Transcript Genotype 1b, no cirrhosis

Hepatitis C:
The rapidly evolving landscape
Steve T. Chen MD, FACP, FACG
Hepatitis C Virus: Morphology and
Characteristics
 Discovered in 1989
 Nucleic Acid: 9.6 kb ssRNA
40-60 nm
 Classification: Flaviviridae,
Hepacivirus
 Genotypes: 1 to 6
 In vivo replication: in
cytoplasm, hepatocyte and
lymphocyte; human and other
primates
Audience response survey
Question 1:
The following patients should be screened for
hepatitis C:
A. Those who have elevated liver enzymes
(ALT,AST).
B. Those who have risk factors (blood products
exposures, IVDA, hemodialysis, etc.)
C. Those born between 1945 and 1965.
D. All of the above.
2012 CDC and USPSTF guidelines for
HCV birth-cohort screening
Screen all “baby boomers” born
1945-1965
•
•
•
•
•
Rationale: 75% of HCV patients are undiagnosed
Baby boomers: 3.27% HCV antibody positivity (5 X higher
than other cohorts). 75% of all HCV positive
Removes barriers of risk-based screening model
Identifies 808,580 additional cases of chronic HCV
Reduces deaths by 121,000 and cost by $35,700 per QALY
(Rein et al, Ann Int Med 2012; 156(4):263-270)
Prevalence of hepatitis C virus antibody, by year of birth — National Health and
Nutrition Examination Survey, United States, 1988–1994 and 1999–2002
Source: Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C
virus infection in the United States, 1999 through 2002. Ann Internal Med
2006;144:705–14.
Alternate Text: The figure is a line graph that displays the prevalence of hepatitis
C virus antibody in persons by year of birth during the 1988-1994 and 1999-2002
National Health and Nutrition Examination Survey.
2012 CDC and USPSTF guidelines for
HCV birth-cohort screening
Screen all “baby boomers” born
1945-1965
•
•
Rationale: 75% of HCV patients are undiagnosed
•
Removes barriers of risk-based screening model
•
•
Identifies 808,580 additional cases of chronic HCV
Reduces deaths by 121,000 and cost by $35,700 per QALY
Baby boomers: 3.27% HCV antibody positivity (5 X higher
than other cohorts). 75% of all HCV positive.
(Rein et al, Ann Int Med 2012; 156(4):263-270)
Management of hepatitis C patients:
PCP’s role
•Counseling about complete alcohol abstinence
•Counseling to avoid potentially hepato-toxic
medications (e.g. acetaminophen over 2000
mg/day)
•Vaccination for hepatitis A and B (if not immune)
•Evaluation for antiviral treatments
•For cirrhotic patients:
•Screening for liver cancer every 6 months
(ultrasound)
•Screening for esophageal varices (EGD)
•Possible referral for liver transplantation evaluation
Key Data for HCV decisions
• HCV RNA positive? Genotype?
• HCV treatment history
– Interferon and ribavirin regimen?
– Protease inhibitor? Sofosbuvir?
• Fibrosis stage?
– Options for fibrosis assessment
– If cirrhosis, is it decompensated?
Child Pugh B or C?
Transplant
evaluation?
http://www.hcvguidelines.org
HCV Genotypes
•
Six major
genotypes found
throughout the
world. Genotype 1
predominant in
Europe, Genotype 3
in South Asia,
Genotype 4 in Africa
and Middle East.
•
Major determinant
of response to
antiviral therapy
Key Data for HCV decisions
• HCV RNA positive? Genotype?
• HCV treatment history
– Interferon and ribavirin regimen?
– Protease inhibitor? Sofosbuvir?
• Fibrosis stage?
– Options for fibrosis assessment
– If cirrhosis, is it decompensated?
Child Pugh B or C?
Transplant
evaluation?
http://www.hcvguidelines.org
Stages of Fibrosis In Chronic Hepatitis
F2 Periportal
F1 Portal
F3 Septal
1
2
3
4
F4 Cirrhosis
Noninvasive assessment of hepatic
fibrosis
• Serologic tests:
•
•
•
Sen.
1.AST to platelet ratio: APRI = (AST elevation/platelet count) x 100
2.FibroTest/FibroSure (alpha-2-macroglobulin, alpha-2-globulin (haptoglobin),
gamma globulin, apolipoprotein A1, GGT, and total bilirubin)
•
•
•
76
Spec.
72
60-75 80-90
similar
3.Hepascore (bilirubin, GGT, hyaluronic acid, alpha-2-macroglobulin, age, and sex)
4.FibroSpect (hyaluronic acid, tissue inhibitor of metalloproteinase-1, and alpha-2-macroglobulin)
77
73
70-87
73-91
85-92
84-91
79-85
76-87
•
• Radiologic tests:
•
•
•
1. ultrasound-based transient elastography
2. magnetic resonance elastography (MRE)
3. acoustic radiation force impulse imaging (ARFI)
HCV Treatment Improves Health
•
Advanced fibrosis
30
– Multicenter study[1]
– 5 hospitals (Europe, Canada)
21.8
•
Early-stage disease
Percent
– 530 pts with HCV
– IFN regimens 1990-2003
– Advanced fibrosis or cirrhosis
– Median follow-up: 8.4 yrs
27.4
26
20
10
8.9
5.1
– Extra-hepatic manifestations[2]
– Health-related quality of life[3]
1.9
0
All cause Liver-related
mortality mortality or
transplant
HCC
10-Yr Cumulative Incidence[1]
SVR
No SVR
1. van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 2. van der Meer AJ. Expert Rev
Gastroenterol Hepatol. 2015;9:559-566. 3. Younossi Z, et al. Clin Gastroenterol Hepatol.
2014;12:1349-1359.
AASLD/IDSA: When and in Whom to
Initiate HCV Therapy
•
•
ALL pts are candidates for HCV therapy, regardless of disease stage
In regions where limited resources preclude treatment of all pts, the
following groups should be prioritized for therapy:
– Highest Priority (based on highest risk for disease complications)
–
–
–
–
Advanced fibrosis (F3) or compensated cirrhosis (F4)
Organ transplant
Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations
Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis
– High Priority (based on high risk for disease complications)
–
–
–
–
HIV-1 coinfection
Fibrosis (Metavir F2)
HBV coinfection
Debilitating fatigue
– Other coexistent liver disease (eg, NASH)
– Type 2 DM (insulin resistant)
– Porphyria cutanea tarda
AASLD/IDSA. HCV Management. http://www.hcvguidelines.org.
Audience response survey
Question 2:
The currently available medications for treating
hepatitis C include the following classes:
A. Pegylated interferon and Ribavirin
B. NS3/4A protease inhibitors
C. NS5B polymerase inhibitor
D. NS5A inhibitor
E. All of the above
The evolution of hepatitis C therapies
2013: The Introduction of IFN-Free HCV Therapy
IFN +
RBV
36%
1991
IFN
6%
1998
BOC or
TVR + P/R
SIM or
SOF + P/R
68-75%
80-90%
2011
2013
GT1
2001
GT2/3
PegIFN
+ RBV
55%
2013
SOF +
RBV
91-94%
HCV-specific enzymes as targets for
DAA therapy
5’ UTR
C E1 E2 NS2 NS3
P7
NS4B NS5A NS5B
3’ UTR
NS4A
NS3 Helicase
domain
NS5B RNA-dependent
RNA polymerase
NS3 Protease
domain
NS3 Bifunctional
protease / helicase
Direct-Acting Antiviral Agents:
Key Characteristics
C
E1
E2
p7
NS2
NS3
NS4A
NS4B
NS5A
NS5B
NS3/4A Protease Inhibitors (PI)
NS5B Nucleos(t)ide Inhibitors (NI)
High potency
Intermediate potency
Limited genotypic coverage
Pangenotypic coverage
Low barrier to resistance
High barrier to resistance
NS5A Inhibitors
NS5B Nonnucleoside Inhibitors (NNI)
High potency
Intermediate potency
Multigenotypic coverage
Limited genotypic coverage
Low barrier to resistance
Low barrier to resistance
Sofosbuvir: NS5B Inhibitor (Sovaldi)


NS5B RNA-dependent RNA polymerase (RdRP) or RNA replicase is an
enzyme that catalyzes the replication of RNA from an RNA template
NS5B nucleoside and non-nucleoside inhibitors fall into two
distinct classes: those that directly target the enzyme’s active site and those
that bind elsewhere on the protein and function as allosteric inhibitors..
Sofosbuvir/Ledipasvir
(Harvoni)
• FDA approved Oct. 2014
• Ledipasvir (NS5A inh)
– high potency against
GT1a and 1b HCV
– Once-daily, oral, 90 mg
• Ledipasvir/Sofosbuvir
Once-daily, oral tablet
(90/400 mg)
NS5A
NS5B
1. Lawitz E, et al. EASL 2011. Abstract 1219.
Sofosbuvir +
daclatasvir
2015
Agents
Sofosbuvir +
ribavirin ±
pegIFN
Ledipasvir/
sofosbuvir
Ombitasvir/
paritaprevir/
ritonavir +
dasabuvir
Simeprevir +
sofosbuvir
Genotype 1 HCV Agents
Protease
Inhibitors
Simeprevir
Paritaprevir/
Ritonavir
Grazoprevir
Azunaprevir
GS9857
GS9451
Polymerase Inhibitors NS5B
Nucleotide
Nonnucleoside
Sofosbuvir
Dasabuvir
Beclabuvir
GS 9669
www.hcvguidelines.org
NS5A
Inhibitors
Other
Ledipasvir
Ribavirin
Ombitasvir
Daclatasvir
Elbasvir
Velpatasvor
(GS5816)
Phase III Studies: SOF/LDV FDC ± RBV
in GT1 Pts
Wk 8
ION-1[1]
Treatment-naive
GT1 HCV;
cirrhosis in 15%
to 17% per arm
(N = 865)
ION-2[2]
Treatmentexperienced
GT1 HCV; 20%
cirrhotics
(N = 440)
ION-3[3]
Treatment-naive,
noncirrhotic pts
with GT1 HCV
(N = 647)
Wk 12
Wk 24
SVR12, %
SOF/LDV (n = 214)
99
SOF/LDV + RBV (n = 217)
97
SOF/LDV (n = 217)
98
SOF/LDV + RBV (n = 217)
99
SOF/LDV (n = 109)
94
SOF/LDV + RBV (n = 111)
96
SOF/LDV (n = 109)
99
SOF/LDV + RBV (n = 111)
99
SOF/LDV (n = 215)
94
SOF/LDV + RBV (n = 216)
93
SOF/LDV (n = 216)
95
1. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 2. Afdhal N, et al. N Engl J
Med. 2014;370:1483-1493.
3. Kowdley KV, et al. N Engl J Med. 2014;370:1879-1888.
Paritaprevir/RTV/Ombitasvir + Dasabuvir
(Viekira Pak)
• Paritaprevir: potent NS3/4A protease
inhibitor
– RTV boosting to increase peak,
trough, and overall exposures of
Paritaprevir, enables once-daily
dosing
• Ombitasvir: potent NS5A inhibitor
• Dasabuvir: nonnucleoside NS5B
polymerase inhibitor
• Used with or without Ribavirin
NS5B
NNI
NS3
NS5A
RBV
Phase III Studies: ABT-450/RTV/Ombitasvir
+ Dasabuvir + RBV in GT1 Pts
Wk 12
SAPPHIRE-I
Tx-naive noncirrhotic
pts with GT1 HCV[1]
(N = 631)
SAPPHIRE-II
Tx-experienced
noncirrhotic pts with
GT1 HCV[2]
(N = 394)
TURQUOISE-II
DAA-naive cirrhotic pts
with GT1 HCV[3];
59% tx experienced,
36% null responders
(N = 380)
ABT-450/RTV/OMB + DBV + RBV (n = 473)
Wk 24 SVR12, %
96
Placebo* (n = 158)
ABT-450/RTV/OMB + DBV + RBV (n = 297)
96
Placebo (n = 97)
ABT-450/RTV/OMB + DBV + RBV (n = 208)
ABT-450/RTV/OMB + DBV + RBV (n = 172)
1S, et al.
*Placebo recipients crossed over to active treatment regimen at Wk 12.
92
96
Genotype 1 HCV: AASLD/IDSARecommended Regimens
Regimen
Simeprevir + peginterferon +
ribavirin
Genotype 1
Regimen Features
Not recommended
QD-QWK; multiple tablets +
injection
Sofosbuvir + peginterferon +
ribavirin
Not recommended
QD-QWK; multiple tablets +
injection
Sofosbuvir + ribavirin
Not recommended
QD; multiple tablets
Ledipasvir/sofosbuvir
Recommended
QD; single-tablet regimen
Ombitasvir/paritaprevir/ritonavir,
dasabuvir, ± ribavirin
Recommended
QD-BID; multiple tablets
Simeprevir + sofosbuvir ± ribavirin
Recommended
QD; multiple tablets
http://www.hcvguidelines.org
Genotype 1 HCV Treatment Naive
• AASLD-IDSA guidelines
– 3 regimens recommended
Ledipasvir/
Sofosbuvir*
Ombitasvir/
Paritaprevir/ Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir
Genotype 1a, no cirrhosis
12 wks
12 wks + RBV
12 wks ± RBV
Genotype 1a, cirrhosis
12 wks
24 wks + RBV
24 wks ± RBV
Genotype 1b, no cirrhosis
12 wks
12 wks
12 wks
Genotype 1b, cirrhosis
12 wks
12 wks + RBV
24 wks
*Ledipasvir/sofosbuvir for 8 wks can be considered in naive, noncirrhotic pts with baseline HCV RNA < 6
million IU/mL.
http://www.hcvguidelines.org
Genotype 1 HCV PegIFN/RBV Treatment
Experienced
• AASLD-IDSA guidelines
– 3 regimens recommended
Genotype 1a, no cirrhosis
Genotype 1a, cirrhosis
Genotype 1b, no cirrhosis
Genotype 1b, cirrhosis
Ledipasvir/
Sofosbuvir
Ombitasvir/
Paritaprevir/
Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir
12 wks
12 wks + RBV
12 wks ± RBV
Genotype 1a,
cirrhosis
24 wks ± RBV
12 wks
12 wks
12 wks ± RBV
24 wks
12 wks + RBV
12 wks + RBV
24 wks ± RBV
24 wks
12 wks + RBV
http://www.hcvguidelines.org
Genotypes 2
• AASLD-IDSA guidelines
Genotype 2
Sofosbuvir + Ribavirin
Peginterferon-α, Ribavirin
+ Sofosbuvir
Treatment naive
12 wks
(16-24 wks for cirrhosis)
None
12-16 wks
12 wks (alternative)
PegIFN/RBV nonresponders
http://www.hcvguidelines.org
HCV GT3 Infection Has a Unique Pathophysiology
Compared to Other Genotypes
• Accelerated fibrosis
• Increased steatosis, as compared to other
genotypes
• Increased risk for HCC
• Lower response to some oral therapies
• Higher risk for late-stage liver events
• Higher mortality compared to other
genotypes
(1. Tapper EB, Afdhal NH. J Viral Hepat. 2013;20:669-677. 2. Nkontchou G et al. J Viral Hepat.
2011;18:e516-e522.)
Daclatasvir:
NS5A Inhibitor (Daklinza)
NS5A

Shaw-Stiffel T. Reference to Hepatitis C Infection. 2004
Adapted from: Asselah T & Marcellin P. Liver Int 2011;31(s1):68–77.
Protein that plays a central role in viral
replication and assembly
AASLD/IDSA Guidance for Naive or
Treatment-Experienced GT3 Pts
Recommended
Population
Naive, no cirrhosis
Naive, cirrhosis
P/R failure, no cirrhosis
P/R failure with cirrhosis,
or SOF/RBV failure
Decompensated cirrhosis
DCV + SOF
SOF + RBV
SOF + RBV
12 wks
12 wks + pegIFN
24 wks†
24 wks ± RBV
12 wks + pegIFN
24 wks†
12 wks
12 wks + pegIFN
Not recommended
24 wks + RBV
‡
Alternative
†
12 wks +
low-dose RBV
12 wks + pegIFN
Up to 48 wks*
Not recommended
Not recommended
 LDV/SOF or OMV/PTV/RTV + DSV not recommended for GT3
*RBV dosed 1000-1200 mg/day based on weight, with consideration for pt’s CrCl and
hemoglobin.
†For IFN-ineligible pts. ‡Pts with GT3 HCV decompensated cirrhosis should be referred to a
medical practitioner with expertise in that condition
AASLD/IDSA. HCV guidelines.
Genotype 4 HCV
Wks
FDA
Approved
AASLD/IDSA
Study
SVR12
Sofosbuvir +
pegIFN/RBV
12
Yes
Recommended
NEUTRINO[1]
27/28*
(96%)
Sofosbuvir + ribavirin
24
No
Recommended
Ruane et al2]
13/15
(87%)
Regimen
Ledipasvir/sofosbuvir
12
No
Recommended
Multiple[3,4]
19/20†[3];
20/22[4]
(91-95%)
Ombitasvir/paritaprevir/
ritonavir, ribavirin
12
Yes
Recommended
PEARL-I[5]
49/49
(100%)
*Study included treatment-naive pts only.
†Treatment-naive and treatment-experienced pts.
1. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. 2. Ruane PJ, et al. J Hepatol.
2015;62:1040-1046.
3. Kapoor R, et al. AASLD 2014. Abstract 240. 4. Abergel A, et al. EASL 2015. Abstract
O056. 5. Hézode C, et al. Lancet. 2015;[Epub ahead of print].
Genotype 4: Ombitasvir, paritaprevir, ritonavir
(Technivie)
Patient Population:
Genotype 4 without cirrhosis
Dose: Two Ombitasvir, paritaprevir, ritonavir 12.5/75/50mg
tablets taken once in the morning + RIBAVIRIN (weight
based)
Duration: 12 weeks
SVR Rate: Naïve: 100% (42/42)
Treatment Experienced: 100% (49/49)
Naïve without Ribavirin: 91% (40/44).
(Hezode C, et al. (PEARL-I): a randomised, open-label trial. Lancet. 2015)
Genotype 5/6 HCV Treatment Naive
• AASLD-IDSA guidelines
Recommended Regimen
Duration
Genotype 5
Sofosbuvir + ribavirin +
peginterferon
12 wks
Genotype 6
Ledipasvir/
sofosbuvir
12 wks
Alternative Regimen
Duration
Genotype 5
Peginterferon + ribavirin
48 wks
Genotype 6
Sofosbuvir + ribavirin +
peginterferon
12 wks
http://www.hcvguidelines.org
Sofosbuvir +
GS-5816
Grazoprevir +
elbasvir
Daclatasvir +
asunaprevir +
beclabuvir
Sofosbuvir +
daclatasvir
Sofosbuvir +
ribavirin
Sofosbuvir +
ledipasvir
Paritaprevir/
ritonavir +
dasabuvir +
ombitasvir
Simeprevir +
sofosbuvir
Future HCV Treatment: Shorter Duration
With Triple-Drug Regimens
• Pts
– Treatment naive, genotype 1
(N = 60)
100
• Design
100
95
95
20/20
20/20
19/20
19/20
19/20
19/20
12 wks
6 wks
6 wks
– Single-center, open-label,
phase IIA trial
• Regimens
– 12 wks of SOF + LDV
– 6 wks of SOF, LDV,
GS-9669
– 6 wks of SOF, LDV,
GS-9451
SVR12 (%)
80
60
40
20
n/N =
0
SOF + LDV SOF + LDV SOF + LDV
+ GS-9669 + GS-9451
Kohli A, et al. Lancet. 2015;385:1107-1113.
Short-Duration Sofosbuvir/
GS-5816(Velpatasvir) +
GS-9857: Efficacy Results
6 Wks
100
93
87
80
SVR12 (%)
4 Wks
67
60
40
20
n/N =
0
27
14/15
13/15
Tx Naive, Txt Naive,
No Cirrhosis Cirrhosis
•
20/30
Txt Exp’d,
+/- Cirrhosis
4/15
Tx Naive,
No Cirrhosis
SVR12 rates for treatment-experienced pts: no
cirrhosis, 68% (17/25 pts); cirrhosis, 60% (3/5 pts)
Gane EJ, et al. EASL 2015. Abstract LP03.
C-EDGE: Grazoprevir/Elbasvir for TxNaive and Tx-Experienced Pts
Tx-Naive: Grazoprevir/Elbasvir for
12 Wks in GT1, 4, or 6 HCV[1]
SVR12 (%)
100
95
92
99
Tx-Exp’d: Grazoprevir/Elbasvir ± RBV
for 12 or 16 Wks in GT1, 4, or 6 HCV[2]
100
80
100
80
80
60
60
40
40
20
n/N =
0
299/
316
144/
157
129/
131
18/
18
8/
10
20
92
94
92
97
97/
105
98/
104
97/
105
103/
106
GZR/
EBV
GZR/EBV
+ RBV
GZR/
EBV
GZR/EBV
+ RBV
0
All Pts
GT1a GT1b GT4
GT6
12 Wks
1. Zeuzem Z, et al. EASL 2015. Abstract G07. 2. Kwo P, et al. EASL 2015. Abstract P0886.
16 Wks
Many other DAA combinations
currently under investigation
Sofosbuvir +
GS-5816
Grazoprevir +
elbasvir
Daclatasvir +
asunaprevir +
beclabuvir
Sofosbuvir +
daclatasvir
Sofosbuvir +
ribavirin
Sofosbuvir +
ledipasvir
Paritaprevir/
ritonavir +
dasabuvir +
ombitasvir
Simeprevir +
sofosbuvir
Cost of Hepatitis C medications:
(2014 US$)
Lorem ipsum dolor sit amet, consectetuer adipiscing elit,
sed diam nonummy nibh euismod:
Costs
Treatment
• Ut wisi enim ad minim veniam
per week
per course (12 wks)
• Quis nostrud exercitation ullamcorper lobortis aliquip
Commodo consequat duis autem vel eum iriure dolor
in hendrerit in vulputate
Harvoni
$7,875.00
$94,500
Velit esse
molestie consequat,
vel dolore eu feugiat:
Olysio
+ Sovaldi
$12,500.00
$150,000
• Nulla facilisis at vero eros
$7,000.00
$84,000
Viekira Pak + Ribavirin
• Dignissim qui blandit praesent
Daklinza + Sovaldi
$12,100
$146,000
• Luptatum zzril delenit augue duis dolore
Peginterferon + Ribavirin $750
$36,000 (48 wks)
Sofosbuvir
$7,000
$84,000
Table 4. Annual costs of care for liver diseases
Annual costs of care
(2014 US$)
Chronic Hepatitis C
$572.69
Compensated
Cirrhosis
$762.99
Decompensated
Cirrhosis
$39,675.48
HCC
$25,862.67
Liver Transplant (1st
year)
$483,057.01
Liver Transplant
(successive year)
$46,515.46
HCV: Future developments
and challenges
• Effective screening yields 1-2 million patients
• Easier and more efficacious treatments cure majority of
patients
• Primary care physicians will assume increased
management roles
• Affordability of treatment is the main drawback
• Competition may lower the cost of medications
• Alternative and novel funding sources may be needed to
allow increased access to treatment
• HCV could become a rare or eradicated disease in the
coming decades
(M. Kabiri, et al. AIM 161:3, 2014)