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Debika Bhattacharya, MD, MS

Associate Clinical Professor of Medicine

University of California Los Angeles School of Medicine

Los Angeles, California

What Clinicians Should Know About

Hepatitis C Virus

San Francisco, California: May 5, 2016

FLOWED: 04/28/16

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Learning Objectives

After attending this presentation, participants will

be able to:

Summarize hepatitis C virus (HCV) screening

recommendations and rationale for screening

Describe the natural history of HCV infection

Describe emerging treatments for HCV and how the

changing landscape will impact treatment decisions in

the near future

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Objectives

Hepatitis C epidemiology and screening

Natural History

Evaluation

Genome and Drug Targets

Current Treatments

What Does SVR Really Mean?

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Objectives

Epidemiology and screening

Natural History

Evaluation

Genome and Drug Targets

Current Treatments

What Does SVR Really Mean?

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HCV Worldwide

170 million infected

Highest Asia & Africa

Egypt > 15%

USA 1.6%– 3-4 million infected

www.cdc.gov

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Worldwide prevalence of each HCV genotype by GBD

HCV genotype 1 (83.4 million cases: 46.2%)- one-third of which are in East Asia.

Genotype 3 (54.3 million: 30.1%); genotypes 2, 4, and 6 (22.8%); genotype 5 <1%.

While genotypes 1 and 3 dominate in most countries irrespective of economic

status: largest proportions of genotypes 4 and 5 are in lower-income countries.

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HCV-related deaths exceed HIV-related deaths

0

1

2

3

4

5

6

7

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Rate

per

100,0

00 p

opula

tion

Year

Hepatitis B

Hepatitis C

HIV

Ly et al. Annals Intern Med 2012, Update at ID week 2015

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Excess HCV associated Hepatic and Extra-hepatic mortality

2394 deaths after an average follow-up of 16.2 years

Lee M et al, J Infect Dis 2012;206:469–477

Causes of death Multivariate-adjusted HR (95% CI)

All causes 1.89 (1.66–2.15)

All liver-related 12.48 (9.34–16.66)

HCC 21.63 (14.83–31.54)

All extrahepatic diseases 1.35 (1.15–1.57)

All cancers, except HCC 1.32 (1.00–1.74)

Diabetes 1.49 (0.91–2.42)

Cardiovascular diseases 1.50 (1.10–2.03)

Nephritis/nephrosis 2.77 (1.49–5.15)

The REVEAL HCV Cohort Study

CI, confidence interval; HBsAg, hepatitis B surface antigen;

HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio

Slide 9 of 33 Holmberg SD et al. New Engl J Med. 2013;368:1859-1861.

Most Americans With Chronic HCV Have Not Been

Diagnosed and Few Have Been Treated

50%(1.6M)

32-38%(1.0-1.2M)

7-11%(220,000-360,000)

5-6%(170,000-200,000)

0%

10%

20%

30%

40%

50%

60%

Diagnosed Referred toCare

Treated SuccessfullyTreated

Overall: 3.2 million of U.S. population with chronic HCV

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HCV Screening

Screen with hepatitis C antibody test

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Hepatitis C Tests

Hepatitis C antibody tests

– Turn positive 8 weeks after exposure

– Immunoassays performed in lab

Sensitivity 99%, Specificity 100%

– Rapid immunoassays

HCV Rapid antibody test

Sensitivity and specificity >99% on blood

– Home-based self-collected tests

HCV RNA test

– Confirm presence or absence of infection

– Quantify HCV RNA

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HCV testing algorithm

Consider simultaneous anti-HCV and HCV RNA

A. Immunocompromised patients• Patients on hemodialysis• Transplant recipients• Advanced HIV

B. Acute HCV / Recent exposure

hcvguidelines.org

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Objectives

Epidemiology & screening

Natural History

Evaluation

Genome and Drug Targets

Current Treatments

What Does SVR Really Mean?

Slide 14 of 70

Slide 14 of 33

Resolved

Stable

Slowly

Progressive

Transplant/Death

~20%

~15% ~85%

~3%-4%/yr

~80%

~75%

~ 20-year progression rate may beaccelerated with HIV, HBV,

alcohol, and steatosis1,2

Exposure(Acute Phase)

Chronic

Cirrhosis

~4%/yr~6%/yr

ESLD HCC

10 20 30Time(yrs)

5-year survival in patients with HCC is <5%*

ESLD: end-stage liver disease

*NIH Consens Statement. June 10-12, 2002;19(3):1-46. NIH Consens Statement. March 24-26, 1997;15(3):1-41.

1. Di Bisceglie AM. Hepatology. 2000;31(4):1014-1018. 2. Bialek SR, Terrault NA. Clin Liver Dis. 2006;10(4):697-715.

Natural History of HCV Infection

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Objectives

Epidemiology & screening

Natural History

Evaluation

Genome and Drug Targets

Current Treatments

What Does SVR Really Mean?

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Evaluation of liver disease: Cirrhosis

Serum markers– Low platelets, low albumin

– Elevated PT/PTT

Clinical exam– Spider nevi (esp. on shoulders)

– Palmar erythema

– Ascites

– Splenomegaly

– Encephalopathy

Imaging– CT

– MRI

Invasive tests– Liver biopsy

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ElastographySerum

Biomarkers

Liver disease staging no longer a barrier to HCV care

Liver

Biopsy

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Evaluation of liver disease: Cirrhosis

Serum markers: APRI & FIB-4

– Fibrosure

– Fibrospect

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Transient Elastography

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Transient Elastography: HCV

2.5 kPa

Affected by weight, access of probe (2 cm), steatosis

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Evaluation of liver disease: Cirrhosis

Compensated

– Asymptomatic

Decompensated

– Symptomatic: ascites, encephalopathy

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Calculate the CTP for all cirrhotics

http://www.hepatitisc.uw.edu/page/clinical-calculators/ctp

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Objectives

Epidemiology & screening

Natural History

Evaluation

Genome and Drug Targets

Current Treatments

What Does SVR Really Mean?

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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

Potential Therapeutic Targets in the HCV

Replication Cycle

Adapted from slide courtesy of Ray ChungSlide 24 of 33

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HCV Armamentarium 2016Antiviral Agent Class

NS3 NS5ANon-Nuc

NS5BNuc

NS5B

Ledipasvir/sofosbuvir FDC

Paritaprevir/r/ombitasvir FDC + dasabuvir

Simeprevir + sofosbuvir

Sofosbuvir + ribavirin

Sofosbuvir + daclatasvir

Ledipasvir/sofosbuvir FDC

Elbasvir/grazoprevir FDC

Sofosbuvir/Velpatasvir FDC

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98 98 9995

100 97 100

0

20

40

60

80

100

SV

R12

(%

)

Velpatasvir/Sofosbuvir highly effective in patients with HCV genotype 1, 2,

3, 4 ,5 and 6 infection

Jacobson IM. HEPDART 2015

Total GT1 GT2 GT3 GT4 GT5 GT6

323

328

237

238

264

277

116

116

34

3541

41

101

5

103

5

1 death2 relapse2 LTFU

1 WC

11 relapse2 others

1 LTFU

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Participants taking velpatasvir/sofosbuvir and placebo reported

similar adverse events

SOF/VEL

12 wk

n=1035

Comparator

Regimens

Placebo

12 Week

(N = 116)Patients, n (%)

Headache 296 (29) 33 (28)

Fatigue 217 (21) 23 (20)

Nausea 135 (13) 13 (11)

Insomnia 87 (8) 11 (10)

Nasopharyngitis 121 (12) 12 (10)

Diarrhea 73 (7) 8 (7)

Cough 57 (6) 4 (3)

Irritability 49 (5) 4 (3)

Arthralgia 56 (5) 9 (8)

Back pain 56 (5) 11 (10)

Asthenia 58 (6) 9 (8)

Jacobson IM. HEPDART 2015

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Don’t rain on my parade

HCV RAVS

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HCV RAVs

Resistance-associated variants (RAV) arise when a specific amino

acid change occurs at a position that modifies the interaction with

a drug

RAVs lead to decreased viral replication (“fitness”)

Baseline prevalence of NS5A RAVs: up to 12%, depending on

sequencing methodology

RAVs increase the concentration of drug needed to inhibit viral

replication (EC50) (“resistance”)

– <2 - >1000-fold more drug needed to inhibit virus

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84%No NS5A polymorphisms

at baseline

0

16%NS5A polymorphisms

at baseline

n=294/318

93% SVR

n=318

n=1629*

*5 Subjects not successfully sequenced

Polymorphisms analyzed by deep sequencing

97% SVR

Effect of Baseline NS5A Resistance-Associated Polymorphisms on SVR

ION Phase 3 Program (ION-1, ION-2, ION-3)

Afdhal N, et al. N Engl J Med 2014; 370: 1889-98;Afdhal N, et al. N Engl J Med 2014; 370: 1483-93;

Kowdley K, et al. N Engl J Med 2014; 370: 1879-88.

AASLD/IDSA. Recommendations for testing, managing, and treating

hepatitis C. http://www.hcvguidelines.org. Accessed July 11, 2014

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NS5A RAVS impact on GT1a HCV

• NS5A RAVS in C-EDGE• Elbasvir/grazoprevir x 12 weeks • 12% (19/154) GT 1a with baseline

NS5A RAVs• 11/19 (58%) achieved SVR 12

• NS5A RAVS with > 5 fold shift to elbasvir

• 2/9 (22%) achieved SVR 12

• C-EDGE Treatment Experienced trial

• Elbasvir + Grazoprevir 16/18 weeks plus ribavirin

• 6/6 (100%) with SVR 12

Zeuzem et al AASLD 2015, Zeuzem et al Annals 2015, Kwo et al EASL 2014

Predictors of SVR 12 with 12 weeks of elbasvir/grazoprevir in treatment naïve pooled efficacy population (TN-PEP)

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Objectives

Epidemiology & screening

Natural History

Evaluation

Genome and Drug Targets

Current Treatments

What Does SVR Really Mean?

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SVR Impact on Liver-Related Outcomes

1Mira JA et al, CID 2013;56:1646-1653

Hepatic Decompensation4• Therapy is effective:

• SVR associated with decreased rates of

hepatic decompensation, hepatocellular

carcinoma, and liver-related mortality1