harvoni and hepatitis c revised

Harvoni and Hepatitis CThomas Huang, Pharmacy Student

Outline1. Learning Objectives2. Hepatitis C

Overview3. Epidemiology4. Clinical Presentation5. A walk down

memory lane6. Life cycle of HCV7. Mechanism of Action

8. Pharmacokinetics9. Clinical Toxicology10.Clinical Trials11.Summary12.References

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

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

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

Clinical PresentationAcute Infecti

on

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

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

Harvoni• First non-interferon/ribavirin treatment approved

for genotype 1 HCV infection• Combination oral product (tablet)• Ledipasvir/Sofosbuvir

Life Cycle of HCV

Ledipasvira) Direct-acting anti-viral agentb) 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

Sofosbuvira) Polymerase inhibitorb) Inhibits HCV NS5B RNA-dependent polymerasec) 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

PharmacokineticsLEDIPASVIR 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

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

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

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 wksGT- 1,4 = genotype 1,4 , LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin

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.

Baseline Characteristic

12-Week Treatment 24-Week Treatment

LDV-SOF n=214

LDV-SOF + RBV

n=217LDV-SOF

n=217LDV-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



for 12 or 24 weeks

GT- 1 Naïve

GT-1 Naïve

n = 214

n = 217

n = 217

n = 217

LDV- SOFLDV-SOF + RBV

Weeks

0 12 24 36

SVR12SVR12

LDV- SOF

LDV-SOF + RBV

SVR12SVR12


GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirin


for 12 or 24 weeks


12 Week Regimen 24 Week Regimen0102030405060708090

100 99 9897 99

ION-1: SVR 12 by Treatment Duration and Regimen

LDV-SOF LDV-SOF+RBV

Patie

nts

(%) w

ith S

VR 1

2

211/214

Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin*Primary end-point by intention-to-treat analysis

211/217

212/217

215/217



Abbreviations: LDV-SOF= ledipasvir-sofosbuvir; RBV = ribavirin*Primary end-point by intention-to-treat analysis

211/217

212/217

215/217

LDV-SOF LDV-SOF + RBV

LDV-SOF LDV-SOF + RBV

0

20

40

60

80

100 100 100 99 10097 100 97 100Without Cirrhosis With Cirrhosis

Patie

nts

(%) w

ith S

VR 1

2

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


12 Week Regimen 24 Week RegimenSafety LDV-SOF LDV-

SOF+RBVLDV-SOF LDV-

SOF+RBVFatigue 21 36 24 38Headache 25 2 25 30Insomnia 8 21 12 22Cough 3 10 7 12Pruritis 5 10 4 9Anemia 0 12 0 10Hgb(<100 g/L)

0 9 0 7


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.


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 StatesInclusion 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.


Baseline Characteristics

8 Weeks 12 Week-Treatment

LDV-SOF n=215

LDV-SOF + RBV n=216

LDV-SOFn=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.


GT- 1 Naïve Non-

Cirrhotic

GT-1 Naïve

n = 215

n = 216

n = 217

LDV- SOFLDV-SOF + RBV

Weeks

0 8 20 24

SVR12SVR12

LDV- SOF SVR12

Abbreviations: GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirinLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

12



LDV-SOF LDV-SOF +RBV LDV-SOF 0

20

40

60

80

10094 93 95

Patie

nts

with

SVR

12

(%)


ION-1: SVR 12 by Treatment Duration and Regimen


Abbreviations: GT- 1 = genotype 1, LDV-SOF = ledipasvir-sofosbuvir (Harvoni), RBV = ribavirinLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg




Safety LDV-SOF LDV-SOF+RBV LDV-SOFFatigue 21 36 24Headache 25 2 25Insomnia 8 21 12Cough 3 10 7Pruritis 5 10 4Anemia 0 12 0Hgb(<100 g/L) 0 9 0

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.

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. ”

Questions?Thank you for listening!

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.

harvoni and hepatitis c revised

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