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Hepatitis C – No Barriers to Cure

Dr. Mauricio Lisker MelmanProfessor of Medicine

Director Hepatology ProgramDivision of Gastroenterology

2018 Digestive Diseases Conference Kansas

Disclosure

The following are my disclosures. Potential conflicts of interest have been resolved.

Research Support / Grants NIHSpeakers Bureau / Honoraria Abbvie

GileadMerckSimplySpeaking

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Over 5.2 Million People Living With Chronic HCV in the US

0

1

2

3

4

5

6

7

8

Num

ber o

f HC

V C

ases

(mill

ions

)

3.2

NHANESEstimate

*Homeless (n=142,761-337,6100); incarcerated (n=372,754-664,826); veterans (n=1,237,461-2,452,006);

active military (n=6805); healthcare workers (n=64,809-259,234); nursing home residents (n=63,609);

chronic hemodialysis (n=20,578); hemophiliacs (n=12,971-17,000).

1.9

HCV Cases Not Included in NHANES*

Chak E, et al. Liver Int. 2011; 31:1090-1101.

3.8

5.2

7.1Conservative estimateUpper limit of estimate

EstimatedTotal HCV Cases

WHO Target for HCV2030

Is it a dream?

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The CDA Foundation. Hepatitis C – USA. Lafayette, CO: CDA Foundation, 2017.Available from http://polarisobservatory.org/ (Accessed 12-19-2017)

The CDA Foundation. Hepatitis C – USA. Lafayette, CO: CDA Foundation, 2017. Available from http://polarisobservatory.org/ (Accessed 12-19-2017)

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7

There is a wide range of prevalence, diagnosis rates, and treatment rates across the European Union

SVK

POLROU

LTUBGR

HRV

GRC

CZE

PRT

ITA

AUT

GBRIRL

ESP

LVA

BELHUN

EST

SVN

NLD

DEU

DNK

FRA

FIN

SWE

LUX

MLT

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Trea

tmen

t Rat

e

Diagnosis Rate

Bubble Diameter: HCV Prevalence 2% 1% 0.5%

Source: Polaris Observatory (http://www.polarisobservatory.com/)

The virus and Sustained Virologic Response

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Sustained Virologic Response (SVR)

Treatment Regimen

0 EOT*

Treatment Durationweeks

(8, 12, 16, 24)

*EOT: End of treatment

SVR

Off Treatment Observationweeks

(12)

M. Lisker Melman, 2017

SVR is significantly associated with reduction in all-cause mortality

Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.

Retrospective analysis of veterans who received pegIFN + RBV at any VA medical facility (2001-2008).

Cum

ulat

ive

Mor

talit

y (%

)

0 1 2 3 4 5 6

Genotype 1(n=12,166)

Years0

0.05

0.1

0.15

0.2

0.25

0.3

Cum

ulat

ive

Mor

talit

y (%

)

0 1 2 3 4 5 6

Genotype 2(n=2904)

Years0

0.05

0.1

0.15

0.2

0.25

0.3

Cum

ulat

ive

Mor

talit

y (%

)

0 1 2 3 4 5 6

Genotype 3(n=1794)

Years0

0.05

0.1

0.15

0.2

0.25

0.3

SVR

Non-SVR

P<0.0001

SVR rate: 35%

SVR

Non-SVR

P<0.0001

SVR rate: 72%

SVR

Non-SVR

P<0.0001

SVR rate: 62%

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Impact of SVR on HCC and liver-related complications

0

20

40

60

80

100

0 2 4 6 8 10 12

HCC

Cum

ulat

ive

Inci

denc

e (%

)

Follow-Up (Years)

SVR

0

20

40

60

80

100Liver-Related Complications

Cum

ulat

ive

Inci

denc

e (%

)0 2 4 6 8 10 12

Follow-Up (Years)

Non-SVR

P<0.001

SVR

Non-SVR

P<0.001

Single-center cohort. Non-SVR in 67% of patients treated with pegIFN + RBV. Median follow-up: 3.5 years.Total patients (n=307). Number of events: HCC (n=46); liver-related complications (n=31).

Cardoso A-C, et al. J Hepatol. 2010;52:652-657.

SVR is associated with improved outcomes

• Sustained viral response– Durable

• 99% stay HCV negative for >10 years

– Leads to improved histology – Leads to clinical benefits– Decreased decompensation – Prevents de novo esophageal varices– Decreased hepatocellular carcinoma– Decreased mortality

Bruno S, et al. Hepatology. 2010;51:2069-2076.Veldt BJ, et al. Ann Intern Med. 2007;147:677-684.Maylin S, et al. Gastroenterology. 2008;135:821-829.

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HCV Therapy: A Successful History

Ribavirin1998

PegylatedInterferons

2001

HCV Therapy: A Successful History

2016…1990 2000 2005 2010 2011 2012 2013 2014

Interferon1991

Pre-DAA Era:Overall SVR rates 40-50%

Genotype 1M. Lisker Melman, 2017

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HCV Treatment Challenges in the IFN Era

Lower efficacy • SVR between

40%-50% for GT 1

• Lower real-world efficacy compared with clinical trials

Tolerability and toxicity• IFN and RBV• Frequent

monitoring

Up to

48Weeks

Longer courses of therapy• Up to 48 weeks• Response-guided

therapy needed for shorter courses

More complicated regimens • Multiple pills daily• Weight-based dosing

Hepatitis C in the USA

100%

0

50%

75%

25%

3.2 million

HCV in USA

1.6 million

Diagnosed

50%

1-1.2 million32-38%

Referredto care

220 000 to360 000

Treated

7-11%

170 000 to200 000

5-6%

Successfully Treated

NEJM 2013;368:1859-1861

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Ribavirin1998

PegylatedInterferons

2001

HCV Therapy: A Successful History

2016…1990 2000 2005 2010 2011 2012 2013 2014

Interferon1991

Telaprevir andboceprevir

2011

Simeprevir or sofosbuvir with IFN (GT1)

Sofosbuvir+RBVwith IFN (GT1)

Pre-DAA Era:Overall SVR rates 40-50%

Genotype 1

Early-DAA Era:Overall SVR rates 65-75%

Genotype 1

Early-DAA EraTelaprevir, Boceprevir

First generation

DAAs

Genotype 1 activity

Improve SVR rates even

further

Increase the burden of AEsX

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The HCV Genome

C E1 E2 NS2 NS3 4A 4B NS5A NS5B

1 384 747 810 1027 1658 1712 1973 2421 3011192

P7

Structural Proteins Non-structural Proteins

5’IRES ~9.6 kb

3’ NCR

Translation

3,000 AA polyproteinProtease Inhibitors

Replicative ComplexInhibitors

PolymeraseInhibitors

Timeline of Recent DAA Therapies

October 2014 – Sofosbuvir/Ledipasvir

December 2014 – Paritaprevir/ritonavir, Ombitasvir, Dasabuvir, Ribavirin

July 2015 – Daclatasvir

July 2015 – Paritaprevir/ritonavir, Ombitasvir

January 2016 – Elbasvir/Grazoprevir

June 2016 – Sofosbuvir/Velpatasvir

July 2017 – Sofos/Velpatas/Voxilaprevir

August 2017 – Glecaprevir/Pibrentasvir

XX

X

DAA Era

X

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DAA Era Regimens

Second generation

DAAs

Improve SVR rates even

further

Pan-genotypic activity

Suitable for some difficult-to-cure

patients

Suitable for some difficult-to-cure

patients

Impact on viral resistance

Reduce the burden of AEs

Sofosbuvir: First in Class

NS5BNucleotide

Active againstall genotypes

~90%

High SVR for mostpatients

12-24Weeks

Shorter durationcompared with

earlier regimens

High barrier toresitance

1 pill, once daily, incombination withother anti-HCV agents

Well tolerated

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Hepatitis C in the USA

100%

0

50%

75%

25%

3.2 million

HCV in USA

1.6 million

Diagnosed

50%

1-1.2 million32-38%

Referredto care

220 000 to360 000

Treated

7-11%

170 000 to200 000

5-6%

Successfully Treated

NEJM 2013;368:1859-1861

750 K

Cured

Since sofosbuvirwas launched

Prevalence by Patient Type (Genotype 1-6)Nationwide 2016-2017 Chart Audit by Phisicians that Treat HCV

Treatment Naïve Non-Cirrhotic

Treatment Naïve CompensatedCirrhotic

All Treatment Experienced

DecompensatedCirrhotic

N = 6250

74%11%

11%4%

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Higher efficacy

• SVR ≥95%

• Real-world evidence confirms clinical-trial data

Shorter courses of therapy

• As short as 8 weeks of therapy with SOF/LDV

• 12 weeks of SOF/VEL for genotype 1-6 patients

Less complicated

regimens • Single-tablet

regimens

• No RBV for most patients

• pIFN-free for most patients

• No baseline resistance testing

Better tolerability and fewer toxicities

• Few discontinuations in randomized clinical trials

• Lower rates of adverse events compared with earlier regimens

• Fewer drug interactions

Challenges Met With New-Based Regimens for Most Patients

Chronic Hepatitis C DAA Treatment Today

Viral load

Genotype/Subtype

Tx Naïve or experienced

Cirrhosis and CPT score

Before or After OLT

Renal Function (eGFR)

HIV, HBV Co-Infection

Drug-to-drug Interactions

Viral Resistance

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Chronic Hepatitis C TreatmentChallenging Issues

Spontaneous HBV Reactivation with Second Generation DAA’s

HBsAg +

HBV DNA + HBV DNAlow / -

Treat Observe

Treat if change

HBsAg –Anti-HBc +

MonitorALT

ALTHBV DNA + Treat

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Drug–drug interactions: Most Frequent Outpatient-Drugs Prescribed

The 10 most common drug classes in regular outpatient medication list Percentage (%)

Proton pump inhibitors 24.1

Beta-blockers (selective) 18.4

Aldosterone antagonists 16.9

Thyroid hormones 16.5

Angiotensin II antagonists 13.0

ACE inhibitors 11.1

Dihydropyridine derivatives 10.7

Thiazides 10.0

Sulphonamides 9.2

Beta-blockers (non-selective) 8.0

Maasoumy B, et al. ISVHLD 2015; Poster presentation P140.

Populations Studied

Post-approval Research

Real-world Studies: Describe how a medication will perform in a broader

populationRandomized vs Real-world

Clinical Trials

ü Differing age groups groupsü Race, ethnicity, and genderü Comorbid conditionsü Concomitant drugsü Lifestyle, smoking and

drinkingü Disease severityü Adherence

Phases I-III

Utliz

atio

n

Population Studied

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HCV Therapeutic DevelopmentIn Pursuit of “Perfectovir”

G J Dore, JJ Feld.

Requirements PerspectiveExtremely High Treatment EfficacyPan-genotypic activity (similar dosing and duration)Maintenance of high efficacy in all patients categoriesincluding decompensated and peri-transplant settingsMinimal toxicities and broad documented safetyincluding renal failure and childrenHigh genetic barrier with minimal HCV resistanceEasy of dosing, preferably 1 tablet per dayLimited Drug-to-Drug interactionsShort treatment durationAffordability