Hepatitis C Virus From Discovery to Cure

David R Nelson MDProfessor of MedicineSenior Vice President for Health Affairs President UF HealthUniversity of FloridaGainesville, USA

Outline

• HCV discovery • Building an interferon-free future

– The beginning of the end • Epidemiology and disease burden

– Prevalence and natural history– Impact of morbidity and mortality– Impact of viral eradication

History of Viral Hepatitis

Blumberg and Alter, 1965

Feinstone, Kapikian & Purcell, 1973

Still large numbers of hepatitis that was not explained by A and B

The New Era of Non-A Non-B hepatitis

NEJM 1975

….

….

HCV was the first virus to be isolated and characterized solely by molecular methods (ie without culture methods)

Viral Life cycle and Development of Direct Acting Antivirals

Translation

HCV NS proteins

NS2

Polyproteinprocessing

NS3

NS4B

NS5A NS5B

HCV RNA

Fusion and uncoating

RNA replication

Viral assembly

Transport and release

Entry and p7 inhibitors

IRES inhibitors

NS3/4A protease inhibitors

NS4B and NS5A inhibitors

NS5B polymerase inhibitors

α-glucosidase inhibitors

CyclophilinInhibitors

NS5A

CypA

NS5B

NS2

NS3

NS4B

Multiple Validated Drug Targets in 20193’UTR5’UTR Core E1 E2 NS2 NS4BNS3 NS5A NS5Bp7 4A

HCV PIs NS5BNon-nucs

ProteasePolymerase

Proteaseinhibitors

NS5AInhibitors NS5B

NucsSimeprevirParitaprevirGrazoprevirVoxilaprevir

Ledipasvir ElbasvirDaclatasvir VelpatasvirOmbitasvir

Sofosbuvir Dasabuvir

Direct Acting Antiviral Regimens Direct Acting Antiviral ClassSofosbuvir + Simeprevir NUC + PI

Sofosbuvir + Ledipasvir NUC + NS5A

Paritaprevir + Ombitasvir + Dasabuvir +/- RBV

PI + NS5B + NNI

Sofosbuvr + Daclatasvir NUC + NS5A

Grazoprevir + Elbasvir PI + NS5A

Sofosbuvir + Velpatasvir NUC + NS5A

Sofosbuvir + Velpatasvir + Voxilaprevir NUC + NS5A + PI

History and Evolving Landscape of HCV Therapy

Discovery of HCV

Ribavirin

pegIFN-

Genotype-Specific

RGT

Telaprevir

Boceprevir

Simeprevir

Sofosbuvir

1989 200520011998 2011 20142013

Ledipasvir / SOF

OBV/PTV-R + DAS

Daclatasvir

2015

SOF / VEL / Vox

Glecaprevir /

Pibrentasvir

2016

Grazoprevir / Elbasvir

SOF / Velpatasvir

2017

6% 20% 40% 54% 65–75% > 90%12%SVR:

pegIFN= peg-interferon; RGT = response-guided therapy; SOF: sofosbuvir; VEL: Velpatasvir

OBV/PTV-R + DAS = ombitasvir/paritaprevir and ritonavir + dasabuvir (or 3D). VOX: Voxilaprevir

Houghton M. Liver Int. 2009;29(Suppl 1):82-88; Carithers RL, et al. Hepatology. 1997;26(3 Suppl 1):S83-S88; Zeuzem S, et al. N Engl J Med. 2000;343(23): 1666-1672; Poynard T, et al. Lancet. 1998;352(9138):1426-1432; McHutchison JG, et al. N Engl J Med. 1998;339(21):1485-1492; Lindsay KL, et al. Hepatology. 2001;34(2):395-403; Fried MW, et al. N Engl J Med. 2002;347(13):975-982; Manns MP, et al. Lancet. 2001;58(9286):958-965; Poordad F, et al. N Engl J Med. 2011;364(13):1195-1206; Jacobson IM, et al. N Engl J Med. 2011;364(25):2405-2416; Lawitz E, et al. N Engl J Med. 2013;368(20):1878-1887; Jacobson IM, et al. Lancet. 2014;384(9941):403-413; Afdhal N, et al. N Engl J Med. 2014;370(20):1889-1898; Nelson DR, et al. Hepatology. 2015;61(4):1127-1135; Zeusem S, et al. Ann Intern Med. 2015;163(1):1-13; Feld JJ, et al. N Engl J Med. 2015;373(27):2599-2607.; Foster GR, et al. N Engl J Med. 2015;373(27):2608-2617.

> 95

IFN

Direct Acting Antiviral Era

AASLD/IDSA Recommendations Therapy for HCV Infection

AASLD/IDSA. HCV guidance. September 2017.

*Only if no baseline NS5A RAS for GT 1a; if NS5A RAS present for GT 1a, EBR/GZR not recommended.†8 wks of LDV/SOF only if non-black race, HIV-uninfected, and HCV RNA < 6 million IU/mL).

HCV GT No Cirrhosis Compensated Cirrhosis

1

EBR/GZR 12 wks*GLE/PIB 8 wks

LDV/SOF 8-12 wks†

SOF/VEL 12 wks

EBR/GZR 12 wks*GLE/PIB 12 wksLDV/SOF 12 wksSOF/VEL 12 wks

HCV GT No Cirrhosis Compensated Cirrhosis

2/3 GLE/PIB 8 wksSOF/VEL 12 wks

GLE/PIB 12 wksSOF/VEL 12 wks*

*Only if no baseline Y93H for GT 3. If Y93H present for GT3, add RBV or choose alternative regimen (consider SOF/VEL//VOX).

Many Previously Challenging Clinical Scenarios Are Now Routine

Population SVR (%) Notes

Black/Hispanic race > 95 Potential for lower efficacy of some regimens with shorter duration (8 wks)

HIV/HCV coinfection > 95 Avoid DDIs between DAAs and ART

Post orthotopic liver transplantation > 95

Clinical trial SVR rates high with:o LDV/SOF + RBVo DCV + SOF + RBVo GLE/PIB o SOF/VEL

Stage 4-5 chronic kidney disease (eGFR < 30 mL/min)

> 95

AASLD/IDSA recommendations for initial therapy: GT1-6: GLE/PIB

• No cirrhosis: 8 wks• Compensated cirrhosis: 12 wks

GT1 or GT4: EBR/GZR 12 wks

AASLD/IDSA. HCV guidance. September 2017.

HCV Epidemiology and Disease Burden

Global Prevalence of HCV (2016)

• Estimated number with viremic HCV

– 71.1 million

– Most common genotypes: 1 and 3 (44% and 25% of infections)

• 6 countries: 51% of all viremic HCV infections

– China (9.8 million)

– Pakistan (7.1 million)

– India (6.2 million)

– Egypt (5.6 million)

– Russia (4.7 million)

– US (2.9 million)

Estimated Global Prevalence of Viremic HCV:1.0% (95% CI 0.8-1.1)

Prevalence (%)No data0-0.60.6-0.80.8-1.31.3-2.92.9-6.7

The Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176.Hill AM, et al. J Virus Erad. 2017;3:117-123.

The Burden of Hepatitis C and theInfluence of Therapy

Patient BurdenBurden of

Liver Disease

Burden on Society

Increased Mortality from Liver Cancer and Chronic Liver Diseases in HCV: REVEAL-HCV Study

Lee M-H et al, 2012.

Mortality and Morbidity Reduced with SVR

30

LR-M

orta

lity

(%)

20

10

01 2 3 4 5 6 7 8 9 100

Time – in years

30

Live

r Fai

lure

(%)

20

10

01 2 3 4 5 6 7 8 9 100

Time – in years

Adjusted HR of SVR:0.07 (95%CI 0.03-0.20)

p < 0.001

p < 0.001

SVR

non-SVR

Adjusted HR of SVR:0.06 (95%CI 0.02-0.19)

p < 0.001

p < 0.001

SVR

non-SVR

30

HCC

(%)

20

10

01 2 3 4 5 6 7 8 9 100

Time – in years

Adjusted HR of SVR:0.19 (95%CI 0.08-0.44)

p < 0.001

p < 0.001

SVR

non-SVR

Van der Meer JAMA 2012

Cumulative Mortality

Live

r Fai

lure

HCC

LR-M

orta

lity

• 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment • 192 (36%) achieved SVR

Achieving a Sustained Virologic Response is Associated With Improved Outcomes

• Sustained viral response

– Durable = cure

• 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.

WHO Targets for HCV Elimination by 2030

• Diagnose 90% and treat 80% by 2030

• 2016 status update*

– Average incidence of diagnosis: 20%

• Leaders: Australia (85%), Sweden (82%), Finland (79%), Canada (71%)

– Average incidence of treatment: 7%

• Leaders: Australia (16%), Japan (12%), Netherlands (12%), Egypt (12%), US (8%),France (8%), Spain (8%)

– Countries which have > 5 cures/new HCV infection

• Australia, Canada, Egypt, Iceland, Israel, Japan, Portugal, Spain, Qatar, USA

*Data from 91 of 210 countries.Net cure: number of (cured+HCV-related deaths) minus new infections as a percentage of the number viremic.

0

20

40

60

80

100Highest Net HCV Cure Rate in 2016

(Overall: 0.43%)

Net

Cur

e (%

)

Iceland Qatar

12% 9%

Japan

35%

15%

26%

8%

Australia

The Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176.Hill AM, et al. J Virus Erad. 2017;3:117-123.WHO. Global Hepatitis Report 2017.

Egypt Netherlands

HCV Elimination ProgressAnalysis of SVR Versus New HCV Infections in 91 Countries

• There are more new HCV infections than cured

– 23 of 91 countries have >5 new infections per cure

– Only 10 of 23 countries have >5 cures/new infection

• The 2% reduction in the worldwide HCV epidemic (2016 to 2017) was not large enough to achieve the WHO target of HCV elimination by 2030

– 6 to 7 million people who have HCV need to be diagnosed and treated each year

Hill AM, et al. J Virus Erad. 2017;3:117-123.

Persons

HCV prevalence 2016 69,563,426

New HCV infections (n=1,597,877)Cures (n=1,512,827)HCV-related deaths (n=347,818)Non-HCV-related deaths (n=1,043,452)

HCV prevalence 2017 68,257,207

Difference (2016-2017)NumberPercent

-1,306,2192

Changes in Global HCV Prevalence(2016-2017)

Linkage to Care ChallengeModel Projections in the HCV Care Cascade

• 2018 estimated status

– Of 4 million persons who have or ever had HCV, 11% have been cured

• 2030 projections

– Of 3.3 million persons who have or ever had HCV, 49% are projected to be cured

– Highest cure rate among Medicare enrollees (91%)

– Lowest cure rate among incarcerated people (<1%)

• Implementing universal HCV screening is estimated to have the biggest impact of improving the cascade of care in 2030

Chhatwal J, et al. Hepatology. 2018;68(suppl S1):918A-919A. Abstract 1613.

0

20

40

60

80

100100%

68%

HCV Persons*

(n=3.3 million)

Projected HCV Care Cascade in 2030

Aware StartedTreatment

49%

Prop

ortio

n of

HC

V Pe

rson

s (%

)

*People alive who have or ever had HCV.

Cured

49%

Screening of Baby Boomers With Linkage to Care May Prevent >120,000 Deaths Due to HCV Infection

› Birth-cohort screening in primary care would identify 86% of all undiagnosed cases in the birth cohort, compared with 21% under risk based screening1

› OneFL data showed only 6% of 1.5M FL baby boomers have been screened (AASLD 2019)› Cost effectiveness of HCV screening is comparable to cervical cancer or cholesterol screening

Markov chain Monte Carol simulation model of prevalence of hepatitis C antibody stratified by age, sex, race/ethnicity, history of injection drug use, and natural history of chronic hepatitis C.*With pegylated interferon and ribavirin plus DAA treatment.†Deaths due to decompensated cirrhosis or hepatocellular carcinoma within 1945-1965 birth cohort. 470,000 deaths under birth cohort screening vs 592,000 deaths under risk-based screening1. Rein D et al. Ann Intern Med. 2012;156(4):263-270; 2. McGarry LJ et al. Hepatology. 2012;55(5):1344-1355.

1,070,840 new cases of HCV identified with birth-cohort screening

552,000 patients treated

364,000 patients cured*

121,000 deaths averted†

20

• HCV has been a remarkable story of discovery• Multiple IFN-free options are available Increased efficacy (most patients SVR > 95%) Access and costs are still issues in US

• SVR leads to significant improvement in morbidity and mortality on all HCV patients

• Focus now on diagnosis and linkage to care

Overall Summary