Jens Rosenau, MD Associate Professor of Medicine Acting Director of Hepatology Division of Digestive Diseases and Nutrition University of Kentucky

2017 Bruce Lucas Hepatology and Liver Transplant Symposium – October 13th 2017

Management of Hepatitis C in Pre- and Post-Transplant Patients

Disclosure Nothing to disclose

Learning Objectives

Principles of HCV Treatment

Where HCV Therapy Stands Now

Interferon is gone in the US; ribavirin . . . not completely

SVR in > 95% of patients

“Difficult-to-cure” populations no longer difficult – Black race – HIV coinfection – Persons who inject drugs (PWID) – Genotype 3 remains more challenging (but not by much)

Cost and access issues persist but improving

– Cirrhosis – Older age

– Renal failure and kidney transplant – Liver transplant

IFN 6 Mos

PegIFN/ RBV

12 Mos

IFN 12 Mos

IFN/RBV 12 Mos

PegIFN 12 Mos

2001 1998

2011 Standard Interferon

Ribavirin

Peginterferon

1991

PegIFN/ RBV + DAA

IFN/RBV 6 Mos

6 16

34 42 39

55 70+

0

20

40

60

80

100

DAA + RBV ± PegIFN

90+ 2013

All–Oral DAA±

RBV

Current 95+

All-Oral Therapy

Direct-Acting

Antivirals

Slide credit: clinicaloptions.com

Nearly Everyone With HCV Can Now Be Treated Successfully Very high SVR rates; therapies highly tolerable All-oral therapy for almost every pt Treatment generally just 12 wks

3’UTR 5’UTR Core E1 E2 NS2 NS3 NS5A NS5B P7

Ribavirin (RBV)

Polymerase

Ledipasvir (LDV) Daclatasvir (DCV) Ombitasvir (OBV)

Elbasvir (EBR) Velpatasvir (VEL) Pibrentasvir (PIB)

Sofosbuvir (SOF)

Dasabuvir (DSV)

NS5B NUC

Inhibitors

NS5A Replication

Complex Inhibitors

NS5B Non-NUC Inhibitors

Simeprevir (SMV) Paritaprevir (PTV/RTV)

Grazoprevir (GZR) Voxilaprevir (VOX) Glecaprevir (GLE)

NS3 Protease Inhibitors

Protease

Approved DAAs From Multiple Classes: Basis of 2017 Combination HCV Regimens

Structural Domain

4A NS4B

Nonstructural Domain

Slide credit: clinicaloptions.com

Treatment Options for Genotype 1

Recommended for GT1 Treatment-Naive or IFN-Experienced Pts Without Cirrhosis

HCV GT Recommended Regimens (All 12 Wks Except as Noted)

1a

SOF/LDV (Harvoni®) 8 wks if tx naive, nonblack, no HIV, and HCV RNA < 6 million IU/mL SOF/VEL (Epclusa®) 12 wks GLE/PIB (Mavyret®) 8 wks GZR/EBR (Zepatier®) 12 wks only if no baseline NS5a EBR RAS/16 if NS5a EBR RAS SOF (Sovaldi®) + DCV (Daklinza®) 12 SOF (Sovaldi®) + SMV (Olysio®) 12 OBV/PTV/RTV/DSV extended release (Viekira XR®) + RBV (Ribavirin) 12 or OBV/PTV/RTV + DSV BID (Viekira Pak®) + RBV (Ribavirin) 12

1b

SOF/LDV 8 wks if tx naive, nonblack, no HIV, and HCV RNA < 6 million IU/mL SOF/VEL 12 GLE/PIB 8 GZR/EBR 12 SOF + DCV 12 SOF + SMV 12 OBV/PTV/RTV/DSV extended release or OBV/PTV/RTV + DSV BID 12

Slide credit: clinicaloptions.com AASLD/IDSA. HCV guidance. October 2017.

Recommended for GT1 Treatment-Naive or IFN-Experienced Pts With Compensated Cirrhosis

HCV GT Recommended Regimens (All 12 Wks)

Treatment Naive IFN/RBV Experienced

1a

SOF/VEL 12 GLE/PIB 12 GZR/EBR* 12/16 SOF/LDV 12

SOF/VEL 12 GLE/PIB 12 GZR/EBR* 12/16 SOF/LDV + RBV 12

1b

SOF/VEL 12 GLE/PIB 12 GZR/EBR 12 LDV/SOF 12 OBV/PTV/RTV+ DSV BID 12

SOF/VEL 12 GLE/PIB 12 GZR/EBR 12 LDV/SOF + RBV 12 OBV/PTV/RTV+ DSV BID 12

*12 weeks only if no baseline NS5A elbasvir RASs detected.

Slide credit: clinicaloptions.com AASLD/IDSA. HCV guidance. October 2017.

Adjust EBR/GZR Duration Based on Baseline NS5A RASs in GT1a

C-EDGE Treatment Naive: 12 Wks of Elbasvir/Grazoprevir SV

R12

(%)

All All No BL NS5A RASs

92 99 99

58

144/157 129/131 133/135 11/19 n/N =

100

80

60

40

20

0 BL NS5A RASs

GT1a GT1b

Slide credit: clinicaloptions.com Zeuzem Z, et al. Ann Intern Med. 2015;163:1-13. Kwo P, et al. J Hepatol. 2015;62(suppl 2):S674-S675.

If NS5A RASs in GT1a, treat with EBR/GZR + RBV for 16 wks (alternative) No baseline RAS testing needed in GT1b pts

Resistance Considerations

Most pts with failure of current DAAs have emergent resistance-associated substitutions (RASs)

– NS5A RASs persist much longer than PI RASs

15% of pts have baseline NS5A RASs with variable effects on GT1a response

Second-generation drugs designed to cover RASs

Which classes are prone to resistance?

Protease, NS5A, and nonnucleotide NS5B

inhibitors

Barrier to PI and NS5A resistance Higher for GT1b vs GT1a

Slide credit: clinicaloptions.com

Glecaprevir/ Pibrentasvir (Mavyret®) in Noncirrhotic Patients:

ENDURANCE Studies

ENDURANCE-1, -2, -3: GLE/PIB for Treatment of GT1, 2, 3 HCV

ENDURANCE-1: randomized, open-label phase III trial[1]

GLE/PIB* (n = 351)

GLE/PIB* (n = 352)

*Dosing: GLE/PIB given as 3 coformulated 100/40-mg tablets QD for a total dose of 300/120 mg. †Treatment experience permitted: IFN or pegIFN ± RBV or SOF + RBV ± pegIFN.

Noncirrhotic pts with GT1 HCV with or without IFN experience or HIV coinfection

(N = 703; 38% tx-experienced†)

Wk 8 Wk 12

GLE/PIB* (n = 202)

Placebo (n = 100)

Noncirrhotic pts with GT2 HCV with or without IFN experience

(N = 302; 29% to 30% tx-experienced†)

ENDURANCE-2: randomized, double-blind, placebo-controlled phase III trial[2]

Slide credit: clinicaloptions.com

ENDURANCE-1, -2 Studies: Efficacy of GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV

*ITT-PS analysis: included all pts receiving ≥ 1 dose of study drug; excluded pts with HIV coinfection or SOF experience. †ITT analysis: excluded pts with SOF experience. ‡ITT analysis.

Slide credit: clinicaloptions.com 1. Zeuzem S, et al. AASLD 2016. Abstract 253. 2. Kowdley KV, et al. AASLD 2016. Abstract 73. 3. Asselah T, et al. AASLD 2016. Abstract 114.

1 case of on-treatment virologic failure at Day 29 in pt with GT1a HCV infection

100

80

60

40

20

0

SVR

12 (%

)

99.1* 99.7* 99†

332/ 335

331/ 332

195/ 196

8 Wks 12 Wks

n/N =

12 Wks

ENDURANCE-1 (GT1)[1]

ENDURANCE-2 (GT2)[2]

ENDURANCE-1, -2 Studies: Safety of GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV

Outcome, %

ENDURANCE-1[1] ENDURANCE-2[2]

GLE/PIB 8 Wks

(n = 351)

GLE/PIB 12 Wks

(n = 352)

GLE/PIB 12 Wks

(n = 202)

PBO 12 Wks

(n = 100) Any AE 62 66 65 58

D/c for AE 0 < 1 0 0

Serious AE 1 1 1 1

Death 0 < 1 0 0

AE in ≥ 10% of pts

Fatigue 9 12 11 10

Headache 19 18 12 12

AST grade ≥ 3* 0 < 1 1 1

ALT grade ≥ 3* 0 0 < 1 2

Total bilirubin grade 3† < 1 < 1 < 1 0

*> 5 times ULN. †3-10 times ULN.

Slide credit: clinicaloptions.com 1. Zeuzem S, et al. AASLD 2016. Abstract 253. 2. Kowdley KV, et al. AASLD 2016. Abstract 73. 3. Asselah T, et al. AASLD 2016. Abstract 114.

Sofosbuvir/ Velpatasvir/ Voxilaprevir (Vosevi®):

POLARIS Studies

POLARIS-1 and -4: SOF/VEL/VOX in DAA-Experienced Pts

SOF/VEL/VOX 400/100/100 mg PO QD

(n = 263)

Placebo PO QD (n = 152)

DAA-experienced pts with GT1-6 HCV and NS5A inhibitor experience with or without

cirrhosis (pts with GT1 HCV randomized between arms;

pts with GT2-6 assigned to SOF/VEL/VOX) (N = 415)

Stratified by cirrhosis status (yes or

no)

Wk 12

Subsequently received deferred SOF/VEL/VOX

Slide credit: clinicaloptions.com References in slidenotes.

SOF/VEL/VOX 400/100/100 mg PO QD

(n = 182)

SOF/VEL 400/100 mg PO QD

(n = 151)

DAA-experienced pts with GT1-6 HCV and no NS5A inhibitor experience with or without cirrhosis (pts with GT1-3 HCV randomized between arms; pts with GT4-6 assigned to

SOF/VEL/VOX) (N = 333)

Stratified by HCV genotype, cirrhosis status (yes vs no)

POLARIS-1: randomized, double-blind, placebo-controlled phase III trial[1,2]

POLARIS-4: randomized, open-label, active-controlled phase III trial[1,3]

FDA approval for adults with genotype 1, 2, 3, 4, 5 or 6 previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor

POLARIS-2, -3: Safety of SOF/VEL/VOX for 8 Wks

Outcome, %

POLARIS-2 POLARIS-3

SOF/VEL/VOX 8 Wks (n = 501)

SOF/VEL 12 Wks

(n = 440)

SOF/VEL/VOX 8 Wks (n = 110)

SOF/VEL 12 Wks

(n = 109) Any AE 72 69 75 74 Serious AE 3 2 2 3 D/c for AE 0 < 1 0 1 Death 0 0 1 0 AE in > 10% of pts

Headache 27 23 25 29

Fatigue 21 20 25 28 Diarrhea 18 7 15 5 Nausea 16 9 21 9

Slide credit: clinicaloptions.com Jacobson IM, et al. Gastroenterology. 2017;[Epub ahead of print].

Treatment of Hepatitis C Pre- and Post Liver Transplantation

- Treatment of Decompensated Cirrhosis

- Special Considerations for post-transplant treatment

1 relapse in pt with GT3a HCV; 1 pt LTFU

GT 1 n=57, GT 2 n=13, GT3 n=24, all non-cirrhotic, F0-1 80%, Tx naïve 66%, Liver Transplant 80%

MAGELLAN-2: GLE/PIB in GT1-6 HCV With Liver or Renal Transplant

Slide credit: clinicaloptions.com Reau N, et al. EASL 2017. Abstract LBO-03. Reproduced with permission.

SVR

12 (%

)

98 99

98/ 100

98/ 99 n/N =

0 20 40 60

80 100

ITT mITT

No deaths during study, 1 pt with transplant rejection (unrelated to DAA)

Safety Outcome, % GLE/PIB (N = 100) Any AE 85

Serious AE DAA related

8 2

AEs leading to d/c DAA related

1 0

AEs in ≥ 10% of pts Headache Fatigue Nausea Pruritus

22 22 12 12

Grade ≥ 3 abnormality AST ALT Total bilirubin CrCl

0 1 1 2

SVR12 With GLE/PIB by ITT or mITT

Linkage to Care

HCV in the US: Gaps in Current Practice Pt

s (%

)

n = 3,500,000 1,743,000 1,514,667 952,726 581,632 555,883 326,859

0

20

40

60

80

100

Chronic HCV

Infected

Diagnosed and

Aware

Access to

Care

HCV RNA Confirmed

Liver Biopsy

Prescribed HCV

Treatment

Achieved SVR

100%

50% 43%

27% 17% 16% 9%

Yehia BR, et al. PLoS One. 2014;9:e101554.

University of Kentucky: Treatment Uptake after Referral to Care

1,049 new consults for HCV

(ICD-9 codes)

Confirmed HCV (RNA positive)

Enrolled (n=881)

RNA undetectable

Excluded (n=136)

RNA unavailable (Did not

complete lab)

Excluded (n=32)

Racho et al., DDW 2017

Patient Characteristics

Summary of cohort, n=881 – Avg age 43 +/- 12 – Born after 1965 (64%) – Male (53%) – White (93%) – Genotype 1 (68%) – Low fibrosis (F0-F2) (64%) – Medicaid insurance (73%) – Lifetime injection drug use (73%)

Age ≤ 30y – 30% Age 31-40y – 39% Age >40y – 30%

Racho et al., DDW 2017

Geographic Distribution of UK HCV referrals 5-year period from 7/2010 to 6/2015

Abdelwadoud et al. AASLD 2017

Project ECHO® (Extension for Community Health Outcomes)

Moving Knowledge Instead of Patients http://echo.unm.edu/

Trea

tmen

t Ini

tiatio

n Ra

te

Treatment Uptake by Insurance Type and Liver Fibrosis Stage

Racho et al., DDW 2017

n = 448

Total n = 881

n = 198 25%

33%

3% 6%

- Motivation: Reasons pat. wants to start HCV treatment, concerns about treatment, importance of treatment. - Information: Knowledge about HCV treatment and one’s own HCV disease status. - Medication Adherence: Current prescribed medications and adherence to them in prior month. - Self-Efficacy: Self-confidence about adhering to HCV treatment. - Social Support and Stability: Stability of financial, housing, and social support resources. - Alcohol and Substance Use: Alcohol and substance use behaviors and current treatment. - Psychiatric Stability: Current psychiatric status, previous and current treatment. - Energy Level: Sleep and fatigue. - Cognitive Functioning: Perceived difficulty with communication, problem-solving ability, and memory.

Psychosocial Readiness Evaluation and Preparation for Hepatitis C Treatment: PREP-C

https://prepc.org

Drug-Drug- Interactions

with Calcineurin Inhibitors