HCV Monoinfection: The End of the Beginning or the Beginning of the End

Andrew Talal, MD, MPHProfessor of MedicineSUNY BuffaloDirector, Center for Research and Clinical Care in Liver Disease

Disclosures• Advisor

• Merck and Co• Gilead Sciences• Abbvie• Abbott Diagnostics• Pfizer

• Research• Merck• Abbvie• Gilead• Abbott Diagnostics• Galectin Pharmaceuticals

Changes in Prevalence of Chronic Liver Diagnoses in US-1988 to 2008 (N=39,750)

0

2

4

6

8

10

12

ALD CH-B HCV(+) NAFLD

1988-1994 (N=15,855) 1999-2004 (N=13,970) 2005-2008 (N=9670)NHANES CYCLES

Prev

alen

ce ra

tes

(%)

• In comparison to the prevalence of other etiologies, NAFLD is the most common cause of chronic liver disease• Because of the increasing wave of obesity in children, the disease burden from NAFLD will continue to increase

Younossi Z et al. Clin Gastro and Hep 2011

HCV vs. HIV vs. HBV PrevalenceTo

tal N

o. In

fect

ed

(mill

ions

)

DiagnosedUndiagnosed

2.7 to 3.9 Million1

75% Unaware of Infection

1.1 Million1

21% Unaware of Infection~800,000 to 1.4 Million1

65% Unaware of Infection

HIV HBV HCV

4

3

2

1

0

Prevalence of Chronic Viral Infections

• Estimated 5.2 million persons in US are HCV infected2

HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus. 1. Institute of Medicine. Washington, DC: The National Academies Press; 2010.2. Chak E, et al. Liver Int. 2011;31(8):1090-1101.

Deaths From HCV vs. HIV

Change in Mortality Rates From 1999 to 2007

Rat

e pe

r 100

,000

Peo

ple

7

6

5

4

3

2

1

01999 2000 2001 2002 2003 2004 2005 2006 2007

Year

HIV

Hepatitis C

Hepatitis B

15,10612,734

1,815

Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.

Majority of HCV-Infected Individuals Are Baby Boomers (Born Between 1945–1965)

Indi

vidu

als,

N

Birth Year Group

0

1,600,0001,400,0001,200,0001,000,000

800,000600,000400,000200,000

1990+1980–1989

1970–1979

1960–1969

1950–1959

1940–1949

1930–1939

1920–1929

<1920

Estimated Prevalence by Age Group

Centers for Disease Control and Prevention. MMWR. 2012;61(RR-4):1-32.

Who Should Be Screened for HCV ?

CDC Recommendations• Everyone born from 1945 through 1965 (one-time)• Persons who ever injected illegal drugs• Persons who received clotting factor concentrates

produced before 1987• Chronic (long-term) hemodialysis• Persons with persistently abnormal ALT levels• Recipients of transfusions or organ transplants prior

to 1992• Persons with recognized occupational exposures• Children born to HCV-positive women• HIV positive persons

USPSTF Grade B Recs*• Everyone born from 1945 through 1965 (one-time)• Past or present injection drug use• Sex with an IDU; other high-risk sex• Blood transfusion prior to 1992• Persons with hemophilia• Long-term hemodialysis• Born to an HCV-infected mother• Incarceration• Intranasal drug use• Receiving an unregulated tattoo• Occupational percutaneous exposure• Surgery before implementation of universal

precautions

*Only pertains to persons with normal liver enzymes; if elevated liver enzymes, need HBV and HCV testingSmith at al. Ann Intern Med 2012; 157:817-822. Moyer et al. Ann Intern Med 2013;159(1):51-60

NYS HCV Screening LawHepatitis C Virus Testing (Chapter 425 of the Laws of 2013)This new law requires a hepatitis C virus screening test to be offered to all patients born between 1945 and 1965 who are receiving health services as a hospital inpatient or receiving primary care services and applies to physician, physician assistant, or nurse practitioner.

The law further requires that the health care provider refer a patient who receives a positive screening test to another provider to receive confirmatory testing and follow-up care.

HCV Can Now Be Cured in Most Patients• Unlike HIV and HBV infection, HCV infection is a curable

disease• What does cure mean?

• Sustained Viral Response• Undetectable HCV RNA 12 weeks after completion of antiviral

therapy for chronic HCV infection1

• Long term morbidity and mortality benefits

1. Ghany MG, et al. Hepatology. 2009;49(4):1335-1374.

SVR Reduces HCC and Liver-Related Complications in Advanced Fibrosis/Cirrhosis

HCC (n=307)

Liver-Related Complications* (n=307)

Cum

ulat

ive

Inci

denc

e (%

)

Follow-Up (years)

Cum

ulat

ive

Inci

denc

e (%

)

Follow-Up (years)*Ascites, variceal bleeding. 307 HCV patients with bridging fibrosis (n=127) or cirrhosis (n=180) were evaluated by Cox regression analysis.Non-SVR in 67% of patients treated with pegylated interferon plus ribavirin. Median follow-up: 3.5 years.Cardoso A-C, et al. J Hepatol. 2010;52:652-657.

SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study

Years Years Years

Cum

ulat

ive

Mor

talit

y (%

)

Genotype 1(n=12,166)

SVR rate: 35%

Genotype 2(n=2904)

SVR rate: 72%

Genotype 3(n=1794)

SVR rate: 62%

Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility (2001-2008).SVR=sustained virological response.Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.

Therapeutic Targets in HCV Lifecycle

Translation

HCV NS proteins

NS2

Polyprotein processing

NS3

NS4B

NS5A NS5B

HCV RNA

Fusion and uncoating

RNA replication

NS5A

CypA

NS5B

NS2

NS3

NS4B

Viral assembly

Transport and release

NS3/4A protease inhibitors NS5A

inhibitors

NS5B polymerase inhibitors

NS5A inhibitors

GENOTYPE 1

Viral targets for direct acting antivirals

C p7 NS2 NS3 NS4B NS5BNS4AE1 E2Core Envelope

GlycoproteinsProtease Serine Helicase

ProteaseSerineProteaseCofactor

RNA-dependent RNA polymerase

NS3-4A protease inhibitors

NS5B polymeraseinhibitors

nucleoside analogues non-nucleoside inhibitors

NS5A

McGovern et al. Hepatology 2008;48:1700-12

Needed for ReplicationAssembly

NS5A inhibitors

IFN-free HCV Treatment Regimens• Currently approved

• Sofosbuvir/ledipasvir FDC• Paritaprevir/r/ombitasvir

FDC + dasabuvir• +Ribavirin (geno 1a only)

• Simeprevir + sofosbuvir• Sofosbuvir + ribavirin• Daclatasvir*+ sofosbuvir

• In development• Grazoprevir/elbasvir +

MK-3682 (nuc)• ABT-493 (PI) + ABT-530

(NS5A)• SOF/GS5816

(NS5A)/GS9857 (PI)

*approved in EU; pending US FDA approval

Characteristics of HCV DAA Classes

CharacteristicProtease inhibitors

(SMV, PAR/r, GRZ)

Nucleos(t)idePolymerase inhibitors

(SOF)

NonnucleosidePolymerase inhibitors

(DAS)

NS5A inhibitors(LDV, OMB, DCV, ELB)

Potency High;Variable among

genotypes

Moderate-highPangenotypic

Variable;variable among

genotypes

High;variable among

genotypes

Barrier to Resistance

Low1a < 1b

High1a = 1b

Very Low1a < 1b

Low1a < 1b

Drug Interaction CYP3A4OATP1B1/3

P-gpUGT1A1

Minimal CYP2C8UGT1A1

OATP1B1/3, BCRP, P-gp

UGT1A1

Dosing QD QD QD to BID QD

Simeprevir + Sofosbuvir +/- RBV: COSMOS• Cohort 1 (n=80): Null

responders F0-2

Lawitz et al. Lancet 2014;384: 1756-65

93.3

79.2

93.3 96

0

25

50

75

100

No Ribavirin Ribavirin

SVR12

12 weeks 24 weeks

93 93100

93

0

25

50

75

100

No Ribavirin Ribavirin

SVR12

12 weeks 24 weeks

• Cohort 2 (n=84): Naïve and null responders F3-4

Ledipasvir/SofosbuvirLedipasvir• Picomolar potency against

HCV GT 1a and 1b1• Effective against NS5B RAV S282T2• Once daily, oral, 90 mgSofosbuvir• Potent antiviral activity against

HCV GT 1–6• High barrier to resistance• Once daily, oral, 400-mg tabletLedipasvir/Sofosbuvir FDC• Once daily, oral fixed-dose

(90/400 mg) combination tablet• No food effect

19

LDVNS5A inhibitor

SOF nucleotide polymerase inhibitor

LDVNS5A inhibitor

SOF nucleotide polymerase inhibitor

LDV/SOF + RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-naïve Patients (ION-1)

SVR

12 (%

)

179/179

178/178

181/182

179/179

12 Weeks 24 Weeks

LDV/SOF + RBV

LDV/SOF + RBV

LDV/SOF

LDV/SOF

Non-cirrhotic Cirrhotic

32/33

33/33

31/32

36/36

LDV/SOF + RBV

LDV/SOF + RBV

LDV/SOF

LDV/SOF

12 Weeks 24 Weeks

SVR

12 (%

)

Afdhal et al. N Eng J Med 2014;370:1889-98

0

20

40

60

80

100

SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV

LDV/SOF + RBV for 12 vs 24 Wks: SVR12 in GT 1 Treatment-experienced (ION-2)

12 weeks 24 weeksAfdhal et al, N Engl J Med 2014;370:1483

110/111 0

20

40

60

80

100

SOF/LDV SOF/LDV+RBV SOF/LDV SOF/LDV+RBV

86 82

100 100

19/22

18/22

22/22

22/22

Cirrhotics94 96 99 99

12 weeks 24 weeks

SV

R12

(%)

SV

R12

(%)

102/109

108/109

107/111

110/111

All participants

LDV/SOF+RBV for 8 vs 12 Wks: SVR12 in GT 1 Treatment-naïve Non-cirrhotics (ION-3)

94 93 95

0

20

40

60

80

100

p=0.70 p=0.30

8 Weeks 12 Weeks

LDV/SOFLDV/SOF LDV/SOF + RBV

201/216202/215 206/216

SV

R12

(%)

p=0.52

Error bars represent 95% confidence intervals.Kowdley KV et al. N Eng J Med 2014; 370:1879-88

GT 1 Treatment Naïve Non-Cirrhotics: Baseline Viral Load Defines Treatment Duration

LDV/SOF8 Weeks(N=215)

LDV/SOF12 Weeks(N=216)

SVR12 94% (202/215) 96% (208/216)

Relapse RatesOverall

<6 M IU/mL>6 M IU/mL

5% (11/215)

2% (2/123)10% (9/92)

1% (3/216)

2% (2/131)1% (1/85)

8 week LDV/SOF regimen should only be considered in GT 1, treatment-naïve, non-cirrhotic patients with BL viral load <6 million IU/mL

Ledipasvir/sofosbuvir (HARVONI™) Prescribing Information. Gilead Sciences, Foster City, CA. October, 2014 (Adapted from Table 6).

Paritaprevir (PI)/ritonavir/Ombitasvir(NS5A) + Dasabuvir (NNI) + RBVSAPPHIRE-1 (Placebo-Controlled); genotype 1, noncirrhotic, 12 weeks

SVR

12 (%

)

96 95 98

455/473 307/322 148/151

Feld JJ et al, N Engl J Med 2014;370:1594-1603

Paritaprevir/r-Ombitasvir + Dasabuvir + RBVSAPPHIRE-1

• Genotype 1, treatment naïve, 12 weeks, n=473

0

20

40

60

80

100

Gender Race Age BMI Fibrosis IL28B HCV RNA RBV dosereduction

95 98 96 96 97 96 97 92

9793

Male Female BlackNon-black <55 >55 <30 >30 F0-2 F3 CC <800K >800K Yes No

97 96 96 969894

Non-CC

Feld JJ et al, N Engl J Med 2014;370:1594-1603

SVR

12 (%

)

GENOTYPES 2 AND 3

Sofosbuvir in Treatment-Naive GT 2, 3 Patients

67

SVR

%

67

78

97

0

20

40

60

80

100

SOF 400 mg + RBV x 12w

PEG-2a q/wk + RBV x 24w

n = 243 70253Overall

67GT2 GT3

5663

183 176

Lawitz E et al., NEJM 2013; 368:1878-87

SOF/RBV GT 2 or 3 Treatment-Naive and Experienced: VALENCE

94 92 9391

68

85

0

25

50

75

100

No cirrhosis Cirrhosis Overall

SVR

12 (%

)

SOF/RBV x 12w (GT2, n = 73) or 24 W (GT3, n = 250) G2 (blue); G3 (red)

Zeuzem et al, N Engl J Med 2014; 370:1993

SOF/RBV for Treatment-Naive and Experienced with GT 2 or 3: VALENCE

Treatment-naive19% w/ cirrhosis

Prior treatment25% w/ cirrhosis

Daclatasvir + sofosbuvir

Daclatasvir + sofosbuvir

ALLY-3

N = 101

N = 51

0 Weeks 12 24EOT SVR

99% 90%

99%

SVR F0-F3 = 96% (105/109)SVR F4 = 63% (20/32)

• No SAEs related to treatment, no premature D/C due to AEs• Most AEs mild: fatigue, headache, nausea, diarrhea• Longer duration being examined for cirrhotics

Nelson D et al, Hepatology 2015;61:1127

86%

SVR12 for SOF + GS-5816 (pangenotypic NS5A) ± RBV for 12 Wk in

Treatment-Naive Patients with GT 1-6 HCV

9691 93

100 10093

0

20

40

60

80

100

GT 1 GT 2 GT 3

SOF + GS‐5816 25mg SOF + GS‐5816 100mg

12 weeks w/o RBVGT 1, 2, 3

Noncirrhotic

Dose finding for GS-5816, pangenotypic NS5A inhibitor

Tran, Abst # 80, AASLD 2014

AASLD, IDSA, IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 12, 2014.

When and in Whom to Initiate HCV Therapy

• Treatment is recommended for patients with chronic HCV infection (Class I, Level A)• Treatment is assigned the highest priority for those patients with

advanced fibrosis (METAVIR F3), those with compensated cirrhosis (METAVIR F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C

• Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications are given high priority

Current Status of HCV in the US: Screening and Linkage to Care Rates Remain Low

US population with chronic HCV infection3.2 million

HCV detected1.6 million (50%)

Referred to care1.0 – 1.2 million (32%-38%)

HCV RNA test630,000 – 750,000 (20-23%)

Treated220,000 – 360,000 (7-11%)

Successfully treated170,000 – 200,000 (5-6%)

Liver biopsy380,000 – 560,000 (12%-18%)

Holmberg SD et al, New Engl J Med. 2013; 1859-1861.

Highly Efficacious Treatments Are Not Enough

100%

20%

10%

Diagnosisand treatment

Cure

All HCVpatients

PEG-IFN/RBV

100%

20%

95% SVR

19%

100%

90%

85%

95% SVR and higher ratesof diagnosis/treatment

Slide courtesy of Prof. Michael Manns

Clinical Liver Program

Liver Regional Biobank

Manhattan

Buffalo

Sites for Sample Collection

BGMC

6

VA

UBSMBS

ECMC

RPCI

Dent Tower

WCHOB

Telemedicine Consultation

HCV Prevention, Evaluation and Treatment• Many OTPs offer on‐site HIV treatment but have not embraced HCV treatment

• Does recent developments (improvements in efficacy and ease of HCV treatment) increase likelihood of OTP initiation of on site HCV therapy?

• Best to build on foundation of OTP that offers HIV treatment • Telemedicine offers opportunity to remotely link patients with physicians geographically  separated.

• Study objectives– To demonstrate feasibility of HCV management via  tele‐care in an OTP.

– To assess staff and patient knowledge and perception changes towards HCV treatment after educational intervention

40

General ExamCamera

Dental IntraoralCamera

Telephonic Stethoscope

Electronic MedicalRecord(EMR)

Video with LCD Monitor

Telemedicine System – Patient End

ENT Scope

Conclusions• Liver Center has brought clinical care and research for

liver disease to Western New York• New treatments for HCV are highly effective

• Minimal side effects • Much shorter treatment duration• No injections!

• Why focus on liver disease?• Common conditions that are underdiagnosed with new therapies

are available (HCV) or will soon be available (fatty liver)

• Strong clinical and educational programs• Facilitate study subject enrollment• Encourages referrals from community physicians• Encourages trainees to participate in research and potentially to

follow research careers.

Acknowledgments• Cornell

– Ira Jacobson, MD– Marija Zeremski, PhD– Samantha Benjamin

• University at Buffalo– Tony Martinez, MD– Rositsa Dimova, PhD– Gene Morse, PharmD– Yvonne Woolwine Cunningham, MS– Jun Qu, PhD– John Tomaszewski, MD

• Financial support– NIH/NIAID and NIDA– Troup Fund of Kaleida Health– Abbvie– CDC Foundation