This document discusses Harvoni and its role in treating Hepatitis C. It provides an overview of Hepatitis C, including epidemiology and clinical presentation. It describes the mechanism of action and pharmacokinetics of the two drugs in Harvoni - Ledipasvir and Sofosbuvir. It summarizes several clinical trials that evaluated Harvoni's efficacy and safety in treating genotype 1 Hepatitis C in treatment-naive and experienced patients, with and without cirrhosis, finding high sustained virologic response rates with 12 weeks of Harvoni treatment.

1. Harvoni and
Hepatitis C
Thomas Huang, Pharmacy Student

2. Outline
1. Learning Objectives
2. Hepatitis C Overview
3. Epidemiology
4. Clinical Presentation
5. A walk down memory
lane
6. Life cycle of HCV
7. Mechanism of Action
8. Pharmacokinetics
9. Clinical Toxicology
10. Clinical Trials
11. Summary
12. References

3. Learning Objectives
Describe the epidemiology and clinical presentation of Hepatitis
C infection
Identify the role of Harvoni in the current treatment regimen of
Hepatitis C patients
Recognize the duration of therapy for different patient
populations, specifically treatment naïve patients with
genotype 1 HCV with or without cirrhosis

4. Hepatitis C Overview
Hepatitis C is a liver disease caused by the hepatitis C
virus (HCV). HCV can cause both acute and chronic
hepatitis infection ranging in severity, from a mild
illness to end-stage liver disease complicated with
liver cancer and potential for mortality
HCV is a single stranded RNA virus

5. Epidemiology
Genotype 1
being most
prevalent
Six different
HCV genotypes
138,600 to
252,000
people affected
Represents
65% of infected
individuals
Estimated 21%
of population
remain
undiagnosed
Huge economic
burden

6. Clinical Presentation
Acute
Infection
Chronic
Hepatitis
Cirrhosis
• Self limited
• 25% will clear
spontaneously
• Hepatic failure (rare)
• Not clinically
apparent
• 5 – 30% will develop
cirrhosis over 20-30
years
• Hepatocyte death
• Compensated
• Decompensated
• Hepatocellular
carcinoma
development
• ↓ perfusion
• ↓ Hepatic function
• Fibrosis

7. Traditional Treatment
Interferon and Ribavirin
Efficacy:
Administered:
48 weeks in patients with G1, G4, G5, and G6
24 weeks in patients with G2 and G3
SVR
G1 – 40 to 50%; G2,G3,G5, and G6 – 80% and G4 50 to 80%
Safety:
Injection site inflammation, fatigue, fever, headache, nausea, myalgia
Cost:
Varies but on average $15,000 - $ 20,000

8. Harvoni
• First non-interferon/ribavirin treatment approved for
genotype 1 HCV infection
• Combination oral product (tablet)
• Ledipasvir/Sofosbuvir

9. Life Cycle of HCV

10. Ledipasvir
a) Direct-acting anti-viral agent
b) Targets and inhibits the HCV NS5A protein (non-structural)
c) NS5A protein is a key player to viral replication, host cell
interaction and pathogenesis, an essential component of the
HCV replicase
d) Inhibition of NS5A leads to inhibition of RNA replication and
virion assembly and secretion of infected cells

11. Sofosbuvir
a) Polymerase inhibitor
b) Inhibits HCV NS5B RNA-dependent polymerase
c) NS5B RNA-dependent polymerase is another essential component
of a multi-protein complex involved in viral replication
- Critical to the viral replication
d) Sofosbuvir is a prodrug that undergoes intracellular
phosphorylation
- Phosphorylation converts the prodrug to the active uridine analogy
triphosphate form
- Incorporation of the activated uridine analog terminates the synthesis
of RNA
e) Viral load decreases rapidly when viral replication is stopped

12. Pharmacokinetics
LEDIPASVIR
Absorption
Well absorbed
Peak: 4 – 4.5 hours
Not affected by food
Distribution
Almost entirely protein bound
High volume of distribution = 90 L;
increased with hepatic impairment
Metabolism
No CYP metabolism detected
Unknown mechanism of slow
oxidative metabolism ~2%
Systemic exposure = 98% parent drug
Elimination
Biliary/feces
SOFOSBUVIR
Absorption
Well absorbed
Peak: 1 hour
Not affected by food
Distribution
61- 65% protein bound
High volume of distribution = 127 L
Metabolism
Prodrug – extensively metabolised in
liver to the active form
(phosphorylation)
Elimination
Urine

13. Clinical Toxicology
Genotoxicity
None shown in In Vivo and In Vitro studies
Carcinogenesis
Ongoing for ledipasvir, none shown for sofosbuvir
Teratogenicity
None observed in ledipasvir and sofosbuvir

14. Clinical Trials
Treatment Naïve (Phase 3)
- ION-1: GT-1 / LDV-SOF +/- RBV x 12 or 24 weeks
- ION-3: GT-1 / LDV-SOF +/- RBV x 8 weeks vs LDV/SOF x 12 weeks
Treatment Experienced (Phase 3)
- ION-2: GT-1 / LDV-SOF +/- RBV x 12 or 24 weeks
Treatment Experienced with Compensated Cirrhosis (Phase 2)
- SIRIUS: GT-1 / LDV-SOF + RBV x 12 weeks or LSV-SOF x 24 weeks
Treatment Naïve or Treatment Experienced (Phase 2)
- LONESTAR: GT-1 / LDV-SOF +/- RBV x 8 or 12 weeks
- ELECTRON (Arms 12-17 & 22): LDV-SOF +/- RBV x 6 or 12 weeks
- ELECTRON-2: experienced GT-1 & naïve GT-3/ LDV-SOF +/- RBV x 12
weeks
GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin

15. Clinical Trials
Prior Sofosbuvir Failure (Phase 2)
- NIAID: GT-1 / LDV-SOF +/- RBV x 12 weeks
- PRIOR Failure in Sofosbuvir Trials: GT-1 / LDV-SOF +/- RBV x 12
weeks
HIV Coinfection: Treatment Naïve (Phase 2)
- ERADICATE: GT 1 / LDV-SOF x 12 weeks +/- HIV antiretrovirals
- ION-4: GT1,4 naïve or treatment exp/ LDV-SOF x 12 weeks
Advanced Liver Disease: Pre and Post Transplant (Phase 2)
- SOLAR-1: GT 1,4 / LDV-SOF + RBV x 12 or 24 wks
GT- 1,4 = genotype 1,4 , LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin

16. Treatment Naïve HCV GT1: ION – 1
for 12 or 24 weeks
ION-1 Trial
Design: Open-label, randomized, phase 3 trial using fixed-dose
combination of ledipasvir-sofosbuvir +/- ribavirin for 12 or 24 weeks
in treatment-naïve patients with GT1 HCV
Setting: 99 sites in United States and Europe
Inclusion Criteria
- Chronic HCV Genotype 1 (n=865)
- 18 years or older
- No prior HCV treatment
- Patients with compensated cirrhosis accepted (up to 20% of
patients)
Primary End-Point: SVR12
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

17. Baseline Characteristic
12-Week Treatment 24-Week Treatment
LDV-SOF
n=214
LDV-SOF + RBV
n=217
LDV-SOF
n=217
LDV-SOF + RBV
n=217
Mean age, y (range) 52 (18–75) 52 (18–78) 53 (22–80) 53 (24–77)
BMI, kg/m2 mean (range) 27 (18–41) 27 (18–42) 27 (18–48) 26 (18–48)
Male sex, n (%) 127 (59) 128 (59) 139 (64) 119 (55)
Race
White, n (%) 187 (87) 188 (87) 177 (82) 183 (84)
Black, n (%) 24 (11) 26 (12) 32 (15) 26 (12)
Hispanic ethnic group, n (%) 26 (12) 20 (9) 29 (13) 26 (12)
HCV Genotype
1a, n (%) 144 (67) 148 (68) 146 (67) 143 (66)
1b, n (%) 66 (31) 68 (31) 68 (31) 71 (33)
IL28B non CC, n (%) 175 (76) 141 (65) 165 (76) 144 (66)
Cirrhosis, n (%) 34 (16) 33 (15) 33 (15) 36 (17)
HCV RNA, log10 IU/ml (mean) 6.4 6.4 6.3 6.3
Treatment Naïve HCV GT1: ION – 1
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

18. Treatment Naïve HCV GT1: ION – 1
for 12 or 24 weeks
GT- 1 Naïve
GT-1 Naïve
n = 214
n = 217
n = 217
n = 217
LDV- SOF
LDV-SOF + RBV
Weeks 0 12 24 36
SVR12
SVR12
LDV- SOF
LDV-SOF + RBV
SVR12
SVR12
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin

19. Treatment Naïve HCV GT1: ION – 1
for 12 or 24 weeks
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
99 9897 99
0
10
20
30
40
50
60
70
80
90
100
12 Week Regimen 24 Week Regimen
Patients(%)withSVR12
ION-1: SVR 12 by Treatment Duration and Regimen
LDV-SOF LDV-SOF+RBV
211/214
Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin
*Primary end-point by intention-to-treat analysis
211/217 212/217 215/217

20. Treatment Naïve HCV GT1: ION – 1 for 12
or 24 weeks
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin
*Primary end-point by intention-to-treat analysis
211/217 212/217 215/217
100 100 99 10097 100 97 100
0
20
40
60
80
100
LDV-SOF LDV-SOF + RBV LDV-SOF LDV-SOF + RBV
Patients(%)withSVR12
Without Cirrhosis With Cirrhosis
32/33179/179 33/33178/178 31/32181/182 36/36179/179
ION-1: SVR 12 by Treatment Duration and Liver Disease
12 Week Regimen 24 Week Regimen

21. Treatment Naïve HCV GT1: ION –
1 for 12 or 24 weeks
12 Week Regimen 24 Week Regimen
Safety LDV-SOF LDV-SOF+RBV LDV-SOF LDV-SOF+RBV
Fatigue 21 36 24 38
Headache 25 2 25 30
Insomnia 8 21 12 22
Cough 3 10 7 12
Pruritis 5 10 4 9
Anemia 0 12 0 10
Hgb(<100 g/L) 0 9 0 7
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

22. Treatment Naïve HCV GT1: ION – 1
for 12 or 24 weeks
Clinical Bottom Line: Treatment naïve HCV
genotype 1 infection treated with ledipasvir-
sofosbuvir±ribavirin once daily for 12 weeks or
24 weeks can achieve very high sustained
virological response.
Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

23. Treatment Naïve HCV GT1: ION – 3
ION-3 Trial
Design: Open-label, randomized, phase 3, comparing ledipasvir-
sofosbuvir with or without ribavirin for 8 weeks and ledipasvir-
sofosbuvir for 12 weeks in treatment-naïve, non-cirrhotic patients
with GT1 HCV
Setting: 58 sites in United States
Inclusion Criteria
- Chronic HCV Genotype 1 (n=647)
- 18 years or older
- No prior HCV treatment
- Patients with cirrhosis were excluded
- HCV RNA ≥ 10,000 IU/ml
- No limits on BMI
Primary End-Point: SVR12
Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

24. Treatment Naïve HCV GT1: ION – 3
Baseline Characteristics
8 Weeks 12 Week-Treatment
LDV-SOF
n=215
LDV-SOF + RBV
n=216
LDV-SOF
n=216
Mean age, y (range) 53 (22–75) 51 (21–71) 53 (20–71)
BMI, kg/m2 mean (range) 28 (18–43) 28 (18–56) 28 (19–45)
Male sex, n (%) 130 (60) 117 (54) 128 (59)
Race
White, n (%) 164 (76) 176 (81) 177 (82)
Black, n (%) 45 (21) 36 (17) 42 (19)
Other, n (%) 6 (3) 4 (2) 7 (3)
HCV Genotype
1a, n (%) 171 (80) 172(68) 172 (80)
1b, n (%) 43 (20) 44 (20) 44 (20)
IL28B non CC, n (%) 159 (74) 156 (72) 160 (74)
F3 fibrosis, n (%) 29 (13) 28 (13) 29 (13)
HCV RNA, log10 IU/ml, mean 6.5 6.4 6.4
Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

25. Treatment Naïve HCV GT1: ION – 3
GT- 1 Naïve
Non-Cirrhotic
GT-1 Naïve
n = 215
n = 216
n = 217
LDV- SOF
LDV-SOF + RBV
Weeks 0 8 20 24
SVR12
SVR12
LDV- SOF SVR12
Abbreviations: GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin
Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily
Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
12
Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.

26. Treatment Naïve HCV GT1: ION – 3
94 93 95
0
20
40
60
80
100
LDV-SOF LDV-SOF +RBV LDV-SOF
PatientswithSVR12(%)
8 Week Regimen 12 Week Regimen
ION-1: SVR 12 by Treatment Duration and Regimen
Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.
Abbreviations: GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin
Ledipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once daily
Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

27. Treatment Naïve HCV GT1: ION – 3
Kowdley, K, et al. N Engl J Med. 2014;370:1879-88.
12 Week Regimen 24 Week Regimen
Safety LDV-SOF LDV-SOF+RBV LDV-SOF
Fatigue 21 36 24
Headache 25 2 25
Insomnia 8 21 12
Cough 3 10 7
Pruritis 5 10 4
Anemia 0 12 0
Hgb(<100 g/L) 0 9 0

28. Treatment Naïve HCV GT1: ION – 1
Clinical Bottom Line: Treatment naïve HCV
genotype 1 infection patients without cirrhosis
treated with ledipasvir-sofosbuvir once daily for
8 weeks achieved high sustained virological
response. No additional benefits conferred with
the inclusion of ribavirin or extended duration
of treatment to 12 weeks.

29. Harvoni Accessibility
Currently there are only five provinces that cover Harvoni:
New Brunswick
Yukon
Manitoba
Ontario
British Columbia
Ontario accessibility through Exceptional Access Program (EAP):
“The requesting physician will receive a letter from the EAP telling them whether or not
coverage will be granted or if more information is required. If the request is approved,
people will have their hepatitis C medications covered for a designated time period. A
request to extend the period of coverage is usually necessary in order for people to have
their medications covered for the duration of their treatment. ”

30. Questions?
Thank you for listening!

31. References
Cashin, J. How to Give a Good Presentation. 2015. Leslie Dan Faculty
of Pharmacy
Myers et al. An update on the management of chronic hepatitis C:
2015 consensus guidelines from the Canadian Association for the
Study of the Liver.
Micaellf et. Al. Spontaneous viral clearance following acute hepatitis
C infection: A systematic review of longitudinal studies. J Viral Hepat
2006;13:34-41
Kowdley, K, et al. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for
Chronic HCV without Cirrhosis. N Engl J Med. 2014;370:1879-88.
Afdhal N, et al. Ledipasvir and Sofosbuvir for Untreated HCV
Genotype 1 Infection. N Engl J Med. 2014;370:1889-98.