Hepatitis C InfectionReview hepatitis and acute viral hepatitis 2. Discuss the epidemiology,...
Transcript of 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
Question 1 Question 2 Question 3
True or False: Most persons are asymptomatic when first contracting hepatitis C infection
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Question 1 Question 2 Question 3
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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Daclatasvir (Daklinza®) 10
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
Daclatasvir (Daklinza®) 10
Special Population
• No renal or hepatic adjustment necessary
Administration
• Administer with or without food
http://apisynthesisint.blogspot.com
Daclatasvir (Daklinza®) 11
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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Daclatasvir (Daklinza®) 11
ALLY-3 Study
• Results
Treatment-naïve Patients
No cirrhosis Cirrhosis
97% (73/75) 58% (11/19)
Treatment-experienced Patients
No cirrhosis Cirrhosis
94% (32/34) 69% (9/13)
All Patients
No cirrhosis Cirrhosis
96% (105/109) 63% (20/32)
Daclatasvir (Daklinza®) 12
European Compassionate Use Program
• Study Design
• 24 week regimen of DCV+SOF versus DCV+SOF+RBV in genotype 3 infection
• Patient population
• Genotype 3, treatment-naïve and experienced patients with and without cirrhosis
• Primary endpoint
• SVR12
Daclatasvir (Daklinza®) 12
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
Core E1 E2 Ns2 Ns3 Ns4A Ns4B Ns5A Ns5B
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
Ledipasvir/Sofosbuvir (Harvoni®)13
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
Ledipasvir/Sofosbuvir (Harvoni®)13
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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
• Patient population
• Genotype 1, treatment-naïve patients with or without cirrhosis
• Primary endpoint
• SVR12
Ledipasvir/Sofosbuvir (Harvoni®)14
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)
Ledipasvir/Sofosbuvir (Harvoni®)14
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
Core E1 E2 Ns2 Ns3 Ns4A Ns4B Ns5A Ns5B
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
Ombitasvir/Paritaprevir/Ritonavir;
Dasabuvir (Viekira Pak®) 15
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
• Patient population
• Genotype 1, treatment-naïve patients without cirrhosis
• Primary endpoints
• SVR12
• Non-inferiority (margin -10.5%) of SVR12 in each study group
Ombitasvir/Paritaprevir/Ritonavir;
Dasabuvir (Viekira Pak®) 16
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
Ombitasvir/Paritaprevir/Ritonavir;
Dasabuvir (Viekira Pak®) 16
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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
Core E1 E2 Ns2 Ns3 Ns4A Ns4B Ns5A Ns5B
Simeprevir (Olysio®) 17
Dosing
Pricing
Dosage
FormCapsule: 150 mg
Genotype
1 or 41 capsule daily
150 mg
(28)$26,544.00
Simeprevir (Olysio®) 17
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
• Primary endpoint
• SVR12
Simeprevir (Olysio®) 18
OPTIMIST-1 Study
• Results
12 week Regimen
97% (150/155)
Treatment-naïve (12 week)
97% (112/115)
Treatment-experienced (12 week)
95% (38/40)
Simeprevir (Olysio®) 18
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
• Primary endpoint
• SVR12
Simeprevir (Olysio®) 19
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OPTIMIST-2 Study
• Results
All patients
83% (86/103)
Genotype 1a
83% (60/72)
Genotype 1b
84% (26/31)
Simeprevir (Olysio®) 19
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
Ribavirin (Copegus®) 20
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
Ribavirin (Copegus®) 20
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
Peginterferon Alfa – 2a (Pegasys®) 21
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
Peginterferon Alfa – 2a (Pegasys®) 21
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
Recommended Regimen6 Duration
Cirrhosis
Genotype 1 Genotype 2 Genotype 3 Genotype 4Genotype
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
Recommended Regimen6 Duration
Without Cirrhosis
DCV + SOF 12 weeks
SOF + RBV 12 weeks
Cirrhosis
Extending treatment to 16 weeks is recommended in patients
with cirrhosis
Genotype 1 Genotype 2 Genotype 3 Genotype 4Genotype
5 or 6
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Recommended Regimen6 Duration
Without Cirrhosis
DCV + SOF 12 weeks
SOF + RBV + PEG-IFN 12 weeks
Cirrhosis
DCV + SOF ± RBV 24 weeks
Genotype 1 Genotype 2 Genotype 3 Genotype 4Genotype
5 or 6
Recommended Regimen6 Duration
LDV-SOF 12 weeks
Viekira Pak* + RBV 12 weeks
SOF + RBV 24 weeks
Genotype 1 Genotype 2 Genotype 3 Genotype 4Genotype
5 or 6
*Regimen does not include twice daily dasabuvir
Recommended Regimen6 Duration
LDV-SOF 12 weeks
Genotype 1 Genotype 2 Genotype 3 Genotype 4Genotype
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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Question 1 Question 2 Question 3
True or False: Hepatitis C infection is preventable with a vaccine
�Answer: False
Question 1 Question 2 Question 3
True or False: Most persons are asymptomatic when first contracting hepatitis C infection
�Answer: True
Question 1 Question 2 Question 3
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]