INDICATIONS AND USAGEHARVONI is indicated for the treatment of adults with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis. HARVONI is used with ribavirin in GT 1 adults with decompensated cirrhosis and in GT 1 or 4 adult liver transplant recipients without cirrhosis or with compensated cirrhosis.

This information is intended for payers only. The HCV-TARGET study was supported by Gilead Sciences, Inc. Real-world experience data were derived from patient medical records. Such data are longitudinal and observational in nature, and are not based on controlled clinical studies. Results from these cohorts may differ from results seen in the membership of a particular payer.

Click here for full Prescribing Information including BOXED WARNING on hepatitis B reactivation.

Update on Real-World Experience With HARVONI®

A RESOURCE FOR PAYERSMAY 2017

Click here for full Prescribing Information including BOXED WARNING. 1

IMPORTANT SAFETY INFORMATION BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HARVONI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Contraindications

• If HARVONI is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

HARVONI is indicated for the treatment of adults with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis. HARVONI is used with ribavirin in GT 1 adults with decompensated cirrhosis and in GT 1 or 4 adult liver transplant recipients without cirrhosis or with compensated cirrhosis.

Pill not actual size

1 TABLET ONCE A DAY

Ledipasvir (90 mg)

An HCV NS5A inhibitor

Sofosbuvir (400 mg)

A nucleotide analog inhibitor of HCV NS5B polymerase

HARVONI

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RECOMMENDED TREATMENT DURATION FOR ADULTS WITH HCV GT 1, 4, 5, 6, INCLUDING THOSE WITH HCV/HIV-1 COINFECTION1

IMPORTANT SAFETY INFORMATION Warnings and Precautions

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with HARVONI due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

• Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with HARVONI

• For patients with HCV/HIV-1 coinfection, follow the dosage recommendations above. Refer to the Drug Interactions section of the HARVONI Prescribing Information for dosage recommendations for concomitant HIV-1 antiretroviral drugs

• No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] <30 mL/min/1.73 m2) or with end-stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite

• Clinical and hepatic laboratory monitoring, as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with HARVONI and RBV

1HARVONI

TABLET DAILY

NO FOOD REQUIREMENT

8 WEEKS

• Can be considered in treatment-naïve (TN) GT 1 patients without cirrhosis and with pre-treatment HCV RNA <6 million IU/mL

12 WEEKS

• TN GT 1 patients without cirrhosis or with compensated cirrhosis (Child-Pugh A)

• Treatment-experienced (TE)a GT 1 patients without cirrhosis• TN or TEa GT 4, GT 5 or GT 6 patients without cirrhosis or with

compensated cirrhosis (Child-Pugh A)

12 WEEKS

• TN and TEa GT 1 patients with decompensated cirrhosis (Child-Pugh B or C)b

• TN and TEa GT 1 or GT 4 liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A)c

24 WEEKS

• TEa GT 1 patients with compensated cirrhosis (Child- Pugh A)d

aTE patients include those who have failed a peginterferon alfa + ribavirin (RBV)-based regimen with or without an HCV protease inhibitor.b In patients with decompensated cirrhosis (Child-Pugh B or C), the starting dosage of RBV is 600 mg and can be titrated up to 1000 mg for patients

<75 kg and 1200 mg for those ≥75 kg in two divided doses with food. If the starting dosage of RBV is not well tolerated, the dosage should be reduced as clinically indicated based on hemoglobin levels.

c The daily dosage of RBV is weight-based (1000 mg for patients <75 kg and 1200 mg for those ≥75 kg) administered orally in two divided doses with food. Refer to the RBV prescribing information.

d HARVONI + RBV for 12 weeks can be considered in TE GT 1 patients with compensated cirrhosis who are eligible for RBV. See footnote c for RBV dosage recommendations.

HARVONI

HARVONI

HARVONI

HARVONI + RBV

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IMPORTANT SAFETY INFORMATION Warnings and Precautions (cont.)

• Risk of Reduced Therapeutic Effect Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with HARVONI as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

HARVONI CLINICAL STUDIES IN ADULTS WITHOUT CIRRHOSIS OR WITH COMPENSATED CIRRHOSIS (CHILD-PUGH A)1

Baseline demographics

ION-11 ION-21 ION-31 ION-41,3 SIRIUS1

N 865 440 647 335 155

Design Randomized, open-label

Randomized, open-label

Randomized, open-label

Single-arm, open-label

Randomized, placebo-controlledc

Cirrhotics 16% (n = 136) 20% (n = 88) None 20% (n = 67) 100% (n = 155)

Prior treatment TN

Peg-IFNa + RBV or

Peg-IFNa + RBV + HCV PI

TN

TN or

RBV +/- PegIFN +/- HCV DAA

Peg-IFNa + RBV followed by

Peg-IFNa + RBV + HCV PI

HCV GT GT 1 GT 1 GT 1 GT 1 or GT 4d GT 1

HCV/HIV-1 coinfection No No No Yes No

DAA = direct-acting antiviral agent; Peg-IFNa = peginterferon alfa.aRBV 1000-1200 mg/day.bRelapse was a secondary endpoint.cIn the 12-week arm, subjects received placebo for 12 weeks followed by HARVONI + RBV for 12 weeks.dGT 1, n = 327; GT 4, n = 8.

Study Weeks

ION

-4SI

RIU

SIO

N-3

ION

-1 a

nd IO

N-2

12 24 0

HARVONI

HARVONI + RBVa

HARVONI

HARVONI + RBVa

HARVONI

HARVONI + RBVa

8

Study Weeks

ION

-4SI

RIU

SIO

N-3

ION

-1 a

nd IO

N-2

12 24 0

HARVONI

HARVONI + RBVa

HARVONI

HARVONI + RBVa

HARVONI

HARVONI + RBVa

8

• Primary endpoint: sustained virologic response (SVR12), defined as HCV RNA <25 IU/mL at 12 weeks after the cessation of treatment1, b

• SVR12 is considered a virologic cure2

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IMPORTANT SAFETY INFORMATION Adverse Reactions

• Most common adverse reactions (≥10%, all grades) were fatigue, headache, and asthenia.

HARVONI CLINICAL STUDIES IN ADULTS WITHOUT CIRRHOSIS OR WITH COMPENSATED CIRRHOSIS (CHILD-PUGH A)1 (cont.)

Adverse reactions (all grades) reported in ≥5% of GT 1 patients receiving HARVONI for 8, 12, or 24 weeks: ION-1, ION-2, and ION-3

HARVONI 8 Weeks(N = 215)

HARVONI12 Weeks(N = 539)

HARVONI24 Weeks(N = 326)

Fatigue 16% 13% 18%

Headache 11% 14% 17%

Nausea 6% 7% 9%

Diarrhea 4% 3% 7%

Insomnia 3% 5% 6%

Adverse reactions reported in ≥5% of TE, CC, GT 1 patients receiving HARVONI for 24 weeks or HARVONI + RBV for 12 weeks versus placebo: SIRIUS

HARVONI24 Weeks(N = 78)

HARVONI + RBV12 Weeks(N = 76)

Placebo12 Weeks(N = 77)

Asthenia 31% 36% 23%

Headache 29% 13% 16%

Fatigue 18% 4% 1%

Cough 5% 11% 1%

Myalgia 9% 4% 0

Dyspnea 3% 9% 1%

Irritability 8% 7% 1%

Dizziness 5% 1% 0

• The safety profile in HCV/HIV-1 coinfected subjects (ION-4) was similar to that observed in HCV monoinfected subjects

– The most common adverse reactions occurring in at least 10% of subjects were headache (20%) and fatigue (17%)

• Direct comparisons across studies should not be made due to differing study designs

GT 1 patients achieving SVR12 with HARVONI ± RBV

Footnotes for all figures:a Subgroup of TN, NC, GT 1 HCV patients with

baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for HARVONI for 8 weeks were 2% (n = 2/123) in patients with baseline HCV RNA <6 million IU/mL and 10% (n = 9/92) in patients with baseline HCV RNA ≥6 million IU/mL.

b Patients with GT 1 or 4 HCV with HIV coinfection.

96%97% 97%99% 96% 95% 96% 100%

0

20

40

60

Patie

nts

(%)

80

100

HARVONI 8 weeks

HARVONI 12 weeks

HARVONI + RBV 12 weeks

HARVONI 24 weeks

n = 123 n = 216 n = 213 n = 335 n = 87 n = 77 n = 77 n = 22

ION-3a ION-3TN, NC TN, NC/CC TN/TE, NC/CC TE, CC TE, CCTE, CC

ION-1 ION-4b SIRIUS SIRIUS ION-2TN, NC TE, NC

ION-2

CC = compensated cirrhosis (Child-Pugh A); NC = noncirrhotic.

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HARVONI REAL-WORLD EXPERIENCE: HCV-TARGET4

IMPORTANT SAFETY INFORMATION Drug Interactions

• In addition to rifampin and St. John’s wort, coadministration of HARVONI is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of HARVONI.

• The HCV-TARGET study evaluated the safety and efficacy of 8, 12, or 24 weeks of HARVONI in real-world GT 1 adult patients in academic or community settings

• HCV-TARGET included GT 1 TN and TE patients without cirrhosis or with compensated cirrhosis (N = 2099)

• SVR12 rates in HCV-TARGET excluded patients lost to follow-up

• The HARVONI regimen was selected and administered at the clinician’s discretion according to local standards of care

• Treatment with HARVONI for 8, 12, or 24 weeks resulted in overall SVR12 rates of 96%

• Of the total of 2356 patients that ended treatment with a HARVONI-containing regimen:

– 2.8% (n = 67) of patients discontinued treatment (13 deaths, 12 were in patients with cirrhosis)

– 8% (n = 190) had insufficient follow-up or were lost to follow-up post-treatment

• Of the 2099 patients in the per-protocol population (virological outcome known), 15% (n = 311) received HARVONI + RBV

HARVONI for 12 weeks is recommended for TN GT 1 patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) and for TE GT 1 patients without cirrhosis. HARVONI for 8 weeks can be considered in TN GT 1 adults without cirrhosis who have pre-treatment HCV RNA <6 million IU/mL. HARVONI for 24 weeks is recommended for TE GT 1 adults with compensated cirrhosis (Child-Pugh A). HARVONI + RBV for 12 weeks can be considered in TE GT 1 patients with compensated cirrhosis (Child-Pugh A) who are eligible for RBV.1

Baseline demographics

HCV-TARGET8 Weeksa

(N = 305)12 Weeks(N = 971)

24 Weeks(N = 552)

Male, n (%) 134 (44) 570 (59) 361 (65)

Median age, years (range) 58 (18-84) 60 (21-87) 61 (23-83)

Black, n (%) 68 (22) 309 (32) 106 (19)

White, n (%) 219 (72) 591 (61) 406 (74)

Prior HCV treatment, n (%) Experienced DAA-experienced

11 (4)2 (1)

350 (36)

89 (9)

494 (90)143 (26)

HCV GT, n (%) 1a 1b

197 (65)97 (32)

646 (67)270 (28)

374 (68)125 (23)

Cirrhosis, n (%) 3 (1) 259 (27) 420 (76)

Decompensated cirrhosis, n (%)b 5 (2) 104 (11) 189 (34)

Median HCV RNA, log10 6.0 6.3 6.2

HIV, n (%) 1 (0.3) 55 (6) 14 (3)

96% 97% 95%

0

20

40

60

Patie

nts

(%)

80

100

8b 12c 24c

Treatment Duration (Weeks)

244/255 881/910 486/510

GT 1 adult patients achieving SVR12 with HARVONIa

aPer-protocol population.b Subgroup of patients treated with HARVONI 8 weeks according to label (ie, GT 1 TN,

noncirrhotic, pretreatment HCV RNA <6 million IU/mL).c Of patients in HCV-TARGET who received HARVONI alone for 12 or 24 weeks, 104 (11%) and 189 (34%) had decompensated cirrhosis, respectively.

DAA = direct-acting antiviral. a HARVONI for 8 weeks can be considered in GT 1 TN, noncirrhotic patients with a

baseline viral load <6 million IU/mL.b The recommended treatment regimen and duration for TN and TE GT 1 patients with

decompensated cirrhosis (Child-Pugh B or C) is HARVONI + ribavirin for 12 weeks.

Click here for full Prescribing Information including BOXED WARNING. 6

HARVONI REAL-WORLD EXPERIENCE: HCV-TARGET4 (cont.)

IMPORTANT SAFETY INFORMATION Drug Interactions (cont.)

• Coadministration of HARVONI is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for HARVONI for more information on potentially significant drug interactions, including clinical comments.

• The overall SVR12 rate with HARVONI treatment was 96% (n = 1788)

GT 1 adult patients achieving SVR12 with HARVONIa

a For 8 (n = 282), 12 (n = 910), or 24 (n = 510) weeks. Only patients who completed treatment with HARVONI and have available virologic outcome included (per-protocol population).

94%96% 98% 96% 97%

0

20

40

60

Patie

nts

(%)

80

100

Overall YesCirrhosis Prior Treatment

No Naïve Experienced

1719/1788 633/677 1086/1111 899/941 819/846

Patients who may be considered for 8 weeks of HARVONI are adults with GT 1 HCV who are treatment-naïve without cirrhosis and have baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for HARVONI for 8 weeks were 2% (n = 2/123) in patients with baseline HCV RNA <6 million IU/mL and 10% (n = 9/92) in patients with baseline HCV RNA ≥6 million IU/mL.1

• Across the ION-1, ION-2, and ION-3 clinical trials, adverse reactions (all grades) reported in ≥5% of subjects receiving 8, 12, or 24 weeks of treatment with HARVONI were fatigue (13%-18%), headache (11%–17%), nausea (6%-9%), diarrhea (3%-7%), and insomnia (3%-6%)1

Adverse events reported in ≥5% of patients receiving HARVONI in HCV-TARGET

HARVONI, n = 1927 (%)

Any adverse event, n (%) 1217 (63) Nausea 155 (8.0)

Fatigue 436 (22.6) Diarrhea 123 (6.4)

Headache 409 (21.2) Insomnia 117 (6.1)

Infections and infestations 159 (8.3)

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HARVONI REAL-WORLD EXPERIENCE4

Efficacy in adult patients who can be considered for 8 weeks of HARVONI

SVR12 rates in GT 1, TN, noncirrhotic patients with baseline HCV RNA <6 million IU/mL

HARVONI in HCV GT 1 adults: Real-world experience from HCV-TARGET

Patients achieving SVR12 with HARVONI

Patients who may be considered for 8 weeks of HARVONI are adults with GT 1 HCV who are treatment-naïve without cirrhosis and have baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for HARVONI for 8 weeks were 2% (n = 2/123) in patients with baseline HCV RNA <6 million IU/mL and 10% (n = 9/92) in patients with baseline HCV RNA ≥6 million IU/mL.1

96% 98%

0

20

40

60

Patie

nts

(%)

80

100

HCV-TARGET

8 weeks

12 weeks

244/255 289/296

96% 97%

0

20

40

60

Patie

nts

(%)

80

100

HARVONI 8 weeks

HARVONI 12 weeks

n = 255 n = 910

HCV-TARGET<6 million IU/mL TN, NC TN, NC/CC

HCV-TARGET

IMPORTANT SAFETY INFORMATION BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with HARVONI. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Click here for full Prescribing Information including BOXED WARNING. 8

HARVONI REAL-WORLD EXPERIENCE: SUMMARY

IMPORTANT SAFETY INFORMATION Contraindications

• If HARVONI is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with HARVONI due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

• Risk of Reduced Therapeutic Effect Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with HARVONI as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Adverse Reactions

Most common adverse reactions (≥10%, all grades) were fatigue, headache, and asthenia.

The HCV-TARGET study was supported by Gilead Sciences, Inc. Real-world experience data were derived from patient medical records. Such data are longitudinal and observational in nature, and are not based on controlled clinical studies. Results from these cohorts may differ from results seen in the membership of a particular payer.

• In HCV-TARGET, overall SVR12 rates of 96% were achieved in GT 1 adult patients regardless of duration of HARVONI (8, 12, or 24 weeks)

– The overall discontinuation rate in HCV-TARGET was 2.8%

– The most common AEs were fatigue and headache

• Among GT 1 adult patients who may be considered for the HARVONI 8-week regimen, SVR12 rates for those who actually received it were similar to SVR12 rates for those who received HARVONI for 12 weeks instead

• Patients who may be considered for 8 weeks of HARVONI are adults with GT 1 HCV who are treatment- naïve without cirrhosis and have a baseline HCV RNA <6 million IU/mL. In ION-3, relapse rates for HARVONI for 8 weeks were 2% (n = 2/123) in patients with baseline HCV RNA <6 million IU/mL and 10% (n = 9/92) in patients with baseline RNA ≥6 million IU/mL

– HARVONI for 12 weeks is the recommended treatment duration for treatment-naïve patients without cirrhosis or with compensated cirrhosis. This does not include patients with decompensated cirrhosis (Child-Pugh B or C) or liver transplant recipients

– In ION-3, adverse reactions (all grades) reported in ≥5% of patients receiving 8 weeks of treatment with HARVONI were fatigue, headache, and nausea

References. 1. HARVONI [package insert]. Foster City, CA: Gilead Sciences, Inc.; April 2017. 2. US Food and Drug Administration. Draft guidance for industry. Chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment. May 2016. 3. Naggie S, et al. N Engl J Med. 2015;373:705-713. 4. Terrault N, et al. Gastroenterology. 2016;151:1131-1140.

HARVONI, the HARVONI Logo, GILEAD, and the GILEAD Logo are trademarks of Gilead Sciences, Inc., or its related companies. ©2017 Gilead Sciences, Inc. All rights reserved. HVNP0955 05/17

IMPORTANT SAFETY INFORMATION Drug Interactions

• In addition to rifampin and St. John’s wort, coadministration of HARVONI is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of HARVONI.

• Coadministration of HARVONI is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for HARVONI for more information on potentially significant drug interactions, including clinical comments.

Click here for full Prescribing Information including BOXED WARNING on hepatitis B reactivation.