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