin, verapamil and ritonavir


Simeprevir (Olysio®) 17

Dosing

Pricing

Dosage

FormCapsule: 150 mg

Genotype

1 or 41 capsule daily

150 mg

(28)$26,544.00


http://www.empr.com

Special Population

• Not studied in patients with CrCl ≤ 30 mL/min or ESRD

Administration

• Administer with food

Simeprevir (Olysio®)17

http://www.who.int

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OPTIMIST-1 Study

• Study Design

• Phase 3, multicenter, randomized, open-label study comparing the efficacy of a 12 week vs 8 week treatment regimen of SMV + SOF

• Patient Population

• Genotype 1, treatment – naïve and experienced patients without cirrhosis


• SVR12


OPTIMIST-1 Study

• Results

12 week Regimen

97% (150/155)

Treatment-naïve (12 week)

97% (112/115)

Treatment-experienced (12 week)

95% (38/40)


8 week Regimen

83% (128/155)

OPTIMIST-2 Study

• Study Design

• Phase 3, randomized, open-label study using SMV + SOF for 12 weeks in patients with compensated cirrhosis

• Patient Population

• Genotype 1, treatment – naïve and experienced patients with cirrhosis


• SVR12


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OPTIMIST-2 Study

• Results

All patients

83% (86/103)

Genotype 1a

83% (60/72)

Genotype 1b

84% (26/31)


With Q80K Without Q80K

74% (25/34) 92% (35/38)

Mechanism of Action

• Nucleoside analog that is incorporated into virus

Contraindications

• Pregnant women and men whose female partners are pregnant

• Hemogloinopathies

• Administration with didanosine

Ribavirin (Copegus®) 20

Dosing

Pricing


Dosage

Form200 mg tablets

Genotype

1& 4

<75 kg =

1000mg daily

≥75kg =

1200 mg daily

Genotype

2 & 3800 mg daily

200 mg

(168)$1,390.00

http://www.hepatitisc.uw.edu

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Special Population

• Approved in adults and children ≥ 2 years

• Dose adjustment in renal impairment

Administration

• Administer with food


http://dailymed.nlm.nih.gov

Mechanism of Action

• Inhibits transcription, translation, protein processing and virus maturation

Contraindications

• Current psychosis

• Severe Depression

• Thrombocytopenia

• Symptomatic heart disease

• Decompensated liver disease

• Uncontrolled seizures

Peginterferon Alfa – 2a (Pegasys®) 21

Dosing

Pricing

Dosage

Form

180 mcg per

0.5mL or 1mL

All

genotypes

180 mcg

subcutaneous

once weekly

180 mcg

(0.5 mL)$1,039.83


http://www.medicine-online.org

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Special Population

• Approved in adults and children ≥ 5 years

• CrCl < 30 mL/min & ESRD: Decrease dosage from 180 mcg to 135 mcg once weekly

Administration

• Administer in the abdomen or thigh, and rotate injection site


http://apps.who.int

Daklinza®10 Harvoni®13 Viekira Pak®15

Diarrhea Insomnia Nausea

Nausea Diarrhea Insomnia

Fatigue NauseaSkin reactions

Headache Headache Diarrhea

Fatigue Cough

Fatigue

Olysio®17 Copegus®20 Pegasys®21

Dyspnea Anemia Thyroid suppression

Myalgia Alopecia Pain

Nausea Neutropenia Anorexia

Fatigue Leukopenia Depression

Skin rash Nausea Myalgia

Fever Fever

Headache Weakness

Fatigue Myelosuppression

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Guidelines

AASLD/IDSA Guideline: 201422

Genotype Recommended

1

IFN eligible:

SOF +PEG/RBV x

12 weeks

IFN ineligible:

SOF + SMW ± RBV x 12

weeks

4

IFN eligible:

SOF +PEG/RBV x 12

weeks

IFN ineligible:

SOF + SMW ± RBV x 24

weeks

Genotype Recommended

2 SOF + RBV x 12 weeks

3 SOF + RBV x 24 weeks

5SOF + PEG/RBV x 12

weeks

AASLD/IDSA Guideline: 20156

Initial Treatment of Chronic HCV Infection

Genotype 1

Genotype 2

Genotype 3

Genotype 4

Genotype

5 or 6

Treatment Naïve Patients

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Recommended Regimen6 Duration

Without Cirrhosis

DCV + SOF 12 weeks

LDV-SOF 12 weeks

Viekira Pak + RBV 12 weeks

SMV + SOF 12 weeks

Genotype 1 Genotype 2 Genotype 3 Genotype 4Genotype

5 or 6


Cirrhosis


5 or 6

DCV + SOF ± RBV 24 weeks

LDV-SOF 12 weeks

Viekira Pak + RBV 24 weeks

SMV+ SOF ± RBV* 24 weeks

*Without Q80K polymorphism


Without Cirrhosis

DCV + SOF 12 weeks

SOF + RBV 12 weeks

Cirrhosis

Extending treatment to 16 weeks is recommended in patients

with cirrhosis


5 or 6

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Without Cirrhosis

DCV + SOF 12 weeks

SOF + RBV + PEG-IFN 12 weeks

Cirrhosis

DCV + SOF ± RBV 24 weeks


5 or 6


LDV-SOF 12 weeks

Viekira Pak* + RBV 12 weeks

SOF + RBV 24 weeks


5 or 6

*Regimen does not include twice daily dasabuvir


LDV-SOF 12 weeks


5 or 6

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Monitoring

Monitoring Parameters6

Quantitative HCV viral load testing

CBC GFR

Hepatic function panel

TSH Physical

examination

Vitals signsPregnancy testing and counseling

Adverse events and

Contraindications

Self-Assessment

Questions

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True or False: Hepatitis C infection is preventable with a vaccine

�Answer: False


True or False: Most persons are asymptomatic when first contracting hepatitis C infection

�Answer: True


True or False: The most common side effect of Harvoni® (ledipasvir and sofosbuvir) is myelosuppression

�Answer: False

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References

1. WHO resource page. World Health Organization website. Available

at: http://www.who.int/features/qa/76/en/. Accessed on November 10,

2015.

2. CDC resource page. Centers for Disease Control and Prevention.

Available at: http://www.cdc.gov/hepatitis/statistics/. Accessed on

November 14, 2015.

3. Dienstag JL. Dienstag J.L. Chapter 304. Acute Viral Hepatitis. In:

Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J.

Longo D.L., Fauci A.S., Kasper D.L., Hauser S.L., Jameson J,

Loscalzo J eds. Harrison's Principles of Internal Medicine, 18e. New

York: McGraw-Hill; 2012.

http://accesspharmacy.mhmedical.com/content.aspx?bookid=331&S

ectionid=40727099. Accessed November 20, 2015.

4. Messina JP, Humphreys I, Flaxman A, et al. Global Distribution and

Prevalence of Hepatitis C Virus Genotypes. Hepatology. 2015 Jan;

61 (1): 7-87.

References

5. Chapter 35. Hepatitis Viruses. In: Brooks GF, Carroll KC, Butel JS, Morse

SA, Mietzner TA. Brooks G.F., Carroll K.C., Butel J.S., Morse S.A.,

Mietzner T.A. eds. Jawetz, Melnick, & Adelberg's Medical Microbiology,

26e. New York: McGraw-Hill; 2013.

http://accesspharmacy.mhmedical.com/content.aspx?bookid=504&Sectio

nid=40999957. Accessed November 20, 2015.

6. IDSA Website. Recommendations for Testing, Managing, and Treating

Hepatitis C. Available at: http://www.hcvguidelines.org/fullreport.

Accessed on November 20, 2015.

7. CDC Website. Centers for Disease Control and Prevention. Available at:

http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-

diseases-related-to-travel/hepatitis-c. Accessed on November 10, 2015.

8. Hepatitis C Online Website. Natural History of Hepatitis C Infection.

Available at: http://www.hepatitisc.uw.edu/pdf/evaluation-staging-

monitoring/natural-history/core-concept/all. Accessed on November 20,

2015.

9. Terrault NA, Chopra S. Diagnosis and evaluation of chronic hepatitis C

virus infection. Marion, DW. Diaphragmatic pacing. In: UpToDate, Post

TW (Ed), UpToDate, Waltham, MA. (Accessed on November 25, 2015.)

References

10. Daklinza [packet insert]. Princeton, NJ: Bristol-Byers Squibb Company;

2015.

11. Nelson DR, Cooper JN, Lalezari JP, et.al. All-Oral 12-Week Treatment

with Daclatasvir Plus Sofosbuvir in Patients with Hepatitis C Virus

Genotype 3 Infection: ALLY-3 Phase III Study. Hepatology. 2015 Apr;

61(4): 1127-1135.

12. HIV and Hepatitis Website. AASLD 2015: Daclatasvir + Sofosbuvir Works

Well for Genotype 3 HCV Patients with Advanced Disease. Available at:

http://www.hivandhepatitis.com/hcv-treatment/approved-hcv-drugs/5490-

aasld-2015-daclatasvir-sofosbuvir-works-well-for-genotype-3-hepatitis-c-

patients-with-advanced-disease. Accessed on November 23, 2015.

13. Harvoni [packet insert]. Foster City, CA: Gilead Sciences, Inc.; 2014.

14. Afdhal N, Zeuzem S, Kwo P, et.al. Ledipasvir and Sofosbuvir for

Untreated HCV Genotype 1 Infection. N Engl J Med 2014; 370: 1889-

1898.

15. Viekira Pak [packet insert]. Foster City, CA: Gilead Sciences, Inc.; 2014.

16. Ferenci P, Bernstein D, Lalezari J, et.al. ABT-450/r-Ombitasvir and

Dasabuvir with or without Ribavirin for HCV. N Engl J Med. 2015 May 22;

370 (21): 1983-92.

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References

17. Olysio [packet insert]. Titusville NJ: Janssen Therapeutics, Division of

Janssen Products, LP; 2015.

18. Kwo P, et.al 50th EASL; 2015. Abstract LB14. Available at:

https://depts.washington.edu/hepstudy/presentations/uploads/156/simepr

eviroptimist1.pdf, Accessed on November 27, 2015.

19. Lawitz E, et al. 50th EASL; 2015. Abstract LP04. Available at:

https://depts.washington.edu/hepstudy/presentations/uploads/157/simepr

eviroptimist2.pdf. Accessed on November 27, 2015.

20. Copegus [packet insert]. South San Francisco, CA: Hoffman-La Roche,

Inch. c/o Genetech, Inc; 2015.

21. Pegays [packet insert]. South San Francisco, CA: Hoffman-La Roche,

Inch. c/o Genetech, Inc; 2015.

22. Recommendations for Testing, Managing, and Treating Hepatitis C.

Infectious disease society of america.

http://www.hcvguidelines.org/sites/default/files/full_report.pdf. Accessed

on November 27, 2015.

Questions

Hepatitis C InfectionTreatment Revolution

Simone Edgerton, PharmD

PGY-1 Pharmacy Resident

Miami VA Healthcare System

Contact Info: [email protected]

Hepatitis C InfectionReview hepatitis and acute viral hepatitis 2. Discuss the epidemiology,...

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