HCV 2014 and beyond the interferon era

Patrick M. Horne, MSN, ARNP, FNP-BCAssistant Director of Hepatology Clinical Research

Division of Gastroenterology, Hepatology and NutritionUniversity of Florida Health

Disclosures and Off-label Discussion• Financial relationships to disclose within

the past 12 months:• Scientific consultant for Gilead Sciences

• Off-label discussion:• Combination sofosbuvir + simeprevir

Objectives• Discuss the history and worldwide

prevalence of hepatitis C• Review the current approved therapeutic

options for HCV therapy based on genotype• Discuss some future treatment options in

development

6%

16%

34%42%

55%

>70%

>90%

Developments in Treatment and Cure RatesS

VR

(%

)

1991

1998

2001

2011

StandardInterferon

Ribavirin

Peginterferon

Direct Acting Antivirals

2013Protease inhibitor

Nucleoside inhibitor

SVR%

TIME

Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide

Americas12-15 M

Africa 30-40M Australia

.2 M

Western Pacific60 MWestern

Europe 5 M

Eastern Europe

10 M

Southeast Asia

30-35 M

1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28.

2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44.

United States5M

Highest Prevalence:

Egypt-4M(45% adults

>40y)

P-DS-D-159

SVR is Associated with Reduced Mortality Among HCV-infected Persons

Van der Meer, et al. JAMA 2012:308:2584-2593.

• 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment

• 192 (36%) achieved SVR

No. at risk Without SVR 405 393 382 363 344 317 295 250

207 164 135

With SVR 192 181 168 162 156 144 125 88 56 40 28

30

20

10

0

All-cause mortality

All-c

ause

mor

talit

y,

%

P<0.001

Time, y0 1 2 3 4 5 6 7 8 9 10

Without SVR With SVR

No. at risk Without SVR 405 392 380 358 334 305 277 229 187 146 119 With SVR 192 181 168 162 156 144 125 88 56 40 28

30

20

10

0

Liver-related mortality or liver transplantation

Live

r-re

late

d m

orta

lity

or li

ver

tran

spla

ntati

on, %

P<0.001

Time, y0 1 2 3 4 5 6 7 8 9 10

Without SVR

With SVR

75% of Infected Individuals Are Not Aware of Their HCV Status

1. Institute of Medicine. Hepatitis and Liver Cancer, A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC. The National Academies Press, 2010; 2.United States Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of Viral Hepatitis. 2011

CDC Releases Birth Cohort Screening Guidelines

• Adults born during 1945–1965 should receive one-time testing for HCV without prior ascertainment of HCV risk

• All persons identified with HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services

Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32.

Case 1• 60 year old Caucasian male presents

recently found to be HCV Ab positive.– Confirmatory testing confirms genotype 1a with

a viral load of 1,245,300 IU/mL.

• Hx of illicit drug use in the 1960s• Medical hx includes

– Hypertension-well controlled– GERD-well controlled with PPI

Case 1• Naïve to treatment• Baseline labs:

– AST 66, ALT 70– Total bilirubin 0.5– Hemoglobin 14.0– Platelet count 175,000– Fibrotest=F2 disease

Case 1• What do you do?

Current options• Approved options

– Pegylated interferon (Peg-INF) and ribavirin (RBV), weight based times 48 weeks

– Peg-INF, RBV plus either telaprevir (TVR) or bocepravir (BOC) for 24-48 weeks

– Peg-INF, RBV plus simeprevir (SIM) for 24-48 weeks

– Peg-INF, RBV plus sofosbuvir (SOF) times 12 weeks or SOF and RBV for 24 weeks

Current options• Not approved option but with good data

– SOF + SIM with or without ribavirin for 12 weeks- COSMOS study

• Wait for something else

Peg-INF/RBV PEG-INF/RBV/TVR or BOC

Peg-INF/RBV/SIM Peg-INF/RBV/SOF SOF/RBV0

10

20

30

40

50

60

70

80

90

100

50%

75% 80%

90%

76%

Package inserts

Recommendations for HCV Genotype 1 Treatment-Naïve

Population Recommended Regimen Duration

Treatment-naïve genotype 1 Sofosbuvir (400 mg) + PEG-INF + RBV (1000-1200 mg/d)

12 weeks

• Alternative regimens:• Simeprevir + PEG-INF+ RBV x 12 wks• SIM + SOF+/- RBV x 12 wks• SOF + RBV x24 wks

• Regimens specifically not recommended:• Peg-INF/RBV x 48 wks with or without TVR or

BOC• Monotherapy with PEG, RBV, or DAA

AASLD/IDSA Treatment Recommendations.www.hcvguidelines.org. Accessed January 31, 2014.

Peg-INF = pegylated interferon; RBV=ribavirin; DAA = direct acting antiviral

Neutrino Study

Overall

HCV GT

1 (1a, 1b, 1a/b)

1a

1b

4, 5, 6

Cirrhosis No

Yes

Race Black

Non-black

HCV RNA level <6 log10 IU/mL

≥6 log10 IU/mL

IL28BCC

Non-CC

60 70 80 90 100

SVR %

Lawitz E, et al. EASL 2013, Abstract 1411; Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

SOF + PEG-IFN + RBV

SVR by Subgroups

SVR

Genotype 1 Treatment OptionsPhase 3 Landscape

2014 (now)

PEG/RBV + SOF

DCV + ASU (1b)

SOF + LPV + RBV

SVR (est)

ABT-450+ 333 + 267 + RBV

2014-201500 1212

90%

> 94%

90%

SOF + SMV (off-label) > 90%

SOF + DCV > 94%

weeks

SOF + RBV (select populations) 60-70%

>94%

0 24-4812

Courtesy of David Nelson, M.D.

Case 2• 55 year old African-American female with

HCV genotype 2b who was a prior relapser to Peg-INF + RBV times 24 weeks.

• Liver biopsy in 2013-F3 fibrosis• Other medical hx:

– Diabetes– Hyperlipidemia– Anxiety

Case 2• Labs:

– HCV RNA 550,000 IU/mL– AST 100, ALT 98– Total bilirubin 1.0– Hemoglobin 12.5– Platelet count 110,000

Case 2• What do you do?

Options• Re-treat with Peg-INF + RBV for 48 weeks

– Prior treatment she required multiple dose reductions of Peg-INF due to side effects

• SOF + RBV for 12 weeks• Wait

Recommendations for HCV Genotype 2 Treatment-Experienced

Population Recommended Regimen Duration

Previous treatment with PEG/RBV

Sofosbuvir (400 mg) + RBV (1000-1200 mg/d)

12 weeks*

AASLD/IDSA Treatment Recommendations.www.hcvguidelines.org. Accessed January 31, 2014.

*Patients with cirrhosis may benefit by extension of therapy to 16 weeks

Population Alternative Regimen Duration

Previous treatment with PEG/RBV

Sofosbuvir (400 mg) + PEG-IFN + RBV (1000-1200 mg/d)

12 weeks

23

GT-2 GT-3

SVR12 rate (%)

FISSION

POSITRON

FUSIONFUSION

16 week

16 week

62%

12 week

12 Week

5656%%

12 week

12 week

12 week

12 week

0 10 20 30 40 50 60 70 80 90 100

Sofosbuvir + RBV in HCV GT 2/3Genotype 2 = 3

Lawitz E, et al. N Engl J Med 2013;368:1878-87. Jacobson IM, et al. N Engl J Med 2013;368:1867-77.

24 weekVALENCE

12 week

FUSION

97%

93%

61%

86%

30%

94%

62%

93%

84%

GT-2

GT-3

Case 3• 54 year old Hispanic male with HCV

genotype 3.– Diagnosed 5 years ago– Relapser to Peg-INF and RBV– Liver biopsy 2013-F1 fibrosis

• Other medical history:– Bipolar disorder– GERD– Arthritis

Case 3• Labs:

– HCV RNA 1,200,000 IU/mL– AST 55, ALT 80– Total bilirubin 0.6– Hemoglobin 13.4– Platelet count 200,000

Treatment options• Peg-INF + RBV for 24 weeks• SOF + RBV for 24 weeks• Peg-INF + RBV + SOF for 12 weeks

Recommendations for HCV Genotype 3, Treatment – Naïve/Experienced

Population Recommended Regimen Duration

Regardless of IFN eligibility Sofosbuvir (400 mg) + RBV (1000-1200 mg/d)

24 weeks

AASLD/IDSA Treatment Recommendations.www.hcvguidelines.org. Accessed January 31, 2014.

Population Alternative Regimen Duration

Consider only if eligible for IFN

Sofosbuvir (400 mg) + Peginterferon + RBV (1000-1200 mg/d)

12 weeks

Not recommended:• PEG/RBV• Telaprevir, boceprevir, simeprevir

28

GT-2 GT-3

SVR12 rate (%)

FISSION

POSITRON

FUSIONFUSION

16 week

16 week

62%

12 week

12 Week

5656%%

12 week

12 week

12 week

12 week

0 10 20 30 40 50 60 70 80 90 100

Sofosbuvir + RBV in HCV GT 2/3Genotype 2 = 3

Lawitz E, et al. N Engl J Med 2013;368:1878-87. Jacobson IM, et al. N Engl J Med 2013;368:1867-77.

24 weekVALENCE

12 week

FUSION

97%

93%

61%

86%

30%

94%

62%

93%

84%

GT-2

GT-3

VALENCE: Sofosbuvir + RBVGenotype 3 IFN naïve, ineligible or treatment failures

SOF+RBV (n=250)G3

Series10

102030405060708090

100

93 9285

60

Naïve Treatment-experienced

Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic

SVR 12 (%)

86/92 12/13 85/100 27/45

Zeuzem S et al, AASLD 2013, #1085

12 240 weeks

100

80

60

40

20

0

37

63

85

19

61 60

No Cirrhosis Cirrhosis

Impact of Duration on Efficacy of SOF in Tx-experienced GT 3

FUSION: 12 Weeks SOF/RBVFUSION: 16 Weeks SOF/RBV

VALENCE: 24 Weeks SOF/RBV

Lawitz E, et al. AASLD 2013. Zeuzem, et al. AASLD 2013.

SV

R12

(%

)

14/38

25/40

85/100

5/26

14/23

27/45

Genotype 3

n/N =

SOF = sofosbuvir; RBV=ribavirin

Lonestar-2

Peg-INF + RBV + SOF times 12 weeks

Lawitz E AASLD 2013

What about waiting?• What may be coming?

• Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.; Clinical Trials.gov

Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 2-3Treatment-Naïve 24 Week Rx

SOF × 7 days, then DCV + SOF SVR12 = 88%

Week 0 24 36

Rx NaïveGT 2 or 3

n = 44

n = 14

n = 16

12

DCV + SOF

n = 14 DCV + SOF + RBV

SVR12 = 93%

SVR12 = 86%

Drug DosingDaclatasvir (DCV): 60 mg once dailySofosbuvir (SOF): 400 mg once daily

Phase 3 Trial (NCT02032901): ongoing, but closed to enrollment

DCV + SOF

Genotype 3 (n= 150) - naïve - experienced

The New Era of HCV TherapyMultiple Direct Acting Antivirals

3’UTR5’UTR Core E1 E2 NS2 NS4BNS3 NS5A NS5Bp7 4A

HCV PIs

NS5A

Inhibitors

NS5B

Nucs

NS5B

Non-nucs

Protease

Viral enzyme

Active site

Telaprevir

Boceprevir

Simeprevir

Faldaprevir

Asunaprevir

ABT-450

MK-5172

Sovaprevir

ACH-2684

Non-enzyme

Replication complex

Daclatasvir

Ledipasvir

ABT-267

GS-5816

ACH-3102

PPI-668

GSK2336805

Samatasvir

MK-8742

Viral enzyme

Active site

Sofosbuvir

VX-135

IDX20963

ACH-3422

Viral enzyme

Allosteric site

ABT-333

Deleobuvir

BMS-791325

PPI-383

GS-9669

TMC647055

Polymerase

Courtsey of David Nelson, M.D.

HCV Future Treatment ParadigmMany Options to Choose From

NS5A + PI

+ NNI + RBVSOF + RBV

PEG-IFN + RBV

+ DAA

SOF + NS5A

+ RBV

NI: nucleotide polymerase inhibitor (SOF), NNI: non-nucleotide polymerase inhibitorPI: protease inhibitor, NS5A: NS5A replication complex inhibitor

SOF + PI

+ RBV

Direct Acting Antivirals

IL28B CC

Summary• Large cohort of patients that have yet to be

diagnosed.• Treatment options are becoming better and

short and more individualized.• More patients will have access to

medications options as we will no longer be limited by contraindications to treatment due to medical co-morbidities or side effects

Thank you!